HA-1 T TCR T Cell Immunotherapy for the Treating of Patients With Relapsed or Refractory Acute Leukemia After Donor Stem Cell Transplant

ClinicalTrials.gov

2018-04-30

HLA-A*0201 HA-1 Positive Cells Present; Minimal Residual Disease; Recurrent Acute Biphenotypic Leukemia; Recurrent Acute Undifferentiated Leukemia; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Refractory Acute Myeloid Leukemia; Refractory Adult Acute Lymphoblastic Leukemia; Refractory Childhood Acute Lymphoblastic Leukemia

Fludarabine Phosphate, Melphalan, Total-Body Irradiation, Donor Stem Cell Transplant in Treating Patients With Hematologic Cancer or Bone Marrow Failure Disorders

ClinicalTrials.gov

2017-11-29

Accelerated Phase Chronic Myelogenous Leukemia; Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Aplastic Anemia; Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Myeloid Leukemia in Remission; Childhood Chronic Myelogenous Leukemia; Childhood Diffuse Large Cell Lymphoma; Childhood Immunoblastic Large Cell Lymphoma; Childhood Myelodysplastic Syndromes; Childhood Nasal Type Extranodal NK/T-cell Lymphoma; Chronic Eosinophilic Leukemia; Chronic Myelomonocytic Leukemia; Chronic Neutrophilic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; de Novo Myelodysplastic Syndromes; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Fanconi Anemia; Juvenile Myelomonocytic Leukemia; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Burkitt Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Noncontiguous Stage II Adult Lymphoblastic Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Paroxysmal Nocturnal Hemoglobinuria; Previously Treated Myelodysplastic Syndromes; Primary Myelofibrosis; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Anaplastic Large Cell Lymphoma; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Multiple Myeloma; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Splenic Marginal Zone Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Small Lymphocytic Lymphoma; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Small Lymphocytic Lymphoma; Waldenström Macroglobulinemia

Alemtuzumab, Fludarabine Phosphate, and Low-Dose Total Body Irradiation Before Donor Stem Cell Transplantation in Treating Patients With Hematological Malignancies

ClinicalTrials.gov

2018-05-24

Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Childhood Burkitt Lymphoma; Childhood Chronic Myelogenous Leukemia; Childhood Diffuse Large Cell Lymphoma; Childhood Immunoblastic Large Cell Lymphoma; Childhood Nasal Type Extranodal NK/T-cell Lymphoma; Chronic Phase Chronic Myelogenous Leukemia; Contiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Contiguous Stage II Grade 1 Follicular Lymphoma; Contiguous Stage II Grade 2 Follicular Lymphoma; Contiguous Stage II Marginal Zone Lymphoma; Contiguous Stage II Small Lymphocytic Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Peripheral T-cell Lymphoma; Previously Treated Myelodysplastic Syndromes; Progressive Hairy Cell Leukemia, Initial Treatment; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Anaplastic Large Cell Lymphoma; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Refractory Multiple Myeloma; Relapsing Chronic Myelogenous Leukemia; Splenic Marginal Zone Lymphoma; Stage I Adult Diffuse Small Cleaved Cell Lymphoma; Stage I Childhood Anaplastic Large Cell Lymphoma; Stage I Childhood Large Cell Lymphoma; Stage I Cutaneous T-cell Non-Hodgkin Lymphoma; Stage I Grade 1 Follicular Lymphoma; Stage I Grade 2 Follicular Lymphoma; Stage I Mantle Cell Lymphoma; Stage I Marginal Zone Lymphoma; Stage I Mycosis Fungoides/Sezary Syndrome; Stage I Small Lymphocytic Lymphoma; Stage II Childhood Anaplastic Large Cell Lymphoma; Stage II Childhood Large Cell Lymphoma; Stage II Cutaneous T-cell Non-Hodgkin Lymphoma; Stage II Mycosis Fungoides/Sezary Syndrome; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Childhood Anaplastic Large Cell Lymphoma; Stage III Childhood Large Cell Lymphoma; Stage III Cutaneous T-cell Non-Hodgkin Lymphoma; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Mycosis Fungoides/Sezary Syndrome; Stage III Small Lymphocytic Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Childhood Anaplastic Large Cell Lymphoma; Stage IV Childhood Large Cell Lymphoma; Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Mycosis Fungoides/Sezary Syndrome; Stage IV Small Lymphocytic Lymphoma; T-cell Large Granular Lymphocyte Leukemia; Waldenström Macroglobulinemia

Tacrolimus and Methotrexate With or Without Sirolimus in Preventing Graft-Versus-Host Disease in Young Patients Undergoing Donor Stem Cell Transplant for Acute Lymphoblastic Leukemia in Complete Remission

ClinicalTrials.gov

2016-12-16

B-cell Childhood Acute Lymphoblastic Leukemia; Childhood Acute Lymphoblastic Leukemia in Remission; Graft Versus Host Disease; L1 Childhood Acute Lymphoblastic Leukemia; L2 Childhood Acute Lymphoblastic Leukemia; T-cell Childhood Acute Lymphoblastic Leukemia

Haploidentical Donor Bone Marrow Transplant in Treating Patients With High-Risk Hematologic Cancer

ClinicalTrials.gov

2017-04-10

Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Myeloid Leukemia in Remission; Childhood Burkitt Lymphoma; Childhood Chronic Myelogenous Leukemia; Childhood Myelodysplastic Syndromes; Childhood Nasal Type Extranodal NK/T-cell Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; de Novo Myelodysplastic Syndromes; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hematopoietic/Lymphoid Cancer; Hepatosplenic T-cell Lymphoma; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Peripheral T-cell Lymphoma; Post-transplant Lymphoproliferative Disorder; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Childhood Anaplastic Large Cell Lymphoma; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Multiple Myeloma; Relapsing Chronic Myelogenous Leukemia; Secondary Myelodysplastic Syndromes; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Stage II Multiple Myeloma; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Hodgkin Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Adult T-cell Leukemia/Lymphoma; Stage III Childhood Hodgkin Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Cutaneous T-cell Non-Hodgkin Lymphoma; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Multiple Myeloma; Stage III Mycosis Fungoides/Sezary Syndrome; Stage III Small Lymphocytic Lymphoma; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Hodgkin Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Adult T-cell Leukemia/Lymphoma; Stage IV Childhood Hodgkin Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Mycosis Fungoides/Sezary Syndrome; Stage IV Small Lymphocytic Lymphoma; Testicular Lymphoma; Waldenström Macroglobulinemia

Tacrolimus and Mycophenolate Mofetil in Preventing Graft-Versus-Host Disease in Patients Who Have Undergone Total-Body Irradiation With or Without Fludarabine Phosphate Followed by Donor Peripheral Blood Stem Cell Transplant for Hematologic Cancer

ClinicalTrials.gov

2017-12-05

Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Blastic Phase Chronic Myelogenous Leukemia; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Myeloid Leukemia in Remission; Childhood Burkitt Lymphoma; Childhood Chronic Myelogenous Leukemia; Childhood Diffuse Large Cell Lymphoma; Childhood Immunoblastic Large Cell Lymphoma; Childhood Myelodysplastic Syndromes; Childhood Nasal Type Extranodal NK/T-cell Lymphoma; Chronic Phase Chronic Myelogenous Leukemia; Contiguous Stage II Adult Burkitt Lymphoma; Contiguous Stage II Adult Diffuse Large Cell Lymphoma; Contiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Contiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Contiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Contiguous Stage II Adult Lymphoblastic Lymphoma; Contiguous Stage II Grade 1 Follicular Lymphoma; Contiguous Stage II Grade 2 Follicular Lymphoma; Contiguous Stage II Grade 3 Follicular Lymphoma; Contiguous Stage II Mantle Cell Lymphoma; Contiguous Stage II Marginal Zone Lymphoma; Contiguous Stage II Small Lymphocytic Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; de Novo Myelodysplastic Syndromes; Essential Thrombocythemia; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Burkitt Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Noncontiguous Stage II Adult Lymphoblastic Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Noncutaneous Extranodal Lymphoma; Peripheral T-cell Lymphoma; Polycythemia Vera; Post-transplant Lymphoproliferative Disorder; Previously Treated Myelodysplastic Syndromes; Primary Myelofibrosis; Prolymphocytic Leukemia; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Anaplastic Large Cell Lymphoma; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Refractory Multiple Myeloma; Relapsing Chronic Myelogenous Leukemia; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Stage I Adult Burkitt Lymphoma; Stage I Adult Diffuse Large Cell Lymphoma; Stage I Adult Diffuse Mixed Cell Lymphoma; Stage I Adult Diffuse Small Cleaved Cell Lymphoma; Stage I Adult Immunoblastic Large Cell Lymphoma; Stage I Adult Lymphoblastic Lymphoma; Stage I Adult T-cell Leukemia/Lymphoma; Stage I Childhood Anaplastic Large Cell Lymphoma; Stage I Childhood Large Cell Lymphoma; Stage I Childhood Lymphoblastic Lymphoma; Stage I Childhood Small Noncleaved Cell Lymphoma; Stage I Chronic Lymphocytic Leukemia; Stage I Cutaneous T-cell Non-Hodgkin Lymphoma; Stage I Grade 1 Follicular Lymphoma; Stage I Grade 2 Follicular Lymphoma; Stage I Grade 3 Follicular Lymphoma; Stage I Mantle Cell Lymphoma; Stage I Marginal Zone Lymphoma; Stage I Multiple Myeloma; Stage I Small Lymphocytic Lymphoma; Stage IA Mycosis Fungoides/Sezary Syndrome; Stage IB Mycosis Fungoides/Sezary Syndrome; Stage II Adult T-cell Leukemia/Lymphoma; Stage II Childhood Anaplastic Large Cell Lymphoma; Stage II Childhood Large Cell Lymphoma; Stage II Childhood Lymphoblastic Lymphoma; Stage II Childhood Small Noncleaved Cell Lymphoma; Stage II Chronic Lymphocytic Leukemia; Stage II Cutaneous T-cell Non-Hodgkin Lymphoma; Stage II Multiple Myeloma; Stage IIA Mycosis Fungoides/Sezary Syndrome; Stage IIB Mycosis Fungoides/Sezary Syndrome; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Adult T-cell Leukemia/Lymphoma; Stage III Childhood Anaplastic Large Cell Lymphoma; Stage III Childhood Large Cell Lymphoma; Stage III Childhood Lymphoblastic Lymphoma; Stage III Childhood Small Noncleaved Cell Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Cutaneous T-cell Non-Hodgkin Lymphoma; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Multiple Myeloma; Stage III Small Lymphocytic Lymphoma; Stage IIIA Mycosis Fungoides/Sezary Syndrome; Stage IIIB Mycosis Fungoides/Sezary Syndrome; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Adult T-cell Leukemia/Lymphoma; Stage IV Childhood Anaplastic Large Cell Lymphoma; Stage IV Childhood Large Cell Lymphoma; Stage IV Childhood Lymphoblastic Lymphoma; Stage IV Childhood Small Noncleaved Cell Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Small Lymphocytic Lymphoma; Stage IVA Mycosis Fungoides/Sezary Syndrome; Stage IVB Mycosis Fungoides/Sezary Syndrome; Testicular Lymphoma; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Adult Acute Myeloid Leukemia; Untreated Childhood Acute Lymphoblastic Leukemia; Untreated Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies; Waldenström Macroglobulinemia

A Two-Step Approach to Reduced Intensity Bone Marrow Transplant for Patients With Hematological Malignancies

ClinicalTrials.gov

2017-12-04

Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Nasal Type Extranodal NK/T-cell Lymphoma; Aplastic Anemia; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Myeloid Leukemia in Remission; Childhood Myelodysplastic Syndromes; Chronic Eosinophilic Leukemia; Chronic Myelomonocytic Leukemia; Chronic Neutrophilic Leukemia; Essential Thrombocythemia; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Juvenile Myelomonocytic Leukemia; Mastocytosis; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Nodal Marginal Zone B-cell Lymphoma; Polycythemia Vera; Previously Treated Myelodysplastic Syndromes; Primary Myelofibrosis; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Refractory Anemia; Refractory Anemia With Ringed Sideroblasts; Refractory Hairy Cell Leukemia; Refractory Multiple Myeloma; Secondary Myelodysplastic Syndromes; Splenic Marginal Zone Lymphoma; T-cell Large Granular Lymphocyte Leukemia; Waldenström Macroglobulinemia

Fludarabine and Total-Body Irradiation Followed By Donor Stem Cell Transplant and Cyclosporine and Mycophenolate Mofetil in Treating HIV-Positive Patients With or Without Cancer

ClinicalTrials.gov

2017-04-17

Accelerated Phase Chronic Myelogenous Leukemia; Acute Undifferentiated Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Grade III Lymphomatoid Granulomatosis; Adult Nasal Type Extranodal NK/T-cell Lymphoma; Aggressive NK-cell Leukemia; AIDS-related Diffuse Large Cell Lymphoma; AIDS-related Diffuse Mixed Cell Lymphoma; AIDS-related Diffuse Small Cleaved Cell Lymphoma; AIDS-related Immunoblastic Large Cell Lymphoma; AIDS-related Lymphoblastic Lymphoma; AIDS-related Peripheral/Systemic Lymphoma; AIDS-related Primary CNS Lymphoma; AIDS-related Small Noncleaved Cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Blastic Phase Chronic Myelogenous Leukemia; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Myeloid Leukemia in Remission; Childhood Burkitt Lymphoma; Childhood Chronic Myelogenous Leukemia; Childhood Diffuse Large Cell Lymphoma; Childhood Grade III Lymphomatoid Granulomatosis; Childhood Immunoblastic Large Cell Lymphoma; Childhood Myelodysplastic Syndromes; Childhood Nasal Type Extranodal NK/T-cell Lymphoma; Chronic Eosinophilic Leukemia; Chronic Myelomonocytic Leukemia; Chronic Neutrophilic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; Contiguous Stage II Adult Burkitt Lymphoma; Contiguous Stage II Adult Diffuse Large Cell Lymphoma; Contiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Contiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Contiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Contiguous Stage II Adult Lymphoblastic Lymphoma; Contiguous Stage II Grade 1 Follicular Lymphoma; Contiguous Stage II Grade 2 Follicular Lymphoma; Contiguous Stage II Grade 3 Follicular Lymphoma; Contiguous Stage II Mantle Cell Lymphoma; Contiguous Stage II Marginal Zone Lymphoma; Contiguous Stage II Small Lymphocytic Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Essential Thrombocythemia; Extramedullary Plasmacytoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; HIV Infection; HIV-associated Hodgkin Lymphoma; Intraocular Lymphoma; Isolated Plasmacytoma of Bone; Juvenile Myelomonocytic Leukemia; Mast Cell Leukemia; Meningeal Chronic Myelogenous Leukemia; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Myeloid/NK-cell Acute Leukemia; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Burkitt Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Noncontiguous Stage II Adult Lymphoblastic Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Noncutaneous Extranodal Lymphoma; Peripheral T-cell Lymphoma; Polycythemia Vera; Post-transplant Lymphoproliferative Disorder; Previously Treated Myelodysplastic Syndromes; Primary Central Nervous System Lymphoma; Primary Myelofibrosis; Primary Systemic Amyloidosis; Progressive Hairy Cell Leukemia, Initial Treatment; Prolymphocytic Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Stage 0 Chronic Lymphocytic Leukemia; Stage I Adult Burkitt Lymphoma; Stage I Adult Diffuse Large Cell Lymphoma; Stage I Adult Diffuse Mixed Cell Lymphoma; Stage I Adult Diffuse Small Cleaved Cell Lymphoma; Stage I Adult Hodgkin Lymphoma; Stage I Adult Immunoblastic Large Cell Lymphoma; Stage I Adult Lymphoblastic Lymphoma; Stage I Adult T-cell Leukemia/Lymphoma; Stage I Childhood Anaplastic Large Cell Lymphoma; Stage I Childhood Hodgkin Lymphoma; Stage I Childhood Large Cell Lymphoma; Stage I Childhood Lymphoblastic Lymphoma; Stage I Childhood Small Noncleaved Cell Lymphoma; Stage I Chronic Lymphocytic Leukemia; Stage I Cutaneous T-cell Non-Hodgkin Lymphoma; Stage I Grade 1 Follicular Lymphoma; Stage I Grade 2 Follicular Lymphoma; Stage I Grade 3 Follicular Lymphoma; Stage I Mantle Cell Lymphoma; Stage I Marginal Zone Lymphoma; Stage I Multiple Myeloma; Stage I Small Lymphocytic Lymphoma; Stage IA Mycosis Fungoides/Sezary Syndrome; Stage IB Mycosis Fungoides/Sezary Syndrome; Stage II Adult Hodgkin Lymphoma; Stage II Adult T-cell Leukemia/Lymphoma; Stage II Childhood Anaplastic Large Cell Lymphoma; Stage II Childhood Hodgkin Lymphoma; Stage II Childhood Large Cell Lymphoma; Stage II Childhood Lymphoblastic Lymphoma; Stage II Childhood Small Noncleaved Cell Lymphoma; Stage II Chronic Lymphocytic Leukemia; Stage II Cutaneous T-cell Non-Hodgkin Lymphoma; Stage II Multiple Myeloma; Stage IIA Mycosis Fungoides/Sezary Syndrome; Stage IIB Mycosis Fungoides/Sezary Syndrome; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Hodgkin Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Adult T-cell Leukemia/Lymphoma; Stage III Childhood Anaplastic Large Cell Lymphoma; Stage III Childhood Hodgkin Lymphoma; Stage III Childhood Large Cell Lymphoma; Stage III Childhood Lymphoblastic Lymphoma; Stage III Childhood Small Noncleaved Cell Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Cutaneous T-cell Non-Hodgkin Lymphoma; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Multiple Myeloma; Stage III Small Lymphocytic Lymphoma; Stage IIIA Mycosis Fungoides/Sezary Syndrome; Stage IIIB Mycosis Fungoides/Sezary Syndrome; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Hodgkin Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Adult T-cell Leukemia/Lymphoma; Stage IV Childhood Anaplastic Large Cell Lymphoma; Stage IV Childhood Hodgkin Lymphoma; Stage IV Childhood Large Cell Lymphoma; Stage IV Childhood Lymphoblastic Lymphoma; Stage IV Childhood Small Noncleaved Cell Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Small Lymphocytic Lymphoma; Stage IVA Mycosis Fungoides/Sezary Syndrome; Stage IVB Mycosis Fungoides/Sezary Syndrome; T-cell Large Granular Lymphocyte Leukemia; Testicular Lymphoma; Unspecified Adult Solid Tumor, Protocol Specific; Unspecified Childhood Solid Tumor, Protocol Specific; Waldenström Macroglobulinemia

A Pilot Study to Evaluate the Co-Infusion of Ex Vivo Expanded Cord Blood Cells With an Unmanipulated Cord Blood Unit in Patients Undergoing Cord Blood Transplant for Hematologic Malignancies

ClinicalTrials.gov

2015-02-10

Accelerated Phase Chronic Myelogenous Leukemia; Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Myeloid Leukemia in Remission; Childhood Burkitt Lymphoma; Childhood Chronic Myelogenous Leukemia; Childhood Diffuse Large Cell Lymphoma; Childhood Immunoblastic Large Cell Lymphoma; Childhood Myelodysplastic Syndromes; Childhood Nasal Type Extranodal NK/T-cell Lymphoma; Chronic Phase Chronic Myelogenous Leukemia; Contiguous Stage II Adult Burkitt Lymphoma; Contiguous Stage II Adult Diffuse Large Cell Lymphoma; Contiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Contiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Contiguous Stage II Adult Lymphoblastic Lymphoma; Contiguous Stage II Grade 3 Follicular Lymphoma; Contiguous Stage II Mantle Cell Lymphoma; de Novo Myelodysplastic Syndromes; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Burkitt Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Noncontiguous Stage II Adult Lymphoblastic Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Previously Treated Myelodysplastic Syndromes; Prolymphocytic Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Childhood Anaplastic Large Cell Lymphoma; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Refractory Anemia; Refractory Anemia With Excess Blasts; Refractory Anemia With Excess Blasts in Transformation; Refractory Chronic Lymphocytic Leukemia; Refractory Multiple Myeloma; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Splenic Marginal Zone Lymphoma; Stage I Adult Burkitt Lymphoma; Stage I Adult Diffuse Large Cell Lymphoma; Stage I Adult Diffuse Mixed Cell Lymphoma; Stage I Adult Immunoblastic Large Cell Lymphoma; Stage I Adult Lymphoblastic Lymphoma; Stage I Childhood Lymphoblastic Lymphoma; Stage I Grade 3 Follicular Lymphoma; Stage I Mantle Cell Lymphoma; Stage II Childhood Lymphoblastic Lymphoma; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Childhood Lymphoblastic Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Childhood Lymphoblastic Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma

Collecting and Storing Malignant, Borderline Malignant Neoplasms, and Related Samples From Young Patients With Cancer

ClinicalTrials.gov

2017-12-11

Acute Undifferentiated Leukemia; Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative; Childhood Acute Lymphoblastic Leukemia; Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies; Childhood Chronic Myelogenous Leukemia; Chronic Lymphocytic Leukemia; Hairy Cell Leukemia; Juvenile Myelomonocytic Leukemia; Mast Cell Leukemia; Neoplasm of Uncertain Malignant Potential; Prolymphocytic Leukemia; Secondary Acute Myeloid Leukemia; T-cell Large Granular Lymphocyte Leukemia; Unspecified Childhood Solid Tumor, Protocol Specific

Treosulfan, Fludarabine Phosphate, and Total-Body Irradiation Before Donor Stem Cell Transplant in Treating Patients With High-Risk Acute Myeloid Leukemia, Myelodysplastic Syndrome, Acute Lymphoblastic Leukemia

ClinicalTrials.gov

2017-04-05

Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Blastic Phase Chronic Myelogenous Leukemia; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Myeloid Leukemia in Remission; Childhood Chronic Myelogenous Leukemia; Childhood Myelodysplastic Syndromes; Chronic Myelomonocytic Leukemia; de Novo Myelodysplastic Syndromes; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Childhood Acute Lymphoblastic Leukemia

Venetoclax and Vincristine Liposomal in Treating Patients With Relapsed or Refractory T-cell or B-cell Acute Lymphoblastic Leukemia

ClinicalTrials.gov

2018-06-07

B Acute Lymphoblastic Leukemia; Lymphoblasts 5 Percent or More of Bone Marrow Nucleated Cells; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Refractory Acute Lymphoblastic Leukemia; T Acute Lymphoblastic Leukemia

Gamma-Secretase Inhibitor RO4929097 in Treating Young Patients With Relapsed or Refractory Solid Tumors, CNS Tumors, Lymphoma, or T-Cell Leukemia

ClinicalTrials.gov

2014-11-04

Childhood Atypical Teratoid/Rhabdoid Tumor; Childhood Central Nervous System Choriocarcinoma; Childhood Central Nervous System Germinoma; Childhood Central Nervous System Mixed Germ Cell Tumor; Childhood Central Nervous System Teratoma; Childhood Central Nervous System Yolk Sac Tumor; Childhood Choroid Plexus Tumor; Childhood Craniopharyngioma; Childhood Ependymoblastoma; Childhood Grade I Meningioma; Childhood Grade II Meningioma; Childhood Grade III Meningioma; Childhood Infratentorial Ependymoma; Childhood Medulloepithelioma; Childhood Mixed Glioma; Childhood Oligodendroglioma; Childhood Supratentorial Ependymoma; Gonadotroph Adenoma; Pituitary Basophilic Adenoma; Pituitary Chromophobe Adenoma; Pituitary Eosinophilic Adenoma; Prolactin Secreting Adenoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Anaplastic Large Cell Lymphoma; Recurrent Childhood Brain Stem Glioma; Recurrent Childhood Central Nervous System Embryonal Tumor; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Ependymoma; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Medulloblastoma; Recurrent Childhood Pineoblastoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Childhood Spinal Cord Neoplasm; Recurrent Childhood Subependymal Giant Cell Astrocytoma; Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor; Recurrent Childhood Visual Pathway and Hypothalamic Glioma; Recurrent Childhood Visual Pathway Glioma; Recurrent Pituitary Tumor; Recurrent/Refractory Childhood Hodgkin Lymphoma; T-cell Childhood Acute Lymphoblastic Leukemia; T-cell Large Granular Lymphocyte Leukemia; TSH Secreting Adenoma; Unspecified Childhood Solid Tumor, Protocol Specific

Sirolimus, Cyclosporine, and Mycophenolate Mofetil in Preventing Graft-versus-Host Disease in Treating Patients With Blood Cancer Undergoing Donor Peripheral Blood Stem Cell Transplant

ClinicalTrials.gov

2017-10-30

Adult Acute Lymphoblastic Leukemia; Adult Acute Myeloid Leukemia; Adult Diffuse Large B-Cell Lymphoma; Adult Myelodysplastic Syndrome; Adult Non-Hodgkin Lymphoma; Aggressive Non-Hodgkin Lymphoma; Childhood Acute Lymphoblastic Leukemia; Childhood Acute Myeloid Leukemia; Childhood Diffuse Large B-Cell Lymphoma; Childhood Myelodysplastic Syndrome; Childhood Non-Hodgkin Lymphoma; Chronic Lymphocytic Leukemia; Chronic Lymphocytic Leukemia in Remission; Chronic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Hematopoietic and Lymphoid Cell Neoplasm; Mantle Cell Lymphoma; Plasma Cell Myeloma; Prolymphocytic Leukemia; Recurrent Chronic Lymphocytic Leukemia; Refractory Chronic Lymphocytic Leukemia; T-Cell Prolymphocytic Leukemia; Waldenstrom Macroglobulinemia; Recurrent Diffuse Large B-Cell Lymphoma; Recurrent Hodgkin Lymphoma

MK2206 in Treating Younger Patients With Recurrent or Refractory Solid Tumors or Leukemia

ClinicalTrials.gov

2014-04-28

Accelerated Phase Chronic Myelogenous Leukemia; Acute Leukemias of Ambiguous Lineage; Acute Myeloid Leukemia/Transient Myeloproliferative Disorder; Acute Undifferentiated Leukemia; Aggressive NK-cell Leukemia; Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative; Blastic Phase Chronic Myelogenous Leukemia; Blastic Plasmacytoid Dendritic Cell Neoplasm; Childhood Burkitt Lymphoma; Childhood Chronic Myelogenous Leukemia; Childhood Diffuse Large Cell Lymphoma; Childhood Grade III Lymphomatoid Granulomatosis; Childhood Immunoblastic Large Cell Lymphoma; Childhood Nasal Type Extranodal NK/T-cell Lymphoma; Chronic Eosinophilic Leukemia; Chronic Myelomonocytic Leukemia; Chronic Neutrophilic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; Intraocular Lymphoma; Juvenile Myelomonocytic Leukemia; Mast Cell Leukemia; Myeloid/NK-cell Acute Leukemia; Noncutaneous Extranodal Lymphoma; Post-transplant Lymphoproliferative Disorder; Primary Central Nervous System Hodgkin Lymphoma; Primary Central Nervous System Non-Hodgkin Lymphoma; Progressive Hairy Cell Leukemia, Initial Treatment; Prolymphocytic Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Anaplastic Large Cell Lymphoma; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Unspecified Childhood Solid Tumor, Protocol Specific; Waldenström Macroglobulinemia

Selective Depletion of CD45RA+ T Cells From Allogeneic Peripheral Blood Stem Cell Grafts in Preventing GVHD in Children

ClinicalTrials.gov

2018-04-23

Accelerated Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Acute Biphenotypic Leukemia; Acute Leukemia of Ambiguous Lineage; Acute Undifferentiated Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Blast Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Myeloid Leukemia in Remission; Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Myelodysplastic Syndrome With Excess Blasts-1; Myelodysplastic Syndrome With Excess Blasts-2; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Refractory Adult Acute Lymphoblastic Leukemia; Refractory Childhood Acute Lymphoblastic Leukemia

Tacrolimus and Mycophenolate Mofetil With or Without Sirolimus in Preventing Acute Graft-Versus-Host Disease in Patients Who Are Undergoing Donor Stem Cell Transplant for Hematologic Cancer

ClinicalTrials.gov

2018-02-08

Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Previously Treated Myelodysplastic Syndrome; Refractory Chronic Lymphocytic Leukemia; Refractory Plasma Cell Myeloma; Waldenstrom Macroglobulinemia; Accelerated Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With t(9;11)(p22;q23); MLLT3-MLL; Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11; Adult Acute Promyelocytic Leukemia With t(15;17)(q22;q12); PML-RARA; Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); RUNX1-RUNX1T1; Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative; Blast Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Myeloid Leukemia in Remission; Childhood Burkitt Lymphoma; Childhood Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Childhood Diffuse Large Cell Lymphoma; Childhood Immunoblastic Lymphoma; Childhood Myelodysplastic Syndrome; Stage II Contiguous Adult Burkitt Lymphoma; Stage II Contiguous Adult Diffuse Large Cell Lymphoma; Stage II Contiguous Adult Diffuse Mixed Cell Lymphoma; Stage II Contiguous Adult Diffuse Small Cleaved Cell Lymphoma; Stage II Adult Contiguous Immunoblastic Lymphoma; Stage II Contiguous Adult Lymphoblastic Lymphoma; Stage II Grade 1 Contiguous Follicular Lymphoma; Stage II Grade 2 Contiguous Follicular Lymphoma; Stage II Grade 3 Contiguous Follicular Lymphoma; Stage II Contiguous Mantle Cell Lymphoma; Stage II Non-Contiguous Adult Burkitt Lymphoma; Stage II Non-Contiguous Adult Diffuse Large Cell Lymphoma; Stage II Non-Contiguous Adult Diffuse Mixed Cell Lymphoma; Stage II Non-Contiguous Adult Diffuse Small Cleaved Cell Lymphoma; Stage II Adult Non-Contiguous Immunoblastic Lymphoma; Stage II Non-Contiguous Adult Lymphoblastic Lymphoma; Stage II Grade 1 Non-Contiguous Follicular Lymphoma; Stage II Grade 2 Non-Contiguous Follicular Lymphoma; Stage II Grade 3 Non-Contiguous Follicular Lymphoma; Stage II Non-Contiguous Mantle Cell Lymphoma; Stage II Small Lymphocytic Lymphoma; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Anaplastic Large Cell Lymphoma; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Burkitt Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Recurrent Childhood Hodgkin Lymphoma; Recurrent Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Secondary Myelodysplastic Syndrome; Stage I Adult Burkitt Lymphoma; Stage I Adult Diffuse Large Cell Lymphoma; Stage I Adult Diffuse Mixed Cell Lymphoma; Stage I Adult Immunoblastic Lymphoma; Stage I Adult Lymphoblastic Lymphoma; Stage I Childhood Anaplastic Large Cell Lymphoma; Stage I Childhood Large Cell Lymphoma; Stage I Childhood Lymphoblastic Lymphoma; Stage I Childhood Burkitt Lymphoma; Stage I Grade 1 Follicular Lymphoma; Stage I Grade 2 Follicular Lymphoma; Stage I Grade 3 Follicular Lymphoma; Stage I Mantle Cell Lymphoma; Stage I Marginal Zone Lymphoma; Stage I Small Lymphocytic Lymphoma; Stage II Childhood Anaplastic Large Cell Lymphoma; Stage II Childhood Lymphoblastic Lymphoma; Stage II Childhood Burkitt Lymphoma; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Immunoblastic Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Childhood Anaplastic Large Cell Lymphoma; Stage III Childhood Large Cell Lymphoma; Stage III Childhood Lymphoblastic Lymphoma; Stage III Childhood Burkitt Lymphoma; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Small Lymphocytic Lymphoma; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Immunoblastic Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Childhood Anaplastic Large Cell Lymphoma; Stage IV Childhood Large Cell Lymphoma; Stage IV Childhood Lymphoblastic Lymphoma; Stage IV Childhood Burkitt Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Small Lymphocytic Lymphoma

Lithium Carbonate in Treating Patients With Acute Intestinal Graft-Versus-Host-Disease (GVHD) After Donor Stem Cell Transplant

ClinicalTrials.gov

2017-01-24

Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Atypical Chronic Myeloid Leukemia, Breakpoint Cluster Region-abl Translocation (BCR-ABL) Negative; Blastic Phase Chronic Myelogenous Leukemia; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Myeloid Leukemia in Remission; Childhood Chronic Myelogenous Leukemia; Childhood Myelodysplastic Syndromes; Chronic Eosinophilic Leukemia; Chronic Myelomonocytic Leukemia; Chronic Neutrophilic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; de Novo Myelodysplastic Syndromes; Disseminated Neuroblastoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Gastrointestinal Complications; Juvenile Myelomonocytic Leukemia; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Burkitt Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Noncontiguous Stage II Adult Lymphoblastic Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Poor Prognosis Metastatic Gestational Trophoblastic Tumor; Previously Treated Childhood Rhabdomyosarcoma; Primary Myelofibrosis; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Rhabdomyosarcoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Malignant Testicular Germ Cell Tumor; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Neuroblastoma; Recurrent Ovarian Epithelial Cancer; Recurrent Ovarian Germ Cell Tumor; Recurrent Small Lymphocytic Lymphoma; Recurrent Wilms Tumor and Other Childhood Kidney Tumors; Recurrent/Refractory Childhood Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Splenic Marginal Zone Lymphoma; Stage I Multiple Myeloma; Stage II Multiple Myeloma; Stage II Ovarian Epithelial Cancer; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Hodgkin Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Malignant Testicular Germ Cell Tumor; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Multiple Myeloma; Stage III Ovarian Epithelial Cancer; Stage III Small Lymphocytic Lymphoma; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Hodgkin Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Breast Cancer; Stage IV Chronic Lymphocytic Leukemia; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Ovarian Epithelial Cancer; Stage IV Small Lymphocytic Lymphoma

Selective Depletion of CD45RA+ T Cells From Allogeneic Peripheral Blood Stem Cell Grafts From HLA-Matched Related and Unrelated Donors in Preventing GVHD

ClinicalTrials.gov

2017-10-25

Accelerated Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Acute Biphenotypic Leukemia; Acute Leukemia of Ambiguous Lineage; Acute Undifferentiated Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Blast Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Blastic Plasmacytoid Dendritic Cell Neoplasm; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Myeloid Leukemia in Remission; Lymphoblastic Lymphoma; Myelodysplastic Syndrome With Excess Blasts; Myelodysplastic Syndrome With Excess Blasts-1; Myelodysplastic Syndrome With Excess Blasts-2; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Refractory Acute Lymphoblastic Leukemia; Refractory Acute Myeloid Leukemia

Cyclophosphamide and Busulfan Followed by Donor Stem Cell Transplant in Treating Patients With Myelofibrosis, Acute Myeloid Leukemia, or Myelodysplastic Syndrome

ClinicalTrials.gov

2017-12-01

Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Childhood Acute Myeloid Leukemia in Remission; Childhood Myelodysplastic Syndromes; de Novo Myelodysplastic Syndromes; Essential Thrombocythemia; Myelodysplastic Syndrome With Isolated Del(5q); Polycythemia Vera; Previously Treated Myelodysplastic Syndromes; Primary Myelofibrosis; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Secondary Myelofibrosis; Untreated Adult Acute Myeloid Leukemia; Untreated Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies

Infusion of Off-the-Shelf Expanded Cord Blood Cells to Augment Cord Blood Transplant in Patients With Hematologic Malignancies

ClinicalTrials.gov

2017-04-05

Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Myeloid Leukemia in Remission; Childhood Chronic Myelogenous Leukemia; Childhood Myelodysplastic Syndromes; Chronic Phase Chronic Myelogenous Leukemia; de Novo Myelodysplastic Syndromes; Previously Treated Myelodysplastic Syndromes; Refractory Anemia; Refractory Anemia With Excess Blasts; Refractory Anemia With Excess Blasts in Transformation; Relapsing Chronic Myelogenous Leukemia; Secondary Myelodysplastic Syndromes

Therapeutic Allogeneic Lymphocytes and Aldesleukin in Treating Patients With High-Risk or Recurrent Myeloid Leukemia After Undergoing Donor Stem Cell Transplant

ClinicalTrials.gov

2017-02-13

Accelerated Phase Chronic Myelogenous Leukemia; Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Blastic Phase Chronic Myelogenous Leukemia; Childhood Chronic Myelogenous Leukemia; Childhood Myelodysplastic Syndromes; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia

Busulfan and Etoposide Followed by Peripheral Blood Stem Cell Transplant and Low-Dose Aldesleukin in Treating Patients With Acute Myeloid Leukemia

ClinicalTrials.gov

2017-05-03

Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Childhood Acute Myeloid Leukemia in Remission; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Myeloid Leukemia

Total Marrow and Lymphoid Irradiation and Chemotherapy Before Donor Stem Cell Transplant in Treating Patients With High-Risk Acute Lymphocytic or Myelogenous Leukemia

ClinicalTrials.gov

2018-03-15

Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia

Fludarabine Phosphate, Busulfan, and Anti-Thymocyte Globulin Followed By Donor Peripheral Blood Stem Cell Transplant, Tacrolimus, and Methotrexate in Treating Patients With Myeloid Malignancies

ClinicalTrials.gov

2016-05-04

Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Blastic Phase Chronic Myelogenous Leukemia; Childhood Acute Myeloid Leukemia in Remission; Childhood Chronic Myelogenous Leukemia; Childhood Myelodysplastic Syndromes; Chronic Phase Chronic Myelogenous Leukemia; de Novo Myelodysplastic Syndromes; Hematopoietic/Lymphoid Cancer; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Relapsing Chronic Myelogenous Leukemia

Low-Dose Total-Body Irradiation and Fludarabine Phosphate Followed by Unrelated Donor Stem Cell Transplant in Treating Patients With Fanconi Anemia

ClinicalTrials.gov

2017-02-16

Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Childhood Acute Myeloid Leukemia in Remission; Childhood Myelodysplastic Syndromes; Fanconi Anemia; Previously Treated Myelodysplastic Syndromes

Low-Dose or High-Dose Conditioning Followed by Peripheral Blood Stem Cell Transplant in Treating Patients With Myelodysplastic Syndrome or Acute Myelogenous Leukemia

ClinicalTrials.gov

2014-10-23

Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome; Acute Myeloid Leukemia/Transient Myeloproliferative Disorder; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Childhood Acute Myeloid Leukemia in Remission; Childhood Myelodysplastic Syndromes; de Novo Myelodysplastic Syndromes; Myelodysplastic Syndrome With Isolated Del(5q); Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes

Beclomethasone Dipropionate in Preventing Acute Graft-Versus-Host Disease in Patients Undergoing a Donor Stem Cell Transplant for Hematologic Cancer

ClinicalTrials.gov

2015-03-05

Hematopoietic/Lymphoid Cancer; Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Atypical Chronic Myeloid Leukemia; Blastic Phase Chronic Myelogenous Leukemia; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Myeloid Leukemia in Remission; Childhood Chronic Myelogenous Leukemia; Childhood Myelodysplastic Syndromes; Chronic Eosinophilic Leukemia; Chronic Myelomonocytic Leukemia; Chronic Neutrophilic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; Contiguous Stage II Adult Burkitt Lymphoma; Contiguous Stage II Adult Diffuse Large Cell Lymphoma; Contiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Contiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Contiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Contiguous Stage II Adult Lymphoblastic Lymphoma; Contiguous Stage II Grade 1 Follicular Lymphoma; Contiguous Stage II Grade 2 Follicular Lymphoma; Contiguous Stage II Grade 3 Follicular Lymphoma; Contiguous Stage II Mantle Cell Lymphoma; Contiguous Stage II Marginal Zone Lymphoma; Contiguous Stage II Small Lymphocytic Lymphoma; de Novo Myelodysplastic Syndromes; Essential Thrombocythemia; Extramedullary Plasmacytoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Graft Versus Host Disease; Isolated Plasmacytoma of Bone; Juvenile Myelomonocytic Leukemia; Meningeal Chronic Myelogenous Leukemia; Myelodysplastic/Myeloproliferative Disease, Unclassifiable; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Burkitt Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Noncontiguous Stage II Adult Lymphoblastic Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Previously Treated Myelodysplastic Syndromes; Primary Myelofibrosis; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Relapsing Chronic Myelogenous Leukemia; Secondary Myelodysplastic Syndromes; Stage I Adult Burkitt Lymphoma; Stage I Adult Diffuse Large Cell Lymphoma; Stage I Adult Diffuse Mixed Cell Lymphoma; Stage I Adult Diffuse Small Cleaved Cell Lymphoma; Stage I Adult Hodgkin Lymphoma; Stage I Adult Immunoblastic Large Cell Lymphoma; Stage I Adult Lymphoblastic Lymphoma; Stage I Adult T-cell Leukemia/Lymphoma; Stage I Childhood Hodgkin Lymphoma; Stage I Chronic Lymphocytic Leukemia; Stage I Cutaneous T-cell Non-Hodgkin Lymphoma; Stage I Grade 1 Follicular Lymphoma; Stage I Grade 2 Follicular Lymphoma; Stage I Grade 3 Follicular Lymphoma; Stage I Mantle Cell Lymphoma; Stage I Marginal Zone Lymphoma; Stage I Multiple Myeloma; Stage I Mycosis Fungoides/Sezary Syndrome; Stage I Small Lymphocytic Lymphoma; Stage II Adult Hodgkin Lymphoma; Stage II Adult T-cell Leukemia/Lymphoma; Stage II Chronic Lymphocytic Leukemia; Stage II Cutaneous T-cell Non-Hodgkin Lymphoma; Stage II Multiple Myeloma; Stage II Mycosis Fungoides/Sezary Syndrome; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Hodgkin Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Adult T-cell Leukemia/Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Cutaneous T-cell Non-Hodgkin Lymphoma; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Multiple Myeloma; Stage III Mycosis Fungoides/Sezary Syndrome; Stage III Small Lymphocytic Lymphoma; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Hodgkin Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Adult T-cell Leukemia/Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Mycosis Fungoides/Sezary Syndrome; Stage IV Small Lymphocytic Lymphoma

Iodine I 131 Monoclonal Antibody BC8, Fludarabine Phosphate, Total Body Irradiation, and Donor Stem Cell Transplant Followed by Cyclosporine and Mycophenolate Mofetil in Treating Patients With Advanced Acute Myeloid Leukemia or Myelodysplastic Syndrome

ClinicalTrials.gov

2018-06-22

Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Childhood Myelodysplastic Syndromes; Chronic Myelomonocytic Leukemia; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Refractory Anemia With Excess Blasts; Refractory Anemia With Excess Blasts in Transformation; Refractory Anemia With Ringed Sideroblasts; Refractory Cytopenia With Multilineage Dysplasia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes

Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Hematologic Malignancies

ClinicalTrials.gov

2017-12-11

Acute Biphenotypic Leukemia; Acute Erythroid Leukemia in Remission; Acute Leukemia in Remission; Acute Megakaryoblastic Leukemia; Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome; Acute Myeloid Leukemia in Remission; Acute Myeloid Leukemia With FLT3/ITD Mutation; Acute Myeloid Leukemia With Inv(3) (q21.3;q26.2) or t(3;3) (q21.3;q26.2); GATA2, MECOM; Acute Myeloid Leukemia With Inv(3) (q21.3;q26.2); GATA2, MECOM; Acute Myeloid Leukemia With Multilineage Dysplasia; Acute Myeloid Leukemia With t(6;9) (p23;q34.1); DEK-NUP214; Acute Undifferentiated Leukemia; Adult Acute Lymphoblastic Leukemia in Complete Remission; B Acute Lymphoblastic Leukemia With t(1;19)(q23;p13.3); E2A-PBX1 (TCF3-PBX1); B Acute Lymphoblastic Leukemia With t(9;22)(q34.1;q11.2); BCR-ABL1; Burkitt Lymphoma; Childhood Acute Lymphoblastic Leukemia in Complete Remission; DS Stage II Plasma Cell Myeloma; DS Stage III Plasma Cell Myeloma; Myelodysplastic Syndrome; Recurrent Anaplastic Large Cell Lymphoma; Recurrent Diffuse Large B-Cell Lymphoma; Recurrent Follicular Lymphoma; Recurrent Hodgkin Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Plasma Cell Myeloma; Refractory Plasma Cell Myeloma; Secondary Acute Myeloid Leukemia; T Lymphoblastic Lymphoma

Risk-Based Classification System of Patients With Newly Diagnosed Acute Lymphoblastic Leukemia

ClinicalTrials.gov

2018-02-22

Adult B Acute Lymphoblastic Leukemia; Adult T Acute Lymphoblastic Leukemia; Childhood B Acute Lymphoblastic Leukemia; Childhood T Acute Lymphoblastic Leukemia; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Childhood Acute Lymphoblastic Leukemia

CD19/CD22 Chimeric Antigen Receptor T Cells and Chemotherapy in Treating Children or Young Adults With Recurrent or Refractory CD19 Positive B Acute Lymphoblastic Leukemia

ClinicalTrials.gov

2017-11-20

B Acute Lymphoblastic Leukemia; CD19 Positive; Minimal Residual Disease; Philadelphia Chromosome Positive; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Refractory Acute Lymphoblastic Leukemia

Total-Body Irradiation and Fludarabine Phosphate Followed by Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Hematologic Malignancies or Kidney Cancer

ClinicalTrials.gov

2017-12-11

Adult Acute Myeloid Leukemia in Remission; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Myeloid Leukemia in Remission; Childhood Myelodysplastic Syndrome; Childhood Renal Cell Carcinoma; Chronic Myelomonocytic Leukemia; Clear Cell Renal Cell Carcinoma; de Novo Myelodysplastic Syndrome; Metastatic Renal Cell Cancer; Previously Treated Myelodysplastic Syndrome; Progression of Multiple Myeloma or Plasma Cell Leukemia; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult Non-Hodgkin Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Non-Hodgkin Lymphoma; Refractory Anemia; Refractory Anemia With Ringed Sideroblasts; Refractory Childhood Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Renal Medullary Carcinoma; Type 1 Papillary Renal Cell Carcinoma; Type 2 Papillary Renal Cell Carcinoma; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Adult Acute Myeloid Leukemia; Untreated Childhood Acute Lymphoblastic Leukemia

T-cell-replete haploidentical stem cell transplantation is highly efficacious for relapsed and refractory childhood acute leukaemia.

PubMed

Kobayashi, S; Ito, M; Sano, H; Mochizuki, K; Akaihata, M; Waragai, T; Ohara, Y; Hosoya, M; Ohto, H; Kikuta, A

2014-10-01

Despite improvements in first-line therapies, the outcomes of relapsed or refractory childhood acute leukaemia that has not achieved complete remission after relapse, has relapsed after stem cell transplantation (SCT), has primary induction failure and has relapsed with a very unfavourable cytogenetic risk profile, are dismal. We evaluated the feasibility and efficacy of T-cell-replete haploidentical peripheral blood stem cell transplantation (haplo-SCT) with low-dose anti-human thymocyte immunoglobulin (ATG), tacrolimus, methotrexate and prednisolone (PSL) in 14 paediatric patients with high-risk childhood acute leukaemia. All patients achieved complete engraftment. The median time to reaching an absolute neutrophil count of more than 0.5 × 10(9) L(-1) was 14 days. Acute graft-vs-host disease (aGVHD) of grades II-IV and III-IV developed in 10 (71%) and 2 (14%) patients, respectively. Treatment-related mortality and relapse occurred in one (7%) patient and six (43%) patients, respectively. Eleven patients were alive and seven of them were disease-free with a median follow-up of 36 months (range: 30-159 months). The probability of event-free survival after 2 years was 50%. These findings indicate that T-cell-replete haplo-SCT, with low-dose ATG and PSL, provides sustained remission with an acceptable risk of GVHD in paediatric patients with advanced haematologic malignancies. © 2014 The Authors. Transfusion Medicine published by John Wiley & Sons Ltd on behalf of British Blood Transfusion Society.

Blood Sample Markers of Reproductive Hormones in Assessing Ovarian Reserve in Younger Patients With Newly Diagnosed Lymphomas

ClinicalTrials.gov

2018-03-02

Adult Grade III Lymphomatoid Granulomatosis; Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Childhood Burkitt Lymphoma; Childhood Diffuse Large Cell Lymphoma; Childhood Grade III Lymphomatoid Granulomatosis; Childhood Immunoblastic Large Cell Lymphoma; Childhood Nasal Type Extranodal NK/T-cell Lymphoma; Contiguous Stage II Adult Burkitt Lymphoma; Contiguous Stage II Adult Diffuse Large Cell Lymphoma; Contiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Contiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Contiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Contiguous Stage II Adult Lymphoblastic Lymphoma; Contiguous Stage II Grade 1 Follicular Lymphoma; Contiguous Stage II Grade 2 Follicular Lymphoma; Contiguous Stage II Grade 3 Follicular Lymphoma; Contiguous Stage II Mantle Cell Lymphoma; Contiguous Stage II Marginal Zone Lymphoma; Contiguous Stage II Small Lymphocytic Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Burkitt Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Noncontiguous Stage II Adult Lymphoblastic Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Noncutaneous Extranodal Lymphoma; Peripheral T-cell Lymphoma; Progressive Hairy Cell Leukemia, Initial Treatment; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Stage 0 Chronic Lymphocytic Leukemia; Stage I Adult Burkitt Lymphoma; Stage I Adult Diffuse Large Cell Lymphoma; Stage I Adult Diffuse Mixed Cell Lymphoma; Stage I Adult Diffuse Small Cleaved Cell Lymphoma; Stage I Adult Hodgkin Lymphoma; Stage I Adult Immunoblastic Large Cell Lymphoma; Stage I Adult Lymphoblastic Lymphoma; Stage I Adult T-cell Leukemia/Lymphoma; Stage I Childhood Anaplastic Large Cell Lymphoma; Stage I Childhood Hodgkin Lymphoma; Stage I Childhood Large Cell Lymphoma; Stage I Childhood Lymphoblastic Lymphoma; Stage I Childhood Small Noncleaved Cell Lymphoma; Stage I Chronic Lymphocytic Leukemia; Stage I Cutaneous T-cell Non-Hodgkin Lymphoma; Stage I Grade 1 Follicular Lymphoma; Stage I Grade 2 Follicular Lymphoma; Stage I Grade 3 Follicular Lymphoma; Stage I Mantle Cell Lymphoma; Stage I Marginal Zone Lymphoma; Stage I Small Lymphocytic Lymphoma; Stage IA Mycosis Fungoides/Sezary Syndrome; Stage IB Mycosis Fungoides/Sezary Syndrome; Stage II Adult Hodgkin Lymphoma; Stage II Adult T-cell Leukemia/Lymphoma; Stage II Childhood Anaplastic Large Cell Lymphoma; Stage II Childhood Hodgkin Lymphoma; Stage II Childhood Large Cell Lymphoma; Stage II Childhood Lymphoblastic Lymphoma; Stage II Childhood Small Noncleaved Cell Lymphoma; Stage II Chronic Lymphocytic Leukemia; Stage II Cutaneous T-cell Non-Hodgkin Lymphoma; Stage IIA Mycosis Fungoides/Sezary Syndrome; Stage IIB Mycosis Fungoides/Sezary Syndrome; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Hodgkin Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Adult T-cell Leukemia/Lymphoma; Stage III Childhood Anaplastic Large Cell Lymphoma; Stage III Childhood Hodgkin Lymphoma; Stage III Childhood Large Cell Lymphoma; Stage III Childhood Lymphoblastic Lymphoma; Stage III Childhood Small Noncleaved Cell Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Cutaneous T-cell Non-Hodgkin Lymphoma; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Small Lymphocytic Lymphoma; Stage IIIA Mycosis Fungoides/Sezary Syndrome; Stage IIIB Mycosis Fungoides/Sezary Syndrome; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Hodgkin Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Adult T-cell Leukemia/Lymphoma; Stage IV Childhood Anaplastic Large Cell Lymphoma; Stage IV Childhood Hodgkin Lymphoma; Stage IV Childhood Large Cell Lymphoma; Stage IV Childhood Lymphoblastic Lymphoma; Stage IV Childhood Small Noncleaved Cell Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Small Lymphocytic Lymphoma; Stage IVA Mycosis Fungoides/Sezary Syndrome; Stage IVB Mycosis Fungoides/Sezary Syndrome; T-cell Large Granular Lymphocyte Leukemia; Testicular Lymphoma; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Childhood Acute Lymphoblastic Leukemia; Untreated Hairy Cell Leukemia; Waldenström Macroglobulinemia

Bortezomib and Combination Chemotherapy in Treating Younger Patients With Recurrent, Refractory, or Secondary Acute Myeloid Leukemia

ClinicalTrials.gov

2018-05-21

Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myelomonocytic Leukemia (M4); Childhood Acute Basophilic Leukemia; Childhood Acute Eosinophilic Leukemia; Childhood Acute Erythroleukemia (M6); Childhood Acute Megakaryocytic Leukemia (M7); Childhood Acute Minimally Differentiated Myeloid Leukemia (M0); Childhood Acute Monoblastic Leukemia (M5a); Childhood Acute Monocytic Leukemia (M5b); Childhood Acute Myeloblastic Leukemia With Maturation (M2); Childhood Acute Myeloblastic Leukemia Without Maturation (M1); Childhood Acute Myelomonocytic Leukemia (M4); Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia

Childhood pre-B cell acute lymphoblastic leukemia with translocation t(1;19)(q21.1;p13.3) and two additional chromosomal aberrations involving chromosomes 1, 6, and 13: a case report.

PubMed

Wafa, Abdulsamad; As'sad, Manar; Liehr, Thomas; Aljapawe, Abdulmunim; Al Achkar, Walid

2017-04-07

The translocation t(1;19)(q23;p13), which results in the TCF3-PBX1 chimeric gene, is one of the most frequent rearrangements observed in B cell acute lymphoblastic leukemia. It appears in both adult and pediatric patients with B cell acute lymphoblastic leukemia at an overall frequency of 3 to 5%. Most cases of pre-B cell acute lymphoblastic leukemia carrying the translocation t(1;19) have a typical immunophenotype with homogeneous expression of CD19, CD10, CD9, complete absence of CD34, and at least diminished CD20. Moreover, the translocation t(1;19) correlates with known clinical high risk factors, such as elevated white blood cell count, high serum lactate dehydrogenase levels, and central nervous system involvement; early reports indicated that patients with translocation t(1;19) had a poor outcome under standard treatment. We report the case of a 15-year-old Syrian boy with pre-B cell acute lymphoblastic leukemia with abnormal karyotype with a der(19)t(1;19)(q21.1;p13.3) and two yet unreported chromosomal aberrations: an interstitial deletion 6q12 to 6q26 and a der(13)t(1;13)(q21.1;p13). According to the literature, cases who are translocation t(1;19)-positive have a significantly higher incidence of central nervous system relapse than patients with acute lymphoblastic leukemia without the translocation. Of interest, central nervous system involvement was also seen in our patient. To the best of our knowledge, this is the first case of childhood pre-B cell acute lymphoblastic leukemia with an unbalanced translocation t(1;19) with two additional chromosomal aberrations, del(6)(q12q26) and t(1;13)(q21.3;p13), which seem to be recurrent and could influence clinical outcome. Also the present case confirms the impact of the translocation t(1;19) on central nervous system relapse, which should be studied for underlying mechanisms in future.

New immunotherapy approach leads to remission in patients with the most common type of childhood cancer | Center for Cancer Research

Cancer.gov

Chimeric antigen receptor (CAR) T-cell immunotherapy has emerged as a promising treatment for pre-B cell acute lymphoblastic leukemia (B-ALL), the most common type of childhood cancer. B-ALL is characterized by an overproduction of immature white blood cells called lymphoblasts. In a trial led by Center for Cancer Research investigators, around 70 to 90 percent of patients whose B-ALL has relapsed or developed resistance to chemotherapy entered remission after CAR T-cell therapy targeting CD19. Read more…

Ondansetron in Preventing Nausea and Vomiting in Patients Undergoing Stem Cell Transplant

ClinicalTrials.gov

2017-04-20

Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Atypical Chronic Myeloid Leukemia, BCR-ABL Negative; Blastic Phase Chronic Myelogenous Leukemia; Chronic Eosinophilic Leukemia; Chronic Myelomonocytic Leukemia; Chronic Neutrophilic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; de Novo Myelodysplastic Syndromes; Disseminated Neuroblastoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Burkitt Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Noncontiguous Stage II Adult Lymphoblastic Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Poor Prognosis Metastatic Gestational Trophoblastic Tumor; Previously Treated Myelodysplastic Syndromes; Primary Myelofibrosis; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Malignant Testicular Germ Cell Tumor; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Neuroblastoma; Recurrent Ovarian Epithelial Cancer; Recurrent Ovarian Germ Cell Tumor; Recurrent Small Lymphocytic Lymphoma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Splenic Marginal Zone Lymphoma; Stage I Multiple Myeloma; Stage II Multiple Myeloma; Stage II Ovarian Epithelial Cancer; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Hodgkin Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Malignant Testicular Germ Cell Tumor; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Multiple Myeloma; Stage III Ovarian Epithelial Cancer; Stage III Small Lymphocytic Lymphoma; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Hodgkin Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Breast Cancer; Stage IV Chronic Lymphocytic Leukemia; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Ovarian Epithelial Cancer; Stage IV Small Lymphocytic Lymphoma

Supersaturated Calcium Phosphate Rinse in Preventing Oral Mucositis in Young Patients Undergoing Autologous or Donor Stem Cell Transplant

ClinicalTrials.gov

2017-03-28

Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Myeloid Leukemia in Remission; Childhood Chronic Myelogenous Leukemia; Childhood Myelodysplastic Syndromes; Chronic Eosinophilic Leukemia; Chronic Myelomonocytic Leukemia; Chronic Neutrophilic Leukemia; de Novo Myelodysplastic Syndromes; Disseminated Neuroblastoma; Juvenile Myelomonocytic Leukemia; Mucositis; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Previously Treated Childhood Rhabdomyosarcoma; Previously Treated Myelodysplastic Syndromes; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Rhabdomyosarcoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Malignant Testicular Germ Cell Tumor; Recurrent Wilms Tumor and Other Childhood Kidney Tumors; Recurrent/Refractory Childhood Hodgkin Lymphoma; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Unspecified Childhood Solid Tumor, Protocol Specific

Etanercept in Treating Young Patients With Idiopathic Pneumonia Syndrome After Undergoing a Donor Stem Cell Transplant

ClinicalTrials.gov

2017-09-01

Accelerated Phase Chronic Myelogenous Leukemia; Blastic Phase Chronic Myelogenous Leukemia; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Myeloid Leukemia in Remission; Childhood Chronic Myelogenous Leukemia; Childhood Myelodysplastic Syndromes; Chronic Phase Chronic Myelogenous Leukemia; de Novo Myelodysplastic Syndromes; Disseminated Neuroblastoma; Juvenile Myelomonocytic Leukemia; Previously Treated Childhood Rhabdomyosarcoma; Previously Treated Myelodysplastic Syndromes; Pulmonary Complications; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Rhabdomyosarcoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Neuroblastoma; Recurrent Wilms Tumor and Other Childhood Kidney Tumors; Recurrent/Refractory Childhood Hodgkin Lymphoma; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes

Caspofungin Acetate or Fluconazole in Preventing Invasive Fungal Infections in Patients With Acute Myeloid Leukemia Who Are Undergoing Chemotherapy

ClinicalTrials.gov

2017-11-13

Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Childhood Acute Erythroleukemia (M6); Childhood Acute Megakaryocytic Leukemia (M7); Childhood Acute Minimally Differentiated Myeloid Leukemia (M0); Childhood Acute Monoblastic Leukemia (M5a); Childhood Acute Monocytic Leukemia (M5b); Childhood Acute Myeloblastic Leukemia With Maturation (M2); Childhood Acute Myeloblastic Leukemia Without Maturation (M1); Childhood Acute Myeloid Leukemia in Remission; Childhood Acute Myelomonocytic Leukemia (M4); Fungal Infection; Neutropenia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia; Untreated Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies

Vorinostat With or Without Isotretinoin in Treating Young Patients With Recurrent or Refractory Solid Tumors, Lymphoma, or Leukemia

ClinicalTrials.gov

2014-06-16

Childhood Acute Promyelocytic Leukemia (M3); Childhood Atypical Teratoid/Rhabdoid Tumor; Childhood Burkitt Lymphoma; Childhood Chronic Myelogenous Leukemia; Childhood Diffuse Large Cell Lymphoma; Childhood Immunoblastic Large Cell Lymphoma; Juvenile Myelomonocytic Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Medulloblastoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor; Recurrent Neuroblastoma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Relapsing Chronic Myelogenous Leukemia; Unspecified Childhood Solid Tumor, Protocol Specific

[Cytopathologic features of childhood acute leukemia at the Hospital de Especialidades Pediátricas, Chiapas, Mexico].

PubMed

Lepe-Zúñiga, José Luis; Jerónimo-López, Francisco Javier; Hernández-Orantes, Jorge Gregorio

Childhood acute leukemia cytological features are unknown in Chiapas, Mexico. Defining these features is important because this is a relatively isolated population with high consanguinity index, and these aspects could determine differences in responses to treatment and outcome. Eighty-one childhood acute leukemia cases treated at the Hospital de Especialidades Pediátricas in Chiapas were characterized by morphology, immunophenotype, genotype, initial risk assignment and status at the time of the study. The proportion of leukemic cell types found in this study was B cell, 75.3%; myeloid, 16%; T cell, 3.7% and NK 1.2%. In B cell leukemia, genetic alterations were present in 40.6% of cases and had a specific outcome regardless of initial risk assessment. Cases with MLL gene alteration died within a month from diagnosis. Translocations were present in 17.5% B cases; t(1;19) was present in those with a favorable outcome. The t(12;21) translocation was related to initial remission and midterm relapse and dead. Hyperdiploidy was present in 20% of B cell cases with good outcome. In 38.5%of myeloid cases were translocations and karyotypic abnormalities. Short-term outcome in this group has been poor; 69% have died or abandoned treatment in relapse from 15 days to 37 months after diagnosis. Relative frequency of different types of acute leukemia in patients treated at a tertiary level pediatric hospital in Chiapas, Mexico, was similar to the one found in other parts of the country. Patients' outcome, under a standardized treatment, differs according to the group, the subgroup and the presence and type of genetic alterations. Copyright © 2017 Hospital Infantil de México Federico Gómez. Publicado por Masson Doyma México S.A. All rights reserved.

New immunotherapy approach leads to remission in patients with the most common type of childhood cancer | Center for Cancer Research

Cancer.gov

Chimeric antigen receptor (CAR) T-cell immunotherapy has emerged as a promising treatment for pre-B cell acute lymphoblastic leukemia (B-ALL), the most common type of childhood cancer. B-ALL is characterized by an overproduction of immature white blood cells called lymphoblasts. In a trial led by Center for Cancer Research investigators, around 70 to 90 percent of patients

miR-192 suppresses T follicular helper cell differentiation by targeting CXCR5 in childhood asthma.

PubMed

Zhang, Defeng; Wu, Yuanbo; Sun, Gengyun

2018-05-01

The aim of this study was to investigate the role of miR-192 in differentiation of T follicular helper cells in childhood asthma. Blood samples were taken from eighteen children with acute asthma attacks and fifteen healthy children (HC). Quantitative real-time PCR and Western blotting were used to detect the expression levels of miR-192, C-X-C chemokine receptor type 5 (CXCR5), B-cell lymphoma 6 (BCL-6) and inducible T-cell costimulator (ICOS). The flow cytometry was performed to detect the proportion of CD4 + CXCR5+ Tfh cells on CD4 + T lymphocytes. The enzyme-linked immunosorbent assay (ELISA) was carried out to determine the plasma concentrations of total IgE and IL-21. The effect of miR-192 on the T follicular helper cells differentiation by targeting CXCR5 was determined by dual-luciferase reporter assay. Children with asthma had lower levels of miR-192 than HC. The proportion of CD4 + CXCR + Tfh cells was significantly higher in the acute asthma group than HC. Similarly, the plasma concentration of total IgE and IL-21 in the acute group markedly increased compared with the HC, and IgE concentration was positively correlated with the proportion of CD4 + CXCR5 + Tfh cells. Furthermore, the expression levels of CXCR5, Bcl-6 and ICOS were significantly higher in the acute group than in the HC. While the proportion of CD4 + CXCR5 + Tfh cells, IL-21, CXCR5, Bcl-6 and ICOS were obviously lower in the CD4 + T cells transfected with miR-192 plasmid than that in miR-192 + CXCR5 group and control group. In conclusion, miR-192 blocks the activation pathway of Tfh cells by targeting CXCR5, which is a reasonable cellular target for therapeutic intervention.

Identifying, Understanding, and Overcoming Barriers to the Use of Clinical Practice Guidelines in Pediatric Oncology

ClinicalTrials.gov

2018-03-15

B-Cell Non-Hodgkin Lymphoma; Chemotherapy-Related Nausea and/or Vomiting; Childhood Acute Myeloid Leukemia; Childhood Burkitt Lymphoma; Childhood Neoplasm; Febrile Neutropenia; Hematopoietic Cell Transplantation Recipient; Recurrent Childhood Acute Lymphoblastic Leukemia; Untreated Childhood Acute Lymphoblastic Leukemia

Tretinoin and Arsenic Trioxide in Treating Patients With Untreated Acute Promyelocytic Leukemia

ClinicalTrials.gov

2017-07-18

Adult Acute Promyelocytic Leukemia With t(15;17)(q22;q12); PML-RARA; Childhood Acute Promyelocytic Leukemia With t(15;17)(q22;q12); PML-RARA; Untreated Adult Acute Myeloid Leukemia; Untreated Childhood Myeloid Neoplasm

Dasatinib and Combination Chemotherapy in Treating Young Patients With Newly Diagnosed Acute Lymphoblastic Leukemia

ClinicalTrials.gov

2016-09-08

Adult B Acute Lymphoblastic Leukemia With t(9;22)(q34;q11.2); BCR-ABL1; Childhood B Acute Lymphoblastic Leukemia With t(9;22)(q34;q11.2); BCR-ABL1; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Childhood Acute Lymphoblastic Leukemia

Rituximab in Treating Patients Undergoing Donor Peripheral Blood Stem Cell Transplant for Relapsed or Refractory B-cell Lymphoma

ClinicalTrials.gov

2017-12-05

B-cell Adult Acute Lymphoblastic Leukemia; B-cell Childhood Acute Lymphoblastic Leukemia; B-cell Chronic Lymphocytic Leukemia; Childhood Burkitt Lymphoma; Childhood Diffuse Large Cell Lymphoma; Childhood Immunoblastic Large Cell Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Post-transplant Lymphoproliferative Disorder; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Testicular Lymphoma; Waldenström Macroglobulinemia

The genomic landscape of pediatric and young adult T-lineage acute lymphoblastic leukemia | Office of Cancer Genomics

Cancer.gov

Genetic alterations that activate NOTCH1 signaling and T cell transcription factors, coupled with inactivation of the INK4/ARF tumor suppressors, are hallmarks of T-lineage acute lymphoblastic leukemia (T-ALL), but detailed genome-wide sequencing of large T-ALL cohorts has not been carried out. Using integrated genomic analysis of 264 T-ALL cases, we identified 106 putative driver genes, half of which had not previously been described in childhood T-ALL (for example, CCND3, CTCF, MYB, SMARCA4, ZFP36L2 and MYCN).

Brain Function in Young Patients Receiving Methotrexate for Acute Lymphoblastic Leukemia

ClinicalTrials.gov

2017-07-19

Childhood B Acute Lymphoblastic Leukemia; Childhood T Acute Lymphoblastic Leukemia; Cognitive Side Effects of Cancer Therapy; Long-Term Effects Secondary to Cancer Therapy in Children; Neurotoxicity Syndrome; Psychological Impact of Cancer; Untreated Childhood Acute Lymphoblastic Leukemia

Targeted sequencing identifies associations between IL7R-JAK mutations and epigenetic modulators in T-cell acute lymphoblastic leukemia

PubMed Central

Vicente, Carmen; Schwab, Claire; Broux, Michaël; Geerdens, Ellen; Degryse, Sandrine; Demeyer, Sofie; Lahortiga, Idoya; Elliott, Alannah; Chilton, Lucy; La Starza, Roberta; Mecucci, Cristina; Vandenberghe, Peter; Goulden, Nicholas; Vora, Ajay; Moorman, Anthony V.; Soulier, Jean; Harrison, Christine J.; Clappier, Emmanuelle; Cools, Jan

2015-01-01

T-cell acute lymphoblastic leukemia is caused by the accumulation of multiple oncogenic lesions, including chromosomal rearrangements and mutations. To determine the frequency and co-occurrence of mutations in T-cell acute lymphoblastic leukemia, we performed targeted re-sequencing of 115 genes across 155 diagnostic samples (44 adult and 111 childhood cases). NOTCH1 and CDKN2A/B were mutated/deleted in more than half of the cases, while an additional 37 genes were mutated/deleted in 4% to 20% of cases. We found that IL7R-JAK pathway genes were mutated in 27.7% of cases, with JAK3 mutations being the most frequent event in this group. Copy number variations were also detected, including deletions of CREBBP or CTCF and duplication of MYB. FLT3 mutations were rare, but a novel extracellular mutation in FLT3 was detected and confirmed to be transforming. Furthermore, we identified complex patterns of pairwise associations, including a significant association between mutations in IL7R-JAK genes and epigenetic regulators (WT1, PRC2, PHF6). Our analyses showed that IL7R-JAK genetic lesions did not confer adverse prognosis in T-cell acute lymphoblastic leukemia cases enrolled in the UK ALL2003 trial. Overall, these results identify interconnections between the T-cell acute lymphoblastic leukemia genome and disease biology, and suggest a potential clinical application for JAK inhibitors in a significant proportion of patients with T-cell acute lymphoblastic leukemia. PMID:26206799

Phase I clinical trial will test multi-targeted immunotherapy in common childhood cancer | Center for Cancer Research

Cancer.gov

Chimeric antigen receptor (CAR) T-cell immunotherapy targeting the protein CD19 has shown promise in treating acute lymphoblastic leukemia (ALL). CD22-CAR T-cell therapy has yielded similarly encouraging results, but many patients relapse after either therapy. In an upcoming phase I clinical trial, Center for Cancer Research investigators will test a new strategy—treating patients with a CAR T-cell therapy that targets CD19 and CD22 simultaneously.

Phase I clinical trial will test multi-targeted immunotherapy in common childhood cancer | Center for Cancer Research

Cancer.gov

Chimeric antigen receptor (CAR) T-cell immunotherapy targeting the protein CD19 has shown promise in treating acute lymphoblastic leukemia (ALL). CD22-CAR T-cell therapy has yielded similarly encouraging results, but many patients relapse after either therapy. In an upcoming phase I clinical trial, Center for Cancer Research investigators will test a new strategy—treating

[Systemic EBV+ T-cell lymphoproliferative disease of childhood].

PubMed

Lemaire, Anne-Sophie; Daussay, Dorothée; Bouchindhomme, Brigitte; Grardel, Nathalie; Botte, Astrid; Copin, Marie-Christine

2014-08-01

Systemic EBV+ T-cell lymphoproliferative disease of childhood is a recent entity described in the 2008 World Health Organisation tumours of haematopoietic system and lymphoid tissues as a clonal T-cell EBV+ systemic proliferation. It occurs after acute or chronic active EBV infection. We report the case of a caucasian, immunocompetent 12-year-old girl, with no particular history, who presented with hemophagocytic lymphohistiocytosis in the aftermath of an infectious mononucleosis. Main symptoms were multiple organ failure, hepatosplenomegaly and pancytopenia. Histopathology of peripheral lymph node and bone marrow revealed a T-cell, CD8+, EBV+ lymphoproliferation. An elevated viral load was detected in blood by PCR. The patient died within 3 weeks. Since most of the cases have been reported in Asia and South America, few cases still have been described in Europe. Unlike B-cell lymphoproliferation in immunocompromised individuals, T-cell EBV+ lymphoproliferation occurs in immunocompetent patients and seems to be the consequence of a proliferative disorder of EBV-infected T-cells, attributed to a cytotoxic T-cell response deficiency. These T-cell proliferations are more frequently immunoreactive for CD8 than CD4. A key feature of the diagnosis might be EBV viral load. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Risk-Adapted Chemotherapy in Treating Younger Patients With Newly Diagnosed Standard-Risk Acute Lymphoblastic Leukemia or Localized B-Lineage Lymphoblastic Lymphoma

ClinicalTrials.gov

2018-03-19

Adult B Lymphoblastic Lymphoma; Childhood B Acute Lymphoblastic Leukemia; Childhood B Acute Lymphoblastic Leukemia With t(9;22)(q34;q11.2); BCR-ABL1; Childhood B Lymphoblastic Lymphoma; Down Syndrome; Stage I B Lymphoblastic Lymphoma; Stage II B Lymphoblastic Lymphoma; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Childhood Acute Lymphoblastic Leukemia

Revealing the Genomic Landscape of Pediatric T-ALL | Office of Cancer Genomics

Cancer.gov

T-lineage acute lymphoblastic leukemia (T-ALL) comprises 15-20% of childhood ALL and has historically been associated with inferior outcome to B-cell  ALL (B-ALL). Recent studies have used genome-wide sequencing approaches to identify new subtypes and targets of mutation in B-ALL, but comprehensive sequencing studies of large cohorts of T-ALL have not been performed.

Potential use of CD40 ligand for immunotherapy of childhood B-cell precursor acute lymphoblastic leukaemia.

PubMed

D'Amico, Giovanna; Marin, Virna; Biondi, Andrea; Bonamino, Martin Hernán

2004-09-01

Around 20% of children affected by B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) still experience a recurrence of the disease after diagnosis, despite a significant improvement in the cure rate (80%). Moreover, standard therapies have high and often unacceptable acute and chronic organ toxicity, with an increased risk for secondary malignancies. Therefore, new strategies are needed to improve overall survival and decrease treatment-associated morbidity. Recent in-vitro and in-vivo studies have demonstrated that CD40 engagement improves tumour immunogenicity and, consequently, generates a strong antitumour immune response. The CD40-CD40 ligand (CD40L) system is of pivotal importance in the immune response via interactions between T cells and antigen-presenting cells. The general aim of this chapter is to review the feasibility of developing cellular strategies to increase childhood BCP-ALL immunogenicity, and the potential use of CD40L as a new strategy to induce an antileukaemia immune response in BCP-ALL.

Pediatric precursor B acute lymphoblastic leukemia: are T helper cells the missing link in the infectious etiology theory?

PubMed

Bürgler, Simone; Nadal, David

2017-12-01

Precursor B acute lymphoblastic leukemia (BCP-ALL), the most common childhood malignancy, arises from an expansion of malignant B cell precursors in the bone marrow. Epidemiological studies suggest that infections or immune responses to infections may promote such an expansion and thus BCP-ALL development. Nevertheless, a specific pathogen responsible for this process has not been identified. BCP-ALL cells critically depend on interactions with the bone marrow microenvironment. The bone marrow is also home to memory T helper (Th) cells that have previously expanded during an immune response in the periphery. In secondary lymphoid organs, Th cells can interact with malignant cells of mature B cell origin, while such interactions between Th cells and malignant immature B cell in the bone marrow have not been described yet. Nevertheless, literature supports a model where Th cells-expanded during an infection in early childhood-migrate to the bone marrow and support BCP-ALL cells as they support normal B cells. Further research is required to mechanistically confirm this model and to elucidate the interaction pathways between leukemia cells and cells of the tumor microenvironment. As benefit, targeting these interactions could be included in current treatment regimens to increase therapeutic efficiency and to reduce relapses.

Prognosis of children with mixed phenotype acute leukemia treated on the basis of consistent immunophenotypic criteria

PubMed Central

Mejstrikova, Ester; Volejnikova, Jana; Fronkova, Eva; Zdrahalova, Katerina; Kalina, Tomas; Sterba, Jaroslav; Jabali, Yahia; Mihal, Vladimir; Blazek, Bohumir; Cerna, Zdena; Prochazkova, Daniela; Hak, Jiri; Zemanova, Zuzana; Jarosova, Marie; Oltova, Alexandra; Sedlacek, Petr; Schwarz, Jiri; Zuna, Jan; Trka, Jan; Stary, Jan; Hrusak, Ondrej

2010-01-01

Background Mixed phenotype acute leukemia (MPAL) represents a diagnostic and therapeutic dilemma. The European Group for the Immunological Classification of Leukemias (EGIL) scoring system unambiguously defines MPAL expressing aberrant lineage markers. Discussions surrounding it have focused on scoring details, and information is limited regarding its biological, clinical and prognostic significance. The recent World Health Organization classification is simpler and could replace the EGIL scoring system after transformation into unambiguous guidelines. Design and Methods Simple immunophenotypic criteria were used to classify all cases of childhood acute leukemia in order to provide therapy directed against acute lymphoblastic leukemia or acute myeloid leukemia. Prognosis, genotype and immunoglobulin/T-cell receptor gene rearrangement status were analyzed. Results The incidences of MPAL were 28/582 and 4/107 for children treated with acute lymphoblastic leukemia and acute myeloid leukemia regimens, respectively. In immunophenotypic principal component analysis, MPAL treated as T-cell acute lymphoblastic leukemia clustered between cases of non-mixed T-cell acute lymphoblastic leukemia and acute myeloid leukemia, while other MPAL cases were included in the respective non-mixed B-cell progenitor acute lymphoblastic leukemia or acute myeloid leukemia clusters. Analogously, immunoglobulin/T-cell receptor gene rearrangements followed the expected pattern in patients treated as having acute myeloid leukemia (non-rearranged, 4/4) or as having B-cell progenitor acute lymphoblastic leukemia (rearranged, 20/20), but were missing in 3/5 analyzed cases of MPAL treated as having T-cell acute lymphobastic leukemia. In patients who received acute lymphoblastic leukemia treatment, the 5-year event-free survival of the MPAL cases was worse than that of the non-mixed cases (53±10% and 76±2% at 5 years, respectively, P=0.0075), with a more pronounced difference among B lineage cases. The small numbers of MPAL cases treated as T-cell acute lymphoblastic leukemia or as acute myeloid leukemia hampered separate statistics. We compared prognosis of all subsets with the prognosis of previously published cohorts. Conclusions Simple immunophenotypic criteria are useful for therapy decisions in MPAL. In B lineage leukemia, MPAL confers poorer prognosis. However, our data do not justify a preferential use of current acute myeloid leukemia-based therapy in MPAL. PMID:20145275

Levofloxacin in Preventing Infection in Young Patients With Acute Leukemia Receiving Chemotherapy or Undergoing Stem Cell Transplantation

ClinicalTrials.gov

2018-05-07

Acute Leukemias of Ambiguous Lineage; Bacterial Infection; Diarrhea; Fungal Infection; Musculoskeletal Complications; Neutropenia; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Untreated Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies

Nilotinib and Imatinib Mesylate After Donor Stem Cell Transplant in Treating Patients With ALL or CML

ClinicalTrials.gov

2017-07-11

Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Blastic Phase Chronic Myelogenous Leukemia; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Chronic Myelogenous Leukemia; Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Chronic Phase Chronic Myelogenous Leukemia; Philadelphia Positive Adult Acute Lymphoblastic Leukemia; Philadelphia Positive Childhood Acute Lymphoblastic Leukemia; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Relapsing Chronic Myelogenous Leukemia; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Childhood Acute Lymphoblastic Leukemia

Lysosomal isoenzyme profiles used to classify a case of acute undifferentiated leukaemia.

PubMed

Eden, O B; Darbyshire, P; Simpson, R M; Besley, G T; Moss, S; Gentle, T

1985-01-01

Lysosomal enzyme activities and isoenzyme profiles were measured in lymphoid and non-lymphoid leukaemic cells from childhood patients. High activities, especially of beta-hexosaminidase and alpha-mannosidase, were associated with leukaemic cells of myeloid or monocytic origin. Leukaemic cells from two children with acute myeloid leukaemia had a relative reduction in the B isoenzyme of beta-hexosaminidase activity, whereas in patients with non T, non B cell acute lymphoblastic leukaemia, intermediate beta-hexosaminidase isoenzymes were expressed. A patient is described on whom conventional marker studies were either negative or equivocal, but lysosomal enzyme markers were consistent with a myeloid leukaemia. This observation was supported by the clinical course of this patient.

Autoimmune hepatitis in children.

PubMed

Mieli-Vergani, Giorgina; Vergani, Diego

2002-08-01

AIH, ASC, and de novo AIH after liver transplantation are childhood liver diseases of an autoimmune nature. The mode of presentation of AIH in childhood is variable, and the disease should be suspected and excluded in all children presenting with symptoms and signs of prolonged or severe acute liver disease. Although corticosteroids are effective in all types of childhood AIH, patients with LKM1 have a higher frequency of acute hepatic failure and relapse after corticosteroid withdrawal than do patients with ANA/SMA. ASC occurs commonly in the absence of inflammatory bowel disease, requires cholangiography for diagnosis, and improves during corticosteroid therapy. The development of AIH de novo in children who undergo liver transplantation for nonautoimmune liver disease may reflect interference with the maturation of T cells by immunosuppressive drugs.

Immunophenotypic analysis of adult patients with T-cell lymphoblastic lymphoma treated with hyper-CVAD.

PubMed

Kato, Harumi; Yamamoto, Kazuhito; Kodaira, Takeshi; Higuchi, Yusuke; Yamamoto, Hideyuki; Saito, Toko; Taji, Hirofumi; Yatabe, Yasushi; Nakamura, Shigeo; Kinoshita, Tomohiro

2018-03-01

Immunophenotype is an important prognostic factor for childhood and adult T-cell acute lymphoblastic leukemia. However, immunophenotypic data from adult patients with T-cell lymphoblastic lymphoma (T-LBL) are scarcely available. Subjects were unselected adult patients with T-LBL who were treated with intensive chemotherapy. Immunophenotyping of tumor cells was performed according to standard techniques. A total of eight patients with a median age of 31 years were analyzed who received hyper-CVAD treatment for LBL. Immunophenotypic analysis showed that the most common tumor type was cortical T-cell type [early T (n = 2), cortical T (n = 4), and medullary T (n = 2)]. Two patients diagnosed with early T-cell type had early disease progression. Assessment of T-cell differentiation stages in malignant T lymphoblasts would be important in choosing treatment strategies for adult patients with T-LBL.

CAR T Cell Immunotherapy Promising in Refractory Leukemia | Center for Cancer Research

Cancer.gov

B-cell acute lymphoblastic leukemia (B-ALL) is a common childhood malignancy that also affects young adults. Although current treatments have significant toxicities, children with chemotherapy susceptible subtypes have high survival rates. However, less than 10 percent of children and young adults with newly-diagnosed or recurrent B-ALL that is insensitive to therapy survive,

High CD45 surface expression determines relapse risk in children with precursor B-cell and T-cell acute lymphoblastic leukemia treated according to the ALL-BFM 2000 protocol

PubMed Central

Cario, Gunnar; Rhein, Peter; Mitlöhner, Rita; Zimmermann, Martin; Bandapalli, Obul R.; Romey, Renja; Moericke, Anja; Ludwig, Wolf-Dieter; Ratei, Richard; Muckenthaler, Martina U.; Kulozik, Andreas E.; Schrappe, Martin; Stanulla, Martin; Karawajew, Leonid

2014-01-01

Further improvement of outcome in childhood acute lymphoblastic leukemia could be achieved by identifying additional high-risk patients who may benefit from intensified treatment. We earlier identified PTPRC (CD45) gene expression as a potential new stratification marker and now analyzed the prognostic relevance of CD45 protein expression. CD45 was measured by flow cytometry in 1065 patients treated according to the ALL-BFM-2000 protocol. The 75th percentile was used as cut-off to distinguish a CD45-high from a CD45-low group. As mean CD45 expression was significantly higher in T-cell acute lymphoblastic leukemia than in B-cell-precursor acute lymphoblastic leukemia (P<0.0001), the analysis was performed separately in both groups. In B-cell-precursor acute lymphoblastic leukemia we observed a significant association of a high CD45 expression with older age, high initial white blood cell count, ETV6/RUNX1 negativity, absence of high hyperdiploidy (P<0.0001), MLL/AF4 positivity (P=0.002), BCR/ABL1 positivity (P=0.007), prednisone poor response (P=0.002) and minimal residual disease (P<0.0001). In T-cell acute lymphoblastic leukemia we observed a significant association with initial white blood cell count (P=0.0003), prednisone poor response (P=0.01), and minimal residual disease (P=0.02). Compared to CD45-low patients, CD45-high patients had a lower event-free survival rate (B-cell-precursor acute lymphoblastic leukemia: 72±3% versus 86±1%, P<0.0001; T-cell acute lymphoblastic leukemia: 60±8% versus 78±4%, P=0.02), which was mainly attributable to a higher cumulative relapse incidence (B-cell-precursor acute lymphoblastic leukemia: 22±3% versus 11±1%, P<0.0001; T-cell acute lymphoblastic leukemia: 31±8% versus 11±3%, P=0.003) and kept its significance in multivariate analysis considering sex, age, initial white blood cell count, and minimal residual disease in B-cell-precursor- and T-cell acute lymphoblastic leukemia, and additionally presence of ETV6/RUNX1, MLL/AF4 and BCR/ABL1 rearrangements in B-cell-precursor acute lymphoblastic leukemia (P=0.002 and P=0.025, respectively). Consideration of CD45 expression may serve as an additional stratification tool in BFM-based protocols. (ClinicalTrials.gov identifier: NCT00430118) PMID:23911702

High CD45 surface expression determines relapse risk in children with precursor B-cell and T-cell acute lymphoblastic leukemia treated according to the ALL-BFM 2000 protocol.

PubMed

Cario, Gunnar; Rhein, Peter; Mitlöhner, Rita; Zimmermann, Martin; Bandapalli, Obul R; Romey, Renja; Moericke, Anja; Ludwig, Wolf-Dieter; Ratei, Richard; Muckenthaler, Martina U; Kulozik, Andreas E; Schrappe, Martin; Stanulla, Martin; Karawajew, Leonid

2014-01-01

Further improvement of outcome in childhood acute lymphoblastic leukemia could be achieved by identifying additional high-risk patients who may benefit from intensified treatment. We earlier identified PTPRC (CD45) gene expression as a potential new stratification marker and now analyzed the prognostic relevance of CD45 protein expression. CD45 was measured by flow cytometry in 1065 patients treated according to the ALL-BFM-2000 protocol. The 75(th) percentile was used as cut-off to distinguish a CD45-high from a CD45-low group. As mean CD45 expression was significantly higher in T-cell acute lymphoblastic leukemia than in B-cell-precursor acute lymphoblastic leukemia (P<0.0001), the analysis was performed separately in both groups. In B-cell-precursor acute lymphoblastic leukemia we observed a significant association of a high CD45 expression with older age, high initial white blood cell count, ETV6/RUNX1 negativity, absence of high hyperdiploidy (P<0.0001), MLL/AF4 positivity (P=0.002), BCR/ABL1 positivity (P=0.007), prednisone poor response (P=0.002) and minimal residual disease (P<0.0001). In T-cell acute lymphoblastic leukemia we observed a significant association with initial white blood cell count (P=0.0003), prednisone poor response (P=0.01), and minimal residual disease (P=0.02). Compared to CD45-low patients, CD45-high patients had a lower event-free survival rate (B-cell-precursor acute lymphoblastic leukemia: 72 ± 3% versus 86 ± 1%, P<0.0001; T-cell acute lymphoblastic leukemia: 60 ± 8% versus 78 ± 4%, P=0.02), which was mainly attributable to a higher cumulative relapse incidence (B-cell-precursor acute lymphoblastic leukemia: 22 ± 3% versus 11 ± 1%, P<0.0001; T-cell acute lymphoblastic leukemia: 31 ± 8% versus 11 ± 3%, P=0.003) and kept its significance in multivariate analysis considering sex, age, initial white blood cell count, and minimal residual disease in B-cell-precursor- and T-cell acute lymphoblastic leukemia, and additionally presence of ETV6/RUNX1, MLL/AF4 and BCR/ABL1 rearrangements in B-cell-precursor acute lymphoblastic leukemia (P=0.002 and P=0.025, respectively). Consideration of CD45 expression may serve as an additional stratification tool in BFM-based protocols. (ClinicalTrials.gov identifier: NCT00430118).

Nanoparticle targeted therapy against childhood acute lymphoblastic leukemia

NASA Astrophysics Data System (ADS)

Satake, Noriko; Lee, Joyce; Xiao, Kai; Luo, Juntao; Sarangi, Susmita; Chang, Astra; McLaughlin, Bridget; Zhou, Ping; Kenney, Elaina; Kraynov, Liliya; Arnott, Sarah; McGee, Jeannine; Nolta, Jan; Lam, Kit

2011-06-01

The goal of our project is to develop a unique ligand-conjugated nanoparticle (NP) therapy against childhood acute lymphoblastic leukemia (ALL). LLP2A, discovered by Dr. Kit Lam, is a high-affinity and high-specificity peptidomimetic ligand against an activated α4β1 integrin. Our study using 11 fresh primary ALL samples (10 precursor B ALL and 1 T ALL) showed that childhood ALL cells expressed activated α4β1 integrin and bound to LLP2A. Normal hematopoietic cells such as activated lymphocytes and monocytes expressed activated α4β1 integrin; however, normal hematopoietic stem cells showed low expression of α4β1 integrin. Therefore, we believe that LLP2A can be used as a targeted therapy for childhood ALL. The Lam lab has developed novel telodendrimer-based nanoparticles (NPs) which can carry drugs efficiently. We have also developed a human leukemia mouse model using immunodeficient NOD/SCID/IL2Rγ null mice engrafted with primary childhood ALL cells from our patients. LLP2A-conjugated NPs will be evaluated both in vitro and in vivo using primary leukemia cells and this mouse model. NPs will be loaded first with DiD near infra-red dye, and then with the chemotherapeutic agents daunorubicin or vincristine. Both drugs are mainstays of current chemotherapy for childhood ALL. Targeting properties of LLP2A-conjugated NPs will be evaluated by fluorescent microscopy, flow cytometry, MTS assay, and mouse survival after treatment. We expect that LLP2A-conjugated NPs will be preferentially delivered and endocytosed to leukemia cells as an effective targeted therapy.

The combination of bortezomib with chemotherapy to treat relapsed/refractory acute lymphoblastic leukaemia of childhood.

PubMed

Bertaina, Alice; Vinti, Luciana; Strocchio, Luisa; Gaspari, Stefania; Caruso, Roberta; Algeri, Mattia; Coletti, Valentina; Gurnari, Carmelo; Romano, Mariateresa; Cefalo, Maria Giuseppina; Girardi, Katia; Trevisan, Valentina; Bertaina, Valentina; Merli, Pietro; Locatelli, Franco

2017-02-01

Achieving complete remission (CR) in childhood relapsed/refractory acute lymphoblastic leukaemia (ALL) is a difficult task. Bortezomib, a proteasome inhibitor, has in vitro activity against ALL blasts. A phase I-II trial, reported by the Therapeutic Advances in Childhood Leukaemia and Lymphoma (TACL) consortium, demonstrated that bortezomib with chemotherapy has acceptable toxicity and remarkable activity in patients with relapsed ALL failing 2-3 previous regimens. We evaluated bortezomib in combination with chemotherapy in 30 and 7 children with B-cell precursor (BCP) and T-cell ALL, respectively. Bortezomib (1·3 mg/m 2 /dose) was administered intravenously on days 1, 4, 8, and 11. Chemotherapy agents were the same as those used in the TACL trial, consisting of dexamethasone, doxorubicin, vincristine and pegylated asparaginase. Three patients (8·1%) died due to infections. Twenty-seven patients (72·9%) achieved CR or CR with incomplete platelet recovery (CRp). Fourteen had minimal residual disease (MRD) lower than 0·1%. Twenty-two of 30 BCP-ALL patients (73·3%) and 5/7 patients (71%) with T-cell ALL achieved CR/CRp. The 2-year overall survival (OS) is 31·3%; CR/CRp patients with an MRD response had a remarkable 2-year OS of 68·4%. These data confirm that the combination of bortezomib with chemotherapy is a suitable/effective option for childhood relapsed/refractory ALL. © 2017 John Wiley & Sons Ltd.

Rituximab, Rasburicase, and Combination Chemotherapy in Treating Young Patients With Newly Diagnosed Advanced B-Cell Leukemia or Lymphoma

ClinicalTrials.gov

2014-09-10

Childhood Burkitt Lymphoma; Childhood Diffuse Large Cell Lymphoma; Childhood Immunoblastic Large Cell Lymphoma; Stage I Childhood Large Cell Lymphoma; Stage I Childhood Small Noncleaved Cell Lymphoma; Stage II Childhood Large Cell Lymphoma; Stage II Childhood Small Noncleaved Cell Lymphoma; Stage III Childhood Large Cell Lymphoma; Stage III Childhood Small Noncleaved Cell Lymphoma; Stage IV Childhood Large Cell Lymphoma; Stage IV Childhood Small Noncleaved Cell Lymphoma; Untreated Childhood Acute Lymphoblastic Leukemia

Tretinoin, Cytarabine, and Daunorubicin Hydrochloride With or Without Arsenic Trioxide Followed by Tretinoin With or Without Mercaptopurine and Methotrexate in Treating Patients With Acute Promyelocytic Leukemia

ClinicalTrials.gov

2013-06-04

Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Promyelocytic Leukemia (M3); Childhood Acute Promyelocytic Leukemia (M3); Untreated Adult Acute Myeloid Leukemia; Untreated Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies

Alisertib in Treating Young Patients With Recurrent or Refractory Solid Tumors or Leukemia

ClinicalTrials.gov

2017-09-21

Hepatoblastoma; Previously Treated Childhood Rhabdomyosarcoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Kidney Neoplasm; Recurrent Childhood Malignant Germ Cell Tumor; Recurrent Childhood Rhabdomyosarcoma; Recurrent Childhood Soft Tissue Sarcoma; Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Recurrent Neuroblastoma; Recurrent Osteosarcoma

MORAb-004 in Treating Young Patients With Recurrent or Refractory Solid Tumors or Lymphoma

ClinicalTrials.gov

2016-01-07

Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Childhood Burkitt Lymphoma; Childhood Diffuse Large Cell Lymphoma; Childhood Immunoblastic Large Cell Lymphoma; Childhood Nasal Type Extranodal NK/T-cell Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Noncutaneous Extranodal Lymphoma; Peripheral T-cell Lymphoma; Post-transplant Lymphoproliferative Disorder; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Childhood Anaplastic Large Cell Lymphoma; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Refractory Hairy Cell Leukemia; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; T-cell Large Granular Lymphocyte Leukemia; Testicular Lymphoma; Unspecified Adult Solid Tumor, Protocol Specific; Unspecified Childhood Solid Tumor, Protocol Specific; Waldenström Macroglobulinemia

Laboratory-Treated Donor Cord Blood Cell Infusion Following Combination Chemotherapy in Treating Younger Patients With Relapsed or Refractory Acute Myeloid Leukemia

ClinicalTrials.gov

2017-06-29

Acute Leukemia of Ambiguous Lineage; Adult Acute Myeloid Leukemia in Remission; Childhood Acute Myeloid Leukemia in Remission; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

Targeting the 5T4 oncofetal glycoprotein with an antibody drug conjugate (A1mcMMAF) improves survival in patient-derived xenograft models of acute lymphoblastic leukemia.

PubMed

McGinn, Owen J; Krishnan, Shekhar; Bourquin, Jean-Pierre; Sapra, Puja; Dempsey, Clare; Saha, Vaskar; Stern, Peter L

2017-06-01

Outcome in childhood acute lymphoblastic leukemia is prognosticated from levels of minimal residual disease after remission induction therapy. Higher levels of minimal residual disease are associated with inferior results even with intensification of therapy, thus suggesting that identification and targeting of minimal residual disease cells could be a therapeutic strategy. Here we identify high expression of 5T4 in subclonal populations of patient-derived xenografts from patients with high, post-induction levels of minimal residual disease. 5T4-positive cells showed preferential ability to overcome the NOD- scid IL2Rγ null mouse xenograft barrier, migrated in vitro on a CXCL12 gradient, preferentially localized to bone marrow in vivo and displayed the ability to reconstitute the original clonal composition on limited dilution engraftment. Treatment with A1mcMMAF (a 5T4-antibody drug conjugate) significantly improved survival without overt toxicity in mice engrafted with a 5T4-positive acute lymphoblastic leukemia cell line. Mice engrafted with 5T4-positive patient-derived xenograft cells were treated with combination chemotherapy or dexamethasone alone and then given A1mcMMAF in the minimal residual disease setting. Combination chemotherapy was toxic to NOD- scid IL2Rγ null mice. While dexamethasone or A1mcMMAF alone improved outcomes, the sequential administration of dexamethasone and A1mcMMAF significantly improved survival ( P =0.0006) over either monotherapy. These data show that specifically targeting minimal residual disease cells improved outcomes and support further investigation of A1mcMMAF in patients with high-risk B-cell precursor acute lymphoblastic leukemia identified by 5T4 expression at diagnosis. Copyright© Ferrata Storti Foundation.

Targeting the 5T4 oncofetal glycoprotein with an antibody drug conjugate (A1mcMMAF) improves survival in patient-derived xenograft models of acute lymphoblastic leukemia

PubMed Central

McGinn, Owen J.; Krishnan, Shekhar; Bourquin, Jean-Pierre; Sapra, Puja; Dempsey, Clare; Saha, Vaskar; Stern, Peter L.

2017-01-01

Outcome in childhood acute lymphoblastic leukemia is prognosticated from levels of minimal residual disease after remission induction therapy. Higher levels of minimal residual disease are associated with inferior results even with intensification of therapy, thus suggesting that identification and targeting of minimal residual disease cells could be a therapeutic strategy. Here we identify high expression of 5T4 in subclonal populations of patient-derived xenografts from patients with high, post-induction levels of minimal residual disease. 5T4-positive cells showed preferential ability to overcome the NOD-scidIL2Rγnull mouse xenograft barrier, migrated in vitro on a CXCL12 gradient, preferentially localized to bone marrow in vivo and displayed the ability to reconstitute the original clonal composition on limited dilution engraftment. Treatment with A1mcMMAF (a 5T4-antibody drug conjugate) significantly improved survival without overt toxicity in mice engrafted with a 5T4-positive acute lymphoblastic leukemia cell line. Mice engrafted with 5T4-positive patient-derived xenograft cells were treated with combination chemotherapy or dexamethasone alone and then given A1mcMMAF in the minimal residual disease setting. Combination chemotherapy was toxic to NOD-scidIL2Rγnull mice. While dexamethasone or A1mcMMAF alone improved outcomes, the sequential administration of dexamethasone and A1mcMMAF significantly improved survival (P=0.0006) over either monotherapy. These data show that specifically targeting minimal residual disease cells improved outcomes and support further investigation of A1mcMMAF in patients with high-risk B-cell precursor acute lymphoblastic leukemia identified by 5T4 expression at diagnosis. PMID:28341731

EBV-Positive T/NK-Cell Lymphoproliferative Disease of Childhood

PubMed Central

Hong, Mineui; Yoo, Keon Hee; Koo, Hong Hoe; Kim, Seok Jin; Kim, Won Seog

2013-01-01

Background Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis (HLH), EBV-positive systemic T-cell lymphoproliferative disease (STLPD) of childhood, and chronic active EBV (CAEBV) infection may develop after primary EBV infection. This study reviewed the clinicopathological spectrum of EBV-associated T- and natural killer (NK)-cell LPD, including STLPD and CAEBV infection, with an analysis of T-cell clonality. Methods Clinicopathological features of seven patients with EBV-associated HLH or STLPD and 12 patients with CAEBV infection were reviewed. Immunohistochemical staining and a T-cell receptor (TCR) gene rearrangement study were performed. Results STLPD and EBV-positive HLH showed significantly overlapping clinicopathological findings. One patient with STLPD and one patient with EBV-positive HLH demonstrated moderate to severe atypia of the infiltrating lymphocytes, whereas the remaining patients lacked significant atypia. Twelve patients had CAEBV infection, four of whom suffered mosquito-bite hypersensitivity, five showed NK lymphocytosis, and one suffered hydroa vacciniforme. Infiltrating lymphocytes were predominantly small and devoid of atypia. Hemophagocytic histiocytosis was found in seven of 11 patients. Monoclonality was detected in three (50%) of the six patients with successful TCR gene analysis. Conclusions EBV-positive HLH and STLPD share similar clinicopathological findings and may constitute a continuous spectrum of acute EBV-associated T- or NK-cell proliferative disorders. The distinction of EBV-positive T-cell LPD from EBV-positive HLH may be difficult during routine diagnoses because of the technical limitations of clonality assessment. PMID:23667373

EBV-Positive T/NK-Cell Lymphoproliferative Disease of Childhood.

PubMed

Hong, Mineui; Ko, Young Hyeh; Yoo, Keon Hee; Koo, Hong Hoe; Kim, Seok Jin; Kim, Won Seog; Park, Heejung

2013-04-01

Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis (HLH), EBV-positive systemic T-cell lymphoproliferative disease (STLPD) of childhood, and chronic active EBV (CAEBV) infection may develop after primary EBV infection. This study reviewed the clinicopathological spectrum of EBV-associated T- and natural killer (NK)-cell LPD, including STLPD and CAEBV infection, with an analysis of T-cell clonality. Clinicopathological features of seven patients with EBV-associated HLH or STLPD and 12 patients with CAEBV infection were reviewed. Immunohistochemical staining and a T-cell receptor (TCR) gene rearrangement study were performed. STLPD and EBV-positive HLH showed significantly overlapping clinicopathological findings. One patient with STLPD and one patient with EBV-positive HLH demonstrated moderate to severe atypia of the infiltrating lymphocytes, whereas the remaining patients lacked significant atypia. Twelve patients had CAEBV infection, four of whom suffered mosquito-bite hypersensitivity, five showed NK lymphocytosis, and one suffered hydroa vacciniforme. Infiltrating lymphocytes were predominantly small and devoid of atypia. Hemophagocytic histiocytosis was found in seven of 11 patients. Monoclonality was detected in three (50%) of the six patients with successful TCR gene analysis. EBV-positive HLH and STLPD share similar clinicopathological findings and may constitute a continuous spectrum of acute EBV-associated T- or NK-cell proliferative disorders. The distinction of EBV-positive T-cell LPD from EBV-positive HLH may be difficult during routine diagnoses because of the technical limitations of clonality assessment.

Systematic Epstein-Barr virus-positive T-cell lymphoproliferative disease presenting as a persistent fever and cough: a case report.

PubMed

Ameli, Fereshteh; Ghafourian, Firouzeh; Masir, Noraidah

2014-08-27

Systemic Epstein-Barr virus-positive T-cell lymphoproliferative childhood disease is an extremely rare disorder and classically arises following primary acute or chronic active Epstein-Barr virus infection. It is characterized by clonal proliferation of Epstein-Barr virus-infected T-cells with an activated cytotoxic phenotype. This disease has a rapid clinical course and is more frequent in Asia and South America, with relatively few cases being reported in Western countries. The clinical and pathological features of the disease overlap with other conditions including infectious mononucleosis, chronic active Epstein-Barr virus infection, hemophagocytic lymphohistiocytosis and natural killer cell malignancies. We describe the rare case of systemic Epstein-Barr virus-positive T-cell lymphoproliferative childhood disease in a 16-year-old Malay boy. He presented with a six-month history of fever and cough, with pulmonary and mediastinal lymphadenopathy and severe pancytopenia. Medium- to large-sized, CD8+ and Epstein-Barr virus-encoded RNA-positive atypical lymphoid cells were present in the bone marrow aspirate. He subsequently developed fatal virus-associated hemophagocytic syndrome and died due to sepsis and multiorgan failure. Although systemic Epstein-Barr virus-positive T-cell lymphoproliferative childhood disease is a disorder which is rarely encountered in clinical practice, our case report underlines the importance of a comprehensive diagnostic approach in the management of this disease. A high level of awareness of the disease throughout the diagnosis process for young patients who present with systemic illness and hemophagocytic syndrome may be of great help for the clinical diagnosis of this disease.

The Spectrum of Epstein-Barr Virus-Associated Lymphoproliferative Disease in Korea: Incidence of Disease Entities by Age Groups

PubMed Central

Cho, Eun-Yoon; Kim, Ki-Hyun; Kim, Won-Seog; Yoo, Keon Hee; Koo, Hong-Hoe

2008-01-01

This study is to identify the spectrum of Epstein-Barr virus (EBV)-positive lymphoproliferative diseases (LPD) and relationships between these diseases in Korea. The EBV status and clinicopathology of 764 patients, including acute EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH), chronic active EBV (CAEBV) infections, B-LPD arising in chronic latent EBV infection, T & natural killer (NK) cell non-Hodgkin's lymphomas (NHL), B-NHLs, and Hodgkin's lymphomas (HD), were analyzed. T or NK cell NHLs were the most common forms of EBV-positive NHLs (107/167, 64%); among these, nasal-type NK/T cell lymphomas were the most common (89/107, 83%). According to the age, Burkitt's lymphoma was the most common in early childhood; in teenagers, chronic (active) EBV infection-associated LPD was the most common type. The incidence of NK/T cell lymphoma began to increase from the twenties and formed the major type of EBV-associated tumor throughout life. Diffuse large B cell lymphoma formed the major type in the sixties and seventies. In conclusion, primary infections in early childhood are complicated by the development of CAEBV infections that are main predisposing factors for EBV-associated T or NK cell malignancies in young adults. In old patients, decreased immunity associated with old age and environmental cofactors may provoke the development of peripheral T cell lymphoma, unspecified, and diffuse large B cell lymphoma. PMID:18436998

The spectrum of Epstein-Barr virus-associated lymphoproliferative disease in Korea: incidence of disease entities by age groups.

PubMed

Cho, Eun-Yoon; Kim, Ki-Hyun; Kim, Won-Seog; Yoo, Keon Hee; Koo, Hong-Hoe; Ko, Young-Hyeh

2008-04-01

This study is to identify the spectrum of Epstein-Barr virus (EBV)-positive lymphoproliferative diseases (LPD) and relationships between these diseases in Korea. The EBV status and clinicopathology of 764 patients, including acute EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH), chronic active EBV (CAEBV) infections, B-LPD arising in chronic latent EBV infection, T & natural killer (NK) cell non-Hodgkin's lymphomas (NHL), B-NHLs, and Hodgkin's lymphomas (HD), were analyzed. T or NK cell NHLs were the most common forms of EBV-positive NHLs (107/167, 64%); among these, nasal-type NK/T cell lymphomas were the most common (89/107, 83%). According to the age, Burkitt's lymphoma was the most common in early childhood; in teenagers, chronic (active) EBV infection-associated LPD was the most common type. The incidence of NK/T cell lymphoma began to increase from the twenties and formed the major type of EBV-associated tumor throughout life. Diffuse large B cell lymphoma formed the major type in the sixties and seventies. In conclusion, primary infections in early childhood are complicated by the development of CAEBV infections that are main predisposing factors for EBV-associated T or NK cell malignancies in young adults. In old patients, decreased immunity associated with old age and environmental cofactors may provoke the development of peripheral T cell lymphoma, unspecified, and diffuse large B cell lymphoma.

Bevacizumab and Cediranib Maleate in Treating Patients With Metastatic or Unresectable Solid Tumor, Lymphoma, Intracranial Glioblastoma, Gliosarcoma or Anaplastic Astrocytoma

ClinicalTrials.gov

2014-02-14

Adult Grade III Lymphomatoid Granulomatosis; Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Childhood Burkitt Lymphoma; Childhood Diffuse Large Cell Lymphoma; Childhood Grade III Lymphomatoid Granulomatosis; Childhood Immunoblastic Large Cell Lymphoma; Childhood Nasal Type Extranodal NK/T-cell Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Noncutaneous Extranodal Lymphoma; Peripheral T-cell Lymphoma; Progressive Hairy Cell Leukemia, Initial Treatment; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Childhood Anaplastic Large Cell Lymphoma; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent/Refractory Childhood Hodgkin Lymphoma; Refractory Hairy Cell Leukemia; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Hodgkin Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Adult T-cell Leukemia/Lymphoma; Stage IV Childhood Anaplastic Large Cell Lymphoma; Stage IV Childhood Hodgkin Lymphoma; Stage IV Childhood Large Cell Lymphoma; Stage IV Childhood Lymphoblastic Lymphoma; Stage IV Childhood Small Noncleaved Cell Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IVA Mycosis Fungoides/Sezary Syndrome; Stage IVB Mycosis Fungoides/Sezary Syndrome; T-cell Large Granular Lymphocyte Leukemia; Testicular Lymphoma; Unspecified Adult Solid Tumor, Protocol Specific; Unspecified Childhood Solid Tumor, Protocol Specific; Waldenström Macroglobulinemia

ETV6-RUNX1 + Acute Lymphoblastic Leukaemia in Identical Twins.

PubMed

Ford, Anthony M; Greaves, Mel

2017-01-01

Acute leukaemia is the major subtype of paediatric cancer with a cumulative risk of 1 in 2000 for children up to the age of 15 years. Childhood acute lymphoblastic leukaemia (ALL) is a biologically and clinically diverse disease with distinctive subtypes; multiple chromosomal translocations exist within the subtypes and each carries its own prognostic relevance. The most common chromosome translocation observed is the t(12;21) that results in an in-frame fusion between the first five exons of ETV6 (TEL) and almost the entire coding region of RUNX1 (AML1).The natural history of childhood ALL is almost entirely clinically silent and is well advanced at the point of diagnosis. It has, however, been possible to backtrack this process through molecular analysis of appropriate clinical samples: (i) leukaemic clones in monozygotic twins that are either concordant or discordant for ALL; (ii) archived neonatal blood spots or Guthrie cards from individuals who later developed leukaemia; and (iii) stored, viable cord blood cells.Here, we outline our studies on the aetiology and pathology of childhood ALL that provide molecular evidence for a monoclonal, prenatal origin of ETV6-RUNX1+ leukaemia in monozygotic identical twins. We provide mechanistic support for the concept that altered patterns of infection during early childhood can deliver the necessary promotional drive for the progression of ETV6-RUNX1+ pre-leukaemic cells into a postnatal overt leukaemia.

Tanespimycin in Treating Young Patients With Recurrent or Refractory Leukemia or Solid Tumors

ClinicalTrials.gov

2013-06-03

Childhood Chronic Myelogenous Leukemia; Childhood Desmoplastic Small Round Cell Tumor; Disseminated Neuroblastoma; Metastatic Childhood Soft Tissue Sarcoma; Metastatic Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Metastatic Osteosarcoma; Previously Treated Childhood Rhabdomyosarcoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Rhabdomyosarcoma; Recurrent Childhood Soft Tissue Sarcoma; Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Recurrent Neuroblastoma; Recurrent Osteosarcoma

Imatinib Mesylate and Combination Chemotherapy in Treating Patients With Newly Diagnosed Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia

ClinicalTrials.gov

2018-05-02

Acute Lymphoblastic Leukemia; B Acute Lymphoblastic Leukemia With t(9;22)(q34.1;q11.2); BCR-ABL1; BCR-ABL1 Fusion Protein Expression; Minimal Residual Disease; Philadelphia Chromosome Positive; T Acute Lymphoblastic Leukemia; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Childhood Acute Lymphoblastic Leukemia

CAR T Cell Immunotherapy Promising in Refractory Leukemia | Center for Cancer Research

Cancer.gov

B-cell acute lymphoblastic leukemia (B-ALL) is a common childhood malignancy that also affects young adults. Although current treatments have significant toxicities, children with chemotherapy susceptible subtypes have high survival rates. However, less than 10 percent of children and young adults with newly-diagnosed or recurrent B-ALL that is insensitive to therapy survive, and this rate has not budged in the last 20 years.

Donor Atorvastatin Treatment in Preventing Severe Acute GVHD After Nonmyeloablative Peripheral Blood Stem Cell Transplant in Patients With Hematological Malignancies

ClinicalTrials.gov

2018-02-08

Aggressive Non-Hodgkin Lymphoma; Blasts Under 5 Percent of Bone Marrow Nucleated Cells; Chronic Lymphocytic Leukemia; Loss of Chromosome 17p; Myelodysplastic/Myeloproliferative Neoplasm; Non-Hodgkin Lymphoma; Prolymphocytic Leukemia; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Aggressive Adult Non-Hodgkin Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Chronic Lymphocytic Leukemia; Recurrent Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Recurrent Diffuse Large B-Cell Lymphoma; Recurrent Hodgkin Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Non-Hodgkin Lymphoma; Recurrent Plasma Cell Myeloma; Recurrent Small Lymphocytic Lymphoma; Waldenstrom Macroglobulinemia

The role of ZAP70 kinase in acute lymphoblastic leukemia infiltration into the central nervous system.

PubMed

Alsadeq, Ameera; Fedders, Henning; Vokuhl, Christian; Belau, Nele M; Zimmermann, Martin; Wirbelauer, Tim; Spielberg, Steffi; Vossen-Gajcy, Michaela; Cario, Gunnar; Schrappe, Martin; Schewe, Denis M

2017-02-01

Central nervous system infiltration and relapse are poorly understood in childhood acute lymphoblastic leukemia. We examined the role of zeta-chain-associated protein kinase 70 in preclinical models of central nervous system leukemia and performed correlative studies in patients. Zeta-chain-associated protein kinase 70 expression in acute lymphoblastic leukemia cells was modulated using short hairpin ribonucleic acid-mediated knockdown or ectopic expression. We show that zeta-chain-associated protein kinase 70 regulates CCR7/CXCR4 via activation of extracellular signal-regulated kinases. High expression of zeta-chain-associated protein kinase 70 in acute lymphoblastic leukemia cells resulted in a higher proportion of central nervous system leukemia in xenografts as compared to zeta-chain-associated protein kinase 70 low expressing counterparts. High zeta-chain-associated protein kinase 70 also enhanced the migration potential towards CCL19/CXCL12 gradients in vitro CCR7 blockade almost abrogated homing of acute lymphoblastic leukemia cells to the central nervous system in xenografts. In 130 B-cell precursor acute lymphoblastic leukemia and 117 T-cell acute lymphoblastic leukemia patients, zeta-chain-associated protein kinase 70 and CCR7/CXCR4 expression levels were significantly correlated. Zeta-chain-associated protein kinase 70 expression correlated with central nervous system disease in B-cell precursor acute lymphoblastic leukemia, and CCR7/CXCR4 correlated with central nervous system involvement in T-cell acute lymphoblastic leukemia patients. In multivariate analysis, zeta-chain-associated protein kinase 70 expression levels in the upper third and fourth quartiles were associated with central nervous system involvement in B-cell precursor acute lymphoblastic leukemia (odds ratio=7.48, 95% confidence interval, 2.06-27.17; odds ratio=6.86, 95% confidence interval, 1.86-25.26, respectively). CCR7 expression in the upper fourth quartile correlated with central nervous system positivity in T-cell acute lymphoblastic leukemia (odds ratio=11.00, 95% confidence interval, 2.00-60.62). We propose zeta-chain-associated protein kinase 70, CCR7 and CXCR4 as markers of central nervous system infiltration in acute lymphoblastic leukemia warranting prospective investigation. Copyright© Ferrata Storti Foundation.

AR-42 and Decitabine in Treating Patients With Acute Myeloid Leukemia

ClinicalTrials.gov

2018-03-12

Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

Effects of Dexrazoxane Hydrochloride on Biomarkers Associated With Cardiomyopathy and Heart Failure After Cancer Treatment

ClinicalTrials.gov

2017-10-27

Recurrent Adult Hodgkin Lymphoma; Recurrent Adult T-Cell Leukemia/Lymphoma; Refractory Childhood Hodgkin Lymphoma; Stage I Adult Hodgkin Lymphoma; Stage I Adult T-Cell Leukemia/Lymphoma; Stage I Childhood Hodgkin Lymphoma; Stage II Adult Hodgkin Lymphoma; Stage II Adult T-Cell Leukemia/Lymphoma; Stage II Childhood Hodgkin Lymphoma; Stage III Adult Hodgkin Lymphoma; Stage III Adult T-Cell Leukemia/Lymphoma; Stage III Childhood Hodgkin Lymphoma; Stage IV Adult Hodgkin Lymphoma; Stage IV Adult T-Cell Leukemia/Lymphoma; Stage IV Childhood Hodgkin Lymphoma

Ipilimumab After Allogeneic Stem Cell Transplant in Treating Patients With Persistent or Progressive Cancer

ClinicalTrials.gov

2013-03-26

Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative; Childhood Myelodysplastic Syndromes; Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Disseminated Neuroblastoma; Malignant Neoplasm; Ovarian Choriocarcinoma; Ovarian Embryonal Carcinoma; Ovarian Immature Teratoma; Ovarian Mature Teratoma; Ovarian Mixed Germ Cell Tumor; Ovarian Monodermal and Highly Specialized Teratoma; Ovarian Polyembryoma; Ovarian Yolk Sac Tumor; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Malignant Testicular Germ Cell Tumor; Recurrent Mantle Cell Lymphoma; Recurrent Neuroblastoma; Recurrent Ovarian Epithelial Cancer; Recurrent Ovarian Germ Cell Tumor; Refractory Chronic Lymphocytic Leukemia; Refractory Multiple Myeloma; Relapsing Chronic Myelogenous Leukemia; Stage I Multiple Myeloma; Stage II Multiple Myeloma; Stage II Ovarian Epithelial Cancer; Stage III Malignant Testicular Germ Cell Tumor; Stage III Multiple Myeloma; Stage III Ovarian Epithelial Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer; Stage IV Ovarian Epithelial Cancer; Testicular Choriocarcinoma; Testicular Choriocarcinoma and Embryonal Carcinoma; Testicular Choriocarcinoma and Seminoma; Testicular Choriocarcinoma and Teratoma; Testicular Choriocarcinoma and Yolk Sac Tumor; Testicular Embryonal Carcinoma; Testicular Embryonal Carcinoma and Seminoma; Testicular Embryonal Carcinoma and Teratoma; Testicular Embryonal Carcinoma and Teratoma With Seminoma; Testicular Embryonal Carcinoma and Yolk Sac Tumor; Testicular Embryonal Carcinoma and Yolk Sac Tumor With Seminoma; Testicular Teratoma; Testicular Yolk Sac Tumor; Testicular Yolk Sac Tumor and Teratoma; Testicular Yolk Sac Tumor and Teratoma With Seminoma

Dose Monitoring of Busulfan and Combination Chemotherapy in Hodgkin or Non-Hodgkin Lymphoma Undergoing Stem Cell Transplant

ClinicalTrials.gov

2015-08-12

Adult Grade III Lymphomatoid Granulomatosis; Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Childhood Burkitt Lymphoma; Childhood Diffuse Large Cell Lymphoma; Childhood Grade III Lymphomatoid Granulomatosis; Childhood Immunoblastic Large Cell Lymphoma; Childhood Nasal Type Extranodal NK/T-cell Lymphoma; Contiguous Stage II Adult Burkitt Lymphoma; Contiguous Stage II Adult Diffuse Large Cell Lymphoma; Contiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Contiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Contiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Contiguous Stage II Adult Lymphoblastic Lymphoma; Contiguous Stage II Grade 1 Follicular Lymphoma; Contiguous Stage II Grade 2 Follicular Lymphoma; Contiguous Stage II Grade 3 Follicular Lymphoma; Contiguous Stage II Mantle Cell Lymphoma; Contiguous Stage II Marginal Zone Lymphoma; Contiguous Stage II Small Lymphocytic Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Burkitt Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Noncontiguous Stage II Adult Lymphoblastic Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Noncutaneous Extranodal Lymphoma; Peripheral T-cell Lymphoma; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Childhood Anaplastic Large Cell Lymphoma; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Refractory Hairy Cell Leukemia; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Stage I Adult Burkitt Lymphoma; Stage I Adult Diffuse Large Cell Lymphoma; Stage I Adult Diffuse Mixed Cell Lymphoma; Stage I Adult Diffuse Small Cleaved Cell Lymphoma; Stage I Adult Hodgkin Lymphoma; Stage I Adult Immunoblastic Large Cell Lymphoma; Stage I Adult Lymphoblastic Lymphoma; Stage I Adult T-cell Leukemia/Lymphoma; Stage I Childhood Anaplastic Large Cell Lymphoma; Stage I Childhood Hodgkin Lymphoma; Stage I Childhood Large Cell Lymphoma; Stage I Childhood Lymphoblastic Lymphoma; Stage I Childhood Small Noncleaved Cell Lymphoma; Stage I Cutaneous T-cell Non-Hodgkin Lymphoma; Stage I Grade 1 Follicular Lymphoma; Stage I Grade 2 Follicular Lymphoma; Stage I Grade 3 Follicular Lymphoma; Stage I Mantle Cell Lymphoma; Stage I Marginal Zone Lymphoma; Stage I Small Lymphocytic Lymphoma; Stage IA Mycosis Fungoides/Sezary Syndrome; Stage IB Mycosis Fungoides/Sezary Syndrome; Stage II Adult Hodgkin Lymphoma; Stage II Adult T-cell Leukemia/Lymphoma; Stage II Childhood Anaplastic Large Cell Lymphoma; Stage II Childhood Hodgkin Lymphoma; Stage II Childhood Large Cell Lymphoma; Stage II Childhood Lymphoblastic Lymphoma; Stage II Childhood Small Noncleaved Cell Lymphoma; Stage II Cutaneous T-cell Non-Hodgkin Lymphoma; Stage IIA Mycosis Fungoides/Sezary Syndrome; Stage IIB Mycosis Fungoides/Sezary Syndrome; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Hodgkin Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Adult T-cell Leukemia/Lymphoma; Stage III Childhood Anaplastic Large Cell Lymphoma; Stage III Childhood Hodgkin Lymphoma; Stage III Childhood Large Cell Lymphoma; Stage III Childhood Lymphoblastic Lymphoma; Stage III Childhood Small Noncleaved Cell Lymphoma; Stage III Cutaneous T-cell Non-Hodgkin Lymphoma; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Small Lymphocytic Lymphoma; Stage IIIA Mycosis Fungoides/Sezary Syndrome; Stage IIIB Mycosis Fungoides/Sezary Syndrome; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Hodgkin Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Adult T-cell Leukemia/Lymphoma; Stage IV Childhood Anaplastic Large Cell Lymphoma; Stage IV Childhood Hodgkin Lymphoma; Stage IV Childhood Large Cell Lymphoma; Stage IV Childhood Lymphoblastic Lymphoma; Stage IV Childhood Small Noncleaved Cell Lymphoma; Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Small Lymphocytic Lymphoma; Stage IVA Mycosis Fungoides/Sezary Syndrome; Stage IVB Mycosis Fungoides/Sezary Syndrome; T-cell Large Granular Lymphocyte Leukemia; Testicular Lymphoma; Waldenström Macroglobulinemia

Revisiting the biology of infant t(4;11)/MLL-AF4+ B-cell acute lymphoblastic leukemia

PubMed Central

Bueno, Clara; Prieto, Cristina; Acha, Pamela; Stam, Ronald W.; Marschalek, Rolf; Menéndez, Pablo

2015-01-01

Infant B-cell acute lymphoblastic leukemia (B-ALL) accounts for 10% of childhood ALL. The genetic hallmark of most infant B-ALL is chromosomal rearrangements of the mixed-lineage leukemia (MLL) gene. Despite improvement in the clinical management and survival (∼85-90%) of childhood B-ALL, the outcome of infants with MLL-rearranged (MLL-r) B-ALL remains dismal, with overall survival <35%. Among MLL-r infant B-ALL, t(4;11)+ patients harboring the fusion MLL-AF4 (MA4) display a particularly poor prognosis and a pro-B/mixed phenotype. Studies in monozygotic twins and archived blood spots have provided compelling evidence of a single cell of prenatal origin as the target for MA4 fusion, explaining the brief leukemia latency. Despite its aggressiveness and short latency, current progress on its etiology, pathogenesis, and cellular origin is limited as evidenced by the lack of mouse/human models recapitulating the disease phenotype/latency. We propose this is because infant cancer is from an etiologic and pathogenesis standpoint distinct from adult cancer and should be seen as a developmental disease. This is supported by whole-genome sequencing studies suggesting that opposite to the view of cancer as a “multiple-and-sequential-hit” model, t(4;11) alone might be sufficient to spawn leukemia. The stable genome of these patients suggests that, in infant developmental cancer, one “big-hit” might be sufficient for overt disease and supports a key contribution of epigenetics and a prenatal cell of origin during a critical developmental window of stem cell vulnerability in the leukemia pathogenesis. Here, we revisit the biology of t(4;11)+ infant B-ALL with an emphasis on its origin, genetics, and disease models. PMID:26463423

Chlorhexidine Gluconate Cleansing in Preventing Central Line Associated Bloodstream Infection and Acquisition of Multi-drug Resistant Organisms in Younger Patients With Cancer or Undergoing Donor Stem Cell Transplant

ClinicalTrials.gov

2018-02-05

Bacterial Infection; Benign Neoplasm; Malignant Neoplasm; Methicillin-Resistant Staphylococcus Aureus Infection; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Untreated Childhood Myeloid Neoplasm

[Chimeric antigen receptors T cells in treatment of a relapsed pediatric acute lymphoblastic leukemia, relapse after allogenetic hematopoietic stem cell transplantation: case report and review of literature review].

PubMed

Zuo, Yingxi; Wang, Jingbo; Lu, Aidong; Jia, Yueping; Wu, Jun; Dong, Lujia; Chang, Lungji; Zhang, Leping

2016-02-01

To evaluate the safety and efficacy of chimeric antigen receptors T cells (CAR-T) in childhood acute B lymphoblastic leukemia (B-ALL). A relapsed B-ALL child after allogeneic hematopoietic stem cell transplantation (allo-HSCT) was treated with CAR-T, and the related literatures were reviewed. An 11-year-old girl with TEL-AML1 fusion gene positive BALL who suffered a bone marrow relapse 28 months after remission from conventional chemotherapy. During the second remission, the patient received haploidentical allo-HSCT. She relapsed with detectable TEL-AML1 fusion gene even after chemotherapy and donor leukocyte infusions. She received an experimental donor-derived fourth generation CD19 CAR-T therapy. After infusion of 1 × 10(6)/kg CAR-T cells, she experienced only mild or moderate cytokine-release syndrome and the minimal residual disease turned negative. Then three maintenance of CAR-T cell infusions [(0.83-1.65)×10(6)/kg] was administered, and the disease-free survival had lasted for 10 months. However, the TEL-AML1 copies in her blood still increased and she died with leukemia relapse after additional CAR-T cell infusion. Treatment of relapsed B-ALL with the fourth generation CAR-T cells directed against CD19 was effective and safe. CAR-T therapy is a novel therapeutic approach that could be useful for patients with relapsed and refractory B-ALL who have failed all other treatment options.

Proteomic changes in a childhood acute lymphoblastic leukemia cell line during the adaptation to vincristine.

PubMed

Guzmán-Ortiz, Ana Laura; Aparicio-Ozores, Gerardo; Valle-Rios, Ricardo; Medina-Contreras, Oscar; Patiño-López, Genaro; Quezada, Héctor

Relapse occurs in approximately 20% of Mexican patients with childhood acute lymphoblastic leukemia (ALL). In this group, chemoresistance may be one of the biggest challenges. An overview of complex cellular processes like drug tolerance can be achieved with proteomic studies. The B-lineage pediatric ALL cell line CCRF-SB was gradually exposed to the chemotherapeutic vincristine until proliferation was observed at 6nM, control cells were cultured in the absence of vincristine. The proteome from each group was analyzed by nanoHPLC coupled to an ESI-ion trap mass spectrometer. The identified proteins were grouped into overrepresented functional categories with the PANTHER classification system. We found 135 proteins exclusively expressed in the presence of vincristine. The most represented functional categories were: Toll receptor signaling pathway, Ras Pathway, B and T cell activation, CCKR signaling map, cytokine-mediated signaling pathway, and oxidative phosphorylation. Our study indicates that signal transduction and mitochondrial ATP production are essential during adaptation of leukemic cells to vincristine, these processes represent potential therapeutic targets. Copyright © 2017 Hospital Infantil de México Federico Gómez. Publicado por Masson Doyma México S.A. All rights reserved.

FR901228 in Treating Children With Refractory or Recurrent Solid Tumors or Leukemia

ClinicalTrials.gov

2013-01-15

Blastic Phase Chronic Myelogenous Leukemia; Childhood Central Nervous System Germ Cell Tumor; Childhood Choroid Plexus Tumor; Childhood Chronic Myelogenous Leukemia; Childhood Craniopharyngioma; Childhood Grade I Meningioma; Childhood Grade II Meningioma; Childhood Grade III Meningioma; Childhood High-grade Cerebral Astrocytoma; Childhood Infratentorial Ependymoma; Childhood Low-grade Cerebral Astrocytoma; Childhood Spinal Cord Neoplasm; Childhood Supratentorial Ependymoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Brain Stem Glioma; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Ependymoma; Recurrent Childhood Medulloblastoma; Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor; Recurrent Childhood Visual Pathway and Hypothalamic Glioma; Refractory Chronic Lymphocytic Leukemia; Relapsing Chronic Myelogenous Leukemia; Unspecified Childhood Solid Tumor, Protocol Specific

Childhood Acute Myeloid Leukemia Treatment (PDQ®)—Patient Version

Cancer.gov

Childhood acute myeloid leukemia and other myeloid malignancies treatment may include chemotherapy, radiation therapy, stem cell transplant, and targeted therapy. Learn more about AML and myelodysplastic/myeloproliferative diseases in this expert-reviewed summary.

Methylenetetrahydrofolate reductase C677T polymorphism: association with risk for childhood acute lymphoblastic leukemia and response during the initial phase of chemotherapy in greek patients.

PubMed

Chatzidakis, Konstantinos; Goulas, Antonis; Athanassiadou-Piperopoulou, Fani; Fidani, Liana; Koliouskas, Dimitrios; Mirtsou, Vassiliki

2006-08-01

As of late, a number of studies have focused on the association of the gene for methyletetrahydrofolate reductase (MTHFR) with risk for acute lymphoblastic leukemia (ALL) in children and in adults, as well as with response to chemotherapy. The degree of this association may vary according to the ethnic background and geographic localization of the population under study, or the phase of treatment when response to chemotherapy is concerned. We have analyzed the MTHFR C677T polymorphism in 52 patients and 88 control individuals, all ethnic Greek residents of northern Greece, and examined the association of this polymorphism with (a) susceptibility to childhood ALL and (b) the distribution of average plasma alanine aminotransferase (ALT) levels, white blood cell counts (WBC), and hemoglobin levels (Hb) during the induction and consolidation phases of treatment. We were able to detect a statistically significant protective effect, with respect to ALL, associated with carriage of the MTHFR 677T allele [OR = 0.387 (95% CI = 0.193-0.776)]. In addition, we observed a general tendency towards lower values in all three parameters studied, associated with the MTHFR 677CC genotype, which was more evident in the transition from the induction to the consolidation phase, indicating that MTHFR genotyping may be of prognostic value in the early phase of treatment for childhood ALL, in our population.

Umbilical Cord Blood Transplant, Cyclophosphamide, Fludarabine Phosphate, and Total-Body Irradiation in Treating Patients With Hematologic Disease

ClinicalTrials.gov

2018-03-23

Acute Biphenotypic Leukemia; Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome; Acute Myeloid Leukemia in Remission; Adult Acute Lymphoblastic Leukemia in Complete Remission; Aggressive Non-Hodgkin Lymphoma; Beta-2-Microglobulin Greater Than 3 g/mL; Blasts Under 5 Percent of Bone Marrow Nucleated Cells; Burkitt Lymphoma; Childhood Acute Lymphoblastic Leukemia in Complete Remission; Chromosome 13 Abnormality; Chronic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Lymphoblastic Lymphoma; Mantle Cell Lymphoma; Myelodysplastic Syndrome With Excess Blasts; Myelofibrosis; Pancytopenia; Plasma Cell Myeloma; Prolymphocytic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Chronic Lymphocytic Leukemia; Recurrent Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Recurrent Follicular Lymphoma; Recurrent Lymphoplasmacytic Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma

Asymptomatic Primary Infection with Epstein-Barr Virus: Observations on Young Adult Cases.

PubMed

Abbott, Rachel J; Pachnio, Annette; Pedroza-Pacheco, Isabela; Leese, Alison M; Begum, Jusnara; Long, Heather M; Croom-Carter, Debbie; Stacey, Andrea; Moss, Paul A H; Hislop, Andrew D; Borrow, Persephone; Rickinson, Alan B; Bell, Andrew I

2017-11-01

Epstein-Barr virus (EBV) is typically acquired asymptomatically in childhood. In contrast, infection later in life often leads to infectious mononucleosis (IM), a febrile illness characterized by anti-EBV IgM antibody positivity, high loads of circulating latently infected B cells, and a marked lymphocytosis caused by hyperexpansion of EBV-specific CD8 + T cells plus a milder expansion of CD56 dim NKG2A + KIR - natural killer (NK) cells. How the two situations compare is unclear due to the paucity of studies on clinically silent infection. Here we describe five prospectively studied patients with asymptomatic infections identified in a seroepidemiologic survey of university entrants. In each case, the key blood sample had high cell-associated viral loads without a marked CD8 lymphocytosis or NK cell disturbance like those seen in patients during the acute phase of IM. Two of the cases with the highest viral loads showed a coincident expansion of activated EBV-specific CD8 + T cells, but overall CD8 + T cell numbers were either unaffected or only mildly increased. Two cases with slightly lower loads, in whom serology suggests the infection may have been caught earlier in the course of infection, also showed no T or NK cell expansion at the time. Interestingly, in another case with a higher viral load, in which T and NK cell responses were undetectable in the primary blood sample in which infection was detected, EBV-specific T cell responses did not appear until several months later, by which time the viral loads in the blood had already fallen. Thus, some patients with asymptomatic primary infections have very high circulating viral loads similar to those in patients during the acute phase of IM and a cell-mediated immune response that is qualitatively similar to that in IM patients but of a lower magnitude. However, other patients may have quite different immune responses that ultimately could reveal novel mechanisms of host control. IMPORTANCE Epstein-Barr virus (EBV) is transmitted orally, replicates in the throat, and then invades the B lymphocyte pool through a growth-transforming latent infection. While primary infection in childhood is usually asymptomatic, delayed infection is associated with infectious mononucleosis (IM), a febrile illness in which patients have high circulating viral loads and an exaggerated virus-induced immune response involving both CD8 + T cells and natural killer (NK) cells. Here we show that in five cases of asymptomatic infection, viral loads in the blood were as high as those in patients during the acute phase of IM, whereas the cell-mediated responses, even when they resembled those in patients during the acute phase of IM in timing and quality, were never as exaggerated. We infer that IM symptoms arise as a consequence not of the virus infection per se but of the hyperactivated immune response. Interestingly, there were idiosyncratic differences among asymptomatic cases in the relationship between the viral load and the response kinetics, emphasizing how much there is still to learn about primary EBV infection. Copyright © 2017 Abbott et al.

Clinical impact of minimal residual disease in children with different subtypes of acute lymphoblastic leukemia treated with Response-Adapted therapy.

PubMed

Pui, C-H; Pei, D; Raimondi, S C; Coustan-Smith, E; Jeha, S; Cheng, C; Bowman, W P; Sandlund, J T; Ribeiro, R C; Rubnitz, J E; Inaba, H; Gruber, T A; Leung, W H; Yang, J J; Downing, J R; Evans, W E; Relling, M V; Campana, D

2017-02-01

To determine the clinical significance of minimal residual disease (MRD) in patients with prognostically relevant subtypes of childhood acute lymphoblastic leukemia (ALL), we analyzed data from 488 patients treated in St Jude Total Therapy Study XV with treatment intensity based mainly on MRD levels measured during remission induction. MRD levels on day 19 predicted treatment outcome for patients with hyperdiploid >50 ALL, National Cancer Institute (NCI) standard-risk B-ALL or T-cell ALL, while MRD levels on day 46 were prognostic for patients with NCI standard-risk or high-risk B-ALL. Patients with t(12;21)/(ETV6-RUNX1) or hyperdiploidy >50 ALL had the best prognosis; those with a negative MRD on day 19 had a particularly low risk of relapse: 1.9% and 3.8%, respectively. Patients with NCI high-risk B-ALL or T-cell ALL had an inferior outcome; even with undetectable MRD on day 46, cumulative risk of relapse was 12.7% and 15.5%, respectively. Among patients with NCI standard-risk B-ALL, the outcome was intermediate overall but was poor if MRD was ⩾1% on day 19 or MRD was detectable at any level on day 46. Our results indicate that the clinical impact of MRD on treatment outcome in childhood ALL varies considerably according to leukemia subtype and time of measurement.

Clinicopathological characteristics of four cases of EBV positive T-cell lymphoproliferative disorders of childhood in China

PubMed Central

Huang, Wenting; Lv, Ning; Ying, Jianming; Qiu, Tian; Feng, Xiaoli

2014-01-01

A new category, “EBV positive T-cell lymphoproliferative disorders (LPD) of childhood”, was proposed in the 2008 World Health Organization’s (WHO) classifications of lymphoma. This series of lymphoproliferative disorders is rare. There are two major types of this series of disorders: systemic EBV positive T-cell LPD of childhood and hydroa vacciniforme-like lymphoma (HVLL). In this study, we describe the distinct features of four cases of EBV positive T-cell LPD of childhood in China. Two were systemic EBV positive T-cell LPD of childhood, one was HVLL and one was chronic active EBV (CAEBV). The main manifestations were lymphadenopathy, fever, hepatosplenomegaly and skin rashes. The structure of the lymph nodes in the patients ranged from preserved to partially or totally destroyed. Small- to medium-sized, atypical T cells had infiltrated the lymph nodes. In HVLL, the neoplastic cells had infiltrated the dermis and subcutaneous region surrounding sweat glands and nerves. All of the cases tested positive for CD8, other T cells, cytotoxic markers and EBV-encoded RNA (EBER) without CD56 expression. Molecular analysis was performed in three cases. All of the three analyses showed a TCRγ rearrangement and one case also had an IGH rearrangement. One of the patients with systemic EBV positive T-cell LPD of childhood experienced rapid evolved and died within five months of onset. CAEBV, systemic EBV-positive T-cell LPD of childhood and HVLL are distinct but overlapping diseases within the category of EBV-positive T-cell LPD of childhood. They constitute a continuous spectrum of EBV-infected associated disorders. PMID:25197370

Childhood diabetes mellitus: recent advances & future prospects.

PubMed

Dejkhamron, Prapai; Menon, Ram K; Sperling, Mark A

2007-03-01

Diabetes mellitus (DM) is a metabolic disease characterized by absolute or relative insulin deficiency. Absolute deficiency of insulin most commonly results from an autoimmune destruction of insulin producing cells in the pancreas and in general, the term Type 1 DM (T1DM) is used to denote childhood diabetes associated with autoimmunity and absolute insulin deficiency. The term Type 2 DM (T2DM) is used to denote diabetes resulting from a relative deficiency of insulin when insulin secretion is inadequate to overcome co-existent resistance to insulin action on carbohydrate, protein or fat metabolism; T2DM is most commonly associated with the prototypic insulin resistant state of obesity. In the western hemisphere DM is one of the most prevalent chronic diseases in childhood, whereas the incidence of T1DM in developing countries is significantly less than that in the western hemisphere. Epidemiological studies indicate that there is gradual but steady increase in the incidence of both T1DM and T2DM in both developed and developing countries. This review provides an overview of the major advances in our understanding of the aetiology, pathogenesis, and clinical management of DM in children with the focus being on T1DM. Genetic predisposition, environmental causes, and emerging concepts of the pathogenesis of T1DM such as the accelerator hypothesis are discussed. The goals of treating a child with DM are to achieve normal growth and development with prevention of acute and chronic complications of DM. These goals are achieved by co-ordinated care delivered by a multidisciplinary team focusing on insulin administrations, glucose monitoring, meal planning, and screening for complications. Newer insulin analogues ("designer" insulin) and automated methods of delivery via programmable pumps have revolutionized the care of the child with diabetes. Though T1DM cannot yet be prevented, ongoing trials and strategies aimed at modulating the autoimmune response and the burgeoning science of embryonic stem cell biology, and isolating and propagating islet cell progenitor cells are discussed in this review.

CD10 is a marker for cycling cells with propensity to apoptosis in childhood ALL

PubMed Central

Cutrona, G; Tasso, P; Dono, M; Roncella, S; Ulivi, M; Carpaneto, E M; Fontana, V; Comis, M; Morabito, F; Spinelli, M; Frascella, E; Boffa, L C; Basso, G; Pistoia, V; Ferrarini, M

2002-01-01

CD10 constitutes a favourable prognostic marker for childhood acute lymphoblastic leukaemia. Since correlations between CD10, cell cycle and apoptotic abilities were demonstrated in various cell types, we investigated whether differences existed in the cycling/apoptotic abilities of CD10-positive and CD10-negative B acute lymphoblastic leukaemia cells. Twenty-eight cases of childhood acute lymphoblastic leukaemia (mean age of 6.8 years) were subdivided into two groups according to high (17 cases, 93.2±4.5%, MRFI 211±82 CD10-positive cells) or low (11 cases, 11.5±6.2%, MRFI 10±7 CD10-negative cells) expression of CD10. CD10-positive acute lymphoblastic leukaemia cells were cycling cells with elevated c-myc levels and propensity to apoptosis, whereas CD10-negative acute lymphoblastic leukaemia cells had lower cycling capacities and c-myc levels, and were resistant to apoptosis in vitro. A close correlation between all these properties was demonstrated by the observations that the few CD10-positive cells found in the CD10-negative acute lymphoblastic leukaemia group displayed elevated c-myc and cycling capacities and were apoptosis prone. Moreover, exposure of CD10-positive acute lymphoblastic leukaemia B cells to a peptide nucleic acid anti-gene specific for the second exon of c-myc caused inhibition of c-myc expression and reduced cell cycling and apoptotic abilities as well as decreased CD10 expression. British Journal of Cancer (2002) 86, 1776–1785. doi:10.1038/sj.bjc.6600329 www.bjcancer.com © 2002 Cancer Research UK PMID:12087466

Clinical characteristics and genetic analysis of childhood acute lymphoblastic leukemia with hemophagocytic lymphohistiocytosis: a Japanese retrospective study by the Kyushu-Yamaguchi Children's Cancer Study Group.

PubMed

Moritake, Hiroshi; Kamimura, Sachiyo; Nunoi, Hiroyuki; Nakayama, Hideki; Suminoe, Aiko; Inada, Hiroko; Inagaki, Jiro; Yanai, Fumio; Okamoto, Yasuhiro; Shinkoda, Yuichi; Shimomura, Maiko; Itonaga, Nobuyoshi; Hotta, Noriko; Hidaka, Yasufumi; Ohara, Osamu; Yanagimachi, Masakatsu; Nakajima, Noriko; Okamura, Jun; Kawano, Yoshifumi

2014-07-01

This present study sought to analyze acute lymphoblastic leukemia (ALL) patients with hemophagocytic lymphohistiocytosis (HLH) registered in Kyushu-Yamaguchi Children's Cancer Study Group studies conducted between 1996 and 2007. Four of 357 patients, including two of 318 patients with B cell precursor acute lymphoblastic leukemia (BCP-ALL) and two of 39 of those with T cell acute lymphoblastic leukemia (T-ALL), were identified. HLH was observed more frequently in the T-ALL patients than in the BCP-ALL patients (P = 0.061). The mean age of 13.0 years at the diagnosis of leukemia in the HLH + ALL group was significantly higher than the 6.05 years observed in the remaining ALL groups (P = 0.001). A female predisposition was noted, as all four patients were female (P = 0.043). In two of four patients, the leukemic cells exhibited deletions on the long arm of chromosome 6 (P = 0.003). Three patients suffered from HLH during maintenance therapy. Parvovirus B19 infection and cytomegalovirus reactivation were identified as causes of HLH in one and two patients, respectively. All four patients are currently in complete remission, although one developed relapse of leukemia after receiving maintenance therapy. Based on the genetic analyses, non-synonymous single nucleotide polymorphisms (SNPs) in UNC13D, syntaxin 11, and STXBP2 were identified in all patients. Clinicians should therefore be aware of the risk of HLH during maintenance therapy, especially in older T-ALL patients with SNPs in familial HLH causative genes.

Childhood Acute Lymphoblastic Leukemia Treatment (PDQ®)—Patient Version

Cancer.gov

Childhood acute lymphoblastic leukemia (ALL) treatment is usually chemotherapy given in phases and determined by risk group. Radiation therapy, targeted therapy and stem cell transplant are sometimes used. Learn more about newly diagnosed and recurrent ALL in this expert reviewed summary.

Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease

PubMed Central

van der Crabben, Saskia N.; Hennus, Marije P.; McGregor, Grant A.; Ritter, Deborah I.; Nagamani, Sandesh C.S.; Wells, Owen S.; Harakalova, Magdalena; Chinn, Ivan K.; Alt, Aaron; Vondrova, Lucie; Hochstenbach, Ron; van Montfrans, Joris M.; Terheggen-Lagro, Suzanne W.; van Lieshout, Stef; van Roosmalen, Markus J.; Renkens, Ivo; Duran, Karen; Nijman, Isaac J.; Kloosterman, Wigard P.; Hennekam, Eric; van Hasselt, Peter M.; Wheeler, David A.; Palecek, Jan J.; Lehmann, Alan R.; Oliver, Antony W.; Pearl, Laurence H.; Plon, Sharon E.; Murray, Johanne M.

2016-01-01

The structural maintenance of chromosomes (SMC) family of proteins supports mitotic proliferation, meiosis, and DNA repair to control genomic stability. Impairments in chromosome maintenance are linked to rare chromosome breakage disorders. Here, we have identified a chromosome breakage syndrome associated with severe lung disease in early childhood. Four children from two unrelated kindreds died of severe pulmonary disease during infancy following viral pneumonia with evidence of combined T and B cell immunodeficiency. Whole exome sequencing revealed biallelic missense mutations in the NSMCE3 (also known as NDNL2) gene, which encodes a subunit of the SMC5/6 complex that is essential for DNA damage response and chromosome segregation. The NSMCE3 mutations disrupted interactions within the SMC5/6 complex, leading to destabilization of the complex. Patient cells showed chromosome rearrangements, micronuclei, sensitivity to replication stress and DNA damage, and defective homologous recombination. This work associates missense mutations in NSMCE3 with an autosomal recessive chromosome breakage syndrome that leads to defective T and B cell function and acute respiratory distress syndrome in early childhood. PMID:27427983

Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease.

PubMed

van der Crabben, Saskia N; Hennus, Marije P; McGregor, Grant A; Ritter, Deborah I; Nagamani, Sandesh C S; Wells, Owen S; Harakalova, Magdalena; Chinn, Ivan K; Alt, Aaron; Vondrova, Lucie; Hochstenbach, Ron; van Montfrans, Joris M; Terheggen-Lagro, Suzanne W; van Lieshout, Stef; van Roosmalen, Markus J; Renkens, Ivo; Duran, Karen; Nijman, Isaac J; Kloosterman, Wigard P; Hennekam, Eric; Orange, Jordan S; van Hasselt, Peter M; Wheeler, David A; Palecek, Jan J; Lehmann, Alan R; Oliver, Antony W; Pearl, Laurence H; Plon, Sharon E; Murray, Johanne M; van Haaften, Gijs

2016-08-01

The structural maintenance of chromosomes (SMC) family of proteins supports mitotic proliferation, meiosis, and DNA repair to control genomic stability. Impairments in chromosome maintenance are linked to rare chromosome breakage disorders. Here, we have identified a chromosome breakage syndrome associated with severe lung disease in early childhood. Four children from two unrelated kindreds died of severe pulmonary disease during infancy following viral pneumonia with evidence of combined T and B cell immunodeficiency. Whole exome sequencing revealed biallelic missense mutations in the NSMCE3 (also known as NDNL2) gene, which encodes a subunit of the SMC5/6 complex that is essential for DNA damage response and chromosome segregation. The NSMCE3 mutations disrupted interactions within the SMC5/6 complex, leading to destabilization of the complex. Patient cells showed chromosome rearrangements, micronuclei, sensitivity to replication stress and DNA damage, and defective homologous recombination. This work associates missense mutations in NSMCE3 with an autosomal recessive chromosome breakage syndrome that leads to defective T and B cell function and acute respiratory distress syndrome in early childhood.

Childhood Leukemia--A Look at the Past, the Present and the Future.

ERIC Educational Resources Information Center

Findeisen, Regina; Barber, William H.

1997-01-01

Provides an overview of childhood leukemia. The causes, the survival period, different types (acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, and hairy cell leukemia), symptoms, treatment, side effects of treatment (including learning problems), and the expected future direction of…

Second Malignant Neoplasms After Treatment of Childhood Acute Lymphoblastic Leukemia

PubMed Central

Schmiegelow, Kjeld; Levinsen, Mette Frandsen; Attarbaschi, Andishe; Baruchel, Andre; Devidas, Meenakshi; Escherich, Gabriele; Gibson, Brenda; Heydrich, Christiane; Horibe, Keizo; Ishida, Yasushi; Liang, Der-Cherng; Locatelli, Franco; Michel, Gérard; Pieters, Rob; Piette, Caroline; Pui, Ching-Hon; Raimondi, Susana; Silverman, Lewis; Stanulla, Martin; Stark, Batia; Winick, Naomi; Valsecchi, Maria Grazia

2013-01-01

Purpose Second malignant neoplasms (SMNs) after diagnosis of childhood acute lymphoblastic leukemia (ALL) are rare events. Patients and Methods We analyzed data on risk factors and outcomes of 642 children with SMNs occurring after treatment for ALL from 18 collaborative study groups between 1980 and 2007. Results Acute myeloid leukemia (AML; n = 186), myelodysplastic syndrome (MDS; n = 69), and nonmeningioma brain tumor (n = 116) were the most common types of SMNs and had the poorest outcome (5-year survival rate, 18.1% ± 2.9%, 31.1% ± 6.2%, and 18.3% ± 3.8%, respectively). Five-year survival estimates for AML were 11.2% ± 2.9% for 125 patients diagnosed before 2000 and 34.1% ± 6.3% for 61 patients diagnosed after 2000 (P < .001); 5-year survival estimates for MDS were 17.1% ± 6.4% (n = 36) and 48.2% ± 10.6% (n = 33; P = .005). Allogeneic stem-cell transplantation failed to improve outcome of secondary myeloid malignancies after adjusting for waiting time to transplantation. Five-year survival rates were above 90% for patients with meningioma, Hodgkin lymphoma, thyroid carcinoma, basal cell carcinoma, and parotid gland tumor, and 68.5% ± 6.4% for those with non-Hodgkin lymphoma. Eighty-nine percent of patients with brain tumors had received cranial irradiation. Solid tumors were associated with cyclophosphamide exposure, and myeloid malignancy was associated with topoisomerase II inhibitors and starting doses of methotrexate of at least 25 mg/m2 per week and mercaptopurine of at least 75 mg/m2 per day. Myeloid malignancies with monosomy 7/5q− were associated with high hyperdiploid ALL karyotypes, whereas 11q23/MLL-rearranged AML or MDS was associated with ALL harboring translocations of t(9;22), t(4;11), t(1;19), and t(12;21) (P = .03). Conclusion SMNs, except for brain tumors, AML, and MDS, have outcomes similar to their primary counterparts. PMID:23690411

Oncogenetic mutations combined with MRD improve outcome prediction in pediatric T-cell acute lymphoblastic leukemia.

PubMed

Petit, Arnaud; Trinquand, Amélie; Chevret, Sylvie; Ballerini, Paola; Cayuela, Jean-Michel; Grardel, Nathalie; Touzart, Aurore; Brethon, Benoit; Lapillonne, Hélène; Schmitt, Claudine; Thouvenin, Sandrine; Michel, Gerard; Preudhomme, Claude; Soulier, Jean; Landman-Parker, Judith; Leverger, Guy; Macintyre, Elizabeth; Baruchel, André; Asnafi, Vahid

2018-01-18

Risk stratification in childhood T-cell acute lymphoblastic leukemia (T-ALL) is mainly based on minimal residual disease (MRD) quantification. Whether oncogenetic mutation profiles can improve the discrimination of MRD-defined risk categories was unknown. Two hundred and twenty FRALLE2000T-treated patients were tested retrospectively for NOTCH1/FBXW7/RAS and PTEN alterations. Patients with NOTCH1/FBXW7 ( N/F ) mutations and RAS/PTEN ( R/P ) germ line (GL) were classified as oncogenetic low risk (gLoR; n = 111), whereas those with N/F GL and R/P GL mutations or N/F and R/P mutations were classified as high risk (gHiR; n = 109). Day 35 MRD status was available for 191 patients. Five-year cumulative incidence of relapse (CIR) and disease-free survival were 36% and 60% for gHiR patients and 11% and 89% for gLoR patients, respectively. Importantly, among the 60% of patients with MRD <10 -4 , 5-year CIR was 29% for gHiR patients and 4% for gLoR patients. Based on multivariable Cox models and stepwise selection, the 3 most discriminating variables were the oncogenetic classifier, MRD, and white blood cell (WBC) count. Patients harboring a WBC count ≥200 × 10 9 /L, gHiR classifier, and MRD ≥10 -4 demonstrated a 5-year CIR of 46%, whereas the 58 patients (30%) with a WBC count <200 × 10 9 /L, gLoR classifier, and MRD <10 -4 had a very low risk of relapse, with a 5-year CIR of only 2%. In childhood T-ALL, the N/F/R/P mutation profile is an independent predictor of relapse. When combined with MRD and a WBC count ≥200 × 10 9 /L, it identifies a significant subgroup of patients with a low risk of relapse. © 2018 by The American Society of Hematology.

Facial manifestations of Epstein-Barr virus-related lymphoproliferative disease in childhood acute lymphoblastic leukemia in remission: Two atypical presentations.

PubMed

Lu, Benjamin Y; Kojima, Lisa; Huang, Mary S; Friedmann, Alison M; Ferry, Judith A; Weinstein, Howard J

2016-11-01

Epstein-Barr virus-related lymphoproliferative disease (EBV-LPD) rarely occurs in patients with acute lymphoblastic leukemia (ALL), who have not received hematopoietic transplantation. We describe EBV-LPD manifesting as facial lesions in two children with ALL in remission. One patient was a 16-year-old male with T-cell ALL with an EBV-positive angiocentric polymorphous lip lesion presenting as right-sided facial swelling. The other patient was a 12-year-old male with B-cell ALL with an EBV-positive polymorphous lymphoplasmacytic infiltrate presenting as bilateral dacryoadenitis. Neither patient had known primary immunodeficiencies. Both cases improved with immunosuppressant de-escalation. These cases suggest that immunosuppression induced by maintenance chemotherapy is sufficient to promote EBV-LPD. © 2016 Wiley Periodicals, Inc.

Clonal origin of Epstein-Barr virus (EBV)-infected T/NK-cell subpopulations in EBV-positive T/NK-cell lymphoproliferative disorders of childhood.

PubMed

Ohga, Shouichi; Ishimura, Masataka; Yoshimoto, Goichi; Miyamoto, Toshihiro; Takada, Hidetoshi; Tanaka, Tamami; Ohshima, Koichi; Ogawa, Yoshiyasu; Imadome, Ken-Ichi; Abe, Yasunobu; Akashi, Koichi; Hara, Toshiro

2011-05-01

In Japan, chronic active Epstein-Barr virus infection (CAEBV) may manifest with infection of T-cells or NK-cells, clonal lymphoid proliferations, and overt lymphoid malignancy. These EBV-positive lymphoproliferative disorders (EBV(+)LPD) of childhood are related to, but distinct from the infectious mononucleosis-like CAEBV seen in Western populations. The clonal nature of viral infection within lymphoid subsets of patients with EBV(+)LPD of childhood is not well described. Viral distribution and clonotype were assessed within T-cell subsets, NK-cells, and CD34(+)stem cells following high purity cell sorting. Six Japanese patients with EBV(+)LPD of childhood (3 T-cell LPD and 3 NK-cell LPD) were recruited. Prior to immunochemotherapy, viral loads and clonal analyses of T-cell subsets, NK-cells, and CD34(+)stem cells were studied by high-accuracy cell sorting (>99.5%), Southern blotting and real-time polymerase chain reaction. Patient 1 had a monoclonal proliferation of EBV-infected γδT-cells and carried a lower copy number of EBV in αβT-cells. Patients 2 and 3 had clonal expansions of EBV-infected CD4(+)T-cells, and lower EBV load in NK-cells. Patients 4, 5 and 6 had EBV(+)NK-cell expansions with higher EBV load than T-cells. EBV-terminal repeats were determined as clonal bands in the minor targeted populations of 5 patients. The size of terminal repeats indicated the same clonotype in minor subsets as in the major subsets of four patients. EBV was not, however, detected in the bone marrow-derived CD34(+)stem cells of patients. A single EBV clonotype may infect multiple NK-cell and T-cell subsets of patients with EBV(+)LPD of childhood. CD34(+)stem cells are spared, suggesting infection of more differentiated elements. Copyright © 2011 Elsevier B.V. All rights reserved.

Childhood tuberculosis is associated with decreased abundance of T cell gene transcripts and impaired T cell function.

PubMed

Hemingway, Cheryl; Berk, Maurice; Anderson, Suzanne T; Wright, Victoria J; Hamilton, Shea; Eleftherohorinou, Hariklia; Kaforou, Myrsini; Goldgof, Greg M; Hickman, Katy; Kampmann, Beate; Schoeman, Johan; Eley, Brian; Beatty, David; Pienaar, Sandra; Nicol, Mark P; Griffiths, Michael J; Waddell, Simon J; Newton, Sandra M; Coin, Lachlan J; Relman, David A; Montana, Giovanni; Levin, Michael

2017-01-01

The WHO estimates around a million children contract tuberculosis (TB) annually with over 80 000 deaths from dissemination of infection outside of the lungs. The insidious onset and association with skin test anergy suggests failure of the immune system to both recognise and respond to infection. To understand the immune mechanisms, we studied genome-wide whole blood RNA expression in children with TB meningitis (TBM). Findings were validated in a second cohort of children with TBM and pulmonary TB (PTB), and functional T-cell responses studied in a third cohort of children with TBM, other extrapulmonary TB (EPTB) and PTB. The predominant RNA transcriptional response in children with TBM was decreased abundance of multiple genes, with 140/204 (68%) of all differentially regulated genes showing reduced abundance compared to healthy controls. Findings were validated in a second cohort with concordance of the direction of differential expression in both TBM (r2 = 0.78 p = 2x10-16) and PTB patients (r2 = 0.71 p = 2x10-16) when compared to a second group of healthy controls. Although the direction of expression of these significant genes was similar in the PTB patients, the magnitude of differential transcript abundance was less in PTB than in TBM. The majority of genes were involved in activation of leucocytes (p = 2.67E-11) and T-cell receptor signalling (p = 6.56E-07). Less abundant gene expression in immune cells was associated with a functional defect in T-cell proliferation that recovered after full TB treatment (p<0.0003). Multiple genes involved in T-cell activation show decreased abundance in children with acute TB, who also have impaired functional T-cell responses. Our data suggest that childhood TB is associated with an acquired immune defect, potentially resulting in failure to contain the pathogen. Elucidation of the mechanism causing the immune paresis may identify new treatment and prevention strategies.

Immature MEF2C-dysregulated T-cell leukemia patients have an early T-cell precursor acute lymphoblastic leukemia gene signature and typically have non-rearranged T-cell receptors

PubMed Central

Zuurbier, Linda; Gutierrez, Alejandro; Mullighan, Charles G.; Canté-Barrett, Kirsten; Gevaert, A. Olivier; de Rooi, Johan; Li, Yunlei; Smits, Willem K.; Buijs-Gladdines, Jessica G.C.A.M.; Sonneveld, Edwin; Look, A. Thomas; Horstmann, Martin; Pieters, Rob; Meijerink, Jules P.P.

2014-01-01

Three distinct immature T-cell acute lymphoblastic leukemia entities have been described including cases that express an early T-cell precursor immunophenotype or expression profile, immature MEF2C-dysregulated T-cell acute lymphoblastic leukemia cluster cases based on gene expression analysis (immature cluster) and cases that retain non-rearranged TRG@ loci. Early T-cell precursor acute lymphoblastic leukemia cases exclusively overlap with immature cluster samples based on the expression of early T-cell precursor acute lymphoblastic leukemia signature genes, indicating that both are featuring a single disease entity. Patients lacking TRG@ rearrangements represent only 40% of immature cluster cases, but no further evidence was found to suggest that cases with absence of bi-allelic TRG@ deletions reflect a distinct and even more immature disease entity. Immature cluster/early T-cell precursor acute lymphoblastic leukemia cases are strongly enriched for genes expressed in hematopoietic stem cells as well as genes expressed in normal early thymocyte progenitor or double negative-2A T-cell subsets. Identification of early T-cell precursor acute lymphoblastic leukemia cases solely by defined immunophenotypic criteria strongly underestimates the number of cases that have a corresponding gene signature. However, early T-cell precursor acute lymphoblastic leukemia samples correlate best with a CD1 negative, CD4 and CD8 double negative immunophenotype with expression of CD34 and/or myeloid markers CD13 or CD33. Unlike various other studies, immature cluster/early T-cell precursor acute lymphoblastic leukemia patients treated on the COALL-97 protocol did not have an overall inferior outcome, and demonstrated equal sensitivity levels to most conventional therapeutic drugs compared to other pediatric T-cell acute lymphoblastic leukemia patients. PMID:23975177

History of Maternal Fetal Loss and Childhood Leukaemia Risk in Subsequent Offspring: Differentials by Miscarriage or Stillbirth History and Disease Subtype.

PubMed

Karalexi, M A; Skalkidou, A; Thomopoulos, T P; Belechri, M; Biniaris-Georgallis, S-I; Bouka, E; Baka, M; Hatzipantelis, E; Kourti, M; Polychronopoulou, S; Sidi, V; Stiakaki, E; Moschovi, M; Dessypris, N; Petridou, E Th

2015-09-01

Despite the putative intrauterine origins of childhood (0-14 years) leukaemia, it is complex to assess the impact of perinatal factors on disease onset. Results on the association of maternal history of fetal loss (miscarriage/stillbirth) with specific disease subtypes in the subsequent offspring are in conflict. We sought to investigate whether miscarriage and stillbirth may have different impacts on the risk of acute lymphoblastic leukaemia (ALL) and of its main immunophenotypes (B-cell and T-cell ALL), as contrasted to acute myeloid leukaemia (AML). One thousand ninety-nine ALL incidents (957 B-ALL) and 131 AML cases along with 1:1 age and gender-matched controls derived from the Nationwide Registry for Childhood Hematological Malignancies and Brain Tumors (1996-2013) were studied. Multivariable regression models were used to assess the roles of previous miscarriage(s) and stillbirth(s) on ALL (overall, B-, T-ALL) and AML, controlling for potential confounders. Statistically significant exposure and disease subtype-specific associations of previous miscarriage(s) exclusively with AML [odds ratio (OR) 1.67, 95% confidence interval (CI) 1.00, 2.81] and stillbirth(s) with ALL [OR 4.82, 95% CI 1.63, 14.24] and B-ALL particularly, emerged. Differential pathophysiological pathways pertaining to genetic polymorphisms or cytogenetic aberrations are likely to create hostile environments leading either to fetal loss or the development of specific leukaemia subtypes in subsequent offspring, notably distinct associations of maternal miscarriage history confined to AML and stillbirth history confined to ALL (specifically B-ALL). If confirmed and further supported by studies revealing underlying mechanisms, these results may shed light on the divergent leukemogenesis processes. © 2015 John Wiley & Sons Ltd.

Epstein–Barr Virus-Positive T/NK-Cell Lymphoproliferative Disorders Manifested as Gastrointestinal Perforations and Skin Lesions

PubMed Central

Xiao, Hai-Juan; Li, Ji; Song, Hong-Mei; Li, Zheng-Hong; Dong, Mei; Zhou, Xiao-Ge

2016-01-01

Abstract Systemic Epstein–Barr virus (EBV)-positive T-cell lymphoproliferative disorders (LPDs) of childhood is a highly aggressive EBV-positive T/natural killer (NK)-cell LPD, which emerges in the background of chronic active EBV infection (CAEBV) or shortly after primary acute EBV infection. The clinical presentations of CAEBV are varied; patients with atypical manifestations are easily misdiagnosed. We described a 14-year-old boy suffering from digestive disorders and intermittent fever for 1 year and 9 months, whose conditions worsened and skin lesions occurred 2 months before hospitalization. He was diagnosed as inflammatory bowel diseases (IBD) and treated accordingly. His other clinical features, hepatosplenomegaly, lymphadenopathy, anemia, hypoalbuminemia, and elevated inflammatory marks, were found in hospitalization. The boy suffered from repeatedly spontaneous intestinal perforations shortly after hospitalization and died of intestinal hemorrhea. The pathological results of intestine and skin both showed EBV-positive T/NK-cell LPD (lymphoma stage). There are rare studies reporting gastrointestinal perforations in EBV-positive T/NK-cell LPD, let alone repeatedly spontaneous perforations. Based on the clinical features and pathological results of this patient, the disease progressed from CAEBV (T-cell type) to systemic EBV-positive T-cell LPD of childhood (lymphoma). Not all the patients with CAEBV could have unusual patterns of anti-EBV antibodies. However, the presence of high EBV loads (EBV-encoded early small ribonucleic acid (RNA) (EBER) in affected tissues and/or EBV deoxyribonucleic acid (DNA) in peripheral blood) is essential for diagnosing CAEBV. Maybe because of his less common clinical features for CAEBV and negative anti-EBV antibodies, the boy was not diagnosed correctly. We should have emphasized the test for EBER or EBV-DNA. Meanwhile, for the IBD patients whose manifestations were not typical, and whose conditions were not improved by suitable therapies against IBD, infectious and malignant diseases should be considered. PMID:26844502

Epstein-Barr Virus-Positive T/NK-Cell Lymphoproliferative Disorders Manifested as Gastrointestinal Perforations and Skin Lesions: A Case Report.

PubMed

Xiao, Hai-Juan; Li, Ji; Song, Hong-Mei; Li, Zheng-Hong; Dong, Mei; Zhou, Xiao-Ge

2016-02-01

Systemic Epstein-Barr virus (EBV)-positive T-cell lymphoproliferative disorders (LPDs) of childhood is a highly aggressive EBV-positive T/natural killer (NK)-cell LPD, which emerges in the background of chronic active EBV infection (CAEBV) or shortly after primary acute EBV infection. The clinical presentations of CAEBV are varied; patients with atypical manifestations are easily misdiagnosed. We described a 14-year-old boy suffering from digestive disorders and intermittent fever for 1 year and 9 months, whose conditions worsened and skin lesions occurred 2 months before hospitalization. He was diagnosed as inflammatory bowel diseases (IBD) and treated accordingly. His other clinical features, hepatosplenomegaly, lymphadenopathy, anemia, hypoalbuminemia, and elevated inflammatory marks, were found in hospitalization. The boy suffered from repeatedly spontaneous intestinal perforations shortly after hospitalization and died of intestinal hemorrhea. The pathological results of intestine and skin both showed EBV-positive T/NK-cell LPD (lymphoma stage).There are rare studies reporting gastrointestinal perforations in EBV-positive T/NK-cell LPD, let alone repeatedly spontaneous perforations. Based on the clinical features and pathological results of this patient, the disease progressed from CAEBV (T-cell type) to systemic EBV-positive T-cell LPD of childhood (lymphoma). Not all the patients with CAEBV could have unusual patterns of anti-EBV antibodies. However, the presence of high EBV loads (EBV-encoded early small ribonucleic acid (RNA) (EBER) in affected tissues and/or EBV deoxyribonucleic acid (DNA) in peripheral blood) is essential for diagnosing CAEBV. Maybe because of his less common clinical features for CAEBV and negative anti-EBV antibodies, the boy was not diagnosed correctly. We should have emphasized the test for EBER or EBV-DNA. Meanwhile, for the IBD patients whose manifestations were not typical, and whose conditions were not improved by suitable therapies against IBD, infectious and malignant diseases should be considered.

Autologous Stem Cell Transplant Followed by Donor Stem Cell Transplant in Treating Patients With Relapsed or Refractory Lymphoma

ClinicalTrials.gov

2018-02-12

Prolymphocytic Leukemia; Recurrent Adult Hodgkin Lymphoma; Recurrent Childhood Hodgkin Lymphoma; Recurrent Childhood Non-Hodgkin Lymphoma; Recurrent Chronic Lymphocytic Leukemia; Recurrent Non-Hodgkin Lymphoma; Recurrent Small Lymphocytic Lymphoma; Refractory Childhood Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hodgkin Lymphoma; Refractory Non-Hodgkin Lymphoma; Refractory Small Lymphocytic Lymphoma; T-Cell Chronic Lymphocytic Leukemia; T-Cell Prolymphocytic Leukemia

Cytogenetic study of a patient with infant acute lymphoblastic leukemia using GTG-banding and chromosome painting.

PubMed

Alter, D; Mark, H F

2000-10-01

Numerical and structural chromosomal abnormalities occur in up to 90% of cases of childhood acute lymphoblastic leukemia (ALL). Two-thirds of these abnormalities are recurrent. The most common abnormalities are pseudodiploidy and t(1;19), occurring 40 and 5-6% of the time. Hyperdiploidy has the best prognosis, with an 80-90% 5-year survival. The 4;11 translocation has the worst prognosis, with a 10-35% 5-year survival. We report a patient with infant acute lymphoblastic leukemia and nonrecurrent rearrangements of chromosomes 10 and 11. Structural rearrangements between chromosomes 10 and 11 have been observed in 0.5% of all cases of childhood ALL with cytogenetic abnormalities. The identification of the apparently unique structural abnormalities was achieved using fluorescent in situ hybridization (FISH) with chromosome 10- and chromosome 11-specific painting probes as an adjunct to conventional cytogenetics. As is often the case, suboptimal preparations often preclude unequivocal identification of complex rearrangements by conventional banding techniques. The cytogenetic diagnosis of our patient was established as 46,XY, der(10)-t(10;11)(p15;q14)t(10;11)(q25;p11), der(11)t(10;11)(p15;q14)t(10;11)-(q25;p11). The benefits of FISH serve to increase the resolution of detection for chromosomal abnormalities and the understanding of the pathogenic mechanisms of childhood ALL. Copyright 2000 Academic Press.

Single or Double Donor Umbilical Cord Blood Transplant in Treating Patients With High-Risk Hematologic Malignancies

ClinicalTrials.gov

2016-07-13

Accelerated Phase Chronic Myelogenous Leukemia; Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Blastic Phase Chronic Myelogenous Leukemia; Cutaneous B-cell Non-Hodgkin Lymphoma; de Novo Myelodysplastic Syndromes; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Intraocular Lymphoma; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Nodal Marginal Zone B-cell Lymphoma; Noncutaneous Extranodal Lymphoma; Peripheral T-cell Lymphoma; Post-transplant Lymphoproliferative Disorder; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Refractory Multiple Myeloma; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; T-cell Large Granular Lymphocyte Leukemia; Testicular Lymphoma; Waldenström Macroglobulinemia

Early Allogeneic Hematopoietic Cell Transplantation in Treating Patients With Relapsed or Refractory High-Grade Myeloid Neoplasms

ClinicalTrials.gov

2018-02-06

Blasts 10 Percent or More of Bone Marrow Nucleated Cells; Chronic Myelomonocytic Leukemia-2; High Grade Malignant Neoplasm; Myelodysplastic Syndrome; Myelodysplastic Syndrome With Excess Blasts-2; Myeloid Neoplasm; Previously Treated Myelodysplastic Syndrome; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Refractory Acute Myeloid Leukemia

Identification of residual leukemic cells by flow cytometry in childhood B-cell precursor acute lymphoblastic leukemia: verification of leukemic state by flow-sorting and molecular/cytogenetic methods.

PubMed

Øbro, Nina F; Ryder, Lars P; Madsen, Hans O; Andersen, Mette K; Lausen, Birgitte; Hasle, Henrik; Schmiegelow, Kjeld; Marquart, Hanne V

2012-01-01

Reduction in minimal residual disease, measured by real-time quantitative PCR or flow cytometry, predicts prognosis in childhood B-cell precursor acute lymphoblastic leukemia. We explored whether cells reported as minimal residual disease by flow cytometry represent the malignant clone harboring clone-specific genomic markers (53 follow-up bone marrow samples from 28 children with B-cell precursor acute lymphoblastic leukemia). Cell populations (presumed leukemic and non-leukemic) were flow-sorted during standard flow cytometry-based minimal residual disease monitoring and explored by PCR and/or fluorescence in situ hybridization. We found good concordance between flow cytometry and genomic analyses in the individual flow-sorted leukemic (93% true positive) and normal (93% true negative) cell populations. Four cases with discrepant results had plausible explanations (e.g. partly informative immunophenotype and antigen modulation) that highlight important methodological pitfalls. These findings demonstrate that with sufficient experience, flow cytometry is reliable for minimal residual disease monitoring in B-cell precursor acute lymphoblastic leukemia, although rare cases require supplementary PCR-based monitoring.

Epstein-Barr virus and regulatory T cells in Egyptian paediatric patients with acute B lymphoblastic leukaemia.

PubMed

Ateyah, Mohamed E; Hashem, Mona E; Abdelsalam, Mohamed

2017-02-01

Acute B lymphoblastic leukaemia (B-ALL) is the most common type of childhood malignancy worldwide but little is known of its origin. Recently, many studies showed both a high incidence of Epstein-Barr virus (EBV) infection and high levels of CD4 + CD25 + Foxp3 + (Treg cells) in children with B-ALL. In our study, we investigated the possible relationship between EBV infection and the onset of B-ALL, and its relation to expression of CD4 + , CD25 high+ Foxp3+ T regulatory cells. We analysed expression and mean fluorescence intensity (MFI) of Treg cells in peripheral blood of 45 children with B-ALL and in 40 apparently healthy children as a control, using flow cytometry. Serum anti-EBV viral capsid antigen (VCA) IgG, anti-EBV nuclear antigen (EBNA) IgG (for latent infection) and anti-EBV VCA IgM (for acute infection) were investigated using ELISA. Analysis of the Treg cells population in patients and controls revealed that expression of CD4 + CD25 high+ T lymphocytes was higher in patients than in controls (mean±SD 15.7±4.1 and 10.61±2.6 in patients and controls, respectively, and MFI of Foxp3 was 30.1±7.1 and 16.7±3.7 in patients and controls, respectively (p<0.001)). There was a high incidence of latent EBV infection in patients (31%) compared with controls (10%) while the incidence of acute infection was 12% in patients and 0% in the control group. To study the role of latent EBV infection in the pathogenesis of acute B-ALL, OR was calculated (OR=4.06, coefficient index 1.2-13.6). These findings suggest a possible role for Treg cells and EBV in the pathogenesis of B-ALL. Further studies are needed on the possible mechanisms of tumour genesis related to Treg cells and EBV in children with B-ALL. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Autologous Peripheral Blood Stem Cell Transplant Followed by Donor Bone Marrow Transplant in Treating Patients With High-Risk Hodgkin Lymphoma, Non-Hodgkin Lymphoma, Multiple Myeloma, or Chronic Lymphocytic Leukemia

ClinicalTrials.gov

2017-12-26

B-Cell Prolymphocytic Leukemia; Hypodiploidy; Loss of Chromosome 17p; Plasma Cell Leukemia; Progression of Multiple Myeloma or Plasma Cell Leukemia; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Non-Hodgkin Lymphoma; Recurrent Childhood Hodgkin Lymphoma; Recurrent Childhood Non-Hodgkin Lymphoma; Recurrent Chronic Lymphocytic Leukemia; Recurrent Plasma Cell Myeloma; Recurrent Small Lymphocytic Lymphoma; Refractory Childhood Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Non-Hodgkin Lymphoma; Refractory Plasma Cell Myeloma; Refractory Small Lymphocytic Lymphoma; t(14;16); t(4;14); T-Cell Prolymphocytic Leukemia; Waldenstrom Macroglobulinemia

Combination Chemotherapy in Treating Young Patients With Down Syndrome and Acute Myeloid Leukemia or Myelodysplastic Syndromes

ClinicalTrials.gov

2017-07-10

Childhood Acute Basophilic Leukemia; Childhood Acute Eosinophilic Leukemia; Childhood Acute Erythroleukemia (M6); Childhood Acute Megakaryocytic Leukemia (M7); Childhood Acute Minimally Differentiated Myeloid Leukemia (M0); Childhood Acute Monoblastic Leukemia (M5a); Childhood Acute Monocytic Leukemia (M5b); Childhood Acute Myeloblastic Leukemia With Maturation (M2); Childhood Acute Myeloblastic Leukemia Without Maturation (M1); Childhood Acute Myelomonocytic Leukemia (M4); Childhood Myelodysplastic Syndromes; de Novo Myelodysplastic Syndromes; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Untreated Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies

Chemo-sensitivity in a panel of B-cell precursor acute lymphoblastic leukemia cell lines, YCUB series, derived from children.

PubMed

Goto, Hiroaki; Naruto, Takuya; Tanoshima, Reo; Kato, Hiromi; Yokosuka, Tomoko; Yanagimachi, Masakatsu; Fujii, Hisaki; Yokota, Shumpei; Komine, Hiromi

2009-10-01

Sensitivity to 10 anticancer drugs was evaluated in 6 childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) cell lines. Authenticity of newly established cell lines was confirmed by genomic fingerprinting. The line YCUB-5R established at relapse was more resistant to 4-hydroperoxy-cyclophosphamide, cytarabine, L-asparaginase, topotecan, fludarabine, and etoposide than YCUB-5 from the same patient at diagnosis. Of the drugs tested, etoposide and SN-38 (irinotecan) showed highest efficacy in the panel, with 50% growth inhibition at 0.22-1.8 microg/ml and 0.57-3.6 ng/ml, respectively. This cell line panel offers an in vitro model for the development of new therapies for childhood BCP-ALL.

Vorinostat and Bortezomib in Treating Young Patients With Refractory or Recurrent Solid Tumors, Including Central Nervous System Tumors and Lymphoma

ClinicalTrials.gov

2013-07-01

Childhood Burkitt Lymphoma; Childhood Central Nervous System Choriocarcinoma; Childhood Central Nervous System Germ Cell Tumor; Childhood Central Nervous System Germinoma; Childhood Central Nervous System Mixed Germ Cell Tumor; Childhood Central Nervous System Teratoma; Childhood Central Nervous System Yolk Sac Tumor; Childhood Choroid Plexus Tumor; Childhood Craniopharyngioma; Childhood Diffuse Large Cell Lymphoma; Childhood Immunoblastic Large Cell Lymphoma; Childhood Medulloepithelioma; Childhood Meningioma; Childhood Mixed Glioma; Childhood Nasal Type Extranodal NK/T-cell Lymphoma; Childhood Oligodendroglioma; Recurrent Childhood Anaplastic Large Cell Lymphoma; Recurrent Childhood Brain Stem Glioma; Recurrent Childhood Central Nervous System Embryonal Tumor; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Ependymoma; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Malignant Germ Cell Tumor; Recurrent Childhood Medulloblastoma; Recurrent Childhood Pineoblastoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Childhood Subependymal Giant Cell Astrocytoma; Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor; Recurrent Childhood Visual Pathway and Hypothalamic Glioma; Recurrent Childhood Visual Pathway Glioma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Unspecified Childhood Solid Tumor, Protocol Specific

Variation in CDKN2A at 9p21.3 influences childhood acute lymphoblastic leukemia risk

PubMed Central

Sherborne, Amy L; Hosking, Fay J; Prasad, Rashmi B; Kumar, Rajiv; Koehler, Rolf; Vijayakrishnan, Jayaram; Papaemmanuil, Elli; Bartram, Claus R; Stanulla, Martin; Schrappe, Martin; Gast, Andreas; Dobbins, Sara E; Ma, Yussanne; Sheridan, Eamonn; Taylor, Malcolm; Kinsey, Sally E; Lightfoot, Tracey; Roman, Eve; Irving, Julie A E; Allan, James M; Moorman, Anthony V; Harrison, Christine J; Tomlinson, Ian P; Richards, Sue; Zimmermann, Martin; Szalai, Csaba; Semsei, Ágnes F; Erdelyi, Daniel J; Krajinovic, Maja; Sinnett, Daniel; Healy, Jasmine; Neira, Anna Gonzalez; Kawamata, Norihiko; Ogawa, Seishi; Koeffler, H Phillip; Hemminki, Kari; Greaves, Mel; Houlston, Richard S

2012-01-01

Using data from a genome-wide association study of 907 individuals with childhood acute lymphoblastic leukemia (cases) and 2,398 controls and with validation in samples totaling 2,386 cases and 2,419 controls, we have shown that common variation at 9p21.3 (rs3731217, intron 1 of CDKN2A) influences acute lymphoblastic leukemia risk (odds ratio = 0.71, P = 3.01 × 10−11), irrespective of cell lineage. PMID:20453839

Exposure to professional pest control treatments and the risk of childhood acute lymphoblastic leukemia.

PubMed

Bailey, Helen D; Armstrong, Bruce K; de Klerk, Nicholas H; Fritschi, Lin; Attia, John; Scott, Rodney J; Smibert, Elizabeth; Milne, Elizabeth

2011-10-01

Previous studies suggest that exposure to pesticides increases the risk of childhood acute lymphoblastic leukemia (ALL). The aim of this analysis was to investigate whether professional pest treatments in or around the home before birth or during childhood increased the risk of childhood ALL. Data from 388 cases and 870 frequency-matched controls were analyzed using unconditional logistic regression, adjusting for study matching variables and potential confounders, to calculate odds ratios (ORs). A meta-analysis of our findings with the published findings of previous studies was also conducted. The ORs for any professional pest control treatments were 1.19 (95% CI 0.83, 1.69) in the year before pregnancy, 1.30 (95% CI 0.86, 1.97) during pregnancy and 1.24 (95% CI 0.93, 1.65) for those done after the child's birth. The ORs for exposure after birth were highest when it occurred between the ages of two and three years. ORs were elevated for termite treatments before birth. ORs were higher for pre-B than T cell ALL and for t(12;21) (ETV6-Runx-1) than other cytogenetic sub-types. The pooled OR from a meta-analysis of our study with three previous studies of professional pest control treatments during pregnancy was 1.37 (95% CI 1.00, 1.88). Our results, and those of our meta-analysis, provide some evidence of a modestly increased risk of ALL for professional pest control treatments done during the index pregnancy and possibly in the child's early years. The analysis of pooled data from international collaborations may provide more certainty regarding these potentially important associations. Copyright © 2011 UICC.

Blinatumomab, a Bi-Specific Anti-CD19/CD3 BiTE® Antibody for the Treatment of Acute Lymphoblastic Leukemia: Perspectives and Current Pediatric Applications

PubMed Central

Hoffman, Lindsey M.; Gore, Lia

2014-01-01

Leukemia is the most common childhood malignancy and acute lymphoblastic leukemia (ALL) represents the largest sub-type. Despite remarkable improvements over the last 40 years, standard therapy fails in 10–20% of newly diagnosed patients. Survival for children with relapsed ALL is poor, and the development and implementation of novel therapeutic strategies in pediatric ALL are critical to further advancements. Immunotherapeutic approaches have been central to more novel ALL therapies. However, more recent innovation in antibody engineering has improved potency and efficacy, and antibody–drug conjugates (ADCs) are an especially attractive option in severely immunocompromised patients. An even more sophisticated antibody design is that of bi-specific T-cell engaging or BiTE® antibodies, which directly recruit effector T cells to augment the anti-neoplastic effect. This review focuses on blinatumomab, a bi-specific anti-CD19/CD3 antibody that has shown efficacy in adult patients with precursor B-ALL and is currently being evaluated in the pediatric setting. PMID:24744989

Heterozygote FANCD2 mutations associated with childhood T Cell ALL and testicular seminoma.

PubMed

Smetsers, Stephanie; Muter, Joanne; Bristow, Claire; Patel, Leena; Chandler, Kate; Bonney, Denise; Wynn, Robert F; Whetton, Anthony D; Will, Andrew M; Rockx, Davy; Joenje, Hans; Strathdee, Gordon; Shanks, Jonathan; Klopocki, Eva; Gille, Johan J P; Dorsman, Josephine; Meyer, Stefan

2012-12-01

Fanconi anaemia (FA) is an inherited disease with congenital and developmental abnormalities characterised by cellular cross linker hypersensitivity. FA is caused by mutations in any of so far 15 identified FANC genes, which encode proteins that interact in a common DNA damage response (DDR) pathway. Individuals with FA have a high risk of developing acute myeloid leukaemia (AML) and squamous cell carcinoma. An increased cancer risk has been firmly established for carriers of mutations in FANCD1/BRCA2, FANCJ/BRIP1, FANCN/PALB2, RAD51C/FANCO and link the FA pathway to inherited breast and ovarian cancer. We describe a pedigree with FANCD2 mutations c.458T > C (p.Leu153Ser) and c.2715 + 1G > A (p.Glu906LeufsX4) with mild phenotype FA in the index case, T cell ALL in the Leu153Ser heterozygous brother and testicular seminoma in the p.Glu906LeufsX4 heterozygous father. Both FANCD2 alleles were present in the T Cell ALL and the seminoma. This links specific FANCD2 mutations to T cell ALL and seminoma without evidence of allelic loss in the tumour tissue.

Donor Peripheral Stem Cell Transplant in Treating Patients With Hematolymphoid Malignancies

ClinicalTrials.gov

2016-11-17

Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Nasal Type Extranodal NK/T-cell Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma; Hepatosplenic T-cell Lymphoma; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Peripheral T-cell Lymphoma; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Relapsing Chronic Myelogenous Leukemia; Splenic Marginal Zone Lymphoma; Waldenstrom Macroglobulinemia

Age-related T cell responses to allergens in childhood.

PubMed

Smart, J M; Suphioglu, C; Kemp, A S

2003-03-01

T cell priming, as determined by allergen-induced proliferative responses, is believed to occur principally in early childhood in both atopic and non-atopic infants under the influence of multiple factors including environmental allergen exposure. It is considered that T cell priming with expansion of Th2 cells is a crucial factor in the development of atopic disease. To examine T cell priming to commonly encountered allergens in childhood in relation to age. In a cross-sectional study T cell proliferation in relation to age was examined for three common allergens, ovalbumin (OVA), house dust mite (HDM) and rye grass pollen (RYE), in atopic and non-atopic children. The effect of age on Th1 (IFN-gamma) and Th2 (IL-5 and IL-13) cytokine production in response to these allergens was investigated to examine the possibility of immune deviation with time. A significant increase in T cell proliferation with age was observed with RYE among atopic children only. However, the same was not observed with the two other allergens studied (i.e. OVA and HDM). In addition, RYE-induced (but not HDM or OVA) cytokine production showed an increased Th2 deviation with age as reflected in the increasing IL-5/IFN-gamma and IL-13/IFN-gamma ratios only among the atopic subjects with rye grass pollen sensitivity. These findings suggest that grass pollen sensitivity in childhood is accompanied by a progressive accumulation of allergen-primed T cells and progressive deviation of the allergen-induced cytokine response towards a Th2 response in atopic subjects throughout childhood.

Acute myeloid/T-lymphoblastic leukaemia (AMTL): a distinct category of acute leukaemias with common pathogenesis in need of improved therapy.

PubMed

Gutierrez, Alejandro; Kentsis, Alex

2018-03-01

Advances in the classification of acute leukaemias have led to improved outcomes for a substantial fraction of patients. However, chemotherapy resistance remains a major problem for specific subsets of acute leukaemias. Here, we propose that a molecularly distinct subtype of acute leukaemia with shared myeloid and T cell lymphoblastic features, which we term acute myeloid/T-lymphoblastic leukaemia (AMTL), is divided across 3 diagnostic categories owing to variable expression of markers deemed to be defining of myeloid and T-lymphoid lineages, such as myeloperoxidase and CD3. This proposed diagnostic group is supported by (i) retained myeloid differentiation potential during early T cell lymphoid development, (ii) recognition that some cases of acute myeloid leukaemia (AML) harbour hallmarks of T cell development, such as T-cell receptor gene rearrangements and (iii) common gene mutations in subsets of AML and T cell acute lymphoblastic leukaemia (T-ALL), including WT1, PHF6, RUNX1 and BCL11B. This proposed diagnostic entity overlaps with early T cell precursor (ETP) T-ALL and T cell/myeloid mixed phenotype acute leukaemias (MPALs), and also includes a subset of leukaemias currently classified as AML with features of T-lymphoblastic development. The proposed classification of AMTL as a distinct entity would enable more precise prospective diagnosis and permit the development of improved therapies for patients whose treatment is inadequate with current approaches. © 2018 John Wiley & Sons Ltd.

The association of folate pathway and DNA repair polymorphisms with susceptibility to childhood acute lymphoblastic leukemia.

PubMed

Goričar, Katja; Erčulj, Nina; Faganel Kotnik, Barbara; Debeljak, Maruša; Hovnik, Tinka; Jazbec, Janez; Dolžan, Vita

2015-05-15

Genetic factors may play an important role in susceptibility to childhood acute lymphoblastic leukemia (ALL). The aim of our study was to evaluate the associations of genetic polymorphisms in folate pathway and DNA repair genes with susceptibility to ALL. In total, 121 children with ALL and 184 unrelated healthy controls of Slovenian origin were genotyped for 14 polymorphisms in seven genes of folate pathway, base excision repair and homologous recombination repair (TYMS, MTHFR, OGG1, XRCC1, NBN, RAD51, and XRCC3). In addition, the exon 6 of NBN was screened for the presence of mutations using denaturing high performance liquid chromatography. Twelve polymorphisms were in Hardy-Weinberg equilibrium in controls and their genotype frequencies were in agreement with those reported in other Caucasian populations. Among the investigated polymorphisms and mutations, NBN Glu185Gln significantly decreased susceptibility to B-cell ALL (p=0.037), while TYMS 3R allele decreased susceptibility to T-cell ALL (p=0.011). Moreover, significantly decreased susceptibility to ALL was observed for MTHFR TA (p=0.030) and RAD51 GTT haplotypes (p=0.016). Susceptibility to ALL increased with the increasing number of risk alleles (ptrend=0.007). We also observed significant influence of hOGG-RAD51 and NBN-RAD51 interactions on susceptibility to ALL. Our results suggest that combination of several polymorphisms in DNA repair and folate pathways may significantly affect susceptibility to childhood ALL. Copyright © 2015 Elsevier B.V. All rights reserved.

SB225002 Induces Cell Death and Cell Cycle Arrest in Acute Lymphoblastic Leukemia Cells through the Activation of GLIPR1

PubMed Central

Leal, Paulo C.; Bhasin, Manoj K.; Zenatti, Priscila Pini; Nunes, Ricardo J.; Yunes, Rosendo A.; Nowill, Alexandre E.; Libermann, Towia A.; Zerbini, Luiz Fernando; Yunes, José Andrés

2015-01-01

Acute Lymphoblastic Leukemia (ALL) is the most frequent childhood malignancy. In the effort to find new anti-leukemic agents, we evaluated the small drug SB225002 (N-(2-hydroxy-4-nitrophenyl)-N’-(2-bromophenyl)urea). Although initially described as a selective antagonist of CXCR2, later studies have identified other cellular targets for SB225002, with potential medicinal use in cancer. We found that SB225002 has a significant pro-apoptotic effect against both B- and T-ALL cell lines. Cell cycle analysis demonstrated that treatment with SB225002 induces G2-M cell cycle arrest. Transcriptional profiling revealed that SB225002-mediated apoptosis triggered a transcriptional program typical of tubulin binding agents. Network analysis revealed the activation of genes linked to the JUN and p53 pathways and inhibition of genes linked to the TNF pathway. Early cellular effects activated by SB225002 included the up-regulation of GLIPR1, a p53-target gene shown to have pro-apoptotic activities in prostate and bladder cancer. Silencing of GLIPR1 in B- and T-ALL cell lines resulted in increased resistance to SB225002. Although SB225002 promoted ROS increase in ALL cells, antioxidant N-Acetyl Cysteine pre-treatment only modestly attenuated cell death, implying that the pro-apoptotic effects of SB225002 are not exclusively mediated by ROS. Moreover, GLIPR1 silencing resulted in increased ROS levels both in untreated and SB225002-treated cells. In conclusion, SB225002 induces cell cycle arrest and apoptosis in different B- and T-ALL cell lines. Inhibition of tubulin function with concurrent activation of the p53 pathway, in particular, its downstream target GLIPR1, seems to underlie the anti-leukemic effect of SB225002. PMID:26302043

Role of CXCR4-mediated bone marrow colonization in CNS infiltration by T cell acute lymphoblastic leukemia.

PubMed

Jost, Tanja Rezzonico; Borga, Chiara; Radaelli, Enrico; Romagnani, Andrea; Perruzza, Lisa; Omodho, Lorna; Cazzaniga, Giovanni; Biondi, Andrea; Indraccolo, Stefano; Thelen, Marcus; Te Kronnie, Geertruy; Grassi, Fabio

2016-06-01

Infiltration of the central nervous system is a severe trait of T cell acute lymphoblastic leukemia. Inhibition of CXC chemokine receptor 4 significantly ameliorates T cell acute lymphoblastic leukemia in murine models of the disease; however, signaling by CXC chemokine receptor 4 is important in limiting the divagation of peripheral blood mononuclear cells out of the perivascular space into the central nervous system parenchyma. Therefore, Inhibition of CXC chemokine receptor 4 potentially may untangle T cell acute lymphoblastic leukemia cells from retention outside the brain. Here, we show that leukemic lymphoblasts massively infiltrate cranial bone marrow, with diffusion to the meninges without invasion of the brain parenchyma, in mice that underwent xenotransplantation with human T cell acute lymphoblastic leukemia cells or that developed leukemia from transformed hematopoietic progenitors. We tested the hypothesis that T cell acute lymphoblastic leukemia neuropathology results from meningeal infiltration through CXC chemokine receptor 4-mediated bone marrow colonization. Inhibition of leukemia engraftment in the bone marrow by pharmacologic CXC chemokine receptor 4 antagonism significantly ameliorated neuropathologic aspects of the disease. Genetic deletion of CXCR4 in murine hematopoietic progenitors abrogated leukemogenesis induced by constitutively active Notch1, whereas lack of CCR6 and CCR7, which have been shown to be involved in T cell and leukemia extravasation into the central nervous system, respectively, did not influence T cell acute lymphoblastic leukemia development. We hypothesize that lymphoblastic meningeal infiltration as a result of bone marrow colonization is responsible for the degenerative alterations of the neuroparenchyma as well as the alteration of cerebrospinal fluid drainage in T cell acute lymphoblastic leukemia xenografts. Therefore, CXC chemokine receptor 4 may constitute a pharmacologic target for T cell acute lymphoblastic leukemia neuropathology. © Society for Leukocyte Biology.

Characterization of T cell repertoire changes in acute Kawasaki disease

PubMed Central

1993-01-01

Kawasaki disease (KD) is an acute multisystem vasculitis of unknown etiology that is associated with marked activation of T cells and monocyte/macrophages. Using a quantitative polymerase chain reaction (PCR) technique, we recently found that the acute phase of KD is associated with the expansion of T cells expressing the V beta 2 and V beta 8.1 gene segments. In the present work, we used a newly developed anti-V beta 2 monoclonal antibody (mAb) and studied a new group of KD patients to extend our previous PCR results. Immunofluorescence analysis confirmed that V beta 2-bearing T cells are selectively increased in patients with acute KD. The increase occurred primarily in the CD4 T cell subset. The percentages of V beta 2+ T cells as determined by mAb reactivity and flow cytometry correlated linearly with V beta expression as quantitated by PCR. However, T cells from acute KD patients appeared to express proportionately higher levels of V beta 2 transcripts per cell as compared with healthy controls or convalescent KD patients. Sequence analysis of T cell receptor beta chain genes of V beta 2 and V beta 8.1 expressing T cells from acute KD patients showed extensive junctional region diversity. These data showing polyclonal expansion of V beta 2+ and V beta 8+ T cells in acute KD provide additional insight into the immunopathogenesis of this disease. PMID:8094737

Genes commonly deleted in childhood B-cell precursor acute lymphoblastic leukemia: association with cytogenetics and clinical features

PubMed Central

Schwab, Claire J.; Chilton, Lucy; Morrison, Heather; Jones, Lisa; Al-Shehhi, Halima; Erhorn, Amy; Russell, Lisa J.; Moorman, Anthony V.; Harrison, Christine J.

2013-01-01

In childhood B-cell precursor acute lymphoblastic leukemia, cytogenetics is important in diagnosis and as an indicator of response to therapy, thus playing a key role in risk stratification of patients for treatment. Little is known of the relationship between different cytogenetic subtypes in B-cell precursor acute lymphoblastic leukemia and the recently reported copy number abnormalities affecting significant leukemia associated genes. In a consecutive series of 1427 childhood B-cell precursor acute lymphoblastic leukemia patients, we have determined the incidence and type of copy number abnormalities using multiplex ligation-dependent probe amplification. We have shown strong links between certain deletions and cytogenetic subtypes, including the novel association between RB1 deletions and intrachromosomal amplification of chromosome 21. In this study, we characterized the different copy number abnormalities and show heterogeneity of PAX5 and IKZF1 deletions and the recurrent nature of RB1 deletions. Whole gene losses are often indicative of larger deletions, visible by conventional cytogenetics. An increased number of copy number abnormalities is associated with NCI high risk, specifically deletions of IKZF1 and CDKN2A/B, which occur more frequently among these patients. IKZF1 deletions and rearrangements of CRLF2 among patients with undefined karyotypes may point to the poor risk BCR-ABL1-like group. In conclusion, this study has demonstrated in a large representative cohort of children with B-cell precursor acute lymphoblastic leukemia that the pattern of copy number abnormalities is highly variable according to the primary genetic abnormality. PMID:23508010

Overexpression of dihydrofolate reductase is a factor of poor survival in acute lymphoblastic leukemia.

PubMed

Organista-Nava, Jorge; Gómez-Gómez, Yazmín; Illades-Aguiar, Berenice; Rivera-Ramírez, Ana Bertha; Saavedra-Herrera, Mónica Virginia; Leyva-Vázquez, Marco Antonio

2018-06-01

Dihydrofolate reductase (DHFR) has an important function in DNA synthesis and is a target of methotrexate, which is a crucial treatment option for acute lymphoblastic leukemia (ALL). However, the number of studies conducted to date on DHFR expression in childhood ALL is limited. The aim of the present study was to determine whether the expression of DHFR is associated with survival in childhood ALL. The expression of DHFR in 96 children with ALL and 100 control individuals was determined using reverse transcription-quantitative polymerase chain reaction. The results of the present study demonstrated that the expression of DHFR mRNA in children with ALL was significantly increased (P<0.001), compared with that in the control group. In addition, increased levels of DHFR mRNA were observed in patients with B-cell lineage, compared with patients with T-cell lineage ALL (P<0.05). The Kaplan-Meier estimator analysis revealed that children with ALL who exhibited increased levels of DHFR mRNA had a decreased overall survival time (P<0.05). It was observed that certain patient prognostic features (including age, sex, white blood cell count and high DHFR expression), are associated with poor survival (log-rank test, P<0.05). Therefore, the results of the present study indicated that DHFR upregulation is a factor for poor survival in ALL.

Absence of Association between CCR5 rs333 Polymorphism and Childhood Acute Lymphoblastic Leukemia

PubMed Central

de Oliveira, Carlos Eduardo Coral; Perim, Aparecida de Lourdes; Ozawa, Patricia Midori Murobushi; Freire Vitiello, Glauco Akelinghton; Losi Guembarovski, Roberta; Watanabe, Maria Angelica Ehara

2014-01-01

Acute lymphoblastic leukemia (ALL) is a malignant disorder that originates from one single hematopoietic precursor committed to B- or T-cell lineage. Ordinarily, these cells express CCR5 chemokine receptor, which directs the immune response to a cellular pattern and is involved in cancer pathobiology. The genetic rs333 polymorphism of CCR5 (Δ32), results in a diminished receptor expression, thus leading to impaired cell trafficking. The objective of the present study was to investigate the effect of CCR5 chemokine receptor rs333 polymorphism in the pathogenesis of ALL. The genotype distribution was studied in 79 patients and compared with 80 control subjects, in a childhood population of Southern Brazil. Genotyping was performed using DNA samples amplified by polymerase chain reaction with sequence-specific primers (PCR-SSP). The homozygous (Δ32/Δ32) deletion was not observed in any subject involved in the study. Heterozygous genotype was not associated with ALL risk (OR 0.7%; 95% CI 0.21–2.32; P > 0.05), nor recurrence status of ALL (OR 0.86; 95% CI 0.13–5.48; P > 0.05). This work demonstrated, for the first time, no significant differences in the frequency of the CCR5/Δ32 genotype between ALL and control groups, indicating no effect of this genetic variant on the ALL susceptibility and recurrence risk. PMID:24822066

Identification of de Novo Fanconi Anemia in Younger Patients With Newly Diagnosed Acute Myeloid Leukemia

ClinicalTrials.gov

2016-05-13

Childhood Acute Erythroleukemia (M6); Childhood Acute Megakaryocytic Leukemia (M7); Childhood Acute Minimally Differentiated Myeloid Leukemia (M0); Childhood Acute Monoblastic Leukemia (M5a); Childhood Acute Monocytic Leukemia (M5b); Childhood Acute Myeloblastic Leukemia With Maturation (M2); Childhood Acute Myeloblastic Leukemia Without Maturation (M1); Childhood Acute Myelomonocytic Leukemia (M4); Childhood Myelodysplastic Syndromes; Chronic Myelomonocytic Leukemia; de Novo Myelodysplastic Syndromes; Fanconi Anemia; Refractory Anemia; Refractory Anemia With Excess Blasts; Refractory Anemia With Excess Blasts in Transformation; Refractory Anemia With Ringed Sideroblasts; Secondary Myelodysplastic Syndromes; Untreated Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies

Idarubicin, Cytarabine, and Tipifarnib in Treating Patients With Newly Diagnosed Myelodysplastic Syndromes or Acute Myeloid Leukemia

ClinicalTrials.gov

2014-05-09

Adult Acute Basophilic Leukemia; Adult Acute Eosinophilic Leukemia; Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Childhood Myelodysplastic Syndromes; Chronic Myelomonocytic Leukemia; de Novo Myelodysplastic Syndromes; Refractory Anemia With Excess Blasts; Refractory Anemia With Excess Blasts in Transformation; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Untreated Adult Acute Myeloid Leukemia

Comparison of Donor Sources in Hematopoietic Stem Cell Transplantation for Childhood Acute Leukemia: A Nationwide Retrospective Study.

PubMed

Sakaguchi, Hirotoshi; Watanabe, Nobuhiro; Matsumoto, Kimikazu; Yabe, Hiromasa; Kato, Shunichi; Ogawa, Atsushi; Inagaki, Jiro; Goto, Hiroaki; Koh, Katsuyoshi; Yoshida, Nao; Kato, Keisuke; Cho, Yuko; Kosaka, Yoshiyuki; Takahashi, Yoshiyuki; Inoue, Masami; Kato, Koji; Atsuta, Yoshiko; Miyamura, Koichi

2016-12-01

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the best therapeutic option for childhood high-risk acute leukemia. However, which donor source is optimal for children lacking an identical sibling remains unclear. To evaluate the clinical impact of donor source on allo-HSCT in childhood acute leukemia, we analyzed data from 577 children who underwent allo-HSCT after a myeloablative regimen during first or second complete remission from 2005 to 2012, using registry data of the Japan Society for Hematopoietic Cell Transplantation, and we compared outcomes of 7/8 to 8/8 HLA allelic-matched unrelated bone marrow transplantation (UR-BMT, n = 218) and 4/6 to 6/6 HLA allelic-matched unrelated cord blood transplantation (UR-CBT, n = 200) to those of HLA-identical related bone marrow transplantation (ID-BMT, n = 159). The median follow-up of survivors was 40.0 months. Three-year overall survival (OS) and leukemia-free survival (LFS) rates for ID-BMT, UR-BMT, and UR-CBT were 74.8% and 69.0%, 75.0% and 69.6%, and 71.8% and 63.8%, respectively. The multivariate analysis demonstrated that OS and LFS for the 3 groups are comparable, although UR-CBT carries a greater risk of nonrelapse mortality (hazard ratio, 2.20; P = .03, compared to ID-BMT) in the myeloablative setting for childhood high-risk acute leukemia. Copyright © 2016 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

17-N-Allylamino-17-Demethoxygeldanamycin and Bortezomib in Treating Patients With Relapsed or Refractory Hematologic Cancer

ClinicalTrials.gov

2013-06-03

Adult Acute Basophilic Leukemia; Adult Acute Eosinophilic Leukemia; Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Nodal Marginal Zone B-cell Lymphoma; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Waldenström Macroglobulinemia

Lenalidomide After Donor Bone Marrow Transplant in Treating Patients With High-Risk Hematologic Cancers

ClinicalTrials.gov

2017-09-22

Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With t(8;21); (q22; q22.1); RUNX1-RUNX1T1; Adult Acute Myeloid Leukemia With t(9;11)(p22.3;q23.3); MLLT3-KMT2A; Adult Acute Promyelocytic Leukemia With PML-RARA; Adult Grade III Lymphomatoid Granulomatosis; Adult Nasal Type Extranodal NK/T-Cell Lymphoma; Alkylating Agent-Related Acute Myeloid Leukemia; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-Cell Lymphoma; Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue; Hepatosplenic T-Cell Lymphoma; Intraocular Lymphoma; Lymphomatous Involvement of Non-Cutaneous Extranodal Site; Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma; Nodal Marginal Zone Lymphoma; Post-Transplant Lymphoproliferative Disorder; Primary Cutaneous B-Cell Non-Hodgkin Lymphoma; Prolymphocytic Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Immunoblastic Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-Cell Leukemia/Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides and Sezary Syndrome; Recurrent Non-Hodgkin Lymphoma; Recurrent Primary Cutaneous T-Cell Non-Hodgkin Lymphoma; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Richter Syndrome; Small Intestinal Lymphoma; Splenic Marginal Zone Lymphoma; T-Cell Large Granular Lymphocyte Leukemia; Testicular Lymphoma; Waldenstrom Macroglobulinemia

Combination Chemotherapy With or Without Bone Marrow Transplantation in Treating Children With Acute Myelogenous Leukemia or Myelodysplastic Syndrome

ClinicalTrials.gov

2013-01-15

Childhood Acute Erythroleukemia (M6); Childhood Acute Megakaryocytic Leukemia (M7); Childhood Acute Monoblastic Leukemia (M5a); Childhood Acute Monocytic Leukemia (M5b); Childhood Acute Myeloblastic Leukemia With Maturation (M2); Childhood Acute Myeloblastic Leukemia Without Maturation (M1); Childhood Acute Myelomonocytic Leukemia (M4); Childhood Myelodysplastic Syndromes; Chronic Myelomonocytic Leukemia; de Novo Myelodysplastic Syndromes; Refractory Anemia; Refractory Anemia With Excess Blasts; Refractory Anemia With Excess Blasts in Transformation; Refractory Anemia With Ringed Sideroblasts; Secondary Myelodysplastic Syndromes; Untreated Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies

A meta-analysis of MTHFR C677T and A1298C polymorphisms and risk of acute lymphoblastic leukemia in children.

PubMed

Yan, Jingrong; Yin, Ming; Dreyer, ZoAnn E; Scheurer, Michael E; Kamdar, Kala; Wei, Qingyi; Okcu, M Fatih

2012-04-01

Methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms have been implicated in childhood acute lymphoblastic leukemia (ALL) risk, but previously published studies were inconsistent and recent meta-analyses were not adequate. In a meta-analysis of 21 publications with 4,706 cases and 7,414 controls, we used more stringent inclusion method and summarized data on associations between MTHFR C677T and A1298C polymorphisms and childhood ALL risk. We found an overall association between 677T variant genotypes and reduced childhood ALL risk. Specifically, in the dominant genetic model, an association was found in a fixed-effect (TT + CT vs. CC: OR = 0.92; 95% CI = 0.85-0.99) but not random-effect model, whereas such an association was observed in both homozygote genetic model (TT vs. CC: OR = 0.80; 95% CI = 0.70-0.93 by fixed effects and OR = 0.78; 95% CI = 0.65-0.93 by random effects) and recessive genetic model (TT vs. CC + CT: OR = 0.83; 95% CI = 0.72-0.95 by fixed effects and OR = 0.84; 95% CI = 0.73-0.97 by random effects). These associations were also observed in subgroups by ethnicity: for Asians in all models except for the dominant genetic model by random effect and for Caucasians in all models except for the recessive genetic model. However, the A1298C polymorphism did not appear to have an effect on childhood ALL risk. These results suggest that the MTHFR C677T, but not A1298C, polymorphism is a potential biomarker for childhood ALL risk. Copyright © 2011 Wiley Periodicals, Inc.

Sunitinib Malate in Treating HIV-Positive Patients With Cancer Receiving Antiretroviral Therapy

ClinicalTrials.gov

2014-03-14

Accelerated Phase Chronic Myelogenous Leukemia; Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome; Acute Undifferentiated Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Grade III Lymphomatoid Granulomatosis; Adult Langerhans Cell Histiocytosis; Adult Nasal Type Extranodal NK/T-cell Lymphoma; Aggressive NK-cell Leukemia; AIDS-related Diffuse Large Cell Lymphoma; AIDS-related Diffuse Mixed Cell Lymphoma; AIDS-related Diffuse Small Cleaved Cell Lymphoma; AIDS-related Immunoblastic Large Cell Lymphoma; AIDS-related Lymphoblastic Lymphoma; AIDS-related Malignancies; AIDS-related Small Noncleaved Cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative; Chronic Eosinophilic Leukemia; Chronic Myelomonocytic Leukemia; Chronic Neutrophilic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; Clear Cell Renal Cell Carcinoma; Cutaneous B-cell Non-Hodgkin Lymphoma; de Novo Myelodysplastic Syndromes; Essential Thrombocythemia; Extramedullary Plasmacytoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; HIV Infection; HIV-associated Hodgkin Lymphoma; Intraocular Lymphoma; Isolated Plasmacytoma of Bone; Light Chain Deposition Disease; Mast Cell Leukemia; Myelodysplastic Syndrome With Isolated Del(5q); Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Myeloid/NK-cell Acute Leukemia; Nodal Marginal Zone B-cell Lymphoma; Noncutaneous Extranodal Lymphoma; Osteolytic Lesions of Multiple Myeloma; Peripheral T-cell Lymphoma; Plasma Cell Neoplasm; Polycythemia Vera; Post-transplant Lymphoproliferative Disorder; Previously Treated Myelodysplastic Syndromes; Primary Myelofibrosis; Primary Systemic Amyloidosis; Progressive Hairy Cell Leukemia, Initial Treatment; Prolymphocytic Leukemia; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Renal Cell Cancer; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Refractory Multiple Myeloma; Relapsing Chronic Myelogenous Leukemia; Stage IV Renal Cell Cancer; T-cell Large Granular Lymphocyte Leukemia; Testicular Lymphoma; Unspecified Adult Solid Tumor, Protocol Specific; Waldenström Macroglobulinemia

Evidence of premature immune aging in patients thymectomized during early childhood

PubMed Central

Sauce, Delphine; Larsen, Martin; Fastenackels, Solène; Duperrier, Anne; Keller, Michael; Grubeck-Loebenstein, Beatrix; Ferrand, Christophe; Debré, Patrice; Sidi, Daniel; Appay, Victor

2009-01-01

While the thymus is known to be essential for the initial production of T cells during early life, its contribution to immune development remains a matter of debate. In fact, during cardiac surgery in newborns, the thymus is completely resected to enable better access to the heart to correct congenital heart defects, suggesting that it may be dispensable during childhood and adulthood. Here, we show that young adults thymectomized during early childhood exhibit an altered T cell compartment. Specifically, absolute CD4+ and CD8+ T cell counts were decreased, and these T cell populations showed substantial loss of naive cells and accumulation of oligoclonal memory cells. A subgroup of these young patients (22 years old) exhibited a particularly altered T cell profile that is usually seen in elderly individuals (more than 75 years old). This condition was directly related to CMV infection and the induction of strong CMV-specific T cell responses, which may exhaust the naive T cell pool in the absence of adequate T cell renewal from the thymus. Together, these marked immunological alterations are reminiscent of the immune risk phenotype, which is defined by a cluster of immune markers predictive of increased mortality in the elderly. Overall, our data highlight the importance of the thymus in maintaining the integrity of T cell immunity during adult life. PMID:19770514

EZH2 mutations and promoter hypermethylation in childhood acute lymphoblastic leukemia.

PubMed

Schäfer, Vivien; Ernst, Jana; Rinke, Jenny; Winkelmann, Nils; Beck, James F; Hochhaus, Andreas; Gruhn, Bernd; Ernst, Thomas

2016-07-01

Acute lymphoblastic leukemia (ALL) is the most common malignancy in children and young adults. The polycomb repressive complex 2 (PRC2) has been identified as one of the most frequently mutated epigenetic protein complexes in hematologic cancers. PRC2 acts as an epigenetic repressor through histone H3 lysine 27 trimethylation (H3K27me3), catalyzed by the histone methyltransferase enhancer of zeste homolog 2 protein (EZH2). To study the prevalence and clinical impact of PRC2 aberrations in an unselected childhood ALL cohort (n = 152), we performed PRC2 mutational screenings by Sanger sequencing and promoter methylation analyses by quantitative pyrosequencing for the three PRC2 core component genes EZH2, suppressor of zeste 12 (SUZ12), and embryonic ectoderm development (EED). Targeted deep next-generation sequencing of 30 frequently mutated genes in leukemia was performed to search for cooperating mutations in patients harboring PRC2 aberrations. Finally, the functional consequence of EZH2 promoter hypermethylation on H3K27me3 was studied by Western blot analyses of primary cells. Loss-of-function EZH2 mutations were detected in 2/152 (1.3 %) patients with common-ALL and early T-cell precursor (ETP)-ALL, respectively. In one patient, targeted deep sequencing identified cooperating mutations in ASXL1 and TET2. EZH2 promoter hypermethylation was found in one patient with ETP-ALL which led to reduced H3K27me3. In comparison with healthy children, the EZH2 promoter was significantly higher methylated in T-ALL patients. No mutations or promoter methylation changes were identified for SUZ12 or EED genes, respectively. Although PRC2 aberrations seem to be rare in childhood ALL, our findings indicate that EZH2 aberrations might contribute to the disease in specific cases. Hereby, EZH2 promoter hypermethylation might have functionally similar consequences as loss-of-function mutations.

Granulysin-Expressing CD4+ T Cells as Candidate Immune Marker for Tuberculosis during Childhood and Adolescence

PubMed Central

Mueller, Henrik; Faé, Kellen C.; Magdorf, Klaus; Ganoza, Christian A.; Wahn, Ulrich; Guhlich, Ute; Feiterna-Sperling, Cornelia; Kaufmann, Stefan H. E.

2011-01-01

Background Granulysin produced by cytolytic T cells directly contributes to immune defense against tuberculosis (TB). We investigated granulysin as a candidate immune marker for childhood and adolescent TB. Methods Peripheral blood mononuclear cells (PBMC) from children and adolescents (1–17 years) with active TB, latent TB infection (LTBI), nontuberculous mycobacteria (NTM) infection and from uninfected controls were isolated and restimulated in a 7-day restimulation assay. Intracellular staining was then performed to analyze antigen-specific induction of activation markers and cytotoxic proteins, notably, granulysin in CD4+ CD45RO+ memory T cells. Results CD4+ CD45RO+ T cells co-expressing granulysin with specificity for Mycobacterium tuberculosis (Mtb) were present in high frequency in TB-experienced children and adolescents. Proliferating memory T cells (CFSElowCD4+CD45RO+) were identified as main source of granulysin and these cells expressed both central and effector memory phenotype. PBMC from study participants after TB drug therapy revealed that granulysin-expressing CD4+ T cells are long-lived, and express several activation and cytotoxicity markers with a proportion of cells being interferon-gamma-positive. In addition, granulysin-expressing T cell lines showed cytolytic activity against Mtb-infected target cells. Conclusions Our data suggest granulysin expression by CD4+ memory T cells as candidate immune marker for TB infection, notably, in childhood and adolescence. PMID:22216262

Childhood acute leukemias are frequent in Mexico City: descriptive epidemiology.

PubMed

Pérez-Saldivar, María Luisa; Fajardo-Gutiérrez, Arturo; Bernáldez-Ríos, Roberto; Martínez-Avalos, Armando; Medina-Sanson, Aurora; Espinosa-Hernández, Laura; Flores-Chapa, José de Diego; Amador-Sánchez, Raquel; Peñaloza-González, José Gabriel; Alvarez-Rodríguez, Francisco Javier; Bolea-Murga, Victoria; Flores-Lujano, Janet; Rodríguez-Zepeda, María Del Carmen; Rivera-Luna, Roberto; Dorantes-Acosta, Elisa María; Jiménez-Hernández, Elva; Alvarado-Ibarra, Martha; Velázquez-Aviña, Martha Margarita; Torres-Nava, José Refugio; Duarte-Rodríguez, David Aldebarán; Paredes-Aguilera, Rogelio; Del Campo-Martínez, María de Los Ángeles; Cárdenas-Cardos, Rocío; Alamilla-Galicia, Paola Hillary; Bekker-Méndez, Vilma Carolina; Ortega-Alvarez, Manuel Carlos; Mejia-Arangure, Juan Manuel

2011-08-17

Worldwide, acute leukemia is the most common type of childhood cancer. It is particularly common in the Hispanic populations residing in the United States, Costa Rica, and Mexico City. The objective of this study was to determine the incidence of acute leukemia in children who were diagnosed and treated in public hospitals in Mexico City. Included in this study were those children, under 15 years of age and residents of Mexico City, who were diagnosed in 2006 and 2007 with leukemia, as determined by using the International Classification of Childhood Cancer. The average annual incidence rates (AAIR), and the standardized average annual incidence rates (SAAIR) per million children were calculated. We calculated crude, age- and sex-specific incidence rates and adjusted for age by the direct method with the world population as standard. We determined if there were a correlation between the incidence of acute leukemias in the various boroughs of Mexico City and either the number of agricultural hectares, the average number of persons per household, or the municipal human development index for Mexico (used as a reference of socio-economic level). Although a total of 610 new cases of leukemia were registered during 2006-2007, only 228 fit the criteria for inclusion in this study. The overall SAAIR was 57.6 per million children (95% CI, 46.9-68.3); acute lymphoblastic leukemia (ALL) was the most frequent type of leukemia, constituting 85.1% of the cases (SAAIR: 49.5 per million), followed by acute myeloblastic leukemia at 12.3% (SAAIR: 6.9 per million), and chronic myeloid leukemia at 1.7% (SAAIR: 0.9 per million). The 1-4 years age group had the highest SAAIR for ALL (77.7 per million). For cases of ALL, 73.2% had precursor B-cell immunophenotype (SAAIR: 35.8 per million) and 12.4% had T-cell immunophenotype (SAAIR 6.3 per million). The peak ages for ALL were 2-6 years and 8-10 years. More than half the children (58.8%) were classified as high risk. There was a positive correlation between the average number of persons per household and the incidence of the pre-B immunophenotype (Pearson's r, 0.789; P = 0.02). The frequency of ALL in Mexico City is among the highest in the world, similar to those found for Hispanics in the United States and in Costa Rica.

[A brief history of treatments for childhood acute lymphoblastic leukaemia].

PubMed

Leverger, Guy; Baruchel, André; Schaison, Gérard

2009-10-01

Acute lymphoblastic leukaemia is the most frequent childhood malignancy. The first effective drugs, which provided only short-lived complete remission, started to be used in the 1950s. All the effective drugs currently in use were discovered in the 1960s, when the first multidrug chemotherapy regimens were shown to confer prolonged complete remission, raising the possibility of a cure. Simultaneously, progress in our knowledge of leukaemic cells, and the identification of prognostic factors such as leukocytosis, age, cytogenetic and molecular abnormalities, and the early therapeutic response of leukaemic cells, led to randomized multicenter national and international trials. As a result, the chance of cure increased gradually over the last three decades. In rich countries, the overall survival rate among children with acute lymphoblastic leukaemia now reaches 85 to 90%.

Decitabine in Treating Children With Relapsed or Refractory Acute Myeloid Leukemia or Acute Lymphoblastic Leukemia

ClinicalTrials.gov

2013-01-22

Childhood Acute Myeloblastic Leukemia With Maturation (M2); Childhood Acute Promyelocytic Leukemia (M3); Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia

Sunitinib in Treating Patients With Idiopathic Myelofibrosis

ClinicalTrials.gov

2014-05-12

Accelerated Phase Chronic Myelogenous Leukemia; Acute Undifferentiated Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative; Blastic Phase Chronic Myelogenous Leukemia; Chronic Myelomonocytic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; Mast Cell Leukemia; Meningeal Chronic Myelogenous Leukemia; Primary Myelofibrosis; Progressive Hairy Cell Leukemia, Initial Treatment; Prolymphocytic Leukemia; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Stage I Chronic Lymphocytic Leukemia; Stage II Chronic Lymphocytic Leukemia; Stage III Chronic Lymphocytic Leukemia; Stage IV Chronic Lymphocytic Leukemia; T-cell Large Granular Lymphocyte Leukemia; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Adult Acute Myeloid Leukemia; Untreated Hairy Cell Leukemia

Germline Genetic IKZF1 Variation and Predisposition to Childhood Acute Lymphoblastic Leukemia.

PubMed

Churchman, Michelle L; Qian, Maoxiang; Te Kronnie, Geertruy; Zhang, Ranran; Yang, Wenjian; Zhang, Hui; Lana, Tobia; Tedrick, Paige; Baskin, Rebekah; Verbist, Katherine; Peters, Jennifer L; Devidas, Meenakshi; Larsen, Eric; Moore, Ian M; Gu, Zhaohui; Qu, Chunxu; Yoshihara, Hiroki; Porter, Shaina N; Pruett-Miller, Shondra M; Wu, Gang; Raetz, Elizabeth; Martin, Paul L; Bowman, W Paul; Winick, Naomi; Mardis, Elaine; Fulton, Robert; Stanulla, Martin; Evans, William E; Relling, Mary V; Pui, Ching-Hon; Hunger, Stephen P; Loh, Mignon L; Handgretinger, Rupert; Nichols, Kim E; Yang, Jun J; Mullighan, Charles G

2018-05-14

Somatic genetic alterations of IKZF1, which encodes the lymphoid transcription factor IKAROS, are common in high-risk B-progenitor acute lymphoblastic leukemia (ALL) and are associated with poor prognosis. Such alterations result in the acquisition of stem cell-like features, overexpression of adhesion molecules causing aberrant cell-cell and cell-stroma interaction, and decreased sensitivity to tyrosine kinase inhibitors. Here we report coding germline IKZF1 variation in familial childhood ALL and 0.9% of presumed sporadic B-ALL, identifying 28 unique variants in 45 children. The majority of variants adversely affected IKZF1 function and drug responsiveness of leukemic cells. These results identify IKZF1 as a leukemia predisposition gene, and emphasize the importance of germline genetic variation in the development of both familial and sporadic ALL. Copyright © 2018 Elsevier Inc. All rights reserved.

Immunosuppression after Sepsis: Systemic Inflammation and Sepsis Induce a Loss of Naïve T-Cells but No Enduring Cell-Autonomous Defects in T-Cell Function

PubMed Central

Markwart, Robby; Condotta, Stephanie A.; Requardt, Robert P.; Borken, Farina; Schubert, Katja; Weigel, Cynthia; Bauer, Michael; Griffith, Thomas S.; Förster, Martin; Brunkhorst, Frank M.; Badovinac, Vladimir P.; Rubio, Ignacio

2014-01-01

Sepsis describes the life-threatening systemic inflammatory response (SIRS) of an organism to an infection and is the leading cause of mortality on intensive care units (ICU) worldwide. An acute episode of sepsis is characterized by the extensive release of cytokines and other mediators resulting in a dysregulated immune response leading to organ damage and/or death. This initial pro-inflammatory burst often transits into a state of immune suppression characterised by loss of immune cells and T-cell dysfunction at later disease stages in sepsis survivors. However, despite these appreciations, the precise nature of the evoked defect in T-cell immunity in post-acute phases of SIRS remains unknown. Here we present an in-depth functional analysis of T-cell function in post-acute SIRS/sepsis. We document that T-cell function is not compromised on a per cell basis in experimental rodent models of infection-free SIRS (LPS or CpG) or septic peritonitis. Transgenic antigen-specific T-cells feature an unaltered cytokine response if challenged in vivo and ex vivo with cognate antigens. Isolated CD4+/CD8+ T-cells from post-acute septic animals do not exhibit defects in T-cell receptor-mediated activation at the the level of receptor-proximal signalling, activation marker upregulation or expansion. However, SIRS/sepsis induced transient lymphopenia and gave rise to an environment of immune attenuation at post acute disease stages. Thus, systemic inflammation has an acute impact on T-cell numbers and adaptive immunity, but does not cause major cell-autonomous enduring functional defects in T-cells. PMID:25541945

VSV-hIFNbeta-NIS in Treating Patients With Relapsed or Refractory Multiple Myeloma, Acute Myeloid Leukemia, or T-cell Lymphoma

ClinicalTrials.gov

2018-03-12

Previously Treated Myelodysplastic Syndrome; Recurrent Adult Acute Myeloid Leukemia; Recurrent Anaplastic Large Cell Lymphoma; Recurrent Angioimmunoblastic T-cell Lymphoma; Recurrent Cutaneous T-Cell Non-Hodgkin Lymphoma; Recurrent Mycosis Fungoides; Recurrent Plasma Cell Myeloma; Recurrent T-Cell Non-Hodgkin Lymphoma; Refractory Anaplastic Large Cell Lymphoma; Refractory Angioimmunoblastic T-cell Lymphoma; Refractory Cutaneous T-Cell Non-Hodgkin Lymphoma; Refractory Mycosis Fungoides; Refractory Peripheral T-Cell Lymphoma, Not Otherwise Specified; Refractory Plasma Cell Myeloma; Refractory T-Cell Non-Hodgkin Lymphoma

Association of methylenetetrahytrofolate reductase (MTHFR) C677T and A1298C polymorphisms with the susceptibility of childhood acute lymphoblastic leukaemia (ALL) in Chinese population.

PubMed

Li, Xiaolei; Liao, Qingchuan; Zhang, Shunguo; Chen, Minling

2014-01-29

The aim of this study was to investigate the relationship between the polymorphisms of the methylenetetrahytrofolate reductase (MTHFR) gene and susceptibility to childhood acute lymphoblastic leukemia (ALL). A case-control study was conducted among 98 children with ALL and 93 age- and sex- matched non-ALL controls. Genotyping of MTHFR C677T and A1298C polymorphisms was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The odds ratios (ORs) of MTHFR genotypes were used to assess the associations of these polymorphisms with childhood ALL susceptibility. No significant differences were observed for frequencies of the 677CC, 677CT and 677TT genotypes between patients and controls. Frequencies of the 1298AA, 1298 AC and 1298CC genotypes between the two groups were significantly different. The risk of ALL with the 1298C allele carriers (AC + CC) was elevated by 1.1 times compared with the AA genotype [OR = 2.100; 95% CI (1.149; 3.837); P = 0.015]. The MTHFR A1298C polymorphism is associated with susceptibility to childhood ALL in the Chinese population.

Systemic Epstein-Barr Virus-positive T-Cell Lymphoproliferative Disease of Childhood With Good Response to Steroid Therapy.

PubMed

Kim, Do-Hoon; Kim, Myungshin; Kim, Yonggoo; Han, Kyungja; Han, Eunhee; Lee, Jae Wook; Chung, Nack-Gyun; Cho, Bin

2017-11-01

Systemic Epstein-Barr virus (EBV)-positive T-cell lymphoproliferative disease of childhood is a rare disease and has a very fulminant clinical course with high mortality. A 21-month-old female patient was referred to our hospital with a 1 week history of fever and was subsequently diagnosed with systemic Epstein-Barr virus-positive T-cell lymphoproliferative disease of childhood. After starting treatment with dexamethasone, she showed early defervescence and improvement of laboratory parameters, and has remained disease-free after stopping steroid treatment, although longer follow-up is necessary. Our report underscores the possibility that this disease entity may be heterogenous in terms of prognosis.

Association of the methylenetetrahydrofolate reductase polymorphism in Korean patients with childhood acute lymphoblastic leukemia.

PubMed

Kim, Nam Keun; Chong, So Young; Jang, Moon Ju; Hong, Seung Ho; Kim, Heung Sik; Cho, Eun Kyung; Lee, Jung Ae; Ahn, Myung Ju; Kim, Chul Soo; Oh, Doyeun

2006-01-01

Methylenetetrahydrofolate reductase plays a central role in converting folate to methyl donor for DNA methylation. Recently, methylenetetrahydrofolate reductase (MTHFR C677T and A1298C) mutations were discovered to be associated with childhood acute lymphoblastic leukemia (ALL), as well as colon cancer, lymphoma, esophageal and stomach cancer. Therefore, it was hypothesized that the MTHFR polymorphisms are associated with the risk of childhood ALL in the Korean population. DNA samples taken from 66 patients with ALL and 100 age-matched controls were analyzed using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay for detection of MTHFR C677T and A1298C mutations. The frequency of the AC genotype for MTHFR A1298C polymorphism was significantly different between the controls and the cases (OR, 2.22; CI, 95% 1.09-4.51, p=0.03). The 1298AC+CC genotype was also significantly different (OR, 2.11; 95% CI, 1.06-4.22; p=0.049). There was, however, no significant difference for MTHFR C677T polymorphism and combined genotype frequencies between the two groups. Although no consistent results on associations between MTHFR A 1298C polymorphism and ALL in the populations studied were obtained, the A1298C polymorphism, at least in Koreans, may be a genetic determinant among childhood ALL patients.

Bioelectrical Impedance Measurement for Predicting Treatment Outcome in Patients With Newly Diagnosed Acute Leukemia

ClinicalTrials.gov

2018-04-26

Acute Undifferentiated Leukemia; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Mast Cell Leukemia; Myeloid/NK-cell Acute Leukemia; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Adult Acute Myeloid Leukemia

Fine specificities of natural regulatory T cells after IVIG therapy in patients with Kawasaki disease

PubMed Central

Burns, Jane C.; Touma, Ranim; Song, Yali; Padilla, Robert L.; Tremoulet, Adriana H.; Sidney, John; Sette, Alessandro; Franco, Alessandra

2016-01-01

The activation of natural regulatory T cells (nTreg) recognizing the heavy constant region (Fc) of IgG is an important mechanism of action of intravenous immunoglobulin (IVIG) therapy in Kawasaki disease (KD). Lack of circulating Fc-specific nTreg in the sub-acute phase of KD is correlated with the development of coronary artery abnormalities (CAA). Here, we characterize the fine specificity of nTreg in sub-acute (2- to 8-week post-IVIG) and convalescent (1- to 10-year post-IVIG) KD subjects by testing the immunogenicity of 64 peptides, 15 amino acids in length with a 10 amino acid-overlap spanning the entire Fc protein. About 12 Fc peptides (6 pools of 2 consecutive peptides) were recognized by nTreg in the cohorts studied, including two patients with CAA. To test whether IVIG expands the same nTreg populations that maintain vascular homeostasis in healthy subjects, we compared these results with results obtained in healthy adult controls. Similar nTreg fine specificities were observed in KD patients after IVIG and in healthy donors. These results suggest that T cell fitness rather than T cell clonal deletion or anergy is responsible for the lack of Fc-specific nTreg in KD patients who develop CAA. Furthermore, we found that adolescents and adults who had KD during childhood without developing CAA did not respond to the Fc protein in vitro, suggesting that the nTreg response induced by IVIG in KD patients is short-lived. Our results support the concept that peptide epitopes may be a viable therapeutic approach to expand Fc-specific nTreg and more effectively prevent CAA in KD patients. PMID:25822882

Early T-cell precursor acute lymphoblastic leukaemia in children treated in AIEOP centres with AIEOP-BFM protocols: a retrospective analysis.

PubMed

Conter, Valentino; Valsecchi, Maria Grazia; Buldini, Barbara; Parasole, Rosanna; Locatelli, Franco; Colombini, Antonella; Rizzari, Carmelo; Putti, Maria Caterina; Barisone, Elena; Lo Nigro, Luca; Santoro, Nicola; Ziino, Ottavio; Pession, Andrea; Testi, Anna Maria; Micalizzi, Concetta; Casale, Fiorina; Pierani, Paolo; Cesaro, Simone; Cellini, Monica; Silvestri, Daniela; Cazzaniga, Giovanni; Biondi, Andrea; Basso, Giuseppe

2016-02-01

Early T-cell precursor acute lymphoblastic leukaemia was recently recognised as a distinct leukaemia and reported as associated with poor outcomes. We aimed to assess the outcome of early T-cell precursor acute lymphoblastic leukaemia in patients from the Italian Association of Pediatric Hematology Oncology (AIEOP) centres treated with AIEOP-Berlin-Frankfurt-Münster (AIEOP-BFM) protocols. In this retrospective analysis, we included all children aged from 1 to less than 18 years with early T-cell precursor acute lymphoblastic leukaemia immunophenotype diagnosed between Jan 1, 2008, and Oct 31, 2014, from AIEOP centres. Early T-cell precursors were defined as being CD1a and CD8 negative, CD5 weak positive or negative, and positive for at least one of the following antigens: CD34, CD117, HLADR, CD13, CD33, CD11b, or CD65. Treatment was based on AIEOP-BFM acute lymphoblastic leukaemia 2000 (NCT00613457) or AIEOP-BFM acute lymphoblastic leukaemia 2009 protocols (European Clinical Trials Database 2007-004270-43). The main differences in treatment and stratification of T-cell acute lymphoblastic leukaemia between the two protocols were that in the 2009 protocol only, pegylated L-asparaginase was substituted for Escherichia coli L-asparaginase, patients with prednisone poor response received an additional dose of cyclophosphamide at day 10 of phase IA, and high minimal residual disease at day 15 assessed by flow cytometry was used as a high-risk criterion. Outcomes were assessed in terms of event-free survival, disease-free survival, and overall survival. Early T-cell precursor acute lymphoblastic leukaemia was diagnosed in 49 patients. Compared with overall T-cell acute lymphoblastic leukaemia, it was associated with absence of molecular markers for PCR detection of minimal residual disease in 25 (56%) of 45 patients; prednisone poor response in 27 (55%) of 49 patients; high minimal residual disease at day 15 after starting therapy in 25 (64%) of 39 patients (bone marrow blasts ≥ 10%, by flow cytometry); no complete remission after phase IA in 7 (15%) of 46 patients (bone marrow blasts ≥ 5%, morphologically); and high PCR minimal residual disease (≥ 5 × 10(-4)) at day 33 after starting therapy in 17 (85%) of 20 patients with markers available. Overall, 38 (78%) of 49 patients are in continuous complete remission, including 13 of 18 after haemopoietic stem cell transplantation, with three deaths in induction, five deaths after haemopoietic stem cell transplantation, and three relapses. Severe adverse events in the 2009 study were reported in 10 (30%) of 33 patients with early T-cell precursor acute lymphoblastic leukaemia versus 24 (15%) of 164 patients without early T-cell precursor acute lymphoblastic leukaemia and life-threatening events in induction phase IA occurred in 4 (12%) of 33 patients with early T-cell precursor acute lymphoblastic leukaemia versus 7 (4%) of 164 patients without early T-cell precursor acute lymphoblastic leukaemia. No difference was seen in the subsequent consolidation phase IB of protocol I. Early T-cell precursor acute lymphoblastic leukaemia is characterised by poor early response to conventional induction treatment. Consolidation phase IB, based on cyclophosphamide, 6-mercaptopurine, and ara-C at conventional (non-high) doses is effective in reducing minimal residual disease. Although the number of patients and observational time are limited, patients with early T-cell precursor acute lymphoblastic leukaemia treated with current BFM stratification and treatment strategy have a favourable outcome compared with earlier reports. The role of innovative therapies and haemopoietic stem cell therapy in early T-cell precursor acute lymphoblastic leukaemia needs to be assessed. None. Copyright © 2016 Elsevier Ltd. All rights reserved.

Recent advances in the management of pediatric acute lymphoblastic leukemia

PubMed Central

Starý, Jan; Hrušák, Ondřej

2016-01-01

Acute lymphoblastic leukemia (ALL) is the most common malignancy in childhood. Despite enormous improvement of prognosis during the last half century, ALL remains a major cause of childhood cancer-related mortality. During the past decade, whole genomic methods have enhanced our knowledge of disease biology. Stratification of therapy according to early treatment response measured by minimal residual disease allows risk group assignment into different treatment arms, ranging from reduction to intensification of treatment. Progress has been achieved in academic clinical trials by optimization of combined chemotherapy, which continues to be the mainstay of contemporary treatment. The availability of suitable volunteer main histocompatibility antigen-matched unrelated donors has increased the rates of hematopoietic stem cell transplantation (HSCT) over the past two decades. Allogeneic HSCT has become an alternative treatment for selected, very-high-risk patients. However, intensive treatment burdens children with severe acute toxic effects that can cause permanent organ damage and even toxic death. Immunotherapeutic approaches have recently come to the forefront in ALL therapy. Monoclonal antibodies blinatumomab and inotuzumab ozogamicin as well as gene-modified T cells directed to specific target antigens have shown efficacy against resistant/relapsed leukemia in phase I/II studies. Integration of these newer modalities into combined regimens with chemotherapy may rescue a subset of children not curable by contemporary therapy. Another major challenge will be to incorporate less toxic regimens into the therapy of patients with low-risk disease who have a nearly 100% chance of being cured, and the ultimate goal is to improve their quality of life while maintaining a high cure rate. PMID:29098074

Contribution of herpesvirus specific CD8 T cells to anti-viral T cell response in humans.

PubMed

Sandalova, Elena; Laccabue, Diletta; Boni, Carolina; Tan, Anthony T; Fink, Katja; Ooi, Eng Eong; Chua, Robert; Shafaeddin Schreve, Bahar; Ferrari, Carlo; Bertoletti, Antonio

2010-08-19

Herpesviruses infect most humans. Their infections can be associated with pathological conditions and significant changes in T cell repertoire but evidences of symbiotic effects of herpesvirus latency have never been demonstrated. We tested the hypothesis that HCMV and EBV-specific CD8 T cells contribute to the heterologous anti-viral immune response. Volume of activated/proliferating virus-specific and total CD8 T cells was evaluated in 50 patients with acute viral infections: 20 with HBV, 12 with Dengue, 12 with Influenza, 3 with Adenovirus infection and 3 with fevers of unknown etiology. Virus-specific (EBV, HCMV, Influenza) pentamer+ and total CD8 T cells were analyzed for activation (CD38/HLA-DR), proliferation (Ki-67/Bcl-2(low)) and cytokine production. We observed that all acute viral infections trigger an expansion of activated/proliferating CD8 T cells, which differs in size depending on the infection but is invariably inflated by CD8 T cells specific for persistent herpesviruses (HCMV/EBV). CD8 T cells specific for other non-related non persistent viral infection (i.e. Influenza) were not activated. IL-15, which is produced during acute viral infections, is the likely contributing mechanism driving the selective activation of herpesvirus specific CD8 T cells. In addition we were able to show that herpesvirus specific CD8 T cells displayed an increased ability to produce the anti-viral cytokine interferon-gamma during the acute phase of heterologous viral infection. Taken together, these data demonstrated that activated herpesvirus specific CD8 T cells inflate the activated/proliferating CD8 T cells population present during acute viral infections in human and can contribute to the heterologous anti-viral T cell response.

Pattern of childhood leukaemia in University College Hospital, Ibadan.

PubMed

Babatunde, T O; Ogun, G O; Brown, B J; Akang, E E; Aken'Ova, Y A

2014-06-01

Leukaemias are haematological malignancies characterized by unregulated clonal proliferation of haematopoietic cells. To determine the pattern of childhood leukaemia in Ibadan. This was a retrospective study of leukaemia cases diagnosed at the University College Hospital (UCH), Ibadan between January 1991 and December 2010 in children less than 15 years of age. Data obtained was subjected to statistical analysis using the Statistical Package for Social Sciences version 20. There were 64 cases of childhood leukaemia, accounting for 10.2% of childhood cancers seen during this study period. The male to female ratio was 2:1 and modal age group was between 10 and 14 years. Thirty (46.9%) cases were acute lymphoblastic leukaemia (ALL), 22 (34.4%) were acute myelogenous leukaemia (AML) and 12 (18.8%) were unspecified acute leukaemias. There was no case of chronic myeloid or lymphocytic leukaemia. There has been a relative increase in the frequency of leukaemia cases at UCH, Ibadan, which may be largely explained by increased awareness and referrals. There is a need for further collaborative multicentre studies of childhood leukaemias in Nigeria and other developing countries and focused research on childhood leukaemias in order to unravel the aetiology.

Functional and quantitative alterations in T lymphocyte subpopulations in acute toxoplasmosis.

PubMed

Luft, B J; Kansas, G; Engleman, E G; Remington, J S

1984-11-01

The cellular immune response to Toxoplasma gondii has been studied in 23 patients with acute toxoplasma infection. Abnormalities of T cell subpopulations included a marked and significant elevation in suppressor (Leu 2) T cells in patients with prolonged symptoms due to acute infection and either a decrease in the number of T helper cells or an increase in the number of suppressor cells--or both--in patients with asymptomatic lymphadenopathy. There was no significant difference in lymphocyte proliferation to phytohemagglutinin or pokeweed mitogen among the various groups tested. The peak lymphocyte response to toxoplasma antigen, however, was significantly depressed in patients with acute infection compared with that in chronically infected control patients. The kinetics of the depression were consistent with the induction of a non-Leu 2 suppressor cell. These results demonstrate marked quantitative alterations in T lymphocyte subpopulations and functional alterations of T cells to toxoplasma antigen during infection with T. gondii.

Treatment Option Overview (Childhood Acute Lymphoblastic Leukemia)

MedlinePlus

... cells are given to the patient through an infusion . These reinfused stem cells grow into (and restore) ... them from spreading. Monoclonal antibodies are given by infusion. They may be used alone or to carry ...

Treatment Options for Childhood Acute Lymphoblastic Leukemia

MedlinePlus

... cells are given to the patient through an infusion . These reinfused stem cells grow into (and restore) ... them from spreading. Monoclonal antibodies are given by infusion. They may be used alone or to carry ...

Risk Groups for Childhood Acute Lymphoblastic Leukemia

MedlinePlus

... cells are given to the patient through an infusion . These reinfused stem cells grow into (and restore) ... them from spreading. Monoclonal antibodies are given by infusion. They may be used alone or to carry ...

CPI-613 and Bendamustine Hydrochloride in Treating Patients With Relapsed or Refractory T-Cell Non-Hodgkin Lymphoma or Hodgkin Lymphoma

ClinicalTrials.gov

2017-12-20

Adult Lymphocyte Depletion Hodgkin Lymphoma; Adult Lymphocyte Predominant Hodgkin Lymphoma; Adult Mixed Cellularity Hodgkin Lymphoma; Adult Nasal Type Extranodal NK/T-cell Lymphoma; Adult Nodular Sclerosis Hodgkin Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Hepatosplenic T-cell Lymphoma; Noncutaneous Extranodal Lymphoma; Peripheral T-cell Lymphoma; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; T-cell Adult Acute Lymphoblastic Leukemia; T-cell Large Granular Lymphocyte Leukemia

Acute Malaria Induces PD1+CTLA4+ Effector T Cells with Cell-Extrinsic Suppressor Function

PubMed Central

Mackroth, Maria Sophia; Abel, Annemieke; Steeg, Christiane; Schulze zur Wiesch, Julian; Jacobs, Thomas

2016-01-01

In acute Plasmodium falciparum (P. falciparum) malaria, the pro- and anti-inflammatory immune pathways must be delicately balanced so that the parasitemia is controlled without inducing immunopathology. An important mechanism to fine-tune T cell responses in the periphery is the induction of coinhibitory receptors such as CTLA4 and PD1. However, their role in acute infections such as P. falciparum malaria remains poorly understood. To test whether coinhibitory receptors modulate CD4+ T cell functions in malaria, blood samples were obtained from patients with acute P. falciparum malaria treated in Germany. Flow cytometric analysis showed a more frequent expression of CTLA4 and PD1 on CD4+ T cells of malaria patients than of healthy control subjects. In vitro stimulation with P. falciparum-infected red blood cells revealed a distinct population of PD1+CTLA4+CD4+ T cells that simultaneously produced IFNγ and IL10. This antigen-specific cytokine production was enhanced by blocking PD1/PDL1 and CTLA4. PD1+CTLA4+CD4+ T cells were further isolated based on surface expression of PD1 and their inhibitory function investigated in-vitro. Isolated PD1+CTLA4+CD4+ T cells suppressed the proliferation of the total CD4+ population in response to anti-CD3/28 and plasmodial antigens in a cell-extrinsic manner. The response to other specific antigens was not suppressed. Thus, acute P. falciparum malaria induces P. falciparum-specific PD1+CTLA4+CD4+ Teffector cells that coproduce IFNγ and IL10, and inhibit other CD4+ T cells. Transient induction of regulatory Teffector cells may be an important mechanism that controls T cell responses and might prevent severe inflammation in patients with malaria and potentially other acute infections. PMID:27802341

Hematological malignancies with t(9;11)(p21-22;q23)--a laboratory and clinical study of 125 cases. European 11q23 Workshop participants.

PubMed

Swansbury, G J; Slater, R; Bain, B J; Moorman, A V; Secker-Walker, L M

1998-05-01

This paper reports clinical and cytogenetic data from 125 cases with t(9;11)(p21-22;q32) which were accepted for a European Union Concerted Action Workshop on 11q23. This chromosome abnormality is known to occur predominantly in acute myeloid leukemia (AML) FAB type M5a and less often in AML M4; in this series it was also found to occur, uncommonly, in other AML FAB types, in childhood acute lymphoblastic leukemia (ALL) (nine cases), in relatively young patients with myelodysplastic syndrome (MDS) (five cases), acute biphenotypic leukemia (two cases), and acute undifferentiated leukemia (one case). All age groups were represented but 50% of the patients were aged less than 15 years. The t(9;11) was the sole abnormality in 57 cases with AML; trisomy 8 was the most common additional abnormality (23 cases, including seven with further abnormalities), and 28 cases had other additional abnormalities. Among the t(9;11)+ve patients with AML, the white cell count (WBC) and age group were significant predictors of event-free survival; central nervous system (CNS) involvement or karyotype class (sole, with trisomy 8, or with other), also contributed to prognosis although our data could not show these to be independent factors. The best outcome was for patients aged 1-9 years, with low WBC, and with absence of CNS disease or presence of trisomy 8. For patients aged less than 15 years, the event-free survival for ALL patients was not significantly worse than that of AML patients.

Comprehensive longitudinal analysis of hepatitis C virus (HCV)-specific T cell responses during acute HCV infection in the presence of existing HIV-1 infection.

PubMed

van den Berg, C H S B; Ruys, T A; Nanlohy, N M; Geerlings, S E; van der Meer, J T; Mulder, J-W; Lange, J A; van Baarle, D

2009-04-01

The aim of this study was to study the development of HCV-specific T cell immunity during acute HCV infection in the presence of an existing HIV-1 infection in four HIV-1 infected men having sex with men. A comprehensive analysis of HCV-specific T cell responses was performed at two time points during acute HCV infection using a T cell expansion assay with overlapping peptide pools spanning the entire HCV genome Three patients with (near) normal CD4+ T cell counts (range 400-970 x 10(6)/L) either resolved (n=1) or temporary suppressed HCV RNA. In contrast, one patient with low CD4+ T cell counts (330 x 10(6)/L), had sustained high HCV RNA levels. All four patients had low HCV-specific CD8+ T cell responses, and similar magnitudes of CD4+ T cell responses. Interestingly, individuals with resolved infection or temporary suppression of HCV-RNA had HCV-specific CD4+ T cell responses predominantly against nonstructural (NS) proteins. While the individual with high HCV RNA plasma concentrations had CD4+ T cell responses predominantly directed against Core. Our data show that an acute HCV infection in an HIV-1 infected person can be suppressed in the presence of HCV-specific CD4+ T cell response targeting non-structural proteins. However further research is needed in a larger group of patients to evaluate the role of HIV-1 on HCV-specific T cell responses in relation to outcome of acute HCV infection.

Vaccine Therapy in Preventing Cytomegalovirus Infection in Patients With Hematological Malignancies Undergoing Donor Stem Cell Transplant

ClinicalTrials.gov

2018-05-16

Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Promyelocytic Leukemia (M3); Adult Nasal Type Extranodal NK/T-cell Lymphoma; Adult Nodular Lymphocyte Predominant Hodgkin Lymphoma; Anaplastic Large Cell Lymphoma; B-cell Adult Acute Lymphoblastic Leukemia; Chronic Eosinophilic Leukemia; Chronic Myelomonocytic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; Contiguous Stage II Adult Burkitt Lymphoma; Contiguous Stage II Adult Diffuse Large Cell Lymphoma; Contiguous Stage II Adult Lymphoblastic Lymphoma; Contiguous Stage II Grade 1 Follicular Lymphoma; Contiguous Stage II Grade 2 Follicular Lymphoma; Contiguous Stage II Grade 3 Follicular Lymphoma; Contiguous Stage II Mantle Cell Lymphoma; Contiguous Stage II Small Lymphocytic Lymphoma; Cytomegalovirus Infection; de Novo Myelodysplastic Syndromes; Essential Thrombocythemia; Extramedullary Plasmacytoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Isolated Plasmacytoma of Bone; Monoclonal Gammopathy of Undetermined Significance; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Burkitt Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Lymphoblastic Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Peripheral T-cell Lymphoma; Polycythemia Vera; Post-transplant Lymphoproliferative Disorder; Previously Treated Myelodysplastic Syndromes; Primary Central Nervous System Hodgkin Lymphoma; Primary Central Nervous System Non-Hodgkin Lymphoma; Primary Myelofibrosis; Progressive Hairy Cell Leukemia, Initial Treatment; Prolymphocytic Leukemia; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Refractory Multiple Myeloma; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Stage I Adult Burkitt Lymphoma; Stage I Adult Diffuse Large Cell Lymphoma; Stage I Adult Hodgkin Lymphoma; Stage I Adult Lymphoblastic Lymphoma; Stage I Adult T-cell Leukemia/Lymphoma; Stage I Chronic Lymphocytic Leukemia; Stage I Cutaneous T-cell Non-Hodgkin Lymphoma; Stage I Grade 1 Follicular Lymphoma; Stage I Grade 2 Follicular Lymphoma; Stage I Grade 3 Follicular Lymphoma; Stage I Mantle Cell Lymphoma; Stage I Multiple Myeloma; Stage I Small Lymphocytic Lymphoma; Stage IA Mycosis Fungoides/Sezary Syndrome; Stage IB Mycosis Fungoides/Sezary Syndrome; Stage II Adult Hodgkin Lymphoma; Stage II Adult T-cell Leukemia/Lymphoma; Stage II Chronic Lymphocytic Leukemia; Stage II Cutaneous T-cell Non-Hodgkin Lymphoma; Stage II Multiple Myeloma; Stage IIA Mycosis Fungoides/Sezary Syndrome; Stage IIB Mycosis Fungoides/Sezary Syndrome; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Hodgkin Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Adult T-cell Leukemia/Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Cutaneous T-cell Non-Hodgkin Lymphoma; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Multiple Myeloma; Stage III Small Lymphocytic Lymphoma; Stage IIIA Mycosis Fungoides/Sezary Syndrome; Stage IIIB Mycosis Fungoides/Sezary Syndrome; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Hodgkin Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Adult T-cell Leukemia/Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Small Lymphocytic Lymphoma; Stage IVA Mycosis Fungoides/Sezary Syndrome; Stage IVB Mycosis Fungoides/Sezary Syndrome; T-cell Adult Acute Lymphoblastic Leukemia; T-cell Large Granular Lymphocyte Leukemia; Untreated Adult Acute Myeloid Leukemia; Untreated Hairy Cell Leukemia; Waldenström Macroglobulinemia

FLT3 mutation and expression did not adversely affect clinical outcome of childhood acute leukaemia: a study of 531 Southeast Asian children by the Ma-Spore study group.

PubMed

Leow, Shuangjie; Kham, Shirley Kow-Yin; Ariffin, Hany; Quah, Thuan Chong; Yeoh, Allen Eng-Juh

2011-12-01

FMS-like tyrosine kinase 3 (FLT3) is critical for normal haematopoiesis and have been reported to be expressed in the majority of acute myeloid and lymphoid malignancies. We correlated the impact of FLT3 mutations and its expression with age, WHO 2008 classification and treatment outcome in 531 childhood acute leukaemias. Of 150 acute myeloid leukaemia (AMLs), 18 (12%) harboured FLT3-ITD while nine (6%) had FLT3-TKD. FLT3-ITD and -TKD were rare in acute megakaryoblastic leukaemia (AMKL; FLT3-ITD 0/26, FLT3-TKD 1/26) and children below 3 years (n = 2/48). Acute promyelocytic leukaemia (APL) with t(15;17);PML-RARα (n = 7/18; 39%) harboured the highest frequency of FLT3 mutations, followed by myelomonocytic (n = 4/18; 22%) and AML with t(8;21);RUNX1-RUNX1T1 (n = 2/21; 9%). FLT3 expression levels were also lowest in AMKL, both in Down's and non-Down's (p = 0.002) followed by patients <3 years (p = 0.001). The rarity of FLT3 mutations and expression levels in AMKL were independent of age. Conversely, only 2% of childhood acute lymphoblastic leukaemia (ALL) harboured FLT3 mutations (ITD = 1/381; TKD = 6/381). FLT3 was highly expressed in hyperdiploid ALL (p < 0.001). Of the 121 AMLs with clinical history, there were no significant differences in 4-year event-free survival (EFS) (46% vs. 38%; p = 0.46) and overall-survival (OS) (55% vs. 43%; p = 0.30) between FLT3-wildtype and ITD+ patients. Similarly, FLT3 expression levels did not influence survival in AML in both the good risk and non-good risk subgroups. FLT3 does not appear to be involved in the pathogenesis of AMKL, both in Down's and non-Down's. Therapeutic targets using FLT3 inhibitors may not be useful in AMKL and in young children with AML. Copyright © 2011 John Wiley & Sons, Ltd.

Immune Responses in Acute and Convalescent Patients with Mild, Moderate and Severe Disease during the 2009 Influenza Pandemic in Norway

PubMed Central

Mohn, Kristin G.-I.; Cox, Rebecca Jane; Tunheim, Gro; Berdal, Jan Erik; Hauge, Anna Germundsson; Jul-Larsen, Åsne; Peters, Bjoern; Oftung, Fredrik

2015-01-01

Increased understanding of immune responses influencing clinical severity during pandemic influenza infection is important for improved treatment and vaccine development. In this study we recruited 46 adult patients during the 2009 influenza pandemic and characterized humoral and cellular immune responses. Those included were either acute hospitalized or convalescent patients with different disease severities (mild, moderate or severe). In general, protective antibody responses increased with enhanced disease severity. In the acute patients, we found higher levels of TNF-α single-producing CD4+T-cells in the severely ill as compared to patients with moderate disease. Stimulation of peripheral blood mononuclear cells (PBMC) from a subset of acute patients with peptide T-cell epitopes showed significantly lower frequencies of influenza specific CD8+ compared with CD4+ IFN-γ T-cells in acute patients. Both T-cell subsets were predominantly directed against the envelope antigens (HA and NA). However, in the convalescent patients we found high levels of both CD4+ and CD8+ T-cells directed against conserved core antigens (NP, PA, PB, and M). The results indicate that the antigen targets recognized by the T-cell subsets may vary according to the phase of infection. The apparent low levels of cross-reactive CD8+ T-cells recognizing internal antigens in acute hospitalized patients suggest an important role for this T-cell subset in protective immunity against influenza. PMID:26606759

5,10-Methylenetetrahydrofolate reductase polymorphisms and acute lymphoblastic leukemia risk: a meta-analysis.

PubMed

Pereira, Tiago Veiga; Rudnicki, Martina; Pereira, Alexandre Costa; Pombo-de-Oliveira, Maria S; Franco, Rendrik França

2006-10-01

There is evidence supporting a role for 5-10 methylenetetrahydrofolate reductase (MTHFR) gene variants in acute lymphoblastic leukemia (ALL). To provide a more robust estimate of the effect of MTHFR polymorphisms on the risk of ALL, we did a meta-analysis to reevaluate the association between the two most commonly studied MTHFR polymorphisms (C677T and A1298C) and ALL risk. All case-control studies investigating an association between the C677T or A1298C polymorphisms and risk of ALL were included. We applied both fixed-effects and random-effects models to combine odds ratio (OR) and 95% confidence intervals (95% CI). Q-statistic was used to evaluate the homogeneity and both Egger and Begg-Mazumdar tests were used to assess publication bias. The meta-analysis of the C677T polymorphism and risk of childhood ALL included 13 studies with a total of 4,894 individuals. Under a fixed-effects model, the TT genotype failed to be associated with a statistically significant reduction of childhood ALL risk (TT versus CT + CC: OR, 0.88; 95% CI, 0.73-1.06; P = 0.18). However, individuals homozygous for the 677T allele exhibited a 2.2-fold decrease in risk of adult ALL (TT versus CT + CC: OR, 0.45; 95% CI, 0.26-0.77; P = 0.004). In both cases, no evidence of heterogeneity was observed. No association between the A1298C variant and susceptibility to both adult and childhood ALL was disclosed. Our findings support the proposal that the common genetic C677T polymorphism in the MTHFR contributes to the risk of adult ALL, but not to the childhood ALL susceptibility.

Deferasirox in Treating Iron Overload Caused By Blood Transfusions in Patients With Hematologic Malignancies

ClinicalTrials.gov

2017-12-22

Acute Undifferentiated Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Grade III Lymphomatoid Granulomatosis; Adult Langerhans Cell Histiocytosis; Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Contiguous Stage II Adult Burkitt Lymphoma; Contiguous Stage II Adult Diffuse Large Cell Lymphoma; Contiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Contiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Contiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Contiguous Stage II Adult Lymphoblastic Lymphoma; Contiguous Stage II Grade 1 Follicular Lymphoma; Contiguous Stage II Grade 2 Follicular Lymphoma; Contiguous Stage II Grade 3 Follicular Lymphoma; Contiguous Stage II Mantle Cell Lymphoma; Contiguous Stage II Marginal Zone Lymphoma; Contiguous Stage II Small Lymphocytic Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; de Novo Myelodysplastic Syndromes; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Intraocular Lymphoma; Mast Cell Leukemia; Myelodysplastic Syndrome With Isolated Del(5q); Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Myeloid/NK-cell Acute Leukemia; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Burkitt Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Noncontiguous Stage II Adult Lymphoblastic Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Noncutaneous Extranodal Lymphoma; Peripheral T-cell Lymphoma; Previously Treated Myelodysplastic Syndromes; Primary Myelofibrosis; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Anemia; Refractory Multiple Myeloma; Secondary Acute Myeloid Leukemia; Secondary Myelofibrosis; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Stage I Adult Burkitt Lymphoma; Stage I Adult Diffuse Large Cell Lymphoma; Stage I Adult Diffuse Mixed Cell Lymphoma; Stage I Adult Diffuse Small Cleaved Cell Lymphoma; Stage I Adult Hodgkin Lymphoma; Stage I Adult Immunoblastic Large Cell Lymphoma; Stage I Adult Lymphoblastic Lymphoma; Stage I Adult T-cell Leukemia/Lymphoma; Stage I Cutaneous T-cell Non-Hodgkin Lymphoma; Stage I Grade 1 Follicular Lymphoma; Stage I Grade 2 Follicular Lymphoma; Stage I Grade 3 Follicular Lymphoma; Stage I Mantle Cell Lymphoma; Stage I Marginal Zone Lymphoma; Stage I Multiple Myeloma; Stage I Mycosis Fungoides/Sezary Syndrome; Stage I Small Lymphocytic Lymphoma; Stage II Adult Hodgkin Lymphoma; Stage II Adult T-cell Leukemia/Lymphoma; Stage II Cutaneous T-cell Non-Hodgkin Lymphoma; Stage II Multiple Myeloma; Stage II Mycosis Fungoides/Sezary Syndrome; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Hodgkin Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Adult T-cell Leukemia/Lymphoma; Stage III Cutaneous T-cell Non-Hodgkin Lymphoma; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Multiple Myeloma; Stage III Mycosis Fungoides/Sezary Syndrome; Stage III Small Lymphocytic Lymphoma; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Hodgkin Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Adult T-cell Leukemia/Lymphoma; Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Mycosis Fungoides/Sezary Syndrome; Stage IV Small Lymphocytic Lymphoma; Testicular Lymphoma; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Adult Acute Myeloid Leukemia; Waldenstrom Macroglobulinemia

Specific expression of novel long non-coding RNAs in high-hyperdiploid childhood acute lymphoblastic leukemia

PubMed Central

Drouin, Simon; Caron, Maxime; St-Onge, Pascal; Gioia, Romain; Richer, Chantal; Oualkacha, Karim; Droit, Arnaud; Sinnett, Daniel

2017-01-01

Pre-B cell childhood acute lymphoblastic leukemia (pre-B cALL) is a heterogeneous disease involving many subtypes typically stratified using a combination of cytogenetic and molecular-based assays. These methods, although widely used, rely on the presence of known chromosomal translocations, which is a limiting factor. There is therefore a need for robust, sensitive, and specific molecular biomarkers unaffected by such limitations that would allow better risk stratification and consequently better clinical outcome. In this study we performed a transcriptome analysis of 56 pre-B cALL patients to identify expression signatures in different subtypes. In both protein-coding and long non-coding RNAs (lncRNA), we identified subtype-specific gene signatures distinguishing pre-B cALL subtypes, particularly in t(12;21) and hyperdiploid cases. The genes up-regulated in pre-B cALL subtypes were enriched in bivalent chromatin marks in their promoters. LncRNAs is a new and under-studied class of transcripts. The subtype-specific nature of lncRNAs suggests they may be suitable clinical biomarkers to guide risk stratification and targeted therapies in pre-B cALL patients. PMID:28346506

Genetic variation in the folate metabolic pathway and risk of childhood leukemia

PubMed Central

Johnston, W. Thomas; Painter, Dan; Simpson, Jill; Roman, Eve; Skibola, Chris F.; Smith, Martyn T.; Allan, James M.; Taylor, G. Malcolm

2010-01-01

Studies of childhood leukemia and the potential etiologic role of genetic variation in folate metabolism have produced conflicting findings and have often been based on small numbers. We investigated the association between polymorphisms in key folate metabolism enzymes (MTHFR 677 C>T, MTHFR 1298 A>C, SHMT1 1420 C>T, MTR 2756 A>G, TS 1494del6, and TS 28bp repeat) in 939 cases of childhood acute lymphoblastic leukemia (ALL) and 89 cases of acute myeloid leukemia (AML) recruited into the United Kingdom Childhood Cancer Study. We also examined the maternal genotypes of 752 of these cases. Data from 824 noncancer controls recruited were used for comparison. No evidence of an association with MTHFR 677 was observed for ALL or AML, either in children or their mothers. However, in children an increased risk of ALL (odds ratio [OR] = 1.88; 95% confidence interval [CI], 1.16-3.07; P = .010) and AML (OR = 2.74; 95% CI, 1.07-7.01; P = .036) was observed with the MTR 2756 GG genotype; the association was most pronounced for cases with the MLL translocation (OR = 4.90; 95% CI, 1.30-18.45; P = .019). These data suggest that genetic variation in methionine synthase could mediate risk of childhood leukemia, either via effects on DNA methylation or via effects on fetal growth and development. PMID:20101025

Methylenetetrahydrofolate reductase gene haplotypes affect toxicity during maintenance therapy for childhood acute lymphoblastic leukemia in Japanese patients.

PubMed

Tanaka, Yoichi; Manabe, Atsushi; Nakadate, Hisaya; Kondoh, Kensuke; Nakamura, Kozue; Koh, Katsuyoshi; Kikuchi, Akira; Komiyama, Takako

2014-05-01

Abstract The aim of this study was to investigate the influence of daily 6-mercaptopurine (6-MP) and low-dose weekly methotrexate (MTX) combination treatment and methylenetetrahydrofolate reductase (MTHFR) haplotypes on toxicity during maintenance therapy in Japanese childhood acute lymphoblastic leukemia (ALL). We retrospectively analyzed the MTHFR C677T and A1298C polymorphisms and influence of haplotypes on toxicity in 73 patients. Patients with the MTHFR 677TT and 677CT + 1298AC were associated with severe liver toxicity (p = 0.014, odds ratio [OR] = 3.82, 95% confidence interval [CI] = 1.27-11.46) and more rapid onset of liver toxicity (p = 0.010). Patients with MTHFR 677TT and 677CT + 1298AC were associated with lower frequency of 6-MP and MTX dose reduction due to leukopenia (p < 0.05). No difference was observed in average drug doses in the MTHFR genotypes. In conclusion, the MTHFR C677T and A1298C haplotypes might be useful for monitoring adverse effects in childhood ALL maintenance therapy in Japanese patients.

Immunological and molecular epidemiological characteristics of acute and fulminant viral hepatitis A.

PubMed

Hussain, Zahid; Husain, Syed A; Almajhdi, Fahad N; Kar, Premashis

2011-05-23

Hepatitis A virus is an infection of liver; it is hyperendemic in vast areas of the world including India. In most cases it causes an acute self limited illness but rarely fulminant. There is growing concern about change in pattern from asymptomatic childhood infection to an increased incidence of symptomatic disease in the adult population. In-depth analysis of immunological, viral quantification and genotype of acute and fulminant hepatitis A virus. Serum samples obtained from 1009 cases of suspected acute viral hepatitis was employed for different biochemical and serological examination. RNA was extracted from blood serum, reverse transcribed into cDNA and amplified using nested PCR for viral quantification, sequencing and genotyping. Immunological cell count from freshly collected whole blood was carried out by fluorescence activated cell sorter. Fulminant hepatitis A was mostly detected with other hepatic viruses. CD8+ T cells count increases in fulminant hepatitis to a significantly high level (P = 0.005) compared to normal healthy control. The immunological helper/suppressor (CD4+/CD8+) ratio of fulminant hepatitis was significantly lower compared to acute cases. The serologically positive patients were confirmed by RT-PCR and total of 72 (69.2%) were quantified and sequenced. The average quantitative viral load of fulminant cases was significantly higher (P < 0.05). There was similar genotypic distribution in both acute and fulminant category, with predominance of genotype IIIA (70%) compared to IA (30%). Immunological factors in combination with viral load defines the severity of the fulminant hepatitis A. Phylogenetic analysis of acute and fulminant hepatitis A confirmed genotypes IIIA as predominant against IA with no preference of disease severity.

Immunological and molecular epidemiological characteristics of acute and fulminant viral hepatitis A

PubMed Central

2011-01-01

Background Hepatitis A virus is an infection of liver; it is hyperendemic in vast areas of the world including India. In most cases it causes an acute self limited illness but rarely fulminant. There is growing concern about change in pattern from asymptomatic childhood infection to an increased incidence of symptomatic disease in the adult population. Objective In-depth analysis of immunological, viral quantification and genotype of acute and fulminant hepatitis A virus. Methods Serum samples obtained from 1009 cases of suspected acute viral hepatitis was employed for different biochemical and serological examination. RNA was extracted from blood serum, reverse transcribed into cDNA and amplified using nested PCR for viral quantification, sequencing and genotyping. Immunological cell count from freshly collected whole blood was carried out by fluorescence activated cell sorter. Results Fulminant hepatitis A was mostly detected with other hepatic viruses. CD8+ T cells count increases in fulminant hepatitis to a significantly high level (P = 0.005) compared to normal healthy control. The immunological helper/suppressor (CD4+/CD8+) ratio of fulminant hepatitis was significantly lower compared to acute cases. The serologically positive patients were confirmed by RT-PCR and total of 72 (69.2%) were quantified and sequenced. The average quantitative viral load of fulminant cases was significantly higher (P < 0.05). There was similar genotypic distribution in both acute and fulminant category, with predominance of genotype IIIA (70%) compared to IA (30%). Conclusions Immunological factors in combination with viral load defines the severity of the fulminant hepatitis A. Phylogenetic analysis of acute and fulminant hepatitis A confirmed genotypes IIIA as predominant against IA with no preference of disease severity. PMID:21605420

THE GENOMIC LANDSCAPE OF PEDIATRIC AND YOUNG ADULT T-LINEAGE ACUTE LYMPHOBLASTIC LEUKEMIA

PubMed Central

Liu, Yu; Easton, John; Shao, Ying; Maciaszek, Jamie; Wang, Zhaoming; Wilkinson, Mark R.; McCastlain, Kelly; Edmonson, Michael; Pounds, Stanley B.; Shi, Lei; Zhou, Xin; Ma, Xiaotu; Sioson, Edgar; Li, Yongjin; Rusch, Michael; Gupta, Pankaj; Pei, Deqing; Cheng, Cheng; Smith, Malcolm A.; Auvil, Jaime Guidry; Gerhard, Daniela S.; Relling, Mary V.; Winick, Naomi J.; Carroll, Andrew J.; Heerema, Nyla A.; Raetz, Elizabeth; Devidas, Meenakshi; Willman, Cheryl L.; Harvey, Richard C.; Carroll, William L.; Dunsmore, Kimberly P.; Winter, Stuart S.; Wood, Brent L; Sorrentino, Brian P.; Downing, James R.; Loh, Mignon L.; Hunger, Stephen P; Zhang, Jinghui; Mullighan, Charles G.

2017-01-01

Genetic alterations activating NOTCH1 signaling and T cell transcription factors, coupled with inactivation of the INK4/ARF tumor suppressors are hallmarks of T-ALL, but detailed genome-wide sequencing of large T-ALL cohorts has not been performed. Using integrated genomic analysis of 264 T-ALL cases, we identify 106 putative driver genes, half of which were not previously described in childhood T-ALL (e.g. CCND3, CTCF, MYB, SMARCA4, ZFP36L2 and MYCN). We described new mechanisms of coding and non-coding alteration, and identify 10 recurrently altered pathways, with associations between mutated genes and pathways, and stage or subtype of T-ALL. For example, NRAS/FLT3 mutations were associated with immature T-ALL, JAK3/STAT5B mutations in HOX1 deregulated ALL, PTPN2 mutations in TLX1 T-ALL, and PIK3R1/PTEN mutations in TAL1 ALL, suggesting that different signaling pathways have distinct roles according to maturational stage. This genomic landscape provides a logical framework for the development of faithful genetic models and new therapeutic approaches. PMID:28671688

Metabolic syndrome in long-term survivors of childhood acute leukemia treated without hematopoietic stem cell transplantation: an L.E.A. study.

PubMed

Saultier, Paul; Auquier, Pascal; Bertrand, Yves; Vercasson, Camille; Oudin, Claire; Contet, Audrey; Plantaz, Dominique; Poirée, Marilyne; Ducassou, Stéphane; Kanold, Justyna; Tabone, Marie-Dominique; Dalle, Jean-Hugues; Lutz, Patrick; Gandemer, Virginie; Sirvent, Nicolas; Thouvenin, Sandrine; Berbis, Julie; Chambost, Hervé; Baruchel, André; Leverger, Guy; Michel, Gérard

2016-12-01

Cardiovascular conditions are serious long-term complications of childhood acute leukemia. However, few studies have investigated the risk of metabolic syndrome, a known predictor of cardiovascular disease, in patients treated without hematopoietic stem cell transplantation. We describe the overall and age-specific prevalence, and the risk factors for metabolic syndrome and its components in the L.E.A. (Leucémie de l'Enfant et de l'Adolescent) French cohort of childhood acute leukemia survivors treated without hematopoietic stem cell transplantation. The study included 650 adult patients (mean age at evaluation: 24.2 years; mean follow-up after leukemia diagnosis: 16.0 years). The prevalence of metabolic syndrome was 6.9% (95% CI 5.1-9.2). The age-specific cumulative prevalence at 20, 25, 30 and 35 years of age was 1.3%, 6.1%, 10.8% and 22.4%, respectively. The prevalence of decreased high-density lipoprotein cholesterol, increased triglycerides, increased fasting glucose, increased blood pressure and increased abdominal circumference was 26.8%, 11.7%, 5.8%, 36.7% and 16.7%, respectively. Risk factors significantly associated with metabolic syndrome in the multivariate analysis were male sex (OR 2.64; 95% CI 1.32-5.29), age at last evaluation (OR 1.10; 95% CI 1.04-1.17) and body mass index at diagnosis (OR 1.15; 95% CI 1.01-1.32). The cumulative steroid dose was not a significant risk factor. Irradiated and non-irradiated patients exhibited different patterns of metabolic abnormalities, with more frequent abdominal obesity in irradiated patients and more frequent hypertension in non-irradiated patients. Survivors of childhood acute leukemia are at risk of metabolic syndrome, even when treated without hematopoietic stem cell transplantation or central nervous system irradiation. A preventive approach with regular screening for cardiovascular risk factors is recommended. clinicaltrials.gov identifier:01756599. Copyright© Ferrata Storti Foundation.

Study of Akt Inhibitor MK2206 in Patients With Relapsed Lymphoma

ClinicalTrials.gov

2015-10-09

Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; B-cell Adult Acute Lymphoblastic Leukemia; B-cell Chronic Lymphocytic Leukemia; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Noncutaneous Extranodal Lymphoma; Peripheral T-cell Lymphoma; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Hairy Cell Leukemia; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; T-cell Adult Acute Lymphoblastic Leukemia; T-cell Large Granular Lymphocyte Leukemia; Testicular Lymphoma; Waldenström Macroglobulinemia

Panobinostat and Everolimus in Treating Patients With Recurrent Multiple Myeloma, Non-Hodgkin Lymphoma, or Hodgkin Lymphoma

ClinicalTrials.gov

2018-04-19

Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; B-cell Adult Acute Lymphoblastic Leukemia; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Post-transplant Lymphoproliferative Disorder; Primary Central Nervous System Non-Hodgkin Lymphoma; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Multiple Myeloma; Splenic Marginal Zone Lymphoma; T-cell Adult Acute Lymphoblastic Leukemia; Waldenström Macroglobulinemia

The Association of Methylenetetrahydrofolate Reductase Genotypes with the Risk of Childhood Leukemia in Taiwan

PubMed Central

Chang, Wen-Shin; Ji, Hong-Xue; Hsiao, Chieh-Lun; Miao, Chia-En; Hsu, Yuan-Nian; Bau, Da-Tian

2015-01-01

Background Acute lymphoblastic leukemia (ALL) is the most prevalent type of pediatric cancer, the causes of which are likely to involve an interaction between genetic and environmental factors. To evaluate the effects of the genotypic polymorphisms in methylenetetrahydrofolate reductase (MTHFR) on childhood ALL risk in Taiwan, two well-known polymorphic genotypes of MTHFR, C677T (rs1801133) and A1298C (rs1801131), were analyzed to examine the extent of their associations with childhood ALL susceptibility and to discuss the MTHFR genotypic contribution to childhood ALL risk among different populations. Methodology/Principal Findings In total, 266 patients with childhood ALL and an equal number of non-cancer controls recruited were genotyped utilizing PCR-RFLP methodology. The MTHFR C677T genotype, but not the A1298C, was differently distributed between childhood ALL and control groups. The CT and TT of MTHFR C677T genotypes were significantly more frequently found in controls than in childhood ALL patients (odds ratios=0.60 and 0.48, 95% confidence intervals=0.42–0.87 and 0.24–0.97, respectively). As for gender, the boys carrying the MTHFR C677T CT or TT genotype conferred a lower odds ratio of 0.51 (95% confidence interval=0.32–0.81, P=0.0113) for childhood ALL. As for age, those equal to or greater than 3.5 years of age at onset of disease carrying the MTHFR C677T CT or TT genotype were of lower risk (odds ratio= 0.43 and 95% confidence interval=0.26–0.71, P=0.0016). Conclusions Our results indicated that the MTHFR C677T T allele was a protective biomarker for childhood ALL in Taiwan, and the association was more significant in male patients and in patients 3.5 years of age or older at onset of disease. PMID:25793509

The association of methylenetetrahydrofolate reductase genotypes with the risk of childhood leukemia in Taiwan.

PubMed

Pei, Jen-Sheng; Hsu, Chin-Mu; Tsai, Chia-Wen; Chang, Wen-Shin; Ji, Hong-Xue; Hsiao, Chieh-Lun; Miao, Chia-En; Hsu, Yuan-Nian; Bau, Da-Tian

2015-01-01

Acute lymphoblastic leukemia (ALL) is the most prevalent type of pediatric cancer, the causes of which are likely to involve an interaction between genetic and environmental factors. To evaluate the effects of the genotypic polymorphisms in methylenetetrahydrofolate reductase (MTHFR) on childhood ALL risk in Taiwan, two well-known polymorphic genotypes of MTHFR, C677T (rs1801133) and A1298C (rs1801131), were analyzed to examine the extent of their associations with childhood ALL susceptibility and to discuss the MTHFR genotypic contribution to childhood ALL risk among different populations. In total, 266 patients with childhood ALL and an equal number of non-cancer controls recruited were genotyped utilizing PCR-RFLP methodology. The MTHFR C677T genotype, but not the A1298C, was differently distributed between childhood ALL and control groups. The CT and TT of MTHFR C677T genotypes were significantly more frequently found in controls than in childhood ALL patients (odds ratios=0.60 and 0.48, 95% confidence intervals=0.42-0.87 and 0.24-0.97, respectively). As for gender, the boys carrying the MTHFR C677T CT or TT genotype conferred a lower odds ratio of 0.51 (95% confidence interval=0.32-0.81, P=0.0113) for childhood ALL. As for age, those equal to or greater than 3.5 years of age at onset of disease carrying the MTHFR C677T CT or TT genotype were of lower risk (odds ratio= 0.43 and 95% confidence interval=0.26-0.71, P=0.0016). Our results indicated that the MTHFR C677T T allele was a protective biomarker for childhood ALL in Taiwan, and the association was more significant in male patients and in patients 3.5 years of age or older at onset of disease.

Acute and chronic rejection: compartmentalization and kinetics of counterbalancing signals in cardiac transplants.

PubMed

Kaul, A M K; Goparaju, S; Dvorina, N; Iida, S; Keslar, K S; de la Motte, C A; Valujskikh, A; Fairchild, R L; Baldwin, W M

2015-02-01

Acute and chronic rejection impact distinct compartments of cardiac allografts. Intramyocardial mononuclear cell infiltrates define acute rejection, whereas chronic rejection affects large arteries. Hearts transplanted from male to female C57BL/6 mice undergo acute rejection with interstitial infiltrates at 2 weeks that resolve by 6 weeks when large arteries develop arteriopathy. These processes are dependent on T cells because no infiltrates developed in T cell-deficient mice and transfer of CD4 T cells restored T cell as well as macrophage infiltrates and ultimately neointima formation. Markers of inflammatory macrophages were up-regulated in the interstitium acutely and decreased as markers of wound healing macrophages increased chronically. Programmed cell death protein, a negative costimulator, and its ligand PDL1 were up-regulated in the interstitium during resolution of acute rejection. Blocking PDL1:PD1 interactions in the acute phase increased interstitial T cell infiltrates. Toll-like receptor (TLR) 4 and its endogenous ligand hyaluronan were increased in arteries with neointimal expansion. Injection of hyaluronan fragments increased intragraft production of chemokines. Our data indicate that negative costimulatory pathways are critical for the resolution of acute interstitial infiltrates. In the arterial compartment recognition of endogenous ligands including hyaluronan by the innate TLRs may support the progression of arteriopathy. © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.

The Role of HDACs Inhibitors in Childhood and Adolescence Acute Leukemias

PubMed Central

Masetti, Riccardo; Serravalle, Salvatore; Biagi, Carlotta; Pession, Andrea

2011-01-01

Acute leukemia is the most common type of childhood and adolescence cancer, characterized by clonal proliferation of variably differentiated myeloid or lymphoid precursors. Recent insights into the molecular pathogenesis of leukemia have shown that epigenetic modifications, such as deacetylation of histones and DNA methylation, play crucial roles in leukemogenesis, by transcriptional silencing of critical genes. Histone deacetylases (HDACs) are potential targets in the treatment of leukaemia, and, as a consequence, inhibitors of HDACs (HDIs) are being studied for therapeutic purposes. HDIs promote or enhance several different anticancer mechanisms, such as apoptosis, cell cycle arrest, and cellular differentiation and, therefore, are in evidence as promising treatment for children and adolescents with acute leukemia, in monotherapy or in association with other anticancer drugs. Here we review the main preclinical and clinical studies regarding the use of HDIs in treating childhood and adolescence leukemia. PMID:21318168

Association of methylenetetrahytrofolate reductase (MTHFR) C677T and A1298C polymorphisms with the susceptibility of childhood acute lymphoblastic leukaemia (ALL) in Chinese population

PubMed Central

2014-01-01

Background The aim of this study was to investigate the relationship between the polymorphisms of the methylenetetrahytrofolate reductase (MTHFR) gene and susceptibility to childhood acute lymphoblastic leukemia (ALL). Methods A case–control study was conducted among 98 children with ALL and 93 age- and sex- matched non-ALL controls. Genotyping of MTHFR C677T and A1298C polymorphisms was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The odds ratios (ORs) of MTHFR genotypes were used to assess the associations of these polymorphisms with childhood ALL susceptibility. Results No significant differences were observed for frequencies of the 677CC, 677CT and 677TT genotypes between patients and controls. Frequencies of the 1298AA, 1298 AC and 1298CC genotypes between the two groups were significantly different. The risk of ALL with the 1298C allele carriers (AC + CC) was elevated by 1.1 times compared with the AA genotype [OR = 2.100; 95% CI (1.149; 3.837); P = 0.015]. Conclusions The MTHFR A1298C polymorphism is associated with susceptibility to childhood ALL in the Chinese population. PMID:24476575

High Throughput Drug Sensitivity Assay and Genomics- Guided Treatment of Patients With Relapsed or Refractory Acute Leukemia

ClinicalTrials.gov

2018-02-28

Acute Leukemia of Ambiguous Lineage; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Refractory Acute Myeloid Leukemia; Refractory Adult Acute Lymphoblastic Leukemia; Refractory Childhood Acute Lymphoblastic Leukemia

Monoclonal Antibody Therapy in Treating Patients With Ovarian Epithelial Cancer, Melanoma, Acute Myeloid Leukemia, Myelodysplastic Syndrome, or Non-Small Cell Lung Cancer

ClinicalTrials.gov

2013-01-09

Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Myeloid Leukemia; Recurrent Melanoma; Recurrent Non-small Cell Lung Cancer; Recurrent Ovarian Epithelial Cancer; Stage IV Melanoma; Stage IV Non-small Cell Lung Cancer

Early acute myeloblastic leukemia treatment for childhood myelodysplastic syndrome with t(3;5) (NPM/MLF1).

PubMed

Sevilla, Julián; Fernández-Plaza, Sandra; Lassaletta, Alvaro; González-Vicent, Marta; Contra, Trinidad; Madero, Luis

2007-12-01

Myelodysplastic syndromes (MDS) in childhood are rare hematologic diseases. MDS with t(3;5) (NPM/MLF1) is an unusual subtype without a well-defined clinical and prognostic pattern. A poor outcome has been reported, suggesting that hematopoietic transplantation is the only treatment option. Here in we described a 2-year-old child diagnosed with the disease, without a suitable hematopoietic donor, treated early in the disease with chemotherapy. He is alive and well 4 years after the end of treatment. This unusual MDS needs further studies to better understand the disease.

Pilot Study of Umbilical Cord Blood Transplantation in Adult Patient With Advanced Hematopoietic Malignancies

ClinicalTrials.gov

2013-08-13

Acute Myeloid Leukemia; Myelodysplasia; Acute Lymphoblastic Leukemia; Chronic Myelogenous Leukemia; Multiple Myeloma; Lymphoma, Large-Cell, Diffuse; Lymphoma, Mantle-Cell; Lymphoma, T-Cell, Peripheral; T-NK Cell Lymphoma; Hodgkin Disease

Pivotal advance: CTLA-4+ T cells exhibit normal antiviral functions during acute viral infection.

PubMed

Raué, Hans-Peter; Slifka, Mark K

2007-05-01

Previous studies have shown that T cells, which are genetically deficient in CTLA-4/CD152 expression, will proliferate uncontrollably, resulting in lethal autoimmune disease. This and other evidence indicate that CTLA-4 plays a critical role in the negative regulation of effector T cell function. In contrast to expectations, BrdU incorporation experiments demonstrated that CTLA-4 expression was associated with normal or even enhanced in vivo proliferation of virus-specific CD4+ and CD8+ T cells following acute lymphocytic choriomeningitis virus or vaccinia virus infection. When compared with CTLA-4- T cells directly ex vivo, CTLA-4+ T cells also exhibited normal antiviral effector functions following stimulation with peptide-coated cells, virus-infected cells, plate-bound anti-CD3/anti-CTLA-4, or the cytokines IL-12 and IL-18. Together, this indicates that CTLA-4 does not directly inhibit antiviral T cell expansion or T cell effector functions, at least not under the normal physiological conditions associated with either of these two acute viral infections.

Childhood acute leukemias are frequent in Mexico City: descriptive epidemiology

PubMed Central

2011-01-01

Background Worldwide, acute leukemia is the most common type of childhood cancer. It is particularly common in the Hispanic populations residing in the United States, Costa Rica, and Mexico City. The objective of this study was to determine the incidence of acute leukemia in children who were diagnosed and treated in public hospitals in Mexico City. Methods Included in this study were those children, under 15 years of age and residents of Mexico City, who were diagnosed in 2006 and 2007 with leukemia, as determined by using the International Classification of Childhood Cancer. The average annual incidence rates (AAIR), and the standardized average annual incidence rates (SAAIR) per million children were calculated. We calculated crude, age- and sex-specific incidence rates and adjusted for age by the direct method with the world population as standard. We determined if there were a correlation between the incidence of acute leukemias in the various boroughs of Mexico City and either the number of agricultural hectares, the average number of persons per household, or the municipal human development index for Mexico (used as a reference of socio-economic level). Results Although a total of 610 new cases of leukemia were registered during 2006-2007, only 228 fit the criteria for inclusion in this study. The overall SAAIR was 57.6 per million children (95% CI, 46.9-68.3); acute lymphoblastic leukemia (ALL) was the most frequent type of leukemia, constituting 85.1% of the cases (SAAIR: 49.5 per million), followed by acute myeloblastic leukemia at 12.3% (SAAIR: 6.9 per million), and chronic myeloid leukemia at 1.7% (SAAIR: 0.9 per million). The 1-4 years age group had the highest SAAIR for ALL (77.7 per million). For cases of ALL, 73.2% had precursor B-cell immunophenotype (SAAIR: 35.8 per million) and 12.4% had T-cell immunophenotype (SAAIR 6.3 per million). The peak ages for ALL were 2-6 years and 8-10 years. More than half the children (58.8%) were classified as high risk. There was a positive correlation between the average number of persons per household and the incidence of the pre-B immunophenotype (Pearson's r, 0.789; P = 0.02). Conclusions The frequency of ALL in Mexico City is among the highest in the world, similar to those found for Hispanics in the United States and in Costa Rica. PMID:21846410

Longevity of T-cell memory following acute viral infection.

PubMed

Walker, Joshua M; Slifka, Mark K

2010-01-01

Investigation of T-cell-mediated immunity following acute viral infection represents an area of research with broad implications for both fundamental immunology research as well as vaccine development. Here, we review techniques that are used to assess T-cell memory including limiting dilution analysis, enzyme-linked immunospot (ELISPOT) assays, intracellular cytokine staining (ICCS) and peptide-MHC Class I tetramer staining. The durability of T-cell memory is explored in the context of several acute viral infections including vaccinia virus (VV), measles virus (MV) and yellow fever virus (YFV). Following acute infection, different virus-specific T-cell subpopulations exhibit distinct cytokine profiles and these profiles change over the course of infection. Differential regulation of the cytotoxic proteins, granzyme A, granzyme B and perforin are also observed in virus-specific T cells following infection. As a result of this work, we have gained a broader understanding of the kinetics and magnitude of antiviral T-cell immunity as well as new insight into the patterns of immunodominance and differential regulation of cytokines and cytotoxicity-associated molecules. This information may eventually lead to the generation of more effective vaccines that elicit T-cell memory with the optimal combination of functional characteristics required for providing protective immunity against infectious disease.

Monitoring of childhood ALL using BCR-ABL1 genomic breakpoints identifies a subgroup with CML-like biology.

PubMed

Hovorkova, Lenka; Zaliova, Marketa; Venn, Nicola C; Bleckmann, Kirsten; Trkova, Marie; Potuckova, Eliska; Vaskova, Martina; Linhartova, Jana; Machova Polakova, Katerina; Fronkova, Eva; Muskovic, Walter; Giles, Jodie E; Shaw, Peter J; Cario, Gunnar; Sutton, Rosemary; Stary, Jan; Trka, Jan; Zuna, Jan

2017-05-18

We used the genomic breakpoint between BCR and ABL1 genes for the DNA-based monitoring of minimal residual disease (MRD) in 48 patients with childhood acute lymphoblastic leukemia (ALL). Comparing the results with standard MRD monitoring based on immunoglobulin/T-cell receptor (Ig/TCR) gene rearrangements and with quantification of IKZF1 deletion, we observed very good correlation for the methods in a majority of patients; however, >20% of children (25% [8/32] with minor and 12.5% [1/8] with major- BCR-ABL1 variants in the consecutive cohorts) had significantly (>1 log) higher levels of BCR-ABL1 fusion than Ig/TCR rearrangements and/or IKZF1 deletion. We performed cell sorting of the diagnostic material and assessed the frequency of BCR-ABL1 -positive cells in various hematopoietic subpopulations; 12% to 83% of non-ALL B lymphocytes, T cells, and/or myeloid cells harbored the BCR-ABL1 fusion in patients with discrepant MRD results. The multilineage involvement of the BCR-ABL1 -positive clone demonstrates that in some patients diagnosed with BCR-ABL1 -positive ALL, a multipotent hematopoietic progenitor is affected by the BCR-ABL1 fusion. These patients have BCR-ABL1 -positive clonal hematopoiesis resembling a chronic myeloid leukemia (CML)-like disease manifesting in "lymphoid blast crisis." The biological heterogeneity of BCR-ABL1 -positive ALL may impact the patient outcomes and optimal treatment (early stem cell transplantation vs long-term administration of tyrosine-kinase inhibitors) as well as on MRD testing. Therefore, we recommend further investigations on CML-like BCR-ABL1 -positive ALL. © 2017 by The American Society of Hematology.

Aberrant Signaling Pathways in T-Cell Acute Lymphoblastic Leukemia

PubMed Central

Bongiovanni, Deborah; Saccomani, Valentina

2017-01-01

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disease caused by the malignant transformation of immature progenitors primed towards T-cell development. Clinically, T-ALL patients present with diffuse infiltration of the bone marrow by immature T-cell blasts high blood cell counts, mediastinal involvement, and diffusion to the central nervous system. In the past decade, the genomic landscape of T-ALL has been the target of intense research. The identification of specific genomic alterations has contributed to identify strong oncogenic drivers and signaling pathways regulating leukemia growth. Notwithstanding, T-ALL patients are still treated with high-dose multiagent chemotherapy, potentially exposing these patients to considerable acute and long-term side effects. This review summarizes recent advances in our understanding of the signaling pathways relevant for the pathogenesis of T-ALL and the opportunities offered for targeted therapy. PMID:28872614

TESTIN Induces Rapid Death and Suppresses Proliferation in Childhood B Acute Lymphoblastic Leukaemia Cells

PubMed Central

Weeks, Robert J.; Ludgate, Jackie L.; LeMée, Gwenn; Morison, Ian M.

2016-01-01

Background Childhood acute lymphoblastic leukaemia (ALL) is the most common malignancy in children. Despite high cure rates, side effects and late consequences of the intensive treatments are common. Unquestionably, the identification of new therapeutic targets will lead to safer, more effective treatments. We identified TES promoter methylation and transcriptional silencing as a very common molecular abnormality in childhood ALL, irrespective of molecular subtype. The aims of the present study were to demonstrate that TES promoter methylation is aberrant, to determine the effects of TES re-expression in ALL, and to determine if those effects are mediated via TP53 activity. Methods Normal fetal and adult tissue DNA was isolated and TES promoter methylation determined by Sequenom MassARRAY. Quantitative RT-PCR and immunoblot were used to confirm re-expression of TES in ALL cell lines after 5’-aza-2’-deoxycytidine (decitabine) exposure or transfection with TES expression plasmids. The effects of TES re-expression on ALL cells were investigated using standard cell proliferation, cell death and cell cycle assays. Results In this study, we confirm that the TES promoter is unmethylated in normal adult and fetal tissues. We report that decitabine treatment of ALL cell lines results in demethylation of the TES promoter and attendant expression of TES mRNA. Re-expression of TESTIN protein in ALL cells using expression plasmid transfection results in rapid cell death or cell cycle arrest independent of TP53 activity. Conclusions These results suggest that TES is aberrantly methylated in ALL and that re-expression of TESTIN has anti-leukaemia effects which point to novel therapeutic opportunities for childhood ALL. PMID:26985820

CMV driven CD8(+) T-cell activation is associated with acute rejection in lung transplantation.

PubMed

Roux, Antoine; Mourin, Gisèle; Fastenackels, Solène; Almeida, Jorge R; Iglesias, Maria Candela; Boyd, Anders; Gostick, Emma; Larsen, Martin; Price, David A; Sacre, Karim; Douek, Daniel C; Autran, Brigitte; Picard, Clément; Miranda, Sandra de; Sauce, Delphine; Stern, Marc; Appay, Victor

2013-07-01

Lung transplantation is the definitive treatment for terminal respiratory disease, but the associated mortality rate is high. Acute rejection of the transplanted lung is a key determinant of adverse prognosis. Furthermore, an epidemiological relationship has been established between the occurrence of acute lung rejection and cytomegalovirus infection. However, the reasons for this association remain unclear. Here, we performed a longitudinal characterization of CMV-specific T-cell responses and immune activation status in the peripheral blood and bronchoalveolar lavage fluid of forty-four lung transplant patients. Acute rejection was associated with high levels of cellular activation in the periphery, reflecting strong CMV-specific CD8(+) T-cell activity post-transplant. Peripheral and lung CMV-specific CD8(+) T-cell responses were very similar, and related to the presence of CMV in the transplanted organ. These findings support that activated CMV-specific CD8(+) T-cells in the lung may play a role in promoting acute rejection. Copyright © 2013 Elsevier Inc. All rights reserved.

Ixabepilone in Treating Young Patients With Solid Tumors or Leukemia That Haven't Responded to Therapy

ClinicalTrials.gov

2012-03-14

Brain and Central Nervous System Tumors; Childhood Germ Cell Tumor; Extragonadal Germ Cell Tumor; Kidney Cancer; Leukemia; Liver Cancer; Neuroblastoma; Ovarian Cancer; Sarcoma; Unspecified Childhood Solid Tumor, Protocol Specific

Distinct gene expression profiles determine molecular treatment response in childhood acute lymphoblastic leukemia.

PubMed

Cario, Gunnar; Stanulla, Martin; Fine, Bernard M; Teuffel, Oliver; Neuhoff, Nils V; Schrauder, André; Flohr, Thomas; Schäfer, Beat W; Bartram, Claus R; Welte, Karl; Schlegelberger, Brigitte; Schrappe, Martin

2005-01-15

Treatment resistance, as indicated by the presence of high levels of minimal residual disease (MRD) after induction therapy and induction consolidation, is associated with a poor prognosis in childhood acute lymphoblastic leukemia (ALL). We hypothesized that treatment resistance is an intrinsic feature of ALL cells reflected in the gene expression pattern and that resistance to chemotherapy can be predicted before treatment. To test these hypotheses, gene expression signatures of ALL samples with high MRD load were compared with those of samples without measurable MRD during treatment. We identified 54 genes that clearly distinguished resistant from sensitive ALL samples. Genes with low expression in resistant samples were predominantly associated with cell-cycle progression and apoptosis, suggesting that impaired cell proliferation and apoptosis are involved in treatment resistance. Prediction analysis using randomly selected samples as a training set and the remaining samples as a test set revealed an accuracy of 84%. We conclude that resistance to chemotherapy seems at least in part to be an intrinsic feature of ALL cells. Because treatment response could be predicted with high accuracy, gene expression profiling could become a clinically relevant tool for treatment stratification in the early course of childhood ALL.

Leu-9 (CD 7) positivity in acute leukemias: a marker of T-cell lineage?

PubMed

Ben-Ezra, J; Winberg, C D; Wu, A; Rappaport, H

1987-01-01

Monoclonal antibody Leu-9 (CD 7) has been reported to be a sensitive and specific marker for T-cell lineage in leukemic processes, since it is positive in patients whose leukemic cells fail to express other T-cell antigens. To test whether Leu-9 is indeed specific for T-cell leukemias, we examined in detail 10 cases of acute leukemia in which reactions were positive for Leu-9 and negative for other T-cell-associated markers including T-11, Leu-1, T-3, and E-rosettes. Morphologically and cytochemically, 2 of these 10 leukemias were classified as lymphoblastic, 4 as myeloblastic, 2 as monoblastic, 1 as megakaryoblastic, and 1 as undifferentiated. The case of acute megakaryoblastic leukemia is the first reported case to be Leu-9 positive. None of the 10 were TdT positive. Of six cases (two monoblastic, one lymphoblastic, one myeloblastic, one megakaryoblastic, and one undifferentiated) in which we evaluated for DNA gene rearrangements, only one, a peroxidase-positive leukemia, showed a novel band on study of the T-cell-receptor beta-chain gene. We therefore conclude that Leu-9 is not a specific marker to T-cell lineage and that, in the absence of other supporting data, Leu-9 positivity should not be used as the sole basis of classifying an acute leukemia as being T-cell derived.

Provision of TCRγδ T Cells and Memory T Cells Plus Selected Use of Blinatumomab in Naïve T-cell Depleted Haploidentical Donor Hematopoietic Cell Transplantation for Hematologic Malignancies Relapsed or Refractory Despite Prior Transplantation

ClinicalTrials.gov

2018-01-03

Acute Lymphoblastic Leukemia (ALL); Acute Myeloid Leukemia (AML); Myeloid Sarcoma; Chronic Myeloid Leukemia (CML); Juvenile Myelomonocytic Leukemia (JMML); Myelodysplastic Syndrome (MDS); Non-Hodgkin Lymphoma (NHL)

Alisertib in Combination With Vorinostat in Treating Patients With Relapsed or Recurrent Hodgkin Lymphoma, B-Cell Non-Hodgkin Lymphoma, or Peripheral T-Cell Lymphoma

ClinicalTrials.gov

2018-04-10

Adult B Acute Lymphoblastic Leukemia; Adult T Acute Lymphoblastic Leukemia; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-Cell Lymphoma; Chronic Lymphocytic Leukemia; Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue; Hepatosplenic T-Cell Lymphoma; Intraocular Lymphoma; Lymphomatous Involvement of Non-Cutaneous Extranodal Site; Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma; Nodal Marginal Zone Lymphoma; Primary Cutaneous B-Cell Non-Hodgkin Lymphoma; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-Cell Leukemia/Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides and Sezary Syndrome; Recurrent Non-Hodgkin Lymphoma; Recurrent Primary Cutaneous T-Cell Non-Hodgkin Lymphoma; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Small Intestinal Lymphoma; Splenic Marginal Zone Lymphoma; T-Cell Large Granular Lymphocyte Leukemia; Testicular Lymphoma; Waldenstrom Macroglobulinemia

T-cell involvement in drug-induced acute generalized exanthematous pustulosis

PubMed Central

Britschgi, Markus; Steiner, Urs C.; Schmid, Simone; Depta, Jan P.H.; Senti, Gabriela; Bircher, Andreas; Burkhart, Christoph; Yawalkar, Nikhil; Pichler, Werner J.

2001-01-01

Acute generalized exanthematous pustulosis (AGEP) is an uncommon eruption most often provoked by drugs, by acute infections with enteroviruses, or by mercury. It is characterized by acute, extensive formation of nonfollicular sterile pustules on erythematous background, fever, and peripheral blood leukocytosis. We present clinical and immunological data on four patients with this disease, which is caused by different drugs. An involvement of T cells could be implied by positive skin patch tests and lymphocyte transformation tests. Immunohistochemistry revealed a massive cell infiltrate consisting of neutrophils in pustules and T cells in the dermis and epidermis. Expression of the potent neutrophil-attracting chemokine IL-8 was elevated in keratinocytes and infiltrating mononuclear cells. Drug-specific T cells were generated from the blood and skin of three patients, and phenotypic characterization showed a heterogeneous distribution of CD4/CD8 phenotype and of T-cell receptor Vβ-expression. Analysis of cytokine/chemokine profiles revealed that IL-8 is produced significantly more by drug-specific T cells from patients with AGEP compared with drug-specific T cells from patients that had non-AGEP exanthemas. In conclusion, our data demonstrate the involvement of drug-specific T cells in the pathomechanism of this rather rare and peculiar form of drug allergy. In addition, they indicate that even in some neutrophil-rich inflammatory responses specific T cells are engaged and might orchestrate the immune reaction. PMID:11390425

Total Marrow and Lymphoid Irradiation and Chemotherapy Before Donor Transplant in Treating Patients With Myelodysplastic Syndrome or Acute Leukemia

ClinicalTrials.gov

2018-03-27

Adult Acute Lymphoblastic Leukemia in Complete Remission; Acute Myeloid Leukemia in Remission; Previously Treated Myelodysplastic Syndrome; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Childhood Acute Lymphoblastic Leukemia in Complete Remission

CD4 T Cell Depletion Exacerbates Acute Mycobacterium tuberculosis While Reactivation of Latent Infection Is Dependent on Severity of Tissue Depletion in Cynomolgus Macaques

PubMed Central

Lin, Philana Ling; Rutledge, Tara; Green, Angela M.; Bigbee, Matthew; Fuhrman, Carl; Klein, Edwin

2012-01-01

Abstract CD4 T cells are believed to be important in protection against Mycobacterium tuberculosis, but the relative contribution to control of initial or latent infection is not known. Antibody-mediated depletion of CD4 T cells in M. tuberculosis-infected cynomolgus macaques was used to study the role of CD4 T cells during acute and latent infection. Anti-CD4 antibody severely reduced levels of CD4 T cells in blood, airways, and lymph nodes. Increased pathology and bacterial burden were observed in CD4-depleted monkeys during the first 8 weeks of infection compared to controls. CD4-depleted monkeys had greater interferon (IFN)-γ expression and altered expression of CD8 T cell activation markers. During latent infection, CD4 depletion resulted in clinical reactivation in only three of six monkeys. Reactivation was associated with lower CD4 T cells in the hilar lymph nodes. During both acute and latent infection, CD4 depletion was associated with reduced percentages of CXCR3+ expressing CD8 T cells, reported to be involved in T cell recruitment, regulatory function, and effector and memory T cell maturation. CXCR3+ CD8 T cells from hilar lymph nodes had more mycobacteria-specific cytokine expression and greater coexpression of multiple cytokines compared to CXCR3− CD8 T cells. CD4 T cells are required for protection against acute infection but reactivation from latent infection is dependent on the severity of depletion in the draining lymph nodes. CD4 depletion influences CD8 T cell function. This study has important implications for human HIV–M. tuberculosis coinfection. PMID:22480184

A phase 1, randomized, controlled dose-escalation study of EP-1300 polyepitope DNA vaccine against Plasmodium falciparum malaria administered via electroporation.

PubMed

Spearman, Paul; Mulligan, Mark; Anderson, Evan J; Shane, Andi L; Stephens, Kathy; Gibson, Theda; Hartwell, Brooke; Hannaman, Drew; Watson, Nora L; Singh, Karnail

2016-11-04

Plasmodium falciparum malaria is one of the leading infectious causes of childhood mortality in Africa. EP-1300 is a polyepitope plasmid DNA vaccine expressing 38 cytotoxic T cell epitopes and 16 helper T cell epitopes derived from P. falciparum antigens expressed predominantly in the liver phase of the parasite's life cycle. We performed a phase 1 randomized, placebo-controlled, dose escalation clinical trial of the EP-1300 DNA vaccine administered via electroporation using the TriGrid Delivery System device (Ichor Medical Systems). Although the delivery of the EP-1300 DNA vaccine via electroporation was safe, tolerability was less than that usually observed with standard needle and syringe intramuscular administration. This was primarily due to acute local discomfort at the administration site during electroporation. Despite the use of electroporation, the vaccine was poorly immunogenic. The reasons for the poor immunogenicity of this polyepitope DNA vaccine remain uncertain. ClinicalTrials.gov NCT01169077. Copyright © 2016 Elsevier Ltd. All rights reserved.

Acute Myeloid Leukemia (AML) (For Parents)

MedlinePlus

... an inorganic compound) is also used to treat kids with APL. Stem cell transplant (also called bone marrow transplant). This ... Juvenile Myelomonocytic Leukemia (JMML) Neutropenia Childhood Cancer Chemotherapy Stem Cell ... Kinds of Cancer Kids Get When Cancer Keeps You Home Types of ...

[Spontaneous bile duct perforation: a rare cause of acute abdominal pain during childhood].

PubMed

Ozdemir, Tunç; Akgül, Ahsen Karagözlü; Arpaz, Yağmur; Arikan, Ahmet

2008-07-01

Spontaneous perforation of the bile duct (SPBD) is a rare cause of acute abdominal pain during childhood. Pancreatico-biliary malfunction has been postulated to contribute to its etiology. Factors related to diagnosis and treatment and difference from the other common causes of acute abdominal pain are emphasized. Five patients (3 boys, 2 girls, mean age 4.6) were admitted with peritonitis and operated with initial diagnosis of perforated appendicitis. During laparotomy, SPBD was detected. Presentation, laboratory findings and operative technique of the patients were evaluated retrospectively. Common complaints were abdominal pain and bilious vomiting. Abdominal distention was present in all patients. Leukocytosis and mild hyperbilirubinemia were detected in 5, elevated serum transaminase levels in 4, hyperglycemia in 1 and constipation in 1 patient(s). Abdominal ultrasonography showed a large amount of free fluid. During laparotomy, sterile bile peritonitis was detected initially. After exploration, SPBD was seen. T-tube drainage of the bile duct was carried out. Patients were discharged after removal of the T-tubes. Pancreatico-biliary malfunction was detected in 4 of 5 patients. In patients with generalized peritonitis, elevated transaminase levels and hyperbilirubinemia, SPBD must be considered. Even though the T-tube drainage is the treatment of choice, Roux-en-Y hepatico-portoenterostomy may be mandatory in certain patients.

Childhood Hematopoietic Cell Transplantation (PDQ®)—Health Professional Version

Cancer.gov

Hematopoietic cell transplantation involves the infusion of blood stem cells (peripheral/umbilical cord blood, bone marrow) into a patient to reconstitute the blood system. Get detailed information about autologous and allogeneic transplant, including cell selection, HLA matching, and preparative regimens, and the acute complications and late effects of treatment in this summary for clinicians.

KU HAPLOINSUFFIENCY CAUSES A LYMPHOPROLIFERATIVE DISORDER OF IMMATURE T-CELL PRECURSORS DUE TO IKAROS MALFUNCTION

PubMed Central

Ozer, Zahide; Qazi, Sanjive; Ishkhanian, Rita; Hasty, Paul; Ma, Hong; Uckun, Fatih M.

2013-01-01

Ikaros (IK) malfunction has been implicated in the pathogenesis of acute lymphoblastic leukemia (ALL), the most common form of childhood cancer. Therefore, a stringent regulation of IK activity is very important. Here we provide unique genetic and biochemical evidence that the Ku protein components Ku70 and Ku80 act as positive regulators of IK function via formation of IK-Ku70 and IK-Ku80 heterodimers with augmented sequence-specific DNA binding activity. siRNA-mediated depletion of Ku70 or Ku80 reduced the sequence-specific DNA binding activity of IK in EMSA as well as the RT-PCR measured IK target gene expression levels in human cells. The interaction of Ku components with IK likely contributes to the anti-leukemic effects of IK as a tumor suppressor, because Ku70 as well as Ku80 haploinsuffiency in mice caused development of a lymphoproliferative disorder (LPD) involving CD2+CD4+CD8+CD1+IL7R+ thymic T-cell precursors with functional IK deficiency. PMID:24478815

Generating and Expanding Autologous Chimeric Antigen Receptor T Cells from Patients with Acute Myeloid Leukemia.

PubMed

Kenderian, Saad S; June, Carl H; Gill, Saar

2017-01-01

Adoptive transfer of genetically engineered T cells can lead to profound and durable responses in patients with hematologic malignancies, generating enormous enthusiasm among scientists, clinicians, patients, and biotechnology companies. The success of adoptive cellular immunotherapy depends upon the ability to manufacture good quality T cells. We discuss here the methodologies and reagents that are used to generate T cells for the preclinical study of chimeric antigen receptor T cell therapy for acute myeloid leukemia (AML).

High-resolution Antibody Array Analysis of Childhood Acute Leukemia Cells*

PubMed Central

Kanderova, Veronika; Kuzilkova, Daniela; Stuchly, Jan; Vaskova, Martina; Brdicka, Tomas; Fiser, Karel; Hrusak, Ondrej; Lund-Johansen, Fridtjof

2016-01-01

Acute leukemia is a disease pathologically manifested at both genomic and proteomic levels. Molecular genetic technologies are currently widely used in clinical research. In contrast, sensitive and high-throughput proteomic techniques for performing protein analyses in patient samples are still lacking. Here, we used a technology based on size exclusion chromatography followed by immunoprecipitation of target proteins with an antibody bead array (Size Exclusion Chromatography-Microsphere-based Affinity Proteomics, SEC-MAP) to detect hundreds of proteins from a single sample. In addition, we developed semi-automatic bioinformatics tools to adapt this technology for high-content proteomic screening of pediatric acute leukemia patients. To confirm the utility of SEC-MAP in leukemia immunophenotyping, we tested 31 leukemia diagnostic markers in parallel by SEC-MAP and flow cytometry. We identified 28 antibodies suitable for both techniques. Eighteen of them provided excellent quantitative correlation between SEC-MAP and flow cytometry (p < 0.05). Next, SEC-MAP was applied to examine 57 diagnostic samples from patients with acute leukemia. In this assay, we used 632 different antibodies and detected 501 targets. Of those, 47 targets were differentially expressed between at least two of the three acute leukemia subgroups. The CD markers correlated with immunophenotypic categories as expected. From non-CD markers, we found DBN1, PAX5, or PTK2 overexpressed in B-cell precursor acute lymphoblastic leukemias, LAT, SH2D1A, or STAT5A overexpressed in T-cell acute lymphoblastic leukemias, and HCK, GLUD1, or SYK overexpressed in acute myeloid leukemias. In addition, OPAL1 overexpression corresponded to ETV6-RUNX1 chromosomal translocation. In summary, we demonstrated that SEC-MAP technology is a powerful tool for detecting hundreds of proteins in clinical samples obtained from pediatric acute leukemia patients. It provides information about protein size and reveals differences in protein expression between particular leukemia subgroups. Forty-seven of SEC-MAP identified targets were validated by other conventional method in this study. PMID:26785729

Identification of germline susceptibility loci in ETV6-RUNX1-rearranged childhood acute lymphoblastic leukemia

PubMed Central

Ellinghaus, E; Stanulla, M; Richter, G; Ellinghaus, D; te Kronnie, G; Cario, G; Cazzaniga, G; Horstmann, M; Panzer Grümayer, R; Cavé, H; Trka, J; Cinek, O; Teigler-Schlegel, A; ElSharawy, A; Häsler, R; Nebel, A; Meissner, B; Bartram, T; Lescai, F; Franceschi, C; Giordan, M; Nürnberg, P; Heinzow, B; Zimmermann, M; Schreiber, S; Schrappe, M; Franke, A

2012-01-01

Acute lymphoblastic leukemia (ALL) is a malignant disease of the white blood cells. The etiology of ALL is believed to be multifactorial and likely to involve an interplay of environmental and genetic variables. We performed a genome-wide association study of 355 750 single-nucleotide polymorphisms (SNPs) in 474 controls and 419 childhood ALL cases characterized by a t(12;21)(p13;q22) — the most common chromosomal translocation observed in childhood ALL — which leads to an ETV6–RUNX1 gene fusion. The eight most strongly associated SNPs were followed-up in 951 ETV6-RUNX1-positive cases and 3061 controls from Germany/Austria and Italy, respectively. We identified a novel, genome-wide significant risk locus at 3q28 (TP63, rs17505102, PCMH=8.94 × 10−9, OR=0.65). The separate analysis of the combined German/Austrian sample only, revealed additional genome-wide significant associations at 11q11 (OR8U8, rs1945213, P=9.14 × 10−11, OR=0.69) and 8p21.3 (near INTS10, rs920590, P=6.12 × 10−9, OR=1.36). These associations and another association at 11p11.2 (PTPRJ, rs3942852, P=4.95 × 10−7, OR=0.72) remained significant in the German/Austrian replication panel after correction for multiple testing. Our findings demonstrate that germline genetic variation can specifically contribute to the risk of ETV6–RUNX1-positive childhood ALL. The identification of TP63 and PTPRJ as susceptibility genes emphasize the role of the TP53 gene family and the importance of proteins regulating cellular processes in connection with tumorigenesis. PMID:22076464

THERAPY-RELATED T/MYELOID MIXED PHENOTYPE ACUTE LEUKEMIA IN A PATIENT TREATED WITH CHEMOTHERAPY FOR CUTANEOUS DIFFUSE LARGE B CELL LYMPHOMA.

PubMed

Roberts, Evans; Oncale, Melody; Safah, Hana; Schmieg, John

2016-01-01

Mixed-phenotype acute leukemia is a rare form of leukemia that is associated with a poor prognosis. Most cases of mixed-phenotype acute leukemia are de novo. However, therapy-related mixed-phenotype acute leukemia can occur, and are often associated with exposure to topoisomerase-II inhibitors and alkylating agents. There are no known treatment guidelines for therapy-related mixed-phenotype acute leukemia. We present a patient with T/myeloid mixed-phenotype acute leukemia secondary to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone R-CHOP chemotherapy for primary cutaneous diffuse large B-cell lymphoma. The patient's leukemic cells express CD34, an immaturity marker, CD3, a T-cell marker, and myeloperoxidase, a myeloid marker, and her history of chemotherapy for previous lymphoma supports the diagnosis of therapy-related T/myeloid mixed phenotype acute leukemia. Clinicians should be aware that this entity could be associated with R-CHOP chemotherapy. Given the complexity in diagnosis, and lack of treatment guidelines, a further understanding of the pathological and genetic principles of therapy-related mixed-phenotype acute leukemia will assist in future efforts to treat and categorize these patients. Mixed phenotype acute leukemia is a rare entity that accounts for two to five percent of all acute leukemias. Therapy- related mixed phenotype acute leukemia is an exceedingly rare hematological neoplasm that accounts for less than one percent of acute leukemias. We describe a case of therapy-related T/myeloid mixed phenotype acute leukemia following rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone R-CHOP chemotherapy for primary cutaneous diffuse large B-cell lymphoma DLBCL. The patient is a 63-year-old female who presented with several cutaneous nodules diagnosed as primary cutaneous DLBCL. The patient received R-CHOP chemotherapy and achieved remission. She remained in remission for four years until she presented with dyspnea, night sweats, weakness, and diffuse lymphadenopathy. Her presentation was initially concerning for recurrent lymphoma; however, a bone marrow biopsy and aspirate and a lymph node biopsy revealed a distinct blast population consistent with T/myeloid mixed phenotype acute leukemia T/M-MPAL. Given the patient's history of previous chemotherapy exposure, our patient represents a case of therapy-related T/myeloid mixed phenotype acute leukemia t-MPAL.

Cytokine Release Syndrome After Chimeric Antigen Receptor T Cell Therapy for Acute Lymphoblastic Leukemia.

PubMed

Fitzgerald, Julie C; Weiss, Scott L; Maude, Shannon L; Barrett, David M; Lacey, Simon F; Melenhorst, J Joseph; Shaw, Pamela; Berg, Robert A; June, Carl H; Porter, David L; Frey, Noelle V; Grupp, Stephan A; Teachey, David T

2017-02-01

Initial success with chimeric antigen receptor-modified T cell therapy for relapsed/refractory acute lymphoblastic leukemia is leading to expanded use through multicenter trials. Cytokine release syndrome, the most severe toxicity, presents a novel critical illness syndrome with limited data regarding diagnosis, prognosis, and therapy. We sought to characterize the timing, severity, and intensive care management of cytokine release syndrome after chimeric antigen receptor-modified T cell therapy. Retrospective cohort study. Academic children's hospital. Thirty-nine subjects with relapsed/refractory acute lymphoblastic leukemia treated with chimeric antigen receptor-modified T cell therapy on a phase I/IIa clinical trial (ClinicalTrials.gov number NCT01626495). All subjects received chimeric antigen receptor-modified T cell therapy. Thirteen subjects with cardiovascular dysfunction were treated with the interleukin-6 receptor antibody tocilizumab. Eighteen subjects (46%) developed grade 3-4 cytokine release syndrome, with prolonged fever (median, 6.5 d), hyperferritinemia (median peak ferritin, 60,214 ng/mL), and organ dysfunction. Fourteen (36%) developed cardiovascular dysfunction treated with vasoactive infusions a median of 5 days after T cell therapy. Six (15%) developed acute respiratory failure treated with invasive mechanical ventilation a median of 6 days after T cell therapy; five met criteria for acute respiratory distress syndrome. Encephalopathy, hepatic, and renal dysfunction manifested later than cardiovascular and respiratory dysfunction. Subjects had a median of 15 organ dysfunction days (interquartile range, 8-20). Treatment with tocilizumab in 13 subjects resulted in rapid defervescence (median, 4 hr) and clinical improvement. Grade 3-4 cytokine release syndrome occurred in 46% of patients following T cell therapy for relapsed/refractory acute lymphoblastic leukemia. Clinicians should be aware of expanding use of this breakthrough therapy and implications for critical care units in cancer centers.

17-N-Allylamino-17-Demethoxygeldanamycin in Treating Young Patients With Relapsed or Refractory Solid Tumors or Leukemia

ClinicalTrials.gov

2013-06-03

Acute Undifferentiated Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Unspecified Childhood Solid Tumor, Protocol Specific

Involvements of γδT Lymphocytes in Acute and Chronic Skin Wound Repair.

PubMed

Xu, Peng; Fu, Xiujun; Xiao, Nin; Guo, Yuanyuan; Pei, Qing; Peng, Yinbo; Zhang, Yifan; Yao, Min

2017-08-01

Wound healing involves three stages including inflammation, proliferation, and tissue remodeling. The underlying mechanisms remain to be further elucidated. The inflammation is characterized by spatially and temporally changing patterns of various leukocyte subsets. It is regarded as the most crucial stage since the inflammatory response is instrumental to supplying various factors and cytokines that orchestrate healing events. As a subtype of T lymphocytes, γδ T cells play an important role in skin homeostasis, tumor immunosurveillance, and wound repair. However, either the dynamics of γδ T cells in healing process or the anticipated association of γδ T cells with chronic or refractory wounds were not well understood. In this study, we determine the dynamics of γδ T cells and γδ T cell-produced effectors during acute and chronic wound repair by establishing a third-degree burn model in mice skin or human skin from diabetic patients. Our data show that the involvement of γδ T cells in acute and chronic skin wound healing. The protein levels and mRNA expressions of γδ T cell-produced effectors were increased in acute healing model, whereas those effectors were decreased in chronic repair, suggesting γδ T cells are essential for wound repair. This study probes into the significant relevance of γδ T cells with effective wound repair and provides new enlightenments for the mechanisms of the formation of chronic and/or refractory wounds.

Early Virological and Immunological Events in Asymptomatic Epstein-Barr Virus Infection in African Children

PubMed Central

Jayasooriya, Shamanthi; de Silva, Thushan I.; Njie-jobe, Jainaba; Sanyang, Chilel; Leese, Alison M.; Bell, Andrew I.; McAulay, Karen A.; Yanchun, Peng; Long, Heather M.; Dong, Tao; Whittle, Hilton C.; Rickinson, Alan B.; Rowland-Jones, Sarah L.; Hislop, Andrew D.; Flanagan, Katie L.

2015-01-01

Epstein-Barr virus (EBV) infection often occurs in early childhood and is asymptomatic. However, if delayed until adolescence, primary infection may manifest as acute infectious mononucleosis (AIM), a febrile illness characterised by global CD8+ T-cell lymphocytosis, much of it reflecting a huge expansion of activated EBV-specific CD8+ T-cells. While the events of AIM have been intensely studied, little is known about how these relate to asymptomatic primary infection. Here Gambian children (14–18 months old, an age at which many acquire the virus) were followed for the ensuing six months, monitoring circulating EBV loads, antibody status against virus capsid antigen (VCA) and both total and virus-specific CD8+ T-cell numbers. Many children were IgG anti-VCA-positive and, though no longer IgM-positive, still retained high virus loads comparable to AIM patients and had detectable EBV-specific T-cells, some still expressing activation markers. Virus loads and the frequency/activation status of specific T-cells decreased over time, consistent with resolution of a relatively recent primary infection. Six children with similarly high EBV loads were IgM anti-VCA-positive, indicating very recent infection. In three of these donors with HLA types allowing MHC-tetramer analysis, highly activated EBV-specific T-cells were detectable in the blood with one individual epitope response reaching 15% of all CD8+ T-cells. That response was culled and the cells lost activation markers over time, just as seen in AIM. However, unlike AIM, these events occurred without marked expansion of total CD8+ numbers. Thus asymptomatic EBV infection in children elicits a virus-specific CD8+ T-cell response that can control the infection without over-expansion; conversely, in AIM it appears the CD8 over-expansion, rather than virus load per se, is the cause of disease symptoms. PMID:25816224

Bortezomib with chemotherapy is highly active in advanced B-precursor acute lymphoblastic leukemia: Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) Study.

PubMed

Messinger, Yoav H; Gaynon, Paul S; Sposto, Richard; van der Giessen, Jeannette; Eckroth, Elena; Malvar, Jemily; Bostrom, Bruce C

2012-07-12

Therapy of relapsed pediatric acute lymphoblastic leukemia (ALL) is hampered by low remission rates and high toxicity, especially in second and subsequent relapses. Our phase 1 study, T2005-003, showed that the combination of bortezomib with vincristine, dexamethasone, pegylated asparaginase, and doxorubicin had acceptable toxicity. We report the phase 2 expansion of this combination in patients with relapsed ALL who failed 2-3 previous regimens. Twenty-two patients with relapsed ALL were treated with bortezomib combined with this regimen; their ages ranged from 1 to 22 years, and they had either B-precursor ALL (n = 20) or T-cell ALL (n = 2). Grade 3 peripheral neuropathy developed in 2 (9%) patients. After 3 patients died from bacterial infections, treatment with vancomycin, levofloxacin, and voriconazole prophylaxis resulted in no further infectious mortality in the last 6 patients. Fourteen patients achieved complete remission (CR), and 2 achieved CR without platelet recovery, for an overall 73% response rate, meeting predefined criteria allowing for early closure. B-precursor patients faired best, with 16 of 20 (80%) CR + CR without platelet recovery, whereas the 2 patients with T-cell ALL did not respond. Thus, this combination of bortezomib with chemotherapy is active in B-precursor ALL, and prophylactic antibiotics may be useful in reducing mortality. Bortezomib merits further evaluation in combination therapy in pediatric B-precursor ALL. This study is registered at http://www.clinicaltrials.gov as NCT00440726.

Irradiated Donor Cells Following Stem Cell Transplant in Controlling Cancer in Patients With Hematologic Malignancies

ClinicalTrials.gov

2018-05-16

Acute Lymphoblastic Leukemia; Acute Myeloid Leukemia in Remission; Hematopoietic Cell Transplantation Recipient; JAK2 Gene Mutation; Loss of Chromosome 17p; Mantle Cell Lymphoma; Minimal Residual Disease; Myelodysplastic Syndrome; Non-Hodgkin Lymphoma; Plasma Cell Myeloma; RAS Family Gene Mutation; Recurrent Diffuse Large B-Cell Lymphoma; Recurrent Hematologic Malignancy; Recurrent Mature T- and NK-Cell Non-Hodgkin Lymphoma; Refractory Diffuse Large B-Cell Lymphoma; Refractory Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma; Therapy-Related Acute Myeloid Leukemia; Therapy-Related Myelodysplastic Syndrome; TP53 Gene Mutation

CAR-pNK Cell Immunotherapy in CD7 Positive Leukemia and Lymphoma

ClinicalTrials.gov

2016-12-04

Acute Myeloid Leukemia; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; T-cell Prolymphocytic Leukemia; T-cell Large Granular Lymphocytic Leukemia; Peripheral T-cell Lymphoma, NOS; Angioimmunoblastic T-cell Lymphoma; Extranodal NK/T-cell Lymphoma, Nasal Type; Enteropathy-type Intestinal T-cell Lymphoma; Hepatosplenic T-cell Lymphoma

Effects of Methylphenidate on Attention Deficits in Childhood Cancer Survivors

ClinicalTrials.gov

2015-03-16

ALL, Childhood; Leukemia, Lymphoblastic; Leukemia, Lymphoblastic, Acute; Leukemia, Lymphoblastic, Acute, L1; Leukemia, Lymphoblastic, Acute, L2; Leukemia, Lymphoblastic, Acute, Philadelphia-Positive; Leukemia, Lymphocytic, Acute; Leukemia, Lymphocytic, Acute, L1; Leukemia, Lymphocytic, Acute, L2; Lymphoblastic Leukemia; Lymphoblastic Leukemia, Acute; Lymphoblastic Leukemia, Acute, Childhood; Lymphoblastic Leukemia, Acute, L1; Lymphoblastic Leukemia, Acute, L2; Lymphoblastic Lymphoma; Lymphocytic Leukemia, Acute; Lymphocytic Leukemia, L1; Lymphocytic Leukemia, L2; Brain Tumors; Cancer of the Brain; Cancer of Brain; Malignant Primary Brain Tumors; Brain Neoplasms, Malignant

Tim-3 directly enhances CD8 T cell responses to acute Listeria monocytogenes infection

PubMed Central

Gorman, Jacob V.; Starbeck-Miller, Gabriel; Pham, Nhat-Long L.; Traver, Geri L.; Rothman, Paul B.; Harty, John T.; Colgan, John D.

2014-01-01

Tim-3 is a surface molecule expressed throughout the immune system that can mediate both stimulatory and inhibitory effects. Previous studies have provided evidence that Tim-3 functions to enforce CD8 T cell exhaustion, a dysfunctional state associated with chronic stimulation. In contrast, the role of Tim-3 in the regulation of CD8 T cell responses to acute and transient stimulation remains undefined. To address this knowledge gap, we examined how Tim-3 affects CD8 T cell responses to acute Listeria monocytogenes (LM) infection. Analysis of wild-type (WT) mice infected with LM revealed that Tim-3 was transiently expressed by activated CD8 T cells and was associated primarily with acquisition of an effector phenotype. Comparison of responses to LM by WT and Tim-3 KO mice showed that the absence of Tim-3 significantly reduced the magnitudes of both primary and secondary CD8 T cell responses, which correlated with decreased IFN-γ production and degranulation by Tim-3 KO cells stimulated with peptide antigen ex vivo. To address the T cell-intrinsic role of Tim-3, we analyzed responses to LM infection by WT and Tim-3 KO TCR-transgenic CD8 T cells following adoptive transfer into a shared WT host. In this setting, the accumulation of CD8 T cells and the generation of cytokine-producing cells were significantly reduced by the lack of Tim-3, demonstrating that this molecule has a direct effect on CD8 T cell function. Combined, our results suggest that Tim-3 can mediate a stimulatory effect on CD8 T cell responses to an acute infection. PMID:24567532

Donor Bone Marrow Transplant With or Without G-CSF in Treating Young Patients With Hematologic Cancer or Other Diseases

ClinicalTrials.gov

2017-03-29

Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Myeloid Leukemia in Remission; Childhood Chronic Myelogenous Leukemia; Childhood Myelodysplastic Syndromes; Chronic Phase Chronic Myelogenous Leukemia; de Novo Myelodysplastic Syndromes; Juvenile Myelomonocytic Leukemia; Previously Treated Myelodysplastic Syndromes; Recurrent Childhood Acute Lymphoblastic Leukemia; Secondary Myelodysplastic Syndromes

A gene expression signature that correlates with CD8+T cell expansion in acute Epstein Barr virus infection1

PubMed Central

Greenough, Thomas C.; Straubhaar, Juerg R.; Kamga, Larisa; Weiss, Eric R.; Brody, Robin M.; McManus, Margaret M.; Lambrecht, Linda K.; Somasundaran, Mohan; Luzuriaga, Katherine F.

2015-01-01

Virus specific CD8+ T cells expand dramatically during acute Epstein Barr virus (EBV) infection, and their persistence is important for lifelong control of EBV-related disease. To better define the generation and maintenance of these effective CD8+ T cell responses, we used microarrays to characterize gene expression in total and EBV-specific CD8+ T cells isolated from the peripheral blood of ten individuals followed from acute infectious mononucleosis (AIM) into convalescence (CONV). In total CD8+ T cells, differential expression of genes in AIM and CONV was most pronounced among those encoding proteins important in T cell activation/differentiation, cell division/metabolism, chemokines/cytokines and receptors, signaling and transcription factors (TF), immune effector functions, and negative regulators. Within these categories, we identified 28 genes that correlated with CD8+ T cell expansion in response to an acute EBV infection. In EBV-specific CD8+ T cells, we identified 33 genes that were differentially expressed in AIM and CONV. Two important TF, T-bet and Eomesodermin (Eomes), were upregulated and maintained at similar levels in both AIM and CONV; by contrast, protein expression declined from AIM to CONV. Expression of these TF varied among cells with different epitope specificities. Altogether, gene and protein expression patterns suggest that a large proportion, if not a majority of CD8+ T cells in AIM are virus-specific, activated, dividing, and primed to exert effector activities. High expression of T-bet and Eomes may help to maintain effector mechanisms in activated cells, and to enable proliferation and transition to earlier differentiation states in CONV. PMID:26416268

Donor Cell Composition and Reactivity Predict Risk of Acute Graft-versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation.

PubMed

Sairafi, Darius; Stikvoort, Arwen; Gertow, Jens; Mattsson, Jonas; Uhlin, Michael

2016-01-01

Background . Graft-versus-host disease (GVHD) is a serious complication after allogeneic hematopoietic stem cell transplantation (HSCT). We designed a functional assay for assessment of individual risk for acute GVHD. Study Design and Methods . Blood samples were collected from patients and donors before HSCT. Two groups of seven patients each were selected, one in which individuals developed acute GVHD grades II-IV and one in which none showed any clinical signs of GVHD. Peripheral blood mononuclear cells (PBMCs) isolated from donors were incubated in mixed lymphocyte cultures (MLCs) with recipient PBMCs. The cells were characterized by flow cytometry before and after MLC. Results . Samples from donors in the GVHD group contained significantly lower frequencies of naïve γδ T-cells and T-cells expressing NK-cell markers CD56 and CD94. Donor samples in this group also exhibited lower frequencies of naïve CD95 + T-cells compared to controls. After MLC, there were dissimilarities in the CD4/CD8 T-cell ratio and frequency of CD69 + T-cells between the two patient groups, with the non-GVHD group showing higher frequencies of CD8 + and CD69 + T-cells. Conclusion . We conclude that a thorough flow cytometric analysis of donor cells for phenotype and allogeneic reactivity may be of value when assessing pretransplant risk for severe acute GVHD.

Gene expression overlap affects karyotype prediction in pediatric acute lymphoblastic leukemia

DOE PAGES

Martin, S. B.; Mosquera-Caro, M. P.; Potter, J. W.; ...

2007-04-05

Leukemia is the most common childhood malignancy in the United States. Acute lymphoblastic leukemia (ALL) accounts for 75% of new leukemia cases in children. Although the outcome for children with ALL has improved dramatically over the past three decades, 25% of children with ALL still develop recurrent disease. Current risk classification schemes in pediatric ALL use clinical and laboratory parameters such as age and initial white blood cell count, as well as the presence of specific ALL-associated cytogenetic or molecular genetic abnormalities. Stratification based on cytogenetic analysis and molecular genetic detection consider B precursor ALL translocations such as t(12;21)(TEL-AML1), t(1;19)(E2A-PBX1)more » and t(9;22)(BCR-ABL), as well as numerical imbalances such as hyperdiploidy, specific chromosome trisomies or hypodiploidy. Despite such efforts, current diagnosis and risk classification schemes in pediatric ALL remain imprecise. In particular, it is likely that a significant number of higher-risk children are currently overtreated and could be cured with less intensive regimens, resulting in fewer toxicities and long-term side effects. Finally and conversely, a significant number of children in lower-risk categories still relapse and precise means to prospectively identify them have remained elusive.« less

CAR-T cells and allogeneic hematopoietic stem cell transplantation for relapsed/refractory B-cell acute lymphoblastic leukemia.

PubMed

Liu, Jun; Zhang, Xi; Zhong, Jiang F; Zhang, Cheng

2017-10-01

Relapsed/refractory acute lymphoblastic leukemia (ALL) has a low remission rate after chemotherapy, a high relapse rate and poor long-term survival even when allogeneic hematopoietic stem cell transplantation (allo-HSCT) is performed. Chimeric antigen receptors redirected T cells (CAR-T cells) can enhance disease remission with a favorable outcome for relapsed/refractory ALL, though some cases quickly relapsed after CAR-T cell treatment. Thus, treatment with CAR-T cells followed by allo-HSCT may be the best way to treat relapsed/refractory ALL. In this review, we first discuss the different types of CAR-T cells. We then discuss the treatment of relapsed/refractory ALL using only CAR-T cells. Finally, we discuss the use of CAR-T cells, followed by allo-HSCT, for the treatment of relapsed/refractory ALL.

Telomere length dynamics in human memory T cells specific for viruses causing acute or latent infections

PubMed Central

2013-01-01

Background Declining telomere length (TL) is associated with T cell senescence. While TL in naïve and memory T cells declines with increasing age, there is limited data on TL dynamics in virus-specific memory CD4+ T cells in healthy adults. We combined BrdU-labeling of virus-stimulated T cells followed with flow cytometry-fluorescent in situ hybridization for TL determination. We analyzed TL in T cells specific for several virus infections: non-recurring acute (vaccinia virus, VACV), recurring-acute (influenza A virus, IAV), and reactivating viruses (varicella-zoster virus, VZV, and cytomegalovirus, CMV) in 10 healthy subjects. Additionally, five subjects provided multiple blood samples separated by up to 10 years. Results VACV- and CMV-specific T cells had longer average TL than IAV-specific CD4+ T cells. Although most virus-specific cells were CD45RA-, we observed a minor population of BrdU+ CD45RA+ T cells characterized by long telomeres. Longitudinal analysis demonstrated a slow decline in average TL in virus-specific T cells. However, in one subject, VZV reactivation led to an increase in average TL in VZV-specific memory T cells, suggesting a conversion of longer TL cells from the naïve T cell repertoire. Conclusions TLs in memory CD4+ T cells in otherwise healthy adults are heterogeneous and follow distinct virus-specific kinetics. These findings suggests that the distribution of TL and the creation and maintenance of long TL memory T cells could be important for the persistence of long-lived T cell memory. PMID:23971624

Telomere length dynamics in human memory T cells specific for viruses causing acute or latent infections.

PubMed

O'Bryan, Joel M; Woda, Marcia; Co, Mary; Mathew, Anuja; Rothman, Alan L

2013-08-26

Declining telomere length (TL) is associated with T cell senescence. While TL in naïve and memory T cells declines with increasing age, there is limited data on TL dynamics in virus-specific memory CD4+ T cells in healthy adults. We combined BrdU-labeling of virus-stimulated T cells followed with flow cytometry-fluorescent in situ hybridization for TL determination. We analyzed TL in T cells specific for several virus infections: non-recurring acute (vaccinia virus, VACV), recurring-acute (influenza A virus, IAV), and reactivating viruses (varicella-zoster virus, VZV, and cytomegalovirus, CMV) in 10 healthy subjects. Additionally, five subjects provided multiple blood samples separated by up to 10 years. VACV- and CMV-specific T cells had longer average TL than IAV-specific CD4+ T cells. Although most virus-specific cells were CD45RA-, we observed a minor population of BrdU+ CD45RA+ T cells characterized by long telomeres. Longitudinal analysis demonstrated a slow decline in average TL in virus-specific T cells. However, in one subject, VZV reactivation led to an increase in average TL in VZV-specific memory T cells, suggesting a conversion of longer TL cells from the naïve T cell repertoire. TLs in memory CD4+ T cells in otherwise healthy adults are heterogeneous and follow distinct virus-specific kinetics. These findings suggests that the distribution of TL and the creation and maintenance of long TL memory T cells could be important for the persistence of long-lived T cell memory.

Acute complications of sickle cell disease in children.

PubMed

2001-05-01

Sickle cell disease is a recessively inherited condition in which synthesis of haemoglobin is abnormal. The disease, which occurs mainly in people of African, African-Caribbean, Indian, Mediterranean and Middle Eastern descent, is characterised by chronic anaemia, susceptibility to infection, bouts of severe pain and organ dysfunction. While the life expectancy for patients has improved, from a median survival age of 14 years in the 1970s among those homozygous for the sickle haemoglobin gene to survival into the mid-40s, childhood remains a period of peak mortality and morbidity. Here, we discuss the acute complications of sickle cell disease in children, concentrating on the management of the acutely unwell child.

Acute Activation of Metabolic Syndrome Components in Pediatric Acute Lymphoblastic Leukemia Patients Treated with Dexamethasone

PubMed Central

Warris, Lidewij T.; van den Akker, Erica L. T.; Bierings, Marc B.; van den Bos, Cor; Zwaan, Christian M.; Sassen, Sebastiaan D. T.; Tissing, Wim J. E.; Veening, Margreet A.; Pieters, Rob; van den Heuvel-Eibrink, Marry M.

2016-01-01

Although dexamethasone is highly effective in the treatment of pediatric acute lymphoblastic leukemia (ALL), it can cause serious metabolic side effects. Because studies regarding the effects of dexamethasone are limited by their small scale, we prospectively studied the direct effects of treating pediatric ALL with dexamethasone administration with respect to activation of components of metabolic syndrome (MetS); in addition, we investigated whether these side effects were correlated with the level of dexamethasone. Fifty pediatric patients (3–16 years of age) with ALL were studied during a 5-day dexamethasone course during the maintenance phase of the Dutch Childhood Oncology Group ALL-10 and ALL-11 protocols. Fasting insulin, glucose, total cholesterol, HDL, LDL, and triglycerides levels were measured at baseline (before the start of dexamethasone; T1) and on the fifth day of treatment (T2). Dexamethasone trough levels were measured at T2. We found that dexamethasone treatment significantly increased the following fasting serum levels (P<0.05): HDL, LDL, total cholesterol, triglycerides, glucose, and insulin. In addition, dexamethasone increased insulin resistance (HOMA-IR>3.4) from 8% to 85% (P<0.01). Dexamethasone treatment also significantly increased the diastolic and systolic blood pressure. Lastly, dexamethasone trough levels (N = 24) were directly correlated with high glucose levels at T2, but not with other parameters. These results indicate that dexamethasone treatment acutely induces three components of the MetS. Together with the weight gain typically associated with dexamethasone treatment, these factors may contribute to the higher prevalence of MetS and cardiovascular risk among survivors of childhood leukemia who received dexamethasone treatment. PMID:27362350

Th17/T regulator cell balance and NK cell numbers in relation to psychosis liability and social stress reactivity.

PubMed

Counotte, J; Drexhage, H A; Wijkhuijs, J M; Pot-Kolder, R; Bergink, V; Hoek, H W; Veling, W

2018-03-01

Psychotic disorders are characterized by a deranged immune system, including altered number and function of Natural Killer (NK) and T cells. Psychotic disorders arise from an interaction between genetic vulnerability and exposure to environmental risk factors. Exposure to social adversity during early life is particularly relevant to psychosis risk and is thought to increase reactivity to subsequent minor daily social stressors. Virtual reality allows controlled experimental exposure to virtual social stressors. To investigate the interplay between social adversity during early life, cell numbers of NK cells and T helper subsets and social stress reactivity in relation to psychosis liability. Circulating numbers of Th1, Th2, Th17, T regulator and NK cells were determined using flow cytometry in 80 participants with low psychosis liability (46 healthy controls and 34 siblings) and 53 participants with high psychosis liability (14 ultra-high risk (UHR) patients and 39 recent-onset psychosis patients), with and without the experience of childhood trauma. We examined if cell numbers predicted subjective stress when participants were exposed to social stressors (crowdedness, hostility and being part of an ethnic minority) in a virtual reality environment. There were no significant group differences in Th1, Th2, Th17, T regulator and NK cell numbers between groups with a high or low liability for psychosis. However, in the high psychosis liability group, childhood trauma was associated with increased Th17 cell numbers (p = 0.028). Moreover, in the high psychosis liability group increased T regulator and decreased NK cell numbers predicted stress experience during exposure to virtual social stressors (p = 0.015 and p = 0.009 for T regulator and NK cells, respectively). A deranged Th17/T regulator balance and a reduced NK cell number are associated intermediate biological factors in the relation childhood trauma, psychosis liability and social stress reactivity. Copyright © 2018 Elsevier Inc. All rights reserved.

Terminal deoxynucleotidyl transferase in the diagnosis of leukemia and malignant lymphoma.

PubMed

Kung, P C; Long, J C; McCaffrey, R P; Ratliff, R L; Harrison, T A; Baltimore, D

1978-05-01

Neoplastic cells from 253 patients with leukemia and 46 patients with malignant lymphoma were studied for the presence of terminal deoxynucleotidyl transferase (TdT) by biochemical and fluorescent antibody technics. TdT was detected in circulating blast cells from 73 of 77 patients with acute lymphoblastic leukemia, 24 of 72 patients with chronic myelogenous leukemia examined during the blastic phase of the disorder and in cell suspensions of lymph nodes from nine of nine patients with diffuse lymphoblastic lymphoma. Blast cells from six of 10 patients with acute undifferentiated leukemia were TdT positive, but the enzyme was found in only two of 55 patients with acute myeloblastic leukemia. TdT was not detected in other lymphocytic or granulocytic leukemias or in other types of malignant lymphomas. The fluorescent antibody assay for TdT permits rapid and specific identification of the enzyme in single cells. The TdT assay is clinically useful in confirming the diagnosis of acute lymphoblastic leukemia, evaluating patients with blastic chronic myelogenous leukemia, and distinguishing patients with lymphoblastic lymphoma, whose natural history includes rapid extranodal dissemination, from patients with other poorly differentiated malignant lymphomas.

BMS-214662 in Treating Patients With Acute Leukemia, Myelodysplastic Syndrome, or Chronic Myeloid Leukemia

ClinicalTrials.gov

2013-01-22

Adult Acute Promyelocytic Leukemia (M3); Blastic Phase Chronic Myelogenous Leukemia; Childhood Myelodysplastic Syndromes; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Refractory Anemia With Excess Blasts; Refractory Anemia With Excess Blasts in Transformation; Relapsing Chronic Myelogenous Leukemia

Acute primary infection with cytomegalovirus (CMV) in kidney transplant recipients results in the appearance of a phenotypically aberrant CD8+ T cell population.

PubMed

van Dam, J G; Damoiseaux, J G; Christiaans, M H; Bruggeman, C A

2000-01-01

Human cytomegalovirus (CMV) is a beta-herpesvirus that causes a chronic subclinical infection in healthy man. The immune system is unable to eliminate the virus completely, allowing virus to persist in a latent state. In the immunocompromised host, this equilibrium is disturbed, resulting in a clinical infection. In immunocompromised rats, clinical CMV infection is associated with an increase in NK cells and CD8+ T cells, including a phenotypically aberrant CD8+ T cell population. Using flow cytometry, we examined the effect of acute CMV infection on the composition of leukocyte subsets in immunocompromised patients. Therefore, we used peripheral blood of CMV seronegative patients receiving a kidney from a seronegative (control group) or a seropositive donor. Of the patients receiving a seropositive kidney, only the patients undergoing acute CMV infection were included (experimental group). Special attention was paid to the phenotype of the cytotoxic T cells. The development of acute CMV infection resulted in an increased NK cell number and an activation of both CD4+ and CD8+ T cells, as determined by HLA-DR expression. An aberrant CD8+ T cell subset with decreased expression of CD8 and TCR alphabeta appeared in the infected patients. Furthermore, the size of this subpopulation of CD8+ T cells is positively correlated with the viral load.

CEOP/IVE/GDP Compared With CEOP as the First-line Therapy for Newly Diagnosed Adult Patients With PTCL

ClinicalTrials.gov

2016-04-18

Peripheral T-Cell Lymphoma; Angioimmunoblastic T Cell Lymphoma; ALK-negative Anaplastic Large Cell Lymphoma; Enteropathy Associated T Cell Lymphoma; Subcutaneous Panniculitis Like T Cell Lymphoma; Acute Adult T-Cell Leukemia/Lymphoma

[Acute lymphoblastic leukemia of T progenitors: from biology to clinics].

PubMed

Genescà, Eulàlia; Ribera, Jordi; Ribera, Josep-Maria

2015-03-09

Acute lymphoblastic leukemia (ALL) is the most common cancer in children and the main cause of morbidity among childhood blood disorders. There are 2 subtypes according to the affected lymphoid progenitor: B-ALL and T-ALL. The T-ALL is the less common and, although historically was associated with poor prognosis in both adults and children, at present, treatment outcomes do not differ significantly between the 2 types of ALL. The T-ALL subtype is the most complex and heterogeneous at the genetic level and currently the one with less new therapeutic alternatives available. This trend is changing thanks to the remarkable progress upon understanding its biology. This review summarizes the most recent and important biological findings in T-ALL and their possible therapeutic implications. Copyright © 2013 Elsevier España, S.L.U. All rights reserved.

Polyclonal proliferation of activated suppressor/cytotoxic T cells with transient depression of natural killer cell function in acute infectious mononucleosis.

PubMed Central

Williams, M L; Loughran, T P; Kidd, P G; Starkebaum, G A

1989-01-01

In acute infectious mononucleosis large numbers of atypical lymphocytes proliferate in response to B cells infected with Epstein-Barr virus, generally resulting in a self-limited illness. Although both T-cells and NK cells are known to be involved, the precise origin of the large granular lymphocytes in this disorder is incompletely understood. Using two-colour immunofluorescent flow cytometry, we sequentially examined the phenotype of selected T cell and NK cell subsets from nine patients with infectious mononucleosis. In parallel, we determined whether these lymphocytes utilized a restricted repertoire of the T cell receptor gene and also measured their NK activity. Our results show that in acute infectious mononucleosis there was a greater than three-fold increase in T lymphocytes with the phenotype CD2+, CD3+, CD8+ and DR+. A modest increase in Leu7(HNK1)+ and CD4+ T cells was also seen. In addition, there was a three-fold increase in cells coexpressing CD3- and CD16+, the phenotype reported to represent most NK cells. In spite of this latter finding, however, a marked decrease in NK function was found at the time of diagnosis, gradually returning to normal by day 28. Finally, Southern blot analysis of DNA from patient lymphocytes showed polyclonal rearrangements of the T cell receptor beta chain gene. These studies indicate that the proliferation of activated suppressor/cytotoxic T lymphocytes in acute infectious mononucleosis is polyclonal and is associated with transient depression of NK function. Images Fig. 2 PMID:2527653

Sirolimus and Mycophenolate Mofetil in Preventing GVHD in Patients With Hematologic Malignancies Undergoing HSCT

ClinicalTrials.gov

2018-04-04

Adult Hodgkin Lymphoma; Adult Myelodysplastic Syndrome; Blast Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Childhood Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Childhood Hodgkin Lymphoma; Childhood Myelodysplastic Syndrome; Chronic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Myelofibrosis; Primary Myelofibrosis; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Non-Hodgkin Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Non-Hodgkin Lymphoma; Recurrent Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Refractory Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Refractory Non-Hodgkin Lymphoma

Breast-feeding and childhood cancer: A systematic review with metaanalysis.

PubMed

Martin, Richard M; Gunnell, David; Owen, Christopher G; Smith, George Davey

2005-12-20

It has been suggested that breast milk may play a role in the prevention of certain childhood cancers. We undertook a systematic review of published studies investigating the association between breast-feeding and childhood cancers using Medline (1966 to June 2004), supplemented with auto alerts and manual searches. Analyses are based on odds ratios for specific cancers among those ever breast-fed compared with those never breast-fed, pooled using random-effects models. Forty-nine publications were potentially relevant; of these, 26 provided odds ratio estimates for at least one childhood cancer outcome and were included in metaanalyses. Overall, 92% of the studies were case-control studies, 85% relied on long-term recall of feeding history, only 8% examined breast-feeding exclusivity and control response rates were under 80% in over half. Metaanalyses suggested lower risks associated with having been breast-fed of 9% (95% CI = 2-16%) for acute lymphoblastic leukemia, 24% (3-40%) for Hodgkin's disease and 41% (22-56%) for neuroblastoma, with little between-study heterogeneity. The estimates for Hodgkin's disease and neuroblastoma, however, were driven by single studies. There was little evidence that breast-feeding was associated with acute nonlymphoblastic leukemia, non-Hodgkin's lymphoma, central nervous system cancers, malignant germ cell tumors, juvenile bone tumors, or other solid cancers. In conclusion, ever having been breast-fed is inversely associated with acute lymphoblastic leukemia, Hodgkin's disease and neuroblastoma in childhood, but noncausal explanations are possible. Even if causal, the public health importance of these associations may be small. Our estimates suggest that increasing breast-feeding from 50% to 100% would prevent at most 5% of cases of childhood acute leukemia or lymphoma. (c) 2005 Wiley-Liss, Inc.

CD47-ligation induced cell death in T-acute lymphoblastic leukemia.

PubMed

Leclair, Pascal; Liu, Chi-Chao; Monajemi, Mahdis; Reid, Gregor S; Sly, Laura M; Lim, Chinten James

2018-05-10

CD47 is a cell-surface marker well recognized for its anti-phagocytic functions. As such, an emerging avenue for targeted cancer therapies involves neutralizing the anti-phagocytic function using monoclonal antibodies (mAbs) to enhance tumour cell immunogenicity. A lesser known consequence of CD47 receptor ligation is the direct induction of tumour cell death. While several mAbs and their derivatives with this property have been studied, the best characterized is the commercially available mAb B6H12, which requires immobilization for induction of cell death. Here, we describe a commercially available mAb, CC2C6, which induces T-cell acute lymphoblastic leukemia (ALL) cell death in soluble form. Soluble CC2C6 induces CD47-dependent cell death in a manner consistent with immobilized B6H12, which is characterized by mitochondrial deficiencies but is independent of caspase activation. Titration studies indicated that CC2C6 shares a common CD47-epitope with B6H12. Importantly, CC2C6 retains the anti-phagocytic neutralizing function, thus possessing dual anti-tumour properties. Although CD47-ligation induced cell death occurs in a caspase-independent manner, CC2C6 was found to stimulate increases in Mcl-1 and NOXA levels, two Bcl-2 family proteins that govern the intrinsic apoptosis pathway. Further analysis revealed that the ratio of Mcl-1:NOXA were minimally altered for cells treated with CC2C6, in comparison to cells treated with agents that induced caspase-dependent apoptosis which alter this ratio in favour of NOXA. Finally, we found that CC2C6 can synergize with low dose chemotherapeutic agents that induce classical apoptosis, giving rise to the possibility of an effective combination treatment with reduced long-term sequelae associated with high-dose chemotherapies in childhood ALL.

Genetically Modified T-cell Immunotherapy in Treating Patients With Relapsed/Refractory Acute Myeloid Leukemia and Persistent/Recurrent Blastic Plasmacytoid Dendritic Cell Neoplasm

ClinicalTrials.gov

2018-03-02

Adult Acute Myeloid Leukemia in Remission; Acute Biphenotypic Leukemia; Early Relapse of Acute Myeloid Leukemia; Late Relapse of Acute Myeloid Leukemia; Recurrent Adult Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Blastic Plasmacytoid Dendritic Cell Neoplasm; Acute Myeloid Leukemia; Adult Acute Lymphoblastic Leukemia; Interleukin-3 Receptor Subunit Alpha Positive; Minimal Residual Disease; Refractory Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

Infection Prophylaxis and Management in Treating Cytomegalovirus (CMV) Infection in Patients With Hematologic Malignancies Previously Treated With Donor Stem Cell Transplant

ClinicalTrials.gov

2015-06-03

Hematopoietic/Lymphoid Cancer; Accelerated Phase Chronic Myelogenous Leukemia; Acute Undifferentiated Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Grade III Lymphomatoid Granulomatosis; Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Aplastic Anemia; Atypical Chronic Myeloid Leukemia, BCR-ABL Negative; Blastic Phase Chronic Myelogenous Leukemia; Chronic Eosinophilic Leukemia; Chronic Myelomonocytic Leukemia; Chronic Neutrophilic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; Contiguous Stage II Adult Burkitt Lymphoma; Contiguous Stage II Adult Diffuse Large Cell Lymphoma; Contiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Contiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Contiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Contiguous Stage II Adult Lymphoblastic Lymphoma; Contiguous Stage II Grade 1 Follicular Lymphoma; Contiguous Stage II Grade 2 Follicular Lymphoma; Contiguous Stage II Grade 3 Follicular Lymphoma; Contiguous Stage II Mantle Cell Lymphoma; Contiguous Stage II Marginal Zone Lymphoma; Contiguous Stage II Small Lymphocytic Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Cytomegalovirus Infection; de Novo Myelodysplastic Syndromes; Essential Thrombocythemia; Extramedullary Plasmacytoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Intraocular Lymphoma; Isolated Plasmacytoma of Bone; Mast Cell Leukemia; Meningeal Chronic Myelogenous Leukemia; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Burkitt Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Noncontiguous Stage II Adult Lymphoblastic Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Polycythemia Vera; Post-transplant Lymphoproliferative Disorder; Previously Treated Myelodysplastic Syndromes; Primary Myelofibrosis; Primary Systemic Amyloidosis; Progressive Hairy Cell Leukemia, Initial Treatment; Prolymphocytic Leukemia; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Refractory Multiple Myeloma; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Secondary Myelofibrosis; Splenic Marginal Zone Lymphoma; Stage 0 Chronic Lymphocytic Leukemia; Stage I Adult Burkitt Lymphoma; Stage I Adult Diffuse Large Cell Lymphoma; Stage I Adult Diffuse Mixed Cell Lymphoma; Stage I Adult Diffuse Small Cleaved Cell Lymphoma; Stage I Adult Hodgkin Lymphoma; Stage I Adult Immunoblastic Large Cell Lymphoma; Stage I Adult Lymphoblastic Lymphoma; Stage I Adult T-cell Leukemia/Lymphoma; Stage I Chronic Lymphocytic Leukemia; Stage I Cutaneous T-cell Non-Hodgkin Lymphoma; Stage I Grade 1 Follicular Lymphoma; Stage I Grade 2 Follicular Lymphoma; Stage I Grade 3 Follicular Lymphoma; Stage I Mantle Cell Lymphoma; Stage I Marginal Zone Lymphoma; Stage I Multiple Myeloma; Stage I Mycosis Fungoides/Sezary Syndrome; Stage I Small Lymphocytic Lymphoma; Stage II Adult Hodgkin Lymphoma; Stage II Adult T-cell Leukemia/Lymphoma; Stage II Chronic Lymphocytic Leukemia; Stage II Cutaneous T-cell Non-Hodgkin Lymphoma; Stage II Multiple Myeloma; Stage II Mycosis Fungoides/Sezary Syndrome; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Hodgkin Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Adult T-cell Leukemia/Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Cutaneous T-cell Non-Hodgkin Lymphoma; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Multiple Myeloma; Stage III Mycosis Fungoides/Sezary Syndrome; Stage III Small Lymphocytic Lymphoma; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Hodgkin Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Adult T-cell Leukemia/Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Mycosis Fungoides/Sezary Syndrome; Stage IV Small Lymphocytic Lymphoma; T-cell Large Granular Lymphocyte Leukemia; Waldenstrom Macroglobulinemia

Epstein-Barr virus-associated T/natural killer-cell lymphoproliferative disorders.

PubMed

Park, Sanghui; Ko, Young H

2014-01-01

Primary infection with Epstein-Barr virus (EBV) is usually asymptomatic and, in a normal host, EBV remains latent in B cells after primary infection for the remainder of life. Uncommonly, EBV can infect T or natural killer (NK) cells in a person with a defect in innate immunity, and EBV infection can cause unique systemic lymphoproliferative diseases (LPD) of childhood. Primary infection in young children can be complicated by hemophagocytic lymphohistiocytosis or fulminant systemic T-cell LPD of childhood. Uncommonly, patients can develop chronic active EBV (CAEBV) disease-type T/NK LPD, which includes CAEBV infection of the systemic form, hydroa vacciniforme-like T-cell LPD, and mosquito-bite hypersensitivity. The clinical course of CAEBV disease-type T/NK LPD can be smoldering, persistent or progressive, depending on the balance between viral factors and host immunity. Aggressive NK-cell leukemia, hydroa vacciniforme-like T-cell lymphoma, or uncommonly extranodal NK/T-cell lymphoma can develop in children and young adults with CAEBV disease-type T/NK-cell LPD. Extranodal T/NK-cell lymphoma is a disease of adults, and its incidence begins to increase in the third decade and comprises the major subtype of T/NK LPD throughout life. Aggressive NK-cell leukemia and nodal T/NK-cell lymphoma of the elderly are fulminant diseases, and immune senescence may be an important pathogenetic factor. This review describes the current progress in identifying different types of EBV-associated T/NK-cell LPD and includes a brief presentation of data from Korea. © 2014 Japanese Dermatological Association.

Parental occupational pesticide exposure and the risk of childhood leukemia in the offspring: Findings from the Childhood Leukemia International Consortium

PubMed Central

Bailey, Helen D; Fritschi, Lin; Infante-Rivard, Claire; Glass, Deborah C; Miligi, Lucia; Dockerty, John D; Lightfoot, Tracy; Clavel, Jacqueline; Roman, Eve; Spector, Logan G; Kaatsch, Peter; Metayer, Catherine; Magnani, Corrado; Milne, Elizabeth; Polychronopoulou, Sophia; Simpson, Jill; Rudant, Jérémie; Sidi, Vasiliki; Rondelli, Roberto; Orsi, Laurent; Kang, Alice; Petridou, Eleni; Schüz, Joachim

2014-01-01

Maternal occupational pesticide exposure during pregnancy and/or paternal occupational pesticide exposure around conception have been suggested to increase risk of leukemia in the offspring. With a view to providing insight in this area we pooled individual level data from 13 case-control studies participating in the Childhood Leukemia International Consortium (CLIC). Occupational data were harmonized to a compatible format. Pooled individual analyses were undertaken using unconditional logistic regression. Using exposure data from mothers of 8,236 cases, and 14,850 controls, and from fathers of 8,169 cases and 14,201 controls the odds ratio (OR) for maternal exposure during pregnancy and the risk of acute lymphoblastic leukemia (ALL) was 1.01 (95% confidence interval (CI) 0.78, 1.30) and for paternal exposure around conception 1.20 (95% 1.06, 1.38). For acute myeloid leukemia (AML), the OR for maternal exposure during pregnancy was 1.94 (CI 1.19, 3.18) and for paternal exposure around conception 0.91 (CI 0.66, 1.24.) based on data from 1,329 case and 12,141 control mothers, and 1,231 case and 11,383 control fathers. Our finding of a significantly increased risk of AML in the offspring with maternal exposure to pesticides during pregnancy is consistent with previous reports. We also found a slight increase in risk of ALL with paternal exposure around conception which appeared to be more evident in children diagnosed at the age of five years or more and those with T cell ALL which raises interesting questions on possible mechanisms. PMID:24700406

[Acute myeloid leukemia].

PubMed

Tabuchi, Ken

2007-02-01

The annual incident rate of pediatric acute myeloid leukemia (AML) is now 10 per million in Japan, against 5 to 9 per million in the USA and Europe. Overall long-term survival has now been achieved for more than 50% of pediatric patients with AML in the USA and in Europe. The prognostic factors of pediatric AML were analyzed,and patients with AML were classified according to prognostic factors. The t(15;17), inv(16) and t(8;21) have emerged as predictors of good prognosis in children with AML. Monosomy 7, monosomy 5 and del (5 q) abnormalities showed a poor prognosis. In addition to chromosomal deletions, FLT 3/ITD identifies pediatric patients with a particularly poor prognosis. Clinical trials of AML feature intensive chemotherapy with or without subsequent stem cell transplantation. Risk group stratification is becoming increasingly important in planning AML therapy. APL can be distinguished from other subtypes of AML by virtue of its excellent response and overall outcome as a result of differentiation therapy with ATRA. Children with Down syndrome and AML have been shown to have a superior prognosis to AML therapy compared to other children with AML. The results of the Japan Cooperative Study Group protocol ANLL 91 was one of the best previously reported in the literature. With the consideration of quality of life (QOL), risk-adapted therapy was introduced in the AML 99 trial conducted by the Japanese Childhood AML Cooperative Study Group. A high survival rate of 79% at 3 years was achieved for childhood de novo AML in the AML 99 trial. To evaluate the efficacy and safety of the treatment strategy according to risk stratification based on leukemia cell biology and response to the initial induction therapy in children with AML, the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) has organized multi-center phase II trials in children with newly diagnosed AML.

Profound CD4+/CCR5+ T cell expansion is induced by CD8+ lymphocyte depletion but does not account for accelerated SIV pathogenesis.

PubMed

Okoye, Afam; Park, Haesun; Rohankhedkar, Mukta; Coyne-Johnson, Lia; Lum, Richard; Walker, Joshua M; Planer, Shannon L; Legasse, Alfred W; Sylwester, Andrew W; Piatak, Michael; Lifson, Jeffrey D; Sodora, Donald L; Villinger, Francois; Axthelm, Michael K; Schmitz, Joern E; Picker, Louis J

2009-07-06

Depletion of CD8(+) lymphocytes during acute simian immunodeficiency virus (SIV) infection of rhesus macaques (RMs) results in irreversible prolongation of peak-level viral replication and rapid disease progression, consistent with a major role for CD8(+) lymphocytes in determining postacute-phase viral replication set points. However, we report that CD8(+) lymphocyte depletion is also associated with a dramatic induction of proliferation among CD4(+) effector memory T (T(EM)) cells and, to a lesser extent, transitional memory T (T(TrM)) cells, raising the question of whether an increased availability of optimal (activated/proliferating), CD4(+)/CCR5(+) SIV "target" cells contributes to this accelerated pathogenesis. In keeping with this, depletion of CD8(+) lymphocytes in SIV(-) RMs led to a sustained increase in the number of potential CD4(+) SIV targets, whereas such depletion in acute SIV infection led to increased target cell consumption. However, we found that the excess CD4(+) T(EM) cell proliferation of CD8(+) lymphocyte-depleted, acutely SIV-infected RMs was completely inhibited by interleukin (IL)-15 neutralization, and that this inhibition did not abrogate the rapidly progressive infection in these RMs. Moreover, although administration of IL-15 during acute infection induced robust CD4(+) T(EM) and T(TrM) cell proliferation, it did not recapitulate the viral dynamics of CD8(+) lymphocyte depletion. These data suggest that CD8(+) lymphocyte function has a larger impact on the outcome of acute SIV infection than the number and/or activation status of target cells available for infection and viral production.

CD19 CAR T Cells for B Cell Malignancies After Allogeneic Transplant

ClinicalTrials.gov

2017-02-14

Philadelphia Chromosome Negative Adult Precursor Acute Lymphoblastic Leukemia; Philadelphia Chromosome Positive Adult Precursor Acute Lymphoblastic Leukemia; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Mantle Cell Lymphoma; Refractory Chronic Lymphocytic Leukemia

Deletions of the long arm of chromosome 5 define subgroups of T-cell acute lymphoblastic leukemia

PubMed Central

La Starza, Roberta; Barba, Gianluca; Demeyer, Sofie; Pierini, Valentina; Di Giacomo, Danika; Gianfelici, Valentina; Schwab, Claire; Matteucci, Caterina; Vicente, Carmen; Cools, Jan; Messina, Monica; Crescenzi, Barbara; Chiaretti, Sabina; Foà, Robin; Basso, Giuseppe; Harrison, Christine J.; Mecucci, Cristina

2016-01-01

Recurrent deletions of the long arm of chromosome 5 were detected in 23/200 cases of T-cell acute lymphoblastic leukemia. Genomic studies identified two types of deletions: interstitial and terminal. Interstitial 5q deletions, found in five cases, were present in both adults and children with a female predominance (chi-square, P=0.012). Interestingly, these cases resembled immature/early T-cell precursor acute lymphoblastic leukemia showing significant down-regulation of five out of the ten top differentially expressed genes in this leukemia group, including TCF7 which maps within the 5q31 common deleted region. Mutations of genes known to be associated with immature/early T-cell precursor acute lymphoblastic leukemia, i.e. WT1, ETV6, JAK1, JAK3, and RUNX1, were present, while CDKN2A/B deletions/mutations were never detected. All patients had relapsed/resistant disease and blasts showed an early differentiation arrest with expression of myeloid markers. Terminal 5q deletions, found in 18 of patients, were more prevalent in adults (chi-square, P=0.010) and defined a subgroup of HOXA-positive T-cell acute lymphoblastic leukemia characterized by 130 up- and 197 down-regulated genes. Down-regulated genes included TRIM41, ZFP62, MAPK9, MGAT1, and CNOT6, all mapping within the 1.4 Mb common deleted region at 5q35.3. Of interest, besides CNOT6 down-regulation, these cases also showed low BTG1 expression and a high incidence of CNOT3 mutations, suggesting that the CCR4-NOT complex plays a crucial role in the pathogenesis of HOXA-positive T-cell acute lymphoblastic leukemia with terminal 5q deletions. In conclusion, interstitial and terminal 5q deletions are recurrent genomic losses identifying distinct subtypes of T-cell acute lymphoblastic leukemia. PMID:27151989

Deletions of the long arm of chromosome 5 define subgroups of T-cell acute lymphoblastic leukemia.

PubMed

La Starza, Roberta; Barba, Gianluca; Demeyer, Sofie; Pierini, Valentina; Di Giacomo, Danika; Gianfelici, Valentina; Schwab, Claire; Matteucci, Caterina; Vicente, Carmen; Cools, Jan; Messina, Monica; Crescenzi, Barbara; Chiaretti, Sabina; Foà, Robin; Basso, Giuseppe; Harrison, Christine J; Mecucci, Cristina

2016-08-01

Recurrent deletions of the long arm of chromosome 5 were detected in 23/200 cases of T-cell acute lymphoblastic leukemia. Genomic studies identified two types of deletions: interstitial and terminal. Interstitial 5q deletions, found in five cases, were present in both adults and children with a female predominance (chi-square, P=0.012). Interestingly, these cases resembled immature/early T-cell precursor acute lymphoblastic leukemia showing significant down-regulation of five out of the ten top differentially expressed genes in this leukemia group, including TCF7 which maps within the 5q31 common deleted region. Mutations of genes known to be associated with immature/early T-cell precursor acute lymphoblastic leukemia, i.e. WT1, ETV6, JAK1, JAK3, and RUNX1, were present, while CDKN2A/B deletions/mutations were never detected. All patients had relapsed/resistant disease and blasts showed an early differentiation arrest with expression of myeloid markers. Terminal 5q deletions, found in 18 of patients, were more prevalent in adults (chi-square, P=0.010) and defined a subgroup of HOXA-positive T-cell acute lymphoblastic leukemia characterized by 130 up- and 197 down-regulated genes. Down-regulated genes included TRIM41, ZFP62, MAPK9, MGAT1, and CNOT6, all mapping within the 1.4 Mb common deleted region at 5q35.3. Of interest, besides CNOT6 down-regulation, these cases also showed low BTG1 expression and a high incidence of CNOT3 mutations, suggesting that the CCR4-NOT complex plays a crucial role in the pathogenesis of HOXA-positive T-cell acute lymphoblastic leukemia with terminal 5q deletions. In conclusion, interstitial and terminal 5q deletions are recurrent genomic losses identifying distinct subtypes of T-cell acute lymphoblastic leukemia. Copyright© Ferrata Storti Foundation.

Significance of 5,10-methylenetetrahydrofolate reductase gene variants in acute lymphoblastic leukemia in Indian population: an experimental, computational and meta-analysis.

PubMed

Bellampalli, Ravishankara; Phani, Nagaraja M; Bhat, Kamalakshi G; Prasad, Krishna; Bhaskaranand, Nalini; Guruprasad, Kanive P; Rai, Padmalatha S; Satyamoorthy, Kapaettu

2015-05-01

Acute lymphoblastic leukemia (ALL) arises due to several genetic alterations in progenitor cells, and methotrexate is frequently used as part of the treatment regimen. Although there is evidence for an effect of 5,10-methylenetetrahydrofolate reductase gene (MTHFR) C677T and A1298C variations on drug response in ALL, its risk association for ALL is still unresolved. In a case-control study of 203 patients with ALL and 246 controls and meta-analysis in the Indian population, we showed an insignificant association of MTHFR C677T and A1298C genotypes with childhood and adult ALL. Comprehensive in silico characterization of non-synonymous single nucleotide polymorphisms (nsSNPs) and SNPs of the 3' untranslated region (UTR) revealed nine nsSNPs as deleterious, and three SNPs in the 3'UTR could possibly alter the binding of miRNAs. The study revealed that several overlooked SNPs may contribute to the risk of ALL susceptibility and further studies of these SNPs with functional characterization in a large sample size are required to understand the significant role of MTHFR in ALL development.

Antiviral therapy during primary simian immunodeficiency virus infection fails to prevent acute loss of CD4+ T cells in gut mucosa but enhances their rapid restoration through central memory T cells.

PubMed

Verhoeven, David; Sankaran, Sumathi; Silvey, Melanie; Dandekar, Satya

2008-04-01

Gut-associated lymphoid tissue (GALT) is an early target of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) and a site for severe CD4+ T-cell depletion. Although antiretroviral therapy (ART) is effective in suppressing HIV replication and restoring CD4+ T cells in peripheral blood, restoration in GALT is delayed. The role of restored CD4+ T-cell help in GALT during ART and its impact on antiviral CD8+ T-cell responses have not been investigated. Using the SIV model, we investigated gut CD4+ T-cell restoration in infected macaques, initiating ART during either the primary stage (1 week postinfection), prior to acute CD4+ cell loss (PSI), or during the chronic stage at 10 weeks postinfection (CSI). ART led to viral suppression in GALT and peripheral blood mononuclear cells of PSI and CSI animals at comparable levels. CSI animals had incomplete CD4+ T-cell restoration in GALT. In PSI animals, ART did not prevent acute CD4+ T-cell loss by 2 weeks postinfection in GALT but supported rapid and complete CD4+ T-cell restoration thereafter. This correlated with an accumulation of central memory CD4+ T cells and better suppression of inflammation. Restoration of CD4+ T cells in GALT correlated with qualitative changes in SIV gag-specific CD8+ T-cell responses, with a dominance of interleukin-2-producing responses in PSI animals, while both CSI macaques and untreated SIV-infected controls were dominated by gamma interferon responses. Thus, central memory CD4+ T-cell levels and qualitative antiviral CD8+ T-cell responses, independent of viral suppression, were the immune correlates of gut mucosal immune restoration during ART.

T-cell Responses to HSV-1 in Persons Who Have Survived Childhood Herpes Simplex Encephalitis.

PubMed

Ott, Mariliis; Jing, Lichen; Lorenzo, Lazaro; Casanova, Jean-Laurent; Zhang, Shen-Ying; Koelle, David M

2017-08-01

Herpes simplex encephalitis (HSE) after primary herpes simplex virus (HSV)-1 infection can occur in children due to inborn errors of cell-intrinsic immunity in the central nervous system. Paradoxically, symptomatic mucocutaneous HSV-1 recurrences are rare survivors of childhood HSE. T-cell-acquired immunity is thought to be involved in control of recurrent mucocutaneous HSV infection. We thus tested HSV-1-specific immunity in HSE survivors. We obtained serum and peripheral blood mononuclear cells (PBMCs) from participants a median of 13.5 years after HSE. HSV-1 and HSV-2 IgG was detected by type-specific immunoblot. PBMCs from subjects passing quality control criteria were tested using enzyme-linked immunospot assay for CD4 interferon-γ responses with an HSV-1 lysate and for CD8 responses using pooled synthetic HSV-1 peptide CD8 T-cell epitopes. Healthy adult PBMCs were used to standardize assays and as comparators. All participants were HSV-1 seropositive. Most (23/24) HSE survivors had human leukocyte antigen class I types matching the human leukocyte antigen restriction of the pooled peptides. We detected HSV-specific CD8 T-cell responses in 14 of 24 (58%) HSE survivors and in 9 of 9 healthy HSV-1 seropositive adults. HSV-specific CD4 T-cell responses were present in all 5 HSE subjects tested and in 8 of 9 healthy adults. Response magnitudes were overlapping between subject groups. The defects in cell-intrinsic immunity leading to failure to control primary central nervous system HSV-1 infection do not preclude the acquisition of specific immunity or the control of recurrent mucocutaneous HSV infections. The rarity and lack of severe or recurrent mucocutaneous HSV infection in survivors of childhood HSE corresponds with intact adaptive T-cell immunity.

Conserved region C functions to regulate PD-1 expression and subsequent CD8 T cell memory1

PubMed Central

Bally, Alexander P. R.; Tang, Yan; Lee, Joshua T.; Barwick, Benjamin G.; Martinez, Ryan; Evavold, Brian D.; Boss, Jeremy M.

2016-01-01

Expression of programmed death 1 (PD-1) on CD8 T cells promotes T cell exhaustion during chronic antigen exposure. During acute infections, PD-1 is transiently expressed and has the potential to modulate CD8 T cell memory formation. Conserved Region C (CR-C), a promoter proximal cis-regulatory element that is critical to PD-1 expression in vitro, responds to NFATc1, FoxO1, and/or NF-κB signaling pathways. Here, a CR-C knockout mouse (CRC−) was established to determine its role on PD-1 expression and corresponding effects on T cell function in vivo. Deletion of CR-C decreased PD-1 expression on CD4 T cells and antigen-specific CD8 T cells during acute and chronic lymphocytic choriomeningitis virus (LCMV) challenges, but did not affect the ability to clear an infection. Following acute LCMV infection, memory CD8 T cells in the CRC− mouse were formed in greater numbers, were more functional, and were more effective at responding to a melanoma tumor than wild-type memory cells. These data implicate a critical role for CR-C in governing PD-1 expression, and a subsequent role in guiding CD8 T cell differentiation. The data suggest the possibility that titrating PD-1 expression during CD8 T cell activation could have important ramifications in vaccine development and clinical care. PMID:27895178

Role of IL-4 receptor α-positive CD4(+) T cells in chronic airway hyperresponsiveness.

PubMed

Kirstein, Frank; Nieuwenhuizen, Natalie E; Jayakumar, Jaisubash; Horsnell, William G C; Brombacher, Frank

2016-06-01

TH2 cells and their cytokines are associated with allergic asthma in human subjects and with mouse models of allergic airway disease. IL-4 signaling through the IL-4 receptor α (IL-4Rα) chain on CD4(+) T cells leads to TH2 cell differentiation in vitro, implying that IL-4Rα-responsive CD4(+) T cells are critical for the induction of allergic asthma. However, mechanisms regulating acute and chronic allergen-specific TH2 responses in vivo remain incompletely understood. This study defines the requirements for IL-4Rα-responsive CD4(+) T cells and the IL-4Rα ligands IL-4 and IL-13 in the development of allergen-specific TH2 responses during the onset and chronic phase of experimental allergic airway disease. Development of acute and chronic ovalbumin (OVA)-induced allergic asthma was assessed weekly in CD4(+) T cell-specific IL-4Rα-deficient BALB/c mice (Lck(cre)IL-4Rα(-/lox)) and respective control mice in the presence or absence of IL-4 or IL-13. During acute allergic airway disease, IL-4 deficiency did not prevent the onset of TH2 immune responses and OVA-induced airway hyperresponsiveness or goblet cell hyperplasia, irrespective of the presence or absence of IL-4Rα-responsive CD4(+) T cells. In contrast, deficiency of IL-13 prevented allergic asthma, irrespective of the presence or absence of IL-4Rα-responsive CD4(+) T cells. Importantly, chronic allergic inflammation and airway hyperresponsiveness were dependent on IL-4Rα-responsive CD4(+) T cells. Deficiency in IL-4Rα-responsive CD4(+) T cells resulted in increased numbers of IL-17-producing T cells and, consequently, increased airway neutrophilia. IL-4-responsive T helper cells are dispensable for acute OVA-induced airway disease but crucial in maintaining chronic asthmatic pathology. Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Inferior outcomes of stage III T lymphoblastic lymphoma relative to stage IV lymphoma and T-acute lymphoblastic leukemia: long-term comparison of outcomes in the JACLS NHL T-98 and ALL T-97 protocols.

PubMed

Kobayashi, Ryoji; Takimoto, Tetsuya; Nakazawa, Atsuko; Fujita, Naoto; Akazai, Ayumi; Yamato, Kazumi; Yazaki, Makoto; Deguchi, Takao; Hashii, Yoshiko; Kato, Koji; Hatakeyama, Naoki; Horibe, Keizo; Hori, Hiroki; Oda, Megumi

2014-06-01

T cell lymphoblastic lymphoma (T-LBL) accounts for 30 % of all childhood non-Hodgkin's lymphomas (NHL) in Japan. Twenty-nine patients with T-LBL in stages III and IV were eligible for and enrolled in the JACLS NHL-T98 trial (1998-2002), and 72 patients with T-ALL were enrolled in the JACLS ALL-T97 trial (1997-2001). The 10-year overall survival (OS) (61.1 ± 11.5 %) and the 10-year event-free survival (EFS) (44.4 ± 11.7 %) of stage III LBL were lower than those of other diseases, and the OS and EFS were nearly the same when comparing stage IV LBL and ALL (OS: stage IV LBL, 80.0 ± 12.7 % vs. ALL, 80.2 ± 4.9 %; EFS: stage IV, LBL 70.0 ± 14.5 % vs. ALL, 70.7 ± 5.5 %). Outcomes were worse for stage III LBL than for stage IV LBL or T-ALL. Given that the treatment results of T-ALL and LBL stage IV did not differ when compared with previous reports, LBL stage III in Japanese children may differ from LBL stage III in children in other countries.

BIRC6/Apollon gene expression in childhood acute leukemia: impact on therapeutic response and prognosis.

PubMed

Ismail, Eman Abdel Rahman; Mahmoud, Hanan Mohamed; Tawfik, Lamis Mohamed; Habashy, Deena Mohamed; Adly, Amira Abdel Moneam; El-Sherif, Nayera Hazaa; Abdelwahab, Mahmoud Ahmed

2012-02-01

Although BIRC6/Apollon seems to play a critical role as an antiapoptotic regulator, its clinical relevance in acute leukemia remains largely elusive. Therefore, we aimed to investigate BIRC6 gene expression in childhood acute leukemia in relation to clinicopathological characteristics at presentation, therapeutic response, and prognosis. BIRC6 expression level was assessed in 75 children with acute leukemia; 30 patients with acute myeloblastic leukemia (AML) and 45 patients with acute lymphoblastic leukemia (ALL) using real-time quantitative reverse transcriptase-polymerase chain reaction. The median level of BIRC6 expression did not differ significantly between AML and ALL patients. BIRC6 expression level was higher in patients with AML and ALL with extramedullary involvement, white blood cell (WBC) count ≥ 10 × 10(9) /L, and unfavorable cytogenetics at diagnosis. BIRC6 gene expression was higher in patients with unfavorable response to therapy at day 14, those who developed relapse or died in both leukemic groups. The best cutoff value of BIRC6 to predict therapeutic response and disease outcome was determined. AML and ALL patients with BIRC6 overexpression had significantly shorter overall and disease free survivals. This is the first report to study BIRC6 gene in pediatric ALL. Our results suggested that BIRC6 gene expression could be considered as an adverse risk factor in childhood acute leukemia and, hence, could be used to guide therapeutic regimens. © 2012 John Wiley & Sons A/S.

New decision support tool for acute lymphoblastic leukemia classification

NASA Astrophysics Data System (ADS)

Madhukar, Monica; Agaian, Sos; Chronopoulos, Anthony T.

2012-03-01

In this paper, we build up a new decision support tool to improve treatment intensity choice in childhood ALL. The developed system includes different methods to accurately measure furthermore cell properties in microscope blood film images. The blood images are exposed to series of pre-processing steps which include color correlation, and contrast enhancement. By performing K-means clustering on the resultant images, the nuclei of the cells under consideration are obtained. Shape features and texture features are then extracted for classification. The system is further tested on the classification of spectra measured from the cell nuclei in blood samples in order to distinguish normal cells from those affected by Acute Lymphoblastic Leukemia. The results show that the proposed system robustly segments and classifies acute lymphoblastic leukemia based on complete microscopic blood images.

Assessing FOXO1A as a potential susceptibility locus for type 2 diabetes and obesity in American Indians.

PubMed

Muller, Yunhua L; Hanson, Robert L; Wiessner, Gregory; Nieboer, Lori; Kobes, Sayuko; Piaggi, Paolo; Abdussamad, Mahdi; Okani, Chidinma; Knowler, William C; Bogardus, Clifton; Baier, Leslie J

2015-10-01

A prior genome-wide association study (GWAS) in Pima Indians identified variation within FOXO1A that modestly associated with early-onset (onset age < 25 years) type 2 diabetes (T2D). FOXO1A encodes the forkhead transcription factor involved in pancreatic β-cell growth and hypothalamic energy balance; therefore, FOXO1A was analyzed as a candidate gene for T2D and obesity in a population-based sample of 7,710 American Indians. Tag SNPs in/near FOXO1A (minor allele frequency ≥ 0.05) were analyzed for association with T2D at early onset (n = 1,060) and all ages (n = 7,710) and with insulin secretion (n = 298). SNPs were also analyzed for association with maximum body mass index (BMI) in adulthood (n = 5,918), maximum BMI z-score in childhood (n = 5,350), and % body fat (n = 555). An intronic SNP rs2297627 associated with early-onset T2D [OR = 1.34 (1.13-1.58), P = 8.7 × 10(-4)] and T2D onset at any age [OR = 1.19 (1.09-1.30), P = 1 × 10(-4) ]. The T2D risk allele also associated with lower acute insulin secretion (β = 0.88, as a multiplier, P = 0.02). Another intronic SNP (rs1334241, D' = 0.99, r(2) = 0.49 with rs2297627) associated with maximum adulthood BMI (β = 1.02, as a multiplier, P = 3 × 10(-5)), maximum childhood BMI z-score (β = 0.08, P = 3 × 10(-4)), and % body fat (β = 0.83%, P = 0.04). Common variation in FOXO1A may modestly affect risk for T2D and obesity in American Indians. © 2015 The Obesity Society.

Combination Chemotherapy With or Without Donor Stem Cell Transplant in Treating Patients With Acute Lymphoblastic Leukemia

ClinicalTrials.gov

2018-04-20

Acute Lymphoblastic Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult B Acute Lymphoblastic Leukemia; Adult B Acute Lymphoblastic Leukemia With t(9;22)(q34.1;q11.2); BCR-ABL1; Adult L1 Acute Lymphoblastic Leukemia; Adult L2 Acute Lymphoblastic Leukemia; Adult T Acute Lymphoblastic Leukemia; Recurrent Adult Acute Lymphoblastic Leukemia; Untreated Adult Acute Lymphoblastic Leukemia

Effective control of acute myeloid leukaemia and acute lymphoblastic leukaemia progression by telomerase specific adoptive T-cell therapy.

PubMed

Sandri, Sara; De Sanctis, Francesco; Lamolinara, Alessia; Boschi, Federico; Poffe, Ornella; Trovato, Rosalinda; Fiore, Alessandra; Sartori, Sara; Sbarbati, Andrea; Bondanza, Attilio; Cesaro, Simone; Krampera, Mauro; Scupoli, Maria T; Nishimura, Michael I; Iezzi, Manuela; Sartoris, Silvia; Bronte, Vincenzo; Ugel, Stefano

2017-10-20

Telomerase (TERT) is a ribonucleoprotein enzyme that preserves the molecular organization at the ends of eukaryotic chromosomes. Since TERT deregulation is a common step in leukaemia, treatments targeting telomerase might be useful for the therapy of hematologic malignancies. Despite a large spectrum of potential drugs, their bench-to-bedside translation is quite limited, with only a therapeutic vaccine in the clinic and a telomerase inhibitor at late stage of preclinical validation. We recently demonstrated that the adoptive transfer of T cell transduced with an HLA-A2-restricted T-cell receptor (TCR), which recognize human TERT with high avidity, controls human B-cell chronic lymphocytic leukaemia (B-CLL) progression without severe side-effects in humanized mice. In the present report, we show the ability of our approach to limit the progression of more aggressive leukemic pathologies, such as acute myeloid leukaemia (AML) and B-cell acute lymphoblastic leukaemia (B-ALL). Together, our findings demonstrate that TERT-based adoptive cell therapy is a concrete platform of T cell-mediated immunotherapy for leukaemia treatment.

Effective control of acute myeloid leukaemia and acute lymphoblastic leukaemia progression by telomerase specific adoptive T-cell therapy

PubMed Central

Lamolinara, Alessia; Boschi, Federico; Poffe, Ornella; Trovato, Rosalinda; Fiore, Alessandra; Sartori, Sara; Sbarbati, Andrea; Bondanza, Attilio; Cesaro, Simone; Krampera, Mauro; Scupoli, Maria T.; Nishimura, Michael I.; Iezzi, Manuela; Sartoris, Silvia; Bronte, Vincenzo; Ugel, Stefano

2017-01-01

Telomerase (TERT) is a ribonucleoprotein enzyme that preserves the molecular organization at the ends of eukaryotic chromosomes. Since TERT deregulation is a common step in leukaemia, treatments targeting telomerase might be useful for the therapy of hematologic malignancies. Despite a large spectrum of potential drugs, their bench-to-bedside translation is quite limited, with only a therapeutic vaccine in the clinic and a telomerase inhibitor at late stage of preclinical validation. We recently demonstrated that the adoptive transfer of T cell transduced with an HLA-A2-restricted T-cell receptor (TCR), which recognize human TERT with high avidity, controls human B-cell chronic lymphocytic leukaemia (B-CLL) progression without severe side-effects in humanized mice. In the present report, we show the ability of our approach to limit the progression of more aggressive leukemic pathologies, such as acute myeloid leukaemia (AML) and B-cell acute lymphoblastic leukaemia (B-ALL). Together, our findings demonstrate that TERT-based adoptive cell therapy is a concrete platform of T cell-mediated immunotherapy for leukaemia treatment. PMID:29152058

Spleen tyrosine kinase contributes to acute renal allograft rejection in the rat

PubMed Central

Ramessur Chandran, Sharmila; Tesch, Greg H; Han, Yingjie; Woodman, Naomi; Mulley, William R; Kanellis, John; Blease, Kate; Ma, Frank Y; Nikolic-Paterson, David J

2015-01-01

Kidney allografts induce strong T-cell and antibody responses which mediate acute rejection. Spleen tyrosine kinase (Syk) is expressed by most leucocytes, except mature T cells, and is involved in intracellular signalling following activation of the Fcγ-receptor, B-cell receptor and some integrins. A role for Syk signalling has been established in antibody-dependent native kidney disease, but little is known of Syk in acute renal allograft rejection. Sprague–Dawley rats underwent bilateral nephrectomy and received an orthotopic Wistar renal allograft. Recipient rats were treated with a Syk inhibitor (CC0482417, 30 mg/kg/bid), or vehicle, from 1 h before surgery until being killed 5 days later. Vehicle-treated recipients developed severe allograft failure with marked histologic damage in association with dense leucocyte infiltration (T cells, macrophages, neutrophils and NK cells) and deposition of IgM, IgG and C3. Immunostaining identified Syk expression by many infiltrating leucocytes. CC0482417 treatment significantly improved allograft function and reduced histologic damage, although allograft injury was still clearly evident. CC0482417 failed to prevent T-cell infiltration and activation within the allograft. However, CC0482417 significantly attenuated acute tubular necrosis, infiltration of macrophages and neutrophils and thrombosis of peritubular capillaries. In conclusion, this study identifies a role for Syk in acute renal allograft rejection. Syk inhibition may be a useful addition to T-cell-based immunotherapy in renal transplantation. PMID:25529862

Sapanisertib in Treating Patients With Relapsed and/or Refractory Acute Lymphoblastic Leukemia

ClinicalTrials.gov

2018-05-23

Acute Lymphoblastic Leukemia in Remission; B Acute Lymphoblastic Leukemia; B Acute Lymphoblastic Leukemia With t(9;22)(q34.1;q11.2); BCR-ABL1; B Acute Lymphoblastic Leukemia, Philadelphia Chromosome Negative; Blasts 10 Percent or More of Bone Marrow Nucleated Cells; Recurrent Adult Acute Lymphoblastic Leukemia; Refractory Adult Acute Lymphoblastic Leukemia; T Acute Lymphoblastic Leukemia

Pretransplant thymic function predicts acute rejection in antithymocyte globulin-treated renal transplant recipients.

PubMed

Bamoulid, Jamal; Courivaud, Cécile; Crepin, Thomas; Carron, Clémence; Gaiffe, Emilie; Roubiou, Caroline; Laheurte, Caroline; Moulin, Bruno; Frimat, Luc; Rieu, Philippe; Mousson, Christiane; Durrbach, Antoine; Heng, Anne-Elisabeth; Rebibou, Jean-Michel; Saas, Philippe; Ducloux, Didier

2016-05-01

Lack of clear identification of patients at high risk of acute rejection hampers the ability to individualize immunosuppressive therapy. Here we studied whether thymic function may predict acute rejection in antithymocyte globulin (ATG)-treated renal transplant recipients in 482 patients prospectively studied during the first year post-transplant of which 86 patients experienced acute rejection. Only CD45RA(+)CD31(+)CD4(+) T cell (recent thymic emigrant [RTE]) frequency (RTE%) was marginally associated with acute rejection in the whole population. This T-cell subset accounts for 26% of CD4(+) T cells. Pretransplant RTE% was significantly associated with acute rejection in ATG-treated patients (hazard ratio, 1.04; 95% confidence interval, 1.01-1.08) for each increased percent in RTE/CD4(+) T cells), but not in anti-CD25 monoclonal (αCD25 mAb)-treated patients. Acute rejection was significantly more frequent in ATG-treated patients with high pretransplant RTE% (31.2% vs. 16.4%) or absolute number of RTE/mm(3) (31.7 vs. 16.1). This difference was not found in αCD25 monclonal antibody-treated patients. Highest values of both RTE% (>31%, hazard ratio, 2.50; 95% confidence interval, 1.09-5.74) and RTE/mm(3) (>200/mm(3), hazard ratio, 3.71; 95% confidence interval, 1.59-8.70) were predictive of acute rejection in ATG-treated patients but not in patients having received αCD25 monoclonal antibody). Results were confirmed in a retrospective cohort using T-cell receptor excision circle levels as a marker of thymic function. Thus, pretransplant thymic function predicts acute rejection in ATG-treated patients. Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Suppression of pro-inflammatory T-cell responses by human mesothelial cells.

PubMed

Lin, Chan-Yu; Kift-Morgan, Ann; Moser, Bernhard; Topley, Nicholas; Eberl, Matthias

2013-07-01

Human γδ T cells reactive to the microbial metabolite (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP) contribute to acute inflammatory responses. We have previously shown that peritoneal dialysis (PD)-associated infections with HMB-PP producing bacteria are characterized by locally elevated γδ T-cell frequencies and poorer clinical outcome compared with HMB-PP negative infections, implying that γδ T cells may be of diagnostic, prognostic and therapeutic value in acute disease. The regulation by local tissue cells of these potentially detrimental γδ T-cell responses remains to be investigated. Freshly isolated γδ or αβ T cells were cultured with primary mesothelial cells derived from omental tissue, or with mesothelial cell-conditioned medium. Stimulation of cytokine production and proliferation by peripheral T cells in response to HMB-PP or CD3/CD28 beads was assessed by flow cytometry. Resting mesothelial cells were potent suppressors of pro-inflammatory γδ T cells as well as CD4+ and CD8+ αβ T cells. The suppression of γδ T-cell responses was mediated through soluble factors released by primary mesothelial cells and could be counteracted by SB-431542, a selective inhibitor of TGF-β and activin signalling. Recombinant TGF-β1 but not activin-A mimicked the mesothelial cell-mediated suppression of γδ T-cell responses to HMB-PP. The present findings indicate an important regulatory function of mesothelial cells in the peritoneal cavity by dampening pro-inflammatory T-cell responses, which may help preserve the tissue integrity of the peritoneal membrane in the steady state and possibly during the resolution of acute inflammation.

Acute B cell lymphoblastic leukaemia in a 12-week-old greyhound.

PubMed

Adams, J; Mellanby, R J; Villiers, E; Baines, S; Woodger, N

2004-11-01

A 12-week-old greyhound had a two-day history of lethargy, inappetence and shifting lameness. Clinical examination revealed pyrexia and hepatosplenomegaly. Haematological examination showed anaemia, thrombocytopenla, neutropenla and large numbers of atypical mononuclear leucocytes. A diagnosis of acute B cell lymphoblastic leukaemia was made following flow cytometric immunophenotyping of the leucocytes. The owner declined further evaluation and the dog was treated symptomatically with antibiotics. After a brief improvement, the dog's condition deteriorated and it was euthanased four days after initial presentation. The case was unusual because acute lymphoid leukaemia in the dog is most frequently reported in mature animals. This is in contrast to humans, where acute leukaemia is one of the most common childhood cancers.

Chimeric Antigen Receptor T-Cells for the Treatment of B-Cell Acute Lymphoblastic Leukemia

PubMed Central

Tomuleasa, Ciprian; Fuji, Shigeo; Berce, Cristian; Onaciu, Anca; Chira, Sergiu; Petrushev, Bobe; Micu, Wilhelm-Thomas; Moisoiu, Vlad; Osan, Ciprian; Constantinescu, Catalin; Pasca, Sergiu; Jurj, Ancuta; Pop, Laura; Berindan-Neagoe, Ioana; Dima, Delia; Kitano, Shigehisa

2018-01-01

Chimeric antigen receptor (CAR) T-cell technology has seen a rapid development over the last decade mostly due to the potential that these cells may have in treating malignant diseases. It is a generally accepted principle that very few therapeutic compounds deliver a clinical response without treatment-related toxicity, and studies have shown that CAR T-cells are not an exception to this rule. While large multinational drug companies are currently investigating the potential role of CAR T-cells in hematological oncology, the potential of such cellular therapies are being recognized worldwide as they are expected to expand in the patient to support the establishment of the immune memory, provide a continuous surveillance to prevent and/or treat a relapse, and keep the targeted malignant cell subpopulation in check. In this article, we present the possible advantages of using CAR T-cells in treating acute lymphoblastic leukemia, presenting the technology and the current knowledge in their preclinical and early clinical trial use. Thus, this article first presents the main present-day knowledge on the standard of care for acute lymphoblastic leukemia. Afterward, current knowledge is presented about the use of CAR T-cells in cancer immunotherapy, describing their design, the molecular constructs, and the preclinical data on murine models to properly explain the background for their clinical use. Last, but certainly not least, this article presents the use of CAR T-cells for the immunotherapy of B-cell acute lymphoblastic leukemia, describing both their potential clinical advantages and the possible side effects. PMID:29515572

Chimeric Antigen Receptor T-Cells for the Treatment of B-Cell Acute Lymphoblastic Leukemia.

PubMed

Tomuleasa, Ciprian; Fuji, Shigeo; Berce, Cristian; Onaciu, Anca; Chira, Sergiu; Petrushev, Bobe; Micu, Wilhelm-Thomas; Moisoiu, Vlad; Osan, Ciprian; Constantinescu, Catalin; Pasca, Sergiu; Jurj, Ancuta; Pop, Laura; Berindan-Neagoe, Ioana; Dima, Delia; Kitano, Shigehisa

2018-01-01

Chimeric antigen receptor (CAR) T-cell technology has seen a rapid development over the last decade mostly due to the potential that these cells may have in treating malignant diseases. It is a generally accepted principle that very few therapeutic compounds deliver a clinical response without treatment-related toxicity, and studies have shown that CAR T-cells are not an exception to this rule. While large multinational drug companies are currently investigating the potential role of CAR T-cells in hematological oncology, the potential of such cellular therapies are being recognized worldwide as they are expected to expand in the patient to support the establishment of the immune memory, provide a continuous surveillance to prevent and/or treat a relapse, and keep the targeted malignant cell subpopulation in check. In this article, we present the possible advantages of using CAR T-cells in treating acute lymphoblastic leukemia, presenting the technology and the current knowledge in their preclinical and early clinical trial use. Thus, this article first presents the main present-day knowledge on the standard of care for acute lymphoblastic leukemia. Afterward, current knowledge is presented about the use of CAR T-cells in cancer immunotherapy, describing their design, the molecular constructs, and the preclinical data on murine models to properly explain the background for their clinical use. Last, but certainly not least, this article presents the use of CAR T-cells for the immunotherapy of B-cell acute lymphoblastic leukemia, describing both their potential clinical advantages and the possible side effects.

Characterization of CD8+ T-cell response in acute and resolved hepatitis A virus infection.

PubMed

Schulte, I; Hitziger, T; Giugliano, S; Timm, J; Gold, H; Heinemann, F M; Khudyakov, Y; Strasser, M; König, C; Castermans, E; Mok, J Y; van Esch, W J E; Bertoletti, A; Schumacher, T N; Roggendorf, M

2011-02-01

In contrast to the infection with other hepatotropic viruses, hepatitis A virus (HAV) always causes acute self-limited hepatitis, although the role for virus-specific CD8 T cells in viral containment is unclear. Herein, we analyzed the T cell response in patients with acute hepatitis by utilizing a set of overlapping peptides and predicted HLA-A2 binders from the polyprotein. A set of 11 predicted peptides from the HAV polyprotein, identified as potential binders, were synthesized. Peripheral blood mononuclear cells (PBMCs) from patients were tested for IFNγ secretion after stimulation with these peptides and ex vivo with HLA-A2 tetramers. Phenotyping was carried out by staining with the activation marker CD38 and the memory marker CD127. Eight out of 11 predicted HLA-A2 binders showed a high binding affinity and five of them were recognized by CD8+ T cells from patients with hepatitis A. There were significant differences in the magnitude of the responses to these five peptides. One was reproducibly immunodominant and the only one detectable ex vivo by tetramer staining of CD8+ T cells. These cells have an activated phenotype (CD38hi CD127lo) during acute infection. Three additional epitopes were identified in HLA-A2 negative patients, most likely representing epitopes restricted by other HLA-class I-alleles (HLA-A11, B35, B40). Patients with acute hepatitis A have a strong multi-specific T cell response detected by ICS. With the tetramer carrying the dominant HLA-A2 epitope, HAV-specific and activated CD8+ T cells could be detected ex vivo. This first description of the HAV specific CTL-epitopes will allow future studies on strength, breadth, and kinetics of the T-cell response in hepatitis A. Copyright © 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Curcumin Attenuates Acute Graft-versus-Host Disease Severity via In Vivo Regulations on Th1, Th17 and Regulatory T Cells

PubMed Central

Lee, Sung-Hee; Yang, Eun-Ji; Min, Jun-Ki; Cho, Seok-Goo; Yang, Chul-Woo; Park, Sung-Hwan; Kim, Ho-Youn; Cho, Mi-La

2013-01-01

Background In this study we examined the in vivo and in vitro effects and mechanisms of action of curcumin on the development of acute graft-versus-host disease (GVHD) using a murine model. Methodology/Principal Findings Mixed lymphocyte reactions were used to determine the in vitro effects of curcumin. Treatment with curcumin attenuated alloreactive T cell proliferation and inhibited the production of interferon (IFN)-γ and interleukin (IL)-17. In a murine acute GVHD model, transplantation of curcumin-treated allogeneic splenocytes into irradiated recipient mice significantly reduced the clinical severity scores of acute GVHD manifested in the liver, skin, colon and lung as compared with animals receiving vehicle-treated splenocytes. c-Fos and c-Jun expression levels in the skin and intestine, which are major target organs, were analyzed using immunohistochemical staining. Expression of both proteins was reduced in epithelial tissues of skin and intestine from curcumin-treated GVHD animals. The IFN-γ-expressing CD4+ splenocytes and IFN-γ-expressing lymph node cells were dramatically decreased in curcumin-treated mice. In contrast, CD4+Foxp3+ splenocytes were increased in the curcumin-treated acute GVHD animals. Flow cytometric analysis revealed that animals transplanted with curcumin-treated allogeneic splenocytes showed increased populations of CD4+ regulatory T cells (Tregs) as well as CD8+ Treg cells, compared to animals administered vehicle-treated splenocytes. Curcumin-treated acute GVHD animals could have a change in B cell subpopulations. Conclusion/Significance In the present study, we investigated the efficacy and mechanism of action of curcumin treatment against acute GVHD. The acute GVHD mice administered with curcumin-treated splenocytes showed significantly reduced severity of acute GVHD. Curcumin exerted in vivo preventive effects on acute GVHD by reciprocal regulation of T helper 1 (Th1) and Treg (both CD4+ and CD8+ Treg) cell lineages as well as B cell homeostasis. PMID:23840617

MicroRNA-101 regulates T-cell acute lymphoblastic leukemia progression and chemotherapeutic sensitivity by targeting Notch1.

PubMed

Qian, Lu; Zhang, Wanggang; Lei, Bo; He, Aili; Ye, Lianhong; Li, Xingzhou; Dong, Xin

2016-11-01

The present study aimed to investigate the role of microRNA (miR)-101 in acute lymphoblastic leukemia progression and chemoresistance. Furthermore, a novel target gene of miR-101 was identified. Here, we confirmed that miR-101 was significantly downregulated in the blood samples of patients with T-cell acute lymphoblastic leukemia (T-ALL) compared with the healthy controls, as determined by reverse transcription quantitative polymerase chain reaction (RTqPCR) analysis. The in vitro experiments demonstrated that miR-101 significantly repressed the proliferation and invasion, and induced potent apoptosis in Jurkat cells, as determined by CCK-8, flow cytometer and cell invasion assays. Luciferase assay confirmed that Notch1 was a target gene of miR-101, and western blotting showed that miR-101 suppressed the expression of Notch1 at the protein level. Moreover, functional restoration assays revealed that Notch1 mediates the effects of miR-101 on Jurkat cell proliferation, apoptosis and invasion. miR-101 enhanced the sensitivity of Jurkat cells to the chemotherapeutic agent adriamycin. Taken together, our results show for the first time that miR-101 acts as a tumor suppressor in T-cell acute lymphoblastic leukaemia and it could enhance chemotherapeutic sensitivity. Furthermore, Notch1 was identified to be a novel target of miR-101. This study indicates that miR-101 may represent a potential therapeutic target for T-cell acute lymphoblastic leukemia intervention.

Transgenic rat model of childhood-onset dermatitis by overexpressing telomerase reverse transcriptase (TERT).

PubMed

Kaneko, Ryosuke; Sato, Atsuko; Hamada, Shun; Yagi, Takeshi; Ohsawa, Ichiro; Ohtsuki, Mamitaro; Kobayashi, Eiji; Hirabayashi, Masumi; Murakami, Takashi

2016-08-01

Childhood-onset dermatitis is one of the most common skin disorders in children. Although various mouse models that mirror aspects of dermatitis have become available, there is still a need for an animal model that develops dermatitis in childhood and is more suitable for performing tissue transplantation experiments. There is emerging evidence that peripheral blood T lymphocytes from patients with dermatitis have significantly increased telomerase activity. Here, we developed telomerase reverse transcriptase (TERT)-expressing transgenic (Tg) rats that spontaneously developed eczematous skin inflammation in childhood. Newborn TERT-Tg rats developed visible dermatitis in 56 % of cases, and the skin lesions microscopically showed spongiosis and acanthosis with infiltration of lymphocytes, eosinophils and mast cells. TERT-Tg rats with dermatitis exhibited increased CD4 (2.5-fold) and CD8 (fivefold) T cell numbers compared with dermatitis-free TERT-Tg rats. Stronger TERT activity was observed in the peripheral lymphocytes of dermatitis-positive TERT-Tg rats than those of dermatitis-free TERT-Tg rats. RT-PCR analysis revealed that IL-4 was markedly elevated in the spleen of dermatitis-positive TERT-Tg rats, and that interferon-gamma was increased in the dermatitis lesions. Moreover, skin grafting of TERT-Tg rats with dermatitis onto T cell-deficient nude rats demonstrated that the inflamed skin lesions could not be maintained. Taken together, the results suggest that TERT activation in T lymphocytes is one of the potential predisposing factors for dermatitis. Moreover, our results demonstrated that the TERT-Tg rats mirror aspects of human childhood-onset dermatitis and that these animals represent a potential animal model system for studying childhood-onset dermatitis.

Molecular characterization of chronic-type adult T-cell leukemia/lymphoma.

PubMed

Yoshida, Noriaki; Karube, Kennosuke; Utsunomiya, Atae; Tsukasaki, Kunihiro; Imaizumi, Yoshitaka; Taira, Naoya; Uike, Naokuni; Umino, Akira; Arita, Kotaro; Suguro, Miyuki; Tsuzuki, Shinobu; Kinoshita, Tomohiro; Ohshima, Koichi; Seto, Masao

2014-11-01

Adult T-cell leukemia/lymphoma (ATL) is a human T-cell leukemia virus type-1-induced neoplasm with four clinical subtypes: acute, lymphoma, chronic, and smoldering. Although the chronic type is regarded as indolent ATL, about half of the cases progress to acute-type ATL. The molecular pathogenesis of acute transformation in chronic-type ATL is only partially understood. In an effort to determine the molecular pathogeneses of ATL, and especially the molecular mechanism of acute transformation, oligo-array comparative genomic hybridization and comprehensive gene expression profiling were applied to 27 and 35 cases of chronic and acute type ATL, respectively. The genomic profile of the chronic type was nearly identical to that of acute-type ATL, although more genomic alterations characteristic of acute-type ATL were observed. Among the genomic alterations frequently observed in acute-type ATL, the loss of CDKN2A, which is involved in cell-cycle deregulation, was especially characteristic of acute-type ATL compared with chronic-type ATL. Furthermore, we found that genomic alteration of CD58, which is implicated in escape from the immunosurveillance mechanism, is more frequently observed in acute-type ATL than in the chronic-type. Interestingly, the chronic-type cases with cell-cycle deregulation and disruption of immunosurveillance mechanism were associated with earlier progression to acute-type ATL. These findings suggested that cell-cycle deregulation and the immune escape mechanism play important roles in acute transformation of the chronic type and indicated that these alterations are good predictive markers for chronic-type ATL. ©2014 American Association for Cancer Research.

Mechanistic mathematical modelling of mercaptopurine effects on cell cycle of human acute lymphoblastic leukaemia cells

PubMed Central

Panetta, J C; Evans, W E; Cheok, M H

2006-01-01

The antimetabolite mercaptopurine (MP) is widely used to treat childhood acute lymphoblastic leukaemia (ALL). To study the dynamics of MP on the cell cycle, we incubated human T-cell leukaemia cell lines (Molt-4 sensitive and resistant subline and P12 resistant) with 10 μM MP and measured total cell count, cell cycle distribution, percent viable, percent apoptotic, and percent dead cells serially over 72 h. We developed a mathematical model of the cell cycle dynamics after treatment with MP and used it to show that the Molt-4 sensitive controls had a significantly higher rate of cells entering apoptosis (2.7-fold, P<0.00001) relative to the resistant cell lines. Additionally, when treated with MP, the sensitive cell line showed a significant increase in the rate at which cells enter apoptosis compared to its controls (2.4-fold, P<0.00001). Of note, the resistant cell lines had a higher rate of antimetabolite incorporation into the DNA of viable cells (>1.4-fold, P<0.01). Lastly, in contrast to the other cell lines, the Molt-4 resistant subline continued to cycle, though at a rate slower relative to its control, rather than proceed to apoptosis. This led to a larger S-phase block in the Molt-4 resistant cell line, but not a higher rate of cell death. Gene expression of apoptosis, cell cycle, and repair genes were consistent with mechanistic dynamics described by the model. In summary, the mathematical model provides a quantitative assessment to compare the cell cycle effects of MP in cells with varying degrees of MP resistance. PMID:16333308

Stages of Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies

MedlinePlus

... and given back to the patient through an infusion . These reinfused stem cells grow into (and restore) ... them from spreading. Monoclonal antibodies are given by infusion. They may be used alone or to carry ...

More Chemotherapy May Help after Initial Treatment for Childhood Leukemia Fails

Cancer.gov

A study suggests that at least some children diagnosed with acute lymphoblastic leukemia who respond poorly to initial chemotherapy may do better if they receive additional chemotherapy rather than a stem cell transplant.

Hepatic Sinusoidal Obstruction Syndrome During Chemotherapy for Childhood Medulloblastoma: Report of a Case and Review of the Literature

PubMed Central

Buckland, Amy; Phillips, Marianne B.; Cole, Catherine H.; Gottardo, Nicholas G.

2014-01-01

Hepatic sinusoidal obstruction syndrome (HSOS), also known as veno-occlusive disease, is a well-recognized toxic complication after autologous and allogeneic hematopoietic stem cell transplant, during treatment of Wilms tumor and rhabdomyosarcoma associated with actinomycin-D, and during acute lymphoblastic leukemia therapy due to oral 6-thioguanine. However, its occurrence in the context of chemotherapy regimens for other childhood malignancies is rare. We report a 5-year-old girl with high-risk anaplastic medulloblastoma, who developed severe HSOS during her second cycle of maintenance chemotherapy, consisting of vincristine, cisplatin, and cyclophosphamide. She was treated with defibrotide with complete resolution of the HSOS. These findings and a review of the literature, highlight the occurrence of HSOS in children outside the established settings of hematopoietic stem cell transplantation, Wilms tumor, rhabdomyosarcoma, and acute lymphoblastic leukemia. PMID:24276042

KPT-330 inhibitor of CRM1 (XPO1)-mediated nuclear export has selective anti-leukaemic activity in preclinical models of T-cell acute lymphoblastic leukaemia and acute myeloid leukaemia.

PubMed

Etchin, Julia; Sanda, Takaomi; Mansour, Marc R; Kentsis, Alex; Montero, Joan; Le, Bonnie T; Christie, Amanda L; McCauley, Dilara; Rodig, Scott J; Kauffman, Michael; Shacham, Sharon; Stone, Richard; Letai, Anthony; Kung, Andrew L; Thomas Look, A

2013-04-01

This study explored the anti-leukaemic efficacy of novel irreversible inhibitors of the major nuclear export receptor, chromosome region maintenance 1 (CRM1, also termed XPO1). We found that these novel CRM1 antagonists, termed SINE (Selective Inhibitors of Nuclear Export), induced rapid apoptosis at low nanomolar concentrations in a panel of 14 human T-cell acute lymphoblastic leukaemia (T-ALL) cell lines representing different molecular subtypes of the disease. To assess in vivo anti-leukaemia cell activity, we engrafted immunodeficient mice intravenously with the human T-ALL MOLT-4 cells, which harbour activating mutations of NOTCH1 and NRAS as well as loss of function of the CDKN2A, PTEN and TP53 tumour suppressors and express a high level of oncogenic transcription factor TAL1. Importantly, we examined the in vivo anti-leukaemic efficacy of the clinical SINE compound KPT-330 against T-ALL and acute myeloid leukaemia (AML) cells. These studies demonstrated striking in vivo activity of KPT-330 against T-ALL and AML cells, with little toxicity to normal murine haematopoietic cells. Taken together, our results show that SINE CRM1 antagonists represent promising 'first-in-class' drugs with a novel mechanism of action and wide therapeutic index, and imply that drugs of this class show promise for the targeted therapy of T-ALL and AML. © 2013 Blackwell Publishing Ltd.

DNA-thioguanine nucleotide concentration and relapse-free survival during maintenance therapy of childhood acute lymphoblastic leukaemia (NOPHO ALL2008): a prospective substudy of a phase 3 trial.

PubMed

Nielsen, Stine Nygaard; Grell, Kathrine; Nersting, Jacob; Abrahamsson, Jonas; Lund, Bendik; Kanerva, Jukka; Jónsson, Ólafur Gísli; Vaitkeviciene, Goda; Pruunsild, Kaie; Hjalgrim, Lisa Lyngsie; Schmiegelow, Kjeld

2017-04-01

Adjustment of mercaptopurine and methotrexate maintenance therapy of acute lymphoblastic leukaemia by leucocyte count is confounded by natural variations. Cytotoxicity is primarily mediated by DNA-incorporated thioguanine nucleotides (DNA-TGN). The aim of this study was to establish whether DNA-TGN concentrations in blood leucocytes during maintenance therapy are associated with relapse-free survival. In this substudy of the NOPHO ALL2008 phase 3 trial done in 23 hospitals in seven European countries (Denmark, Estonia, Finland, Iceland, Lithuania, Norway, and Sweden), we analysed data from centralised and blinded analyses of 6-mercaptopurine and methotrexate metabolites in blood samples from patients with non-high-risk childhood acute lymphoblastic leukaemia. Eligible patients were aged 1·0-17·9 years; had been diagnosed with non-high-risk precursor B-cell or T-cell leukaemia; had been treated according to the Nordic Society of Pediatric Hematology and Oncology ALL2008 protocol; and had reached maintenance therapy in first remission. Maintenance therapy was (mercaptopurine 75 mg/m 2 once per day and methotrexate 20 mg/m 2 once per week, targeted to a leucocyte count of 1·5-3·0 × 10 9 cells per L). We measured DNA-TGN and erythrocyte concentrations of TGN nucleotides, methylated mercaptopurine metabolites, and methotrexate polyglutamates. The primary objective was the association of DNA-TGN concentrations and 6-mercaptopurine and methotrexate metabolites with relapse-free survival. The secondary endpoint was the assessment of DNA-TGN concentration and 6-mercaptopurine and methotrexate metabolites during maintenance therapy phase 2. Between Nov 26, 2008 and June 14, 2016, 1509 patients from the NOPHO ALL2008 study were assessed for eligibility in the DNA-TGN substudy, of which 918 (89%) of 1026 eligible patients had at least one DNA-TGN measurement and were included in the analyses. Median follow-up was 4·6 years (IQR 3·1-6·1). Relapse-free survival was significantly associated with DNA-TGN concentration (adjusted hazard ratio 0·81 per 100 fmol/μg DNA increase, 95% CI 0·67-0·98; p=0·029). In patients with at least five blood samples, erythrocyte concentrations of TGN, methylated mercaptopurine metabolites, and methotrexate polyglutamates were associated with DNA-TGN concentration (all p<0·0001). Our results suggest the need for intervention trials to identify clinically applicable strategies for individualised drug dosing to increase DNA-TGN concentration, and randomised studies to investigate whether such strategies improve cure rates compared with current dose adjustments based on white blood cell counts. Danish Cancer Society, Childhood Cancer Foundation (Denmark), Childhood Cancer Foundation (Sweden), Nordic Cancer Union, Otto Christensen Foundation, University Hospital Rigshospitalet, and Novo Nordic Foundation. Copyright © 2017 Elsevier Ltd. All rights reserved.

Children's Oncology Group's 2013 blueprint for research: acute myeloid leukemia.

PubMed

Gamis, Alan S; Alonzo, Todd A; Perentesis, John P; Meshinchi, Soheil

2013-06-01

For the 365 children diagnosed with acute myeloid leukemia in the US annually, 5-year survival for patients on COG trials with low, intermediate, and high risk disease is 83%, 62%, and 23%, respectively. Recent advances include improved therapeutic stratification, improved survival with dose intensification, and further elucidation of the heterogeneity specific to childhood AML. These discoveries now guide current strategy incorporating targeted agents to pathways specific to childhood AML as well as evaluating methods to increase the sensitivity of the leukemic stem cell, first in Phase II feasibility trials followed by Phase III efficacy trials of the most promising agents. Acute myeloid leukemia in children, though with similar subgroups to adults, remains uniquely different based upon quite different prevalence of subtypes as well as overall response to therapy. The Children's Oncology Group's research agenda builds upon earlier efforts to better elucidate the leukemogenic steps distinct to childhood AML in order to more scientifically develop and test novel therapeutic approaches to the treatment and ultimate cure for children with this disorder. Pediatr Blood Cancer 2013; 60: 964-971. © 2012 Wiley Periodicals, Inc. Copyright © 2012 Wiley Periodicals, Inc.

Loss of CD28 on Peripheral T Cells Decreases the Risk for Early Acute Rejection after Kidney Transplantation

PubMed Central

Dedeoglu, Burç; Meijers, Ruud W. J.; Klepper, Mariska; Hesselink, Dennis A.; Baan, Carla C.; Litjens, Nicolle H. R.; Betjes, Michiel G. H.

2016-01-01

Background End-stage renal disease patients have a dysfunctional, prematurely aged peripheral T-cell system. Here we hypothesized that the degree of premature T-cell ageing before kidney transplantation predicts the risk for early acute allograft rejection (EAR). Methods 222 living donor kidney transplant recipients were prospectively analyzed. EAR was defined as biopsy proven acute allograft rejection within 3 months after kidney transplantation. The differentiation status of circulating T cells, the relative telomere length and the number of CD31+ naive T cells were determined as T-cell ageing parameters. Results Of the 222 patients analyzed, 30 (14%) developed an EAR. The donor age and the historical panel reactive antibody score were significantly higher (p = 0.024 and p = 0.039 respectively) and the number of related donor kidney transplantation was significantly lower (p = 0.018) in the EAR group. EAR-patients showed lower CD4+CD28null T-cell numbers (p<0.01) and the same trend was observed for CD8+CD28null T-cell numbers (p = 0.08). No differences regarding the other ageing parameters were found. A multivariate Cox regression analysis showed that higher CD4+CD28null T-cell numbers was associated with a lower risk for EAR (HR: 0.65, p = 0.028). In vitro, a significant lower percentage of alloreactive T cells was observed within CD28null T cells (p<0.001). Conclusion Immunological ageing-related expansion of highly differentiated CD28null T cells is associated with a lower risk for EAR. PMID:26950734

Hematologic problems in pediatric patients.

PubMed

Cahill, M

1996-02-01

To provide a review of the common hematologic disorders of childhood: iron deficiency anemia, aplastic anemia, sickle cell disease, and hemophilia. Review articles and book chapters pertaining to the care and treatment of children with hematologic disorders. These common hematologic disorders of childhood have the potential to cause not only acute illness but chronic medical problems, particularly in the growing child. Anticipating and preventing the long-term effects of the illness and treatment are the primary goals of care. Nursing assessment, patient education, and long-term follow-up are major factors in the care of children with hematologic disorders. Nurse-managed comprehensive care clinics have provided successful programs directed at acute care and maintenance care for these children and their families.

Childhood Cancer: Leukemia (For Parents)

MedlinePlus

... of Leukemia In general, leukemias are classified into acute (rapidly developing) and chronic (slowly developing) forms. In children, most leukemias are acute. Acute childhood leukemias are also divided into acute ...

Conserved Region C Functions To Regulate PD-1 Expression and Subsequent CD8 T Cell Memory.

PubMed

Bally, Alexander P R; Tang, Yan; Lee, Joshua T; Barwick, Benjamin G; Martinez, Ryan; Evavold, Brian D; Boss, Jeremy M

2017-01-01

Expression of programmed death 1 (PD-1) on CD8 T cells promotes T cell exhaustion during chronic Ag exposure. During acute infections, PD-1 is transiently expressed and has the potential to modulate CD8 T cell memory formation. Conserved region C (CR-C), a promoter proximal cis-regulatory element that is critical to PD-1 expression in vitro, responds to NFATc1, FoxO1, and/or NF-κB signaling pathways. Here, a CR-C knockout mouse was established to determine its role on PD-1 expression and the corresponding effects on T cell function in vivo. Deletion of CR-C decreased PD-1 expression on CD4 T cells and Ag-specific CD8 T cells during acute and chronic lymphocytic choriomeningitis virus challenges, but did not affect the ability to clear an infection. Following acute lymphocytic choriomeningitis virus infection, memory CD8 T cells in the CR-C knockout mouse were formed in greater numbers, were more functional, and were more effective at responding to a melanoma tumor than wild-type memory cells. These data implicate a critical role for CR-C in governing PD-1 expression, and a subsequent role in guiding CD8 T cell differentiation. The data suggest the possibility that titrating PD-1 expression during CD8 T cell activation could have important ramifications in vaccine development and clinical care. Copyright © 2016 by The American Association of Immunologists, Inc.

Identification of a novel functional JAK1 S646P mutation in acute lymphoblastic leukemia

PubMed Central

Hu, Liangding; Ning, Hongmei; Jiang, Min; Wang, Danhong; Liu, Tingting; Zhang, Bin; Chen, Hu

2017-01-01

The survival rate of childhood acute lymphoblastic leukemia (ALL) is approaching 90%, while the prognosis of adults remains poor due to the limited therapeutic approaches. In order to identify new targets for ALL, we performed whole-exome sequencing on four adults with B-ALL and discovered a somatic JAK1 S646P mutation. Sanger sequencing of JAK1 was conducted on 53 ALL patients, and two cases exhibited A639G and P960S mutations separately. Functional studies demonstrated that only JAK1 S646P mutation could activate multiple signaling pathways, drive cytokine-independent cell growth, and promote proliferation of malignant cells in nude mice. Moreover, a high sensitivity to the JAK1/2 inhibitor ruxolitinib was observed in S646P mutant model. Exploration in a total of 209 ALL cases showed that JAK1 mutations occur at a frequency of 10.5% in T-ALL (2/19) and 1.6% in B-ALL (3/190). Collectively, our results suggested that JAK1 S646P is an activating mutation in vitro and in vivo. JAK-STAT pathway might represent a promising therapeutic target for ALL. PMID:28410228

Identification of a novel functional JAK1 S646P mutation in acute lymphoblastic leukemia.

PubMed

Li, Qian; Li, Botao; Hu, Liangding; Ning, Hongmei; Jiang, Min; Wang, Danhong; Liu, Tingting; Zhang, Bin; Chen, Hu

2017-05-23

The survival rate of childhood acute lymphoblastic leukemia (ALL) is approaching 90%, while the prognosis of adults remains poor due to the limited therapeutic approaches. In order to identify new targets for ALL, we performed whole-exome sequencing on four adults with B-ALL and discovered a somatic JAK1 S646P mutation. Sanger sequencing of JAK1 was conducted on 53 ALL patients, and two cases exhibited A639G and P960S mutations separately. Functional studies demonstrated that only JAK1 S646P mutation could activate multiple signaling pathways, drive cytokine-independent cell growth, and promote proliferation of malignant cells in nude mice. Moreover, a high sensitivity to the JAK1/2 inhibitor ruxolitinib was observed in S646P mutant model. Exploration in a total of 209 ALL cases showed that JAK1 mutations occur at a frequency of 10.5% in T-ALL (2/19) and 1.6% in B-ALL (3/190). Collectively, our results suggested that JAK1 S646P is an activating mutation in vitro and in vivo. JAK-STAT pathway might represent a promising therapeutic target for ALL.

Polarized type 2 alloreactive CD4+ and CD8+ donor T cells fail to induce experimental acute graft-versus-host disease.

PubMed

Krenger, W; Snyder, K M; Byon, J C; Falzarano, G; Ferrara, J L

1995-07-15

Acute graft-vs-host disease (GVHD) is thought to be mediated by alloreactive T cells with a type 1 cytokine phenotype. To prevent the development of acute GVHD, we have successfully polarized mature donor T cells toward a type 2 cytokine phenotype ex-vivo by incubating them with murine rIL-4 in a primary MLC. Polarized type 2 T cells were then transplanted with T cell-depleted bone marrow cells into irradiated recipients across either MHC class II (bm12-->C57BL/6) or class I (bm1-->C57BL/6) barriers, and the intensity of GVHD was measured by assessment of several in vitro and in vivo parameters. The injection of polarized type 2 T cells abrogated the mitogen-induced production of IFN-gamma by splenocytes from transplanted hosts on day 13 after bone marrow transplantation (BMT). Injection of polarized type 2 T cells failed to induce secretion of the effector phase cytokine TNF-alpha by splenocytes stimulated with LPS both in vitro and in vivo, and survival of transplanted mice after i.v. injection with LPS was significantly improved. Furthermore, cell-mixing experiments revealed that polarized type 2 T cells were able to inhibit type 1 cytokine responses induced by naive T cells after BMT. These data demonstrate that both polarized CD4+ and CD8+ type 2 alloreactive donor T cells can be generated in vitro from mature T cell populations. These cells function in vivo to inhibit type 1 T cell responses, and such inhibition attenuates the systemic morbidity of GVHD after BMT across both MHC class II or class I barriers in mice.

Relationship between Functional Profile of HIV-1 Specific CD8 T Cells and Epitope Variability with the Selection of Escape Mutants in Acute HIV-1 Infection

PubMed Central

Goonetilleke, Nilu; Liu, Michael K. P.; Turnbull, Emma L.; Salazar-Gonzalez, Jesus F.; Hawkins, Natalie; Self, Steve; Watson, Sydeaka; Betts, Michael R.; Gay, Cynthia; McGhee, Kara; Pellegrino, Pierre; Williams, Ian; Tomaras, Georgia D.; Haynes, Barton F.; Gray, Clive M.; Borrow, Persephone; Roederer, Mario; McMichael, Andrew J.; Weinhold, Kent J.

2011-01-01

In the present study, we analyzed the functional profile of CD8+ T-cell responses directed against autologous transmitted/founder HIV-1 isolates during acute and early infection, and examined whether multifunctionality is required for selection of virus escape mutations. Seven anti-retroviral therapy-naïve subjects were studied in detail between 1 and 87 weeks following onset of symptoms of acute HIV-1 infection. Synthetic peptides representing the autologous transmitted/founder HIV-1 sequences were used in multiparameter flow cytometry assays to determine the functionality of HIV-1-specific CD8+ T memory cells. In all seven patients, the earliest T cell responses were predominantly oligofunctional, although the relative contribution of multifunctional cell responses increased significantly with time from infection. Interestingly, only the magnitude of the total and not of the poly-functional T-cell responses was significantly associated with the selection of escape mutants. However, the high contribution of MIP-1β-producing CD8+ T-cells to the total response suggests that mechanisms not limited to cytotoxicity could be exerting immune pressure during acute infection. Lastly, we show that epitope entropy, reflecting the capacity of the epitope to tolerate mutational change and defined as the diversity of epitope sequences at the population level, was also correlated with rate of emergence of escape mutants. PMID:21347345

Early-Life Stress Affects Stress-Related Prefrontal Dopamine Activity in Healthy Adults, but Not in Individuals with Psychotic Disorder

PubMed Central

Kasanova, Zuzana; Hernaus, Dennis; Vaessen, Thomas; van Amelsvoort, Thérèse; Winz, Oliver; Heinzel, Alexander; Pruessner, Jens; Mottaghy, Felix M.

2016-01-01

Early life stress may have a lasting impact on the developmental programming of the dopamine (DA) system implicated in psychosis. Early adversity could promote resilience by calibrating the prefrontal stress-regulatory dopaminergic neurotransmission to improve the individual’s fit with the predicted stressful environment. Aberrant reactivity to such match between proximal and distal environments may, however, enhance psychosis disease risk. We explored the combined effects of childhood adversity and adult stress by exposing 12 unmedicated individuals with a diagnosis of non-affective psychotic disorder (NAPD) and 12 healthy controls (HC) to psychosocial stress during an [18F]fallypride positron emission tomography. Childhood trauma divided into early (ages 0–11 years) and late (12–18 years) was assessed retrospectively using a questionnaire. A significant group x childhood trauma interaction on the spatial extent of stress-related [18F]fallypride displacement was observed in the mPFC for early (b = -8.45, t(1,23) = -3.35, p = .004) and late childhood trauma (b = -7.86, t(1,23) = -2.48, p = .023). In healthy individuals, the spatial extent of mPFC DA activity under acute psychosocial stress was positively associated with the severity of early (b = 7.23, t(11) = 3.06, p = .016) as well as late childhood trauma (b = -7.86, t(1,23) = -2.48, p = .023). Additionally, a trend-level main effect of early childhood trauma on subjective stress response emerged within this group (b = -.7, t(11) = -2, p = .07), where higher early trauma correlated with lower subjective stress response to the task. In the NAPD group, childhood trauma was not associated with the spatial extent of the tracer displacement in mPFC (b = -1.22, t(11) = -0.67), nor was there a main effect of trauma on the subjective perception of stress within this group (b = .004, t(11) = .01, p = .99). These findings reveal a potential mechanism of neuroadaptation of prefrontal DA transmission to early life stress and suggest its role in resilience and vulnerability to psychosis. PMID:27007554

Genetic heterogeneity of RPMI-8402, a T-acute lymphoblastic leukemia cell line

PubMed Central

STOCZYNSKA-FIDELUS, EWELINA; PIASKOWSKI, SYLWESTER; PAWLOWSKA, ROZA; SZYBKA, MALGORZATA; PECIAK, JOANNA; HULAS-BIGOSZEWSKA, KRYSTYNA; WINIECKA-KLIMEK, MARTA; RIESKE, PIOTR

2016-01-01

Thorough examination of genetic heterogeneity of cell lines is uncommon. In order to address this issue, the present study analyzed the genetic heterogeneity of RPMI-8402, a T-acute lymphoblastic leukemia (T-ALL) cell line. For this purpose, traditional techniques such as fluorescence in situ hybridization and immunocytochemistry were used, in addition to more advanced techniques, including cell sorting, Sanger sequencing and massive parallel sequencing. The results indicated that the RPMI-8402 cell line consists of several genetically different cell subpopulations. Furthermore, massive parallel sequencing of RPMI-8402 provided insight into the evolution of T-ALL carcinogenesis, since this cell line exhibited the genetic heterogeneity typical of T-ALL. Therefore, the use of cell lines for drug testing in future studies may aid the progress of anticancer drug research. PMID:26870252

From the outside, from within: Biological and therapeutic relevance of signal transduction in T-cell acute lymphoblastic leukemia.

PubMed

Oliveira, Mariana L; Akkapeddi, Padma; Alcobia, Isabel; Almeida, Afonso R; Cardoso, Bruno A; Fragoso, Rita; Serafim, Teresa L; Barata, João T

2017-10-01

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological cancer that arises from clonal expansion of transformed T-cell precursors. In this review we summarize the current knowledge on the external stimuli and cell-intrinsic lesions that drive aberrant activation of pivotal, pro-tumoral intracellular signaling pathways in T-cell precursors, driving transformation, leukemia expansion, spread or resistance to therapy. In addition to their pathophysiological relevance, receptors and kinases involved in signal transduction are often attractive candidates for targeted drug development. As such, we discuss also the potential of T-ALL signaling players as targets for therapeutic intervention. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

B and T cell screen

MedlinePlus

... Cancer of white blood cell called a lymphoblast ( acute lymphoblastic leukemia ) Cancer of white blood cells called ... cell count may be due to: HIV/AIDS Acute lymphoblastic leukemia Immunodeficiency disorders Risks Veins and arteries ...

Involvement of MTHFR and TPMT genes in susceptibility to childhood acute lymphoblastic leukemia (ALL) in Mexicans.

PubMed

Gutiérrez-Álvarez, Ossyneidee; Lares-Asseff, Ismael; Galaviz-Hernández, Carlos; Reyes-Espinoza, Elio-Aarón; Almanza-Reyes, Horacio; Sosa-Macías, Martha; Chairez Hernández, Isaías; Salas-Pacheco, José-Manuel; Bailón-Soto, Claudia E

2016-03-01

Folate metabolism plays an essential role in the processes of DNA synthesis and methylation. Deviations in the folate flux resulting from single-nucleotide polymorphisms in genes encoding folate-dependent enzymes may affect the susceptibility to leukemia. This case-control study aimed to assess associations among MTHFR (C677T, A1298C) and TPMT (*2, *3A) mutations as well as to evaluate the synergistic effects of combined genotypes for both genes. Therefore, these genetic variants may lead to childhood acute lymphoblastic leukemia (ALL) susceptibility, in a Mexican population study. DNA samples obtained from 70 children with ALL and 152 age-matched controls (range, 1-15 years) were analyzed by real-time reverse transcription polymerase chain reaction (RT-qPCR) to detect MTHFR C677T and A1298C and TPMT*2 and TPMT*3A genotypes. The frequency of the MTHFR A1298C CC genotype was statistically significant (odds ratio [OR], 6.48; 95% 95% confidence intervals [CI], 1.26-33.2; p=0.025). In addition, the combined 677CC+1298AC genotype exhibited a statistically significant result (OR, 0.23; 95% CI, 0.06-0.82; p=0.023). No significant results were obtained from the MTHFR (C677T CT, C677T TT) or TPMT (*2, *3A) genotypes. More importantly, no association between the synergistic effects of either gene (MTHFR and/or TPMT) and susceptibility to ALL was found. The MTHFR A1298C CC genotype was associated with an increased risk of developing childhood ALL. However, a decreased risk to ALL with the combination of MTHFR 677CC+1298AC genotypes was found.

ZFX controls propagation and prevents differentiation of acute T-lymphoblastic and myeloid leukemia

PubMed Central

Weisberg, Stuart P.; Smith-Raska, Matthew R.; Esquilin, Jose M.; Zhang, Ji; Arenzana, Teresita L.; Lau, Colleen M.; Churchill, Michael; Pan, Haiyan; Klinakis, Apostolos; Dixon, Jack E.; Mirny, Leonid A.; Mukherjee, Siddhartha; Reizis, Boris

2014-01-01

Summary Tumor-propagating cells in acute leukemia maintain a stem/progenitor-like immature phenotype and proliferative capacity. Acute myeloid leukemia (AML) and acute T-lymphoblastic leukemia (T-ALL) originate from different lineages through distinct oncogenic events such as MLL fusions and Notch signaling, respectively. We found that Zfx, a transcription factor that controls hematopoietic stem cell self-renewal, controls the initiation and maintenance of AML caused by MLL-AF9 fusion and of T-ALL caused by Notch1 activation. In both leukemia types, Zfx prevents differentiation and activates gene sets characteristic of immature cells of the respective lineages. In addition, endogenous Zfx contributes to gene induction and transformation by Myc overexpression in myeloid progenitors. Key Zfx target genes include the mitochondrial enzymes Ptpmt1 and Idh2, whose overexpression partially rescues the propagation of Zfx-deficient AML. These results show that distinct leukemia types maintain their undifferentiated phenotype and self-renewal by exploiting a common stem cell-related genetic regulator. PMID:24485662

Acute Viral Respiratory Infection Rapidly Induces a CD8+ T Cell Exhaustion-like Phenotype.

PubMed

Erickson, John J; Lu, Pengcheng; Wen, Sherry; Hastings, Andrew K; Gilchuk, Pavlo; Joyce, Sebastian; Shyr, Yu; Williams, John V

2015-11-01

Acute viral infections typically generate functional effector CD8(+) T cells (TCD8) that aid in pathogen clearance. However, during acute viral lower respiratory infection, lung TCD8 are functionally impaired and do not optimally control viral replication. T cells also become unresponsive to Ag during chronic infections and cancer via signaling by inhibitory receptors such as programmed cell death-1 (PD-1). PD-1 also contributes to TCD8 impairment during viral lower respiratory infection, but how it regulates TCD8 impairment and the connection between this state and T cell exhaustion during chronic infections are unknown. In this study, we show that PD-1 operates in a cell-intrinsic manner to impair lung TCD8. In light of this, we compared global gene expression profiles of impaired epitope-specific lung TCD8 to functional spleen TCD8 in the same human metapneumovirus-infected mice. These two populations differentially regulate hundreds of genes, including the upregulation of numerous inhibitory receptors by lung TCD8. We then compared the gene expression of TCD8 during human metapneumovirus infection to those in acute or chronic lymphocytic choriomeningitis virus infection. We find that the immunophenotype of lung TCD8 more closely resembles T cell exhaustion late into chronic infection than do functional effector T cells arising early in acute infection. Finally, we demonstrate that trafficking to the infected lung alone is insufficient for TCD8 impairment or inhibitory receptor upregulation, but that viral Ag-induced TCR signaling is also required. Our results indicate that viral Ag in infected lungs rapidly induces an exhaustion-like state in lung TCD8 characterized by progressive functional impairment and upregulation of numerous inhibitory receptors. Copyright © 2015 by The American Association of Immunologists, Inc.

Hematopoietic cell transplantation and cellular therapeutics in the treatment of childhood malignancies.

PubMed

Mallhi, Kanwaldeep; Lum, Lawrence G; Schultz, Kirk R; Yankelevich, Maxim

2015-02-01

Hematopoietic cell transplantation (HCT) represents the most common and effective form of immunotherapy for childhood malignancies. The role of the graft-versus-leukemia effect in allogeneic HCT has been well established in childhood malignancies, but is also associated with short-term and long-term morbidity. HCT may be ineffective in some settings at obtaining control of the malignancy, and as such, cannot be used as a universal cancer immunotherapy. Novel therapies using dendritic cell vaccinations, tumor-infiltrating lymphocytes, and chimeric antigen receptor T cells are being evaluated as potential adjuvants to HCT. Copyright © 2015 Elsevier Inc. All rights reserved.

Chimeric Antigen Receptor–Modified T Cells for Acute Lymphoid Leukemia

PubMed Central

Barrett, David; Aplenc, Richard; Porter, David L.; Rheingold, Susan R.; Teachey, David T.; Chew, Anne; Hauck, Bernd; Wright, J. Fraser; Milone, Michael C.; Levine, Bruce L.; June, Carl H.

2014-01-01

Summary Chimeric antigen receptor–modified T cells with specificity for CD19 have shown promise in the treatment of chronic lymphocytic leukemia (CLL). It remains to be established whether chimeric antigen receptor T cells have clinical activity in acute lymphoblastic leukemia (ALL). Two children with relapsed and refractory pre–B-cell ALL received infusions of T cells transduced with anti-CD19 antibody and a T-cell signaling molecule (CTL019 chimeric antigen receptor T cells), at a dose of 1.4×106 to 1.2×107 CTL019 cells per kilogram of body weight. In both patients, CTL019 T cells expanded to a level that was more than 1000 times as high as the initial engraftment level, and the cells were identified in bone marrow. In addition, the chimeric antigen receptor T cells were observed in the cerebrospinal fluid (CSF), where they persisted at high levels for at least 6 months. Eight grade 3 or 4 adverse events were noted. The cytokine-release syndrome and B-cell aplasia developed in both patients. In one child, the cytokine-release syndrome was severe; cytokine blockade with etanercept and tocilizumab was effective in reversing the syndrome and did not prevent expansion of chimeric antigen receptor T cells or reduce anti-leukemic efficacy. Complete remission was observed in both patients and is ongoing in one patient at 11 months after treatment. The other patient had a relapse, with blast cells that no longer expressed CD19, approximately 2 months after treatment. Chimeric antigen receptor–modified T cells are capable of killing even aggressive, treatment-refractory acute leukemia cells in vivo. The emergence of tumor cells that no longer express the target indicates a need to target other molecules in addition to CD19 in some patients with ALL. PMID:23527958

Chimeric antigen receptor-modified T cells for acute lymphoid leukemia.

PubMed

Grupp, Stephan A; Kalos, Michael; Barrett, David; Aplenc, Richard; Porter, David L; Rheingold, Susan R; Teachey, David T; Chew, Anne; Hauck, Bernd; Wright, J Fraser; Milone, Michael C; Levine, Bruce L; June, Carl H

2013-04-18

Chimeric antigen receptor-modified T cells with specificity for CD19 have shown promise in the treatment of chronic lymphocytic leukemia (CLL). It remains to be established whether chimeric antigen receptor T cells have clinical activity in acute lymphoblastic leukemia (ALL). Two children with relapsed and refractory pre-B-cell ALL received infusions of T cells transduced with anti-CD19 antibody and a T-cell signaling molecule (CTL019 chimeric antigen receptor T cells), at a dose of 1.4×10(6) to 1.2×10(7) CTL019 cells per kilogram of body weight. In both patients, CTL019 T cells expanded to a level that was more than 1000 times as high as the initial engraftment level, and the cells were identified in bone marrow. In addition, the chimeric antigen receptor T cells were observed in the cerebrospinal fluid (CSF), where they persisted at high levels for at least 6 months. Eight grade 3 or 4 adverse events were noted. The cytokine-release syndrome and B-cell aplasia developed in both patients. In one child, the cytokine-release syndrome was severe; cytokine blockade with etanercept and tocilizumab was effective in reversing the syndrome and did not prevent expansion of chimeric antigen receptor T cells or reduce antileukemic efficacy. Complete remission was observed in both patients and is ongoing in one patient at 11 months after treatment. The other patient had a relapse, with blast cells that no longer expressed CD19, approximately 2 months after treatment. Chimeric antigen receptor-modified T cells are capable of killing even aggressive, treatment-refractory acute leukemia cells in vivo. The emergence of tumor cells that no longer express the target indicates a need to target other molecules in addition to CD19 in some patients with ALL.

The TEL-AML1 fusion protein of acute lymphoblastic leukemia modulates IRF3 activity during early B-cell differentiation.

PubMed

de Laurentiis, A; Hiscott, J; Alcalay, M

2015-12-03

The t(12;21) translocation is the most common genetic rearrangement in childhood acute lymphoblastic leukemia (ALL) and gives rise to the TEL-AML1 fusion gene. Many studies on TEL-AML1 describe specific properties of the fusion protein, but a thorough understanding of its function is lacking. We exploited a pluripotent hematopoietic stem/progenitor cell line, EML1, and generated a cell line (EML-TA) stably expressing the TEL-AML1 fusion protein. EML1 cells differentiate to mature B-cells following treatment with IL7; whereas EML-TA display an impaired differentiation capacity and remain blocked at an early stage of maturation. Global gene expression profiling of EML1 cells at different stages of B-lymphoid differentiation, compared with EML-TA, identified the interferon (IFN)α/β pathway as a primary target of repression by TEL-AML1. In particular, expression and phosphorylation of interferon-regulatory factor 3 (IRF3) was decreased in EML-TA cells; strikingly, stable expression of IRF3 restored the capacity of EML-TA cells to differentiate into mature B-cells. Similarly, IRF3 silencing in EML1 cells by siRNA was sufficient to block B-lymphoid differentiation. The ability of TEL-AML1 to block B-cell differentiation and downregulate the IRF3-IFNα/β pathway was confirmed in mouse and human primary hematopoietic precursor cells (Lin- and CD34+ cells, respectively), and in a patient-derived cell line expressing TEL-AML1 (REH). Furthermore, treatment of TEL-AML1 expressing cells with IFNα/β was sufficient to overcome the maturation block. Our data provide new insight on TEL-AML1 function and may offer a new therapeutic opportunity for B-ALL.

T-cell expression of AhR inhibits the maintenance of pTreg cells in the gastrointestinal tract in acute GVHD.

PubMed

Dant, Trisha A; Lin, Kaifeng L; Bruce, Danny W; Montgomery, Stephanie A; Kolupaev, Oleg V; Bommiasamy, Hemamalini; Bixby, Lisa M; Woosley, John T; McKinnon, Karen P; Gonzalez, Frank J; Blazar, Bruce R; Vincent, Benjamin G; Coghill, James M; Serody, Jonathan S

2017-07-20

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that affects the function and development of immune cells. Here, we show that recipient mice receiving AhR -/- T cells have improved survival and decreased acute graft-versus-host disease (aGVHD) in 2 different murine allogeneic bone marrow transplant (BMT) models. We also show that CD4 + T cells lacking AhR demonstrate reduced accumulation in secondary lymphoid tissue because of low levels of proliferation 4 days after BMT. Additionally, we found a significant increase in the quantity of peripherally induced regulatory donor T (pT reg ) cells in the colon of recipients transplanted with AhR -/- T cells 14 days after transplant. Blockade of AhR using a clinically available AhR antagonist greatly enhanced the in vitro generation of inducible T reg (iT reg ) cells from naïve CD4 + human T cells. We have identified AhR as a novel target on donor T cells that is critical to the pathogenesis of aGVHD.

Escape is a more common mechanism than avidity reduction for evasion of CD8+ T cell responses in primary human immunodeficiency virus type 1 infection

PubMed Central

2011-01-01

Background CD8+ T cells play an important role in control of viral replication during acute and early human immunodeficiency virus type 1 (HIV-1) infection, contributing to containment of the acute viral burst and establishment of the prognostically-important persisting viral load. Understanding mechanisms that impair CD8+ T cell-mediated control of HIV replication in primary infection is thus of importance. This study addressed the relative extent to which HIV-specific T cell responses are impacted by viral mutational escape versus reduction in response avidity during the first year of infection. Results 18 patients presenting with symptomatic primary HIV-1 infection, most of whom subsequently established moderate-high persisting viral loads, were studied. HIV-specific T cell responses were mapped in each individual and responses to a subset of optimally-defined CD8+ T cell epitopes were followed from acute infection onwards to determine whether they were escaped or declined in avidity over time. During the first year of infection, sequence variation occurred in/around 26/33 epitopes studied (79%). In 82% of cases of intra-epitopic sequence variation, the mutation was confirmed to confer escape, although T cell responses were subsequently expanded to variant sequences in some cases. In contrast, < 10% of responses to index sequence epitopes declined in functional avidity over the same time-frame, and a similar proportion of responses actually exhibited an increase in functional avidity during this period. Conclusions Escape appears to constitute a much more important means of viral evasion of CD8+ T cell responses in acute and early HIV infection than decline in functional avidity of epitope-specific T cells. These findings support the design of vaccines to elicit T cell responses that are difficult for the virus to escape. PMID:21635736

Atorvastatin inhibits the immediate-early response gene EGR1 and improves the functional pro of CD4+T-lymphocytes in acute coronary syndromes

PubMed Central

Campioni, Mara; Flego, Davide; Angelini, Giulia; Pedicino, Daniela; Giglio, Ada Francesca; Trotta, Francesco; Giubilato, Simona; Pazzano, Vincenzo; Lucci, Claudia; Iaconelli, Antonio; Ruggio, Aureliano; Biasucci, Luigi Marzio

2017-01-01

Background- Adaptive immune-response is associated with a worse outcome in acute coronary syndromes. Statins have anti-inflammatory activity beyond lowering lipid levels. We investigated the effects of ex-vivo and in-vivo atorvastatin treatment in acute coronary syndromes on CD4+T-cells, and the underlying molecular mechanisms. Approach and results- Blood samples were collected from 50 statin-naïve acute coronary syndrome patients. We assessed CD4+T-cell activation by flow-cytometry, the expression of 84 T-helper transcription-factors and 84 T-cell related genes by RT-qPCR, and protein expression by Western-blot, before and after 24-hours incubation with increasing doses of atorvastatin: 3-10-26 g/ml (corresponding to blood levels achieved with doses of 10-40-80 mg, respectively). After incubation, we found a significant decrease in interferon-?-producing CD4+CD28nullT-cells (P = 0.009) and a significant increase in interleukin-10-producing CD4+CD25highT-cells (P < 0.001). Atorvastatin increased the expression of 2 genes and decreased the expression of 12 genes (in particular, EGR1, FOS,CCR2 and toll like receptor-4; >3-fold changes). The in-vivo effects of atorvastatin were analyzed in 10 statin-free acute coronary syndrome patients at baseline, and after 24h and 48h of atorvastatin therapy (80 mg/daily): EGR1-gene expression decreased at 24h (P = 0.01) and 48h (P = 0.005); EGR1-protein levels decreased at 48h (P = 0.03). Conclusions-In acute coronary syndromes, the effects of atorvastatin on immune system might be partially related to the inhibition of the master regulator gene EGR1. Our finding might offer a causal explanation on why statins improve the early outcome in acute coronary syndromes. PMID:28407684

C-Rel is an essential transcription factor for the development of acute graft-versus-host disease in mice

PubMed Central

Yu, Yu; Wang, Dapeng; Kaosaard, Kane; Liu, Chen; Fu, Jianing; Haarberg, Kelley; Anasetti, Claudio; Beg, Amer A.; Yu, Xue-Zhong

2014-01-01

Transcription factor of the Rel/NF-κB family are known to play different roles in immunity and inflammation, although the putative role of c-Rel in transplant tolerance and GVHD remains elusive. We report here that T cells deficient for c-Rel have a dramatically reduced ability to cause acute graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (BMT) using major and minor histocompatibility mismatched murine models. In the study to understand the underlying mechanisms, we found that c-Rel-/- T cells had reduced ability to expand in lymphoid organs and to infiltrate in GVHD target organs in allogeneic recipients. c-Rel-/- T cells were defective in the differentiation into Th1 cells after encountering alloantigens, but were enhanced in the differentiation towards Foxp3+ regulatory T cells (Tregs). Furthermore, c-Rel-/- T cells had largely preserved activity to mediate graft-versus leukemia (GVL) response. Taken together, our findings indicate that c-Rel plays an essential role in T cells in the induction of acute GVHD, and suggest that c-Rel can be a potential target for therapeutic intervention in allogeneic HCT in clinic. PMID:23716202

Dasatinib in Treating Patients With Solid Tumors or Lymphomas That Are Metastatic or Cannot Be Removed By Surgery

ClinicalTrials.gov

2015-06-30

Adult Acute Lymphoblastic Leukemia in Remission; Adult B Acute Lymphoblastic Leukemia; Adult Hepatocellular Carcinoma; Adult Nasal Type Extranodal NK/T-Cell Lymphoma; Adult Solid Neoplasm; Adult T Acute Lymphoblastic Leukemia; Advanced Adult Hepatocellular Carcinoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-Cell Lymphoma; Chronic Lymphocytic Leukemia; Cutaneous B-Cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue; Hepatosplenic T-Cell Lymphoma; Intraocular Lymphoma; Localized Non-Resectable Adult Liver Carcinoma; Localized Resectable Adult Liver Carcinoma; Lymphomatous Involvement of Non-Cutaneous Extranodal Site; Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma; Nodal Marginal Zone Lymphoma; Progressive Hairy Cell Leukemia Initial Treatment; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Lymphoma; Recurrent Adult Liver Carcinoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-Cell Leukemia/Lymphoma; Recurrent Cutaneous T-Cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides and Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Small Intestinal Lymphoma; Splenic Marginal Zone Lymphoma; Stage II Small Lymphocytic Lymphoma; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Hodgkin Lymphoma; Stage III Adult Immunoblastic Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Adult T-Cell Leukemia/Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Cutaneous T-Cell Non-Hodgkin Lymphoma; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Small Lymphocytic Lymphoma; Stage IIIA Mycosis Fungoides and Sezary Syndrome; Stage IIIB Mycosis Fungoides and Sezary Syndrome; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Hodgkin Lymphoma; Stage IV Adult Immunoblastic Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Adult T-Cell Leukemia/Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Cutaneous T-Cell Non-Hodgkin Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Small Lymphocytic Lymphoma; Stage IVA Mycosis Fungoides and Sezary Syndrome; Stage IVB Mycosis Fungoides and Sezary Syndrome; T-Cell Large Granular Lymphocyte Leukemia; Testicular Lymphoma; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Hairy Cell Leukemia; Waldenstrom Macroglobulinemia

IL-2 promotes early Treg reconstitution after allogeneic hematopoietic cell transplantation.

PubMed

Betts, Brian C; Pidala, Joseph; Kim, Jongphil; Mishra, Asmita; Nishihori, Taiga; Perez, Lia; Ochoa-Bayona, Jose Leonel; Khimani, Farhad; Walton, Kelly; Bookout, Ryan; Nieder, Michael; Khaira, Divis K; Davila, Marco; Alsina, Melissa; Field, Teresa; Ayala, Ernesto; Locke, Frederick L; Riches, Marcie; Kharfan-Dabaja, Mohamed; Fernandez, Hugo; Anasetti, Claudio

2017-05-01

Graft- versus -host disease (GvHD) remains a major cause of transplant-related mortality. Interleukin-2 (IL-2) plus sirolimus (SIR) synergistically reduces acute GvHD in rodents and promotes regulatory T cells. This phase II trial tested the hypothesis that IL-2 would facilitate STAT5 phosphorylation in donor T cells, expand regulatory T cells, and ameliorate GvHD. Between 16 th April 2014 and 19 th December 2015, 20 patients received IL-2 (200,000 IU/m 2 thrice weekly, days 0 to +90) with SIR (5-14 ng/mL) and tacrolimus (TAC) (3-7 ng/mL) after HLA-matched related or unrelated allogeneic hematopoietic cell transplantation (HCT). The study was designed to capture an increase in regulatory T cells from 16.0% to more than 23.2% at day +30. IL-2/SIR/TAC significantly increased regulatory T cells at day +30 compared to our published data with SIR/TAC (23.8% vs. 16.0%, P =0.0016; 0.052 k/uL vs. 0.037 k/uL, P =0.0163), achieving the primary study end point. However, adding IL-2 to SIR/TAC led to a fall in regulatory T cells by day +90 and did not reduce acute or chronic GvHD. Patients who discontinued IL-2 before day +100 showed a suggested trend toward less grade II-IV acute GvHD (16.7% vs. 50%, P =0.1475). We surmise that the reported accumulation of IL-2 receptors in circulation over time may neutralize IL-2, lead to progressive loss of regulatory T cells, and offset its clinical efficacy. The amount of phospho-STAT3 + CD4 + T cells correlated with donor T-cell activation and acute GvHD incidence despite early T-cell STAT5 phosphorylation by IL-2. Optimizing IL-2 dosing and overcoming cytokine sequestration by soluble IL-2 receptor may sustain lasting regulatory T cells after transplantation. However, an approach to target STAT3 is needed to enhance GvHD prevention. ( clinicaltrials.gov identifier: 01927120 ). Copyright© Ferrata Storti Foundation.

Role of PD-1 during effector CD8 T cell differentiation.

PubMed

Ahn, Eunseon; Araki, Koichi; Hashimoto, Masao; Li, Weiyan; Riley, James L; Cheung, Jeanne; Sharpe, Arlene H; Freeman, Gordon J; Irving, Bryan A; Ahmed, Rafi

2018-05-01

PD-1 (programmed cell death-1) is the central inhibitory receptor regulating CD8 T cell exhaustion during chronic viral infection and cancer. Interestingly, PD-1 is also expressed transiently by activated CD8 T cells during acute viral infection, but the role of PD-1 in modulating T cell effector differentiation and function is not well defined. To address this question, we examined the expression kinetics and role of PD-1 during acute lymphocytic choriomeningitis virus (LCMV) infection of mice. PD-1 was rapidly up-regulated in vivo upon activation of naive virus-specific CD8 T cells within 24 h after LCMV infection and in less than 4 h after peptide injection, well before any cell division had occurred. This rapid PD-1 expression by CD8 T cells was driven predominantly by antigen receptor signaling since infection with a LCMV strain with a mutation in the CD8 T cell epitope did not result in the increase of PD-1 on antigen-specific CD8 T cells. Blockade of the PD-1 pathway using anti-PD-L1 or anti-PD-1 antibodies during the early phase of acute LCMV infection increased mTOR signaling and granzyme B expression in virus-specific CD8 T cells and resulted in faster clearance of the infection. These results show that PD-1 plays an inhibitory role during the naive-to-effector CD8 T cell transition and that the PD-1 pathway can also be modulated at this stage of T cell differentiation. These findings have implications for developing therapeutic vaccination strategies in combination with PD-1 blockade.

Altered Memory Circulating T Follicular Helper-B Cell Interaction in Early Acute HIV Infection

PubMed Central

Muir, Roshell; Metcalf, Talibah; Tardif, Virginie; Takata, Hiroshi; Phanuphak, Nittaya; Kroon, Eugene; Colby, Donn J.; Trichavaroj, Rapee; Valcour, Victor; Robb, Merlin L.; Michael, Nelson L.; Ananworanich, Jintanat; Trautmann, Lydie; Haddad, Elias K.

2016-01-01

The RV254 cohort of HIV-infected very early acute (4thG stage 1 and 2) (stage 1/2) and late acute (4thG stage 3) (stage 3) individuals was used to study T helper- B cell responses in acute HIV infection and the impact of early antiretroviral treatment (ART) on T and B cell function. To investigate this, the function of circulating T follicular helper cells (cTfh) from this cohort was examined, and cTfh and memory B cell populations were phenotyped. Impaired cTfh cell function was observed in individuals treated in stage 3 when compared to stage 1/2. The cTfh/B cell cocultures showed lower B cell survival and IgG secretion at stage 3 compared to stage 1/2. This coincided with lower IL-10 and increased RANTES and TNF-α suggesting a role for inflammation in altering cTfh and B cell responses. Elevated plasma viral load in stage 3 was found to correlate with decreased cTfh-mediated B cell IgG production indicating a role for increased viremia in cTfh impairment and dysfunctional humoral response. Phenotypic perturbations were also evident in the mature B cell compartment, most notably a decrease in resting memory B cells in stage 3 compared to stage 1/2, coinciding with higher viremia. Our coculture assay also suggested that intrinsic memory B cell defects could contribute to the impaired response despite at a lower level. Overall, cTfh-mediated B cell responses are significantly altered in stage 3 compared to stage 1/2, coinciding with increased inflammation and a reduction in memory B cells. These data suggest that early ART for acutely HIV infected individuals could prevent immune dysregulation while preserving cTfh function and B cell memory. PMID:27463374

Childhood cancer and residential proximity to power lines. UK Childhood Cancer Study Investigators.

PubMed

2000-12-01

In the United Kingdom Childhood Cancer Study, a population-based case-control study covering the whole of England, Scotland and Wales, measured power-frequency magnetic fields were not found to be associated with risk for any malignancy. To examine further the risk associated with residential proximity to electricity supply equipment, distances to high-voltage lines, underground cables, substations and distribution circuits were collected for 3380 cases and 3390 controls. Magnetic field exposure from this equipment was calculated using distance, load and other circuit information. There was no evidence that either proximity to electrical installations or the magnetic field levels they produce in the UK is associated with increased risk of childhood leukaemia or any other cancer. Odds ratios of 0.73 (95% CI = 0.42-1.26) for acute lymphoblastic leukaemia, 0.75 (95% CI = 0.45-1.25) for all leukaemias, 1.08 (95% CI = 0.56-2.09) for central nervous system cancers and 0.92 (95% CI = 0.64-1.34) for all malignancies were obtained for residence within 50 m of an overhead line. When individuals with a calculated magnetic field exposure > or = 0.2 microT were compared to those in a reference category of exposure <0.1 microT, odds ratios of 0.51 (95% CI = 0.11-2.33) for acute lymphoblastic leukaemia, 0.41 (95% CI = 0. 09-1.87) for total leukaemia, 0.48 (95% CI =0.06-3.76) for central nervous system cancers and 0.62 (95% CI = 0.24-1.61) for all malignancies were obtained. Copyright 2000 Cancer Research Campaign.

Organ-Sparing Marrow-Targeted Irradiation Before Stem Cell Transplant in Treating Patients With High-Risk Hematologic Malignancies

ClinicalTrials.gov

2017-10-09

Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); de Novo Myelodysplastic Syndromes; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Adult Acute Myeloid Leukemia

Donor Umbilical Cord Blood Transplant in Treating Patients With Hematologic Cancer

ClinicalTrials.gov

2018-01-17

Acute Lymphoblastic Leukemia; Acute Myeloid Leukemia; Aggressive Non-Hodgkin Lymphoma; Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Chronic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Indolent Non-Hodgkin Lymphoma; Lymphoma; Mixed Phenotype Acute Leukemia; Myelodysplastic Syndrome; Myeloproliferative Neoplasm; Recurrent Chronic Lymphocytic Leukemia; Recurrent Follicular Lymphoma; Recurrent Lymphoplasmacytic Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Plasma Cell Myeloma; Recurrent Small Lymphocytic Lymphoma; Recurrent T-Cell Non-Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Refractory Follicular Lymphoma; Refractory Hodgkin Lymphoma; Refractory Lymphoplasmacytic Lymphoma; Refractory Mantle Cell Lymphoma; Refractory Small Lymphocytic Lymphoma; T-Cell Non-Hodgkin Lymphoma

Regulatory cells induced by acute toxoplasmosis prevent the development of allergic lung inflammation.

PubMed

Fenoy, Ignacio M; Sanchez, Vanesa R; Soto, Ariadna S; Picchio, Mariano S; Maglioco, Andrea; Corigliano, Mariana G; Dran, Graciela I; Martin, Valentina; Goldman, Alejandra

2015-05-01

The increased prevalence of allergies in developed countries has been attributed to a reduction of some infections. Supporting epidemiological studies, we previously showed that both acute and chronic Toxoplasma gondii infection can diminish allergic airway inflammation in BALB/c mice. The mechanisms involved when sensitization occurs during acute phase would be related to the strong Th1 response induced by the parasite. Here, we further investigated the mechanisms involved in T. gondii allergy protection in mice sensitized during acute T. gondii infection. Adoptive transference assays and ex vivo co-cultures experiments showed that not only thoracic lymph node cells from infected and sensitized mice but also from non-sensitized infected animals diminished both allergic lung inflammation and the proliferation of effector T cells from allergic mice. This ability was found to be contact-independent and correlated with high levels of CD4(+)FoxP3(+) cells. IL-10 would not be involved in allergy suppression since IL-10-deficient mice behaved similar to wild type mice. Our results extend earlier work and show that, in addition to immune deviation, acute T. gondii infection can suppress allergic airway inflammation through immune suppression. Copyright © 2014 Elsevier GmbH. All rights reserved.

Administration of herpes simplex-thymidine kinase-expressing donor T cells with a T-cell-depleted allogeneic marrow graft.

PubMed

Tiberghien, P; Ferrand, C; Lioure, B; Milpied, N; Angonin, R; Deconinck, E; Certoux, J M; Robinet, E; Saas, P; Petracca, B; Juttner, C; Reynolds, C W; Longo, D L; Hervé, P; Cahn, J Y

2001-01-01

Administration of donor T cells expressing the herpes simplex-thymidine kinase (HS-tk) with a hematopoietic stem cell (HSC) transplantation could allow, if graft-versus-host disease (GVHD) was to occur, a selective in vivo depletion of these T cells by the use of ganciclovir (GCV). The study evaluates the feasibility of such an approach. Escalating numbers of donor HS-tk-expressing CD3(+) gene-modified cells (GMCs) are infused with a T-cell-depleted bone marrow transplantation (BMT). Twelve patients with hematological malignancies received 2 x 10(5) (n = 5), 6 x 10(5) (n = 5), or 20 x 10(5) (n = 2) donor CD3(+) GMCs/kg with a BMT from a human leukocyte antigen (HLA)-identical sibling. No acute toxicity was associated with GMC administration. An early increase of circulating GMCs followed by a progressive decrease and long-lasting circulation of GMCs was documented. GCV treatment resulted in significant rapid decrease in circulating GMCs. Three patients developed acute GVHD, with a grade of at least II, while one patient developed chronic GVHD. Treatment with GCV alone was associated with a complete remission (CR) in 2 patients with acute GVHD, while the addition of glucocorticoids was necessary to achieve a CR in the last case. Long-lasting CR occurred with GCV treatment in the patient with chronic GVHD. Unfortunately, Epstein-Barr virus-lymphoproliferative disease occurred in 3 patients. Overall, the administration of low numbers of HS-tk-expressing T cells early following an HLA-identical BMT is associated with no acute toxicity, persistent circulation of the GMCs, and GCV-sensitive GVHD. Such findings open the way to the infusion of higher numbers of gene-modified donor T cells to enhance post-BMT immune competence while preserving GCV-sensitive alloreactivity.

How to train your T cell: genetically engineered chimeric antigen receptor T cells versus bispecific T-cell engagers to target CD19 in B acute lymphoblastic leukemia.

PubMed

Ruella, Marco; Gill, Saar

2015-06-01

Antigen-specific T cell-based immunotherapy is getting its day in the sun. The contemporaneous development of two potent CD19-specific immunotherapeutic modalities for the treatment of B-cell malignancies provides exciting opportunities for patients, physicians and scientists alike. Patients with relapsed, refractory or poor-risk B-cell acute lymphoblastic leukemia (ALL) previously had few therapeutic options and now have two potential new lifelines. Physicians will have the choice between two powerful modalities and indeed could potentially enroll some patients on trials exploring both modalities if needed. For scientists interested in tumor immunology, the advent of chimeric antigen receptor T-cell therapy and of bispecific T-cell engagers (BiTEs) provides unprecedented opportunities to explore the promise and limitations of antigen-specific T-cell therapy in the context of human leukemia. In this article, we compare chimeric antigen receptor T cells and BiTEs targeting CD19 in B-cell ALL in the setting of the available clinical literature.

Novel in vivo model of inducible multidrug resistance in acute lymphoblastic leukemia with chromosomal translocation t(4;11)

USDA-ARS?s Scientific Manuscript database

Acute lymphoblastic leukemia (ALL) with translocation t(4;11) is found in 60-85% of infants with ALL and is classified as high-risk due to the generally poor prognosis for survival. Using the SEM cell line established from a patient with t(4;11) ALL, we evaluated the resistance of these cells to the...

Resveratrol given intraperitoneally does not inhibit growth of high-risk t(4;11) acute lymphoblastic leukemia cells in NOD/SCID mouse model

USDA-ARS?s Scientific Manuscript database

The efficacy of the phytochemical resveratrol as a preventive agent against the growth of t(4;11) acute lymphoblastic leukemia (ALL) was evaluated in NOD.CB17-Prkdcscid/J mice engrafted with the human t(4;11) ALL line SEM. SEM cells were injected into the tail vein and engraftment was monitored by ...

Timing and magnitude of type I interferon responses by distinct sensors impact CD8 T cell exhaustion and chronic viral infection

PubMed Central

Wang, Yaming; Swiecki, Melissa; Cella, Marina; Alber, Gottfried; Schreiber, Robert D; Gilfillan, Susan; Colonna, Marco

2013-01-01

Summary Type I Interferons (IFN-I) promote antiviral CD8+T cell responses, but the contribution of different IFN-I sources and signaling pathways are ill-defined. While plasmacytoid dendritic cells (pDCs) produce IFN-I upon TLR stimulation, IFN-I are induced in most cells by helicases like MDA5. Using acute and chronic lymphocytic choriomeningitis virus (LCMV) infection models, we determined that pDCs transiently produce IFN-I that minimally impacts CD8+T cell responses and viral persistence. Rather, MDA5 is the key sensor that induces IFN-I required for CD8+T cell responses. In the absence of MDA5, CD8+T cell responses to acute infection rely on CD4+T cell help, and loss of both CD4+T cells and MDA5 results in CD8+T cell exhaustion and persistent infection. Chronic LCMV infection rapidly attenuates IFN-I responses, but early administration of exogenous IFN-I rescues CD8+T cells, promoting viral clearance. Thus, effective antiviral CD8+T cell responses depend on the timing and magnitude of IFN-I responses. PMID:22704623

Timing and magnitude of type I interferon responses by distinct sensors impact CD8 T cell exhaustion and chronic viral infection.

PubMed

Wang, Yaming; Swiecki, Melissa; Cella, Marina; Alber, Gottfried; Schreiber, Robert D; Gilfillan, Susan; Colonna, Marco

2012-06-14

Type I interferon (IFN-I) promotes antiviral CD8(+)T cell responses, but the contribution of different IFN-I sources and signaling pathways are ill defined. While plasmacytoid dendritic cells (pDCs) produce IFN-I upon TLR stimulation, IFN-I is induced in most cells by helicases like MDA5. Using acute and chronic lymphocytic choriomeningitis virus (LCMV) infection models, we determined that pDCs transiently produce IFN-I that minimally impacts CD8(+)T cell responses and viral persistence. Rather, MDA5 is the key sensor that induces IFN-I required for CD8(+)T cell responses. In the absence of MDA5, CD8(+)T cell responses to acute infection rely on CD4(+)T cell help, and loss of both CD4(+)T cells and MDA5 results in CD8(+)T cell exhaustion and persistent infection. Chronic LCMV infection rapidly attenuates IFN-I responses, but early administration of exogenous IFN-I rescues CD8(+)T cells, promoting viral clearance. Thus, effective antiviral CD8(+)T cell responses depend on the timing and magnitude of IFN-I production. Copyright © 2012 Elsevier Inc. All rights reserved.

T-cell-dependent control of acute Giardia lamblia infections in mice.

PubMed

Singer, S M; Nash, T E

2000-01-01

We have studied immune mechanisms responsible for control of acute Giardia lamblia and Giardia muris infections in adult mice. Association of chronic G. lamblia infection with hypogammaglobulinemia and experimental infections of mice with G. muris have led to the hypothesis that antibodies are required to control these infections. We directly tested this hypothesis by infecting B-cell-deficient mice with either G. lamblia or G. muris. Both wild-type mice and B-cell-deficient mice eliminated the vast majority of parasites between 1 and 2 weeks postinfection with G. lamblia. G. muris was also eliminated in both wild-type and B-cell-deficient mice. In contrast, T-cell-deficient and scid mice failed to control G. lamblia infections, as has been shown previously for G. muris. Treatment of wild-type or B-cell-deficient mice with antibodies to CD4 also prevented elimination of G. lamblia, confirming a role for T cells in controlling infections. By infecting mice deficient in either alphabeta- or gammadelta-T-cell receptor (TCR)-expressing T cells, we show that the alphabeta-TCR-expressing T cells are required to control parasites but that the gammadelta-TCR-expressing T cells are not. Finally, infections in mice deficient in production of gamma interferon or interleukin 4 (IL-4) and mice deficient in responding to IL-4 and IL-13 revealed that neither the Th1 nor the Th2 subset is absolutely required for protection from G. lamblia. We conclude that a T-cell-dependent mechanism is essential for controlling acute Giardia infections and that this mechanism is independent of antibody and B cells.

The PD-1: PD-L1 pathway promotes development of brain-resident memory T cells following acute viral encephalitis.

PubMed

Prasad, Sujata; Hu, Shuxian; Sheng, Wen S; Chauhan, Priyanka; Singh, Amar; Lokensgard, James R

2017-04-13

Previous work from our laboratory has demonstrated that during acute viral brain infection, glial cells modulate antiviral T cell effector responses through the PD-1: PD-L1 pathway, thereby limiting the deleterious consequences of unrestrained neuroinflammation. Here, we evaluated the PD-1: PD-L1 pathway in development of brain-resident memory T cells (bT RM ) following murine cytomegalovirus (MCMV) infection. Flow cytometric analysis of immune cells was performed at 7, 14, and 30 days post-infection (dpi) to assess the shift of brain-infiltrating CD8 + T cell populations from short-lived effector cells (SLEC) to memory precursor effector cells (MPEC), as well as generation of bT RMs . In wild-type (WT) animals, we observed a switch in the phenotype of brain-infiltrating CD8 + T cell populations from KLRG1 + CD127 - (SLEC) to KLRG1 - CD127 + (MPEC) during transition from acute through chronic phases of infection. At 14 and 30 dpi, the majority of CD8 + T cells expressed CD127, a marker of memory cells. In contrast, fewer CD8 + T cells expressed CD127 within brains of infected, PD-L1 knockout (KO) animals. Notably, in WT mice, a large population of CD8 + T cells was phenotyped as CD103 + CD69 + , markers of bT RM , and differences were observed in the numbers of these cells when compared to PD-L1 KOs. Immunohistochemical studies revealed that brain-resident CD103 + bT RM cells were localized to the parenchyma. Higher frequencies of CXCR3 were also observed among WT animals in contrast to PD-L1 KOs. Taken together, our results indicate that bT RMs are present within the CNS following viral infection and the PD-1: PD-L1 pathway plays a role in the generation of this brain-resident population.

Stages of Adult Acute Lymphoblastic Leukemia

MedlinePlus

... Childhood ALL Treatment Childhood AML Treatment Research Adult Acute Lymphoblastic Leukemia Treatment (PDQ®)–Patient Version General Information About Adult Acute Lymphoblastic Leukemia Go to Health Professional Version Key ...

Activated but not resting T cells or thymocytes express colony-stimulating factor 1 mRNA without co-expressing c-fms mRNA.

PubMed

Cerdan, C; Courcoul, M; Razanajaona, D; Pierrès, A; Maroc, N; Lopez, M; Mannoni, P; Mawas, C; Olive, D; Birg, F

1990-02-01

Following the observation that, besides acute myeloid leukemia cells, acute lymphoid leukemia cells of either B or T phenotype could express the transcript for the colony-stimulating factor 1 (CSF-1), a growth factor known to be restricted to the monocytic-macrophage lineage, various sources of resting and/or activated T cells and thymocytes were screened for expression of this hemopoietic growth factor. We report here that the CSF-1 transcript was rapidly (7 h) induced in T cells by a variety of stimuli, but was not detectable in either resting T cells or thymocytes. In addition, secretion of CSF-1 was detectable in the supernatants of activated T cells by 72 h, with a peak around 92-120 h. In contrast to activated monocytes, the transcript of the c-fms proto-oncogene, the product of which is the receptor for CSF-1, was not detectable in either resting or activated T cells. This observation could be relevant to the intimate relationships between T cells and antigen-presenting cells during immune responses.

T- and B-cell subpopulations in infectious mononucleosis

PubMed Central

Papamichail, M.; Sheldon, P. J.; Holborow, E. J.

1974-01-01

Mononuclear cells separated from the blood in fourteen cases of infectious mononucleosis at various intervals from the onset were tested for the presence of surface immunoglobulin and for ability to form spontaneous rosettes with washed sheep red blood cells. The mononucleosis during the acute phase of the illness consisted largely of a T lymphocytosis. The absolute count of T lymphocytes returned to the normal range approximately 2 months after the onset of the illness. B cells (bearing surface immunoglobulin) were only slightly increased in the acute phase. In four cases appreciable numbers of fluorescent rosetting cells were also present, and investigation suggested that these were T cells coated with anti-T-cell autoantibody. During the first 2 weeks of the illness responsiveness to phytohaemagglutinin was severely depressed, but thereafter returned towards normal. It is thought likely that in infectious mononucleosis the vast majority of atypical mononuclear cells are T cells proliferating in response to E-B virus-infected B cells, and cytotoxic towards them. ImagesFig. 3 PMID:4549622

CD19/CD22 Chimeric Antigen Receptor T Cells and Chemotherapy in Treating Patients With Recurrent or Refractory CD19 Positive Diffuse Large B-Cell Lymphoma or B Acute Lymphoblastic Leukemia

ClinicalTrials.gov

2018-01-25

B Acute Lymphoblastic Leukemia; CD19 Positive; Diffuse Large B-Cell Lymphoma Associated With Chronic Inflammation; Diffuse Large B-Cell Lymphoma, Not Otherwise Specified; Epstein-Barr Virus Positive Diffuse Large B-Cell Lymphoma of the Elderly; Minimal Residual Disease; Philadelphia Chromosome Positive; Recurrent Diffuse Large B-Cell Lymphoma; Recurrent Mediastinal (Thymic) Large B-Cell Cell Lymphoma; Refractory Diffuse Large B-Cell Lymphoma; Refractory Mediastinal (Thymic) Large B-Cell Cell Lymphoma; T-Cell/Histiocyte-Rich Large B-Cell Lymphoma

Treatment Option Overview (Adult Acute Lymphoblastic Leukemia)

MedlinePlus

... Childhood ALL Treatment Childhood AML Treatment Research Adult Acute Lymphoblastic Leukemia Treatment (PDQ®)–Patient Version General Information About Adult Acute Lymphoblastic Leukemia Go to Health Professional Version Key ...

Treatment Options for Adult Acute Lymphoblastic Leukemia

MedlinePlus

... Childhood ALL Treatment Childhood AML Treatment Research Adult Acute Lymphoblastic Leukemia Treatment (PDQ®)–Patient Version General Information About Adult Acute Lymphoblastic Leukemia Go to Health Professional Version Key ...

Conventional alpha beta (αβ) T cells do not contribute to acute intestinal ischemia-reperfusion injury in mice.

PubMed

Yu, Yi; Feng, Xiaoyan; Vieten, Gertrud; Dippel, Stephanie; Imvised, Tawan; Gueler, Faikah; Ure, Benno M; Kuebler, Jochen F; Klemann, Christian

2017-01-01

Ischemia-reperfusion injury (IRI) is associated with significant patient mortality and morbidity. The complex cascade of IRI is incompletely understood, but inflammation is known to be a key mediator. In addition to the predominant innate immune responses, previous research has also indicated that αβ T cells contribute to IRI in various organ models. The aim of this study was to clarify the role αβ T cells play in IRI to the gut. Adult wild-type (WT) and αβ T cell-deficient mice were subjected to acute intestinal IRI with 30min ischemia followed by 4h reperfusion. The gene expression of pro-inflammatory cytokines was measured by qPCR, and the influx of leukocyte subpopulations in the gut was assessed via flow cytometry and histology. Pro-inflammatory cytokines in the serum were measured, and transaminases were assessed as an indicator of distant organ IRI. Intestinal IRI led to an increased expression of pro-inflammatory cytokines in the gut tissue and an influx of leukocytes that predominantly consisted of neutrophils and macrophages. Furthermore, intestinal IRI increased serum IL-6, TNF-α, and ALT/AST levels. The αβ T cell-deficient mice did not exhibit a more significant increase in pro-inflammatory cytokines in the gut or serum following IR than the WT mice. There was also no difference between WT- and αβ T cell-deficient mice in terms of neutrophil infiltration or macrophage activation. Furthermore, the increase in transaminases was equal in both groups indicating that the level of distant organ injury was comparable. An increasing body of evidence demonstrates that αβ T cells play a key role in IRI. In the gut, however, αβ T cells are not pivotal in the first hours following acute IRI as deficiency does not impact cytokine production, neutrophil recruitment, macrophage activation, or distant organ injury. Thus, αβ T cells may be considered innocent bystanders during the acute phase of intestinal IRI.

Increased alpha-Amylase Response to an Acute Psychosocial Stress Challenge in Healthy Adults with Childhood Adversity

PubMed Central

Kuras, Yuliya I.; McInnis, Christine M.; Thoma, Myriam V.; Chen, Xuejie; Hanlin, Luke; Gianferante, Danielle; Rohleder, Nicolas

2017-01-01

Childhood adversity is highly prevalent and linked to lasting psychological and physiological consequences. A potential mechanism for negative health outcomes is altered stress reactivity. While previous research has addressed associations of childhood adversity with stress system reactivity, sympathetic nervous system (SNS) stress reactivity is understudied. We therefore set out here to examing salivary alpha-amylase (sAA) reactivity in relation with childhood adversity. Forty-one healthy adult subjects (n=24 male; n=17 female) aged 18-34 years underwent the Trier Social Stress Test (TSST) and completed the Childhood Trauma Questionnaire (CTQ). Saliva for measurement of sAA was collected at three time points; before the TSST, immediately after, and 10 minutes post-TSST. We found that those with childhood trauma had a higher overall sAA response to the TSST, as seen in a repeated measures ANOVA (CTQ by time interaction: F(1.8,71.5)=6.46, p=.01) and an independent samples t-test indicating higher sAA baseline to peak response (t=3.22, p=.003). There was also a positive correlation between sAA reactivity and the CTQ subscales of childhood physical abuse (r=.46, p=.005) and emotional abuse (r=.37, p=.024). Healthy adults with low-to-moderate childhood adversity had a heightened sAA response immediately following the stressor. Higher SNS reactivity could be a link to negative health outcomes in adults with early adversity. Future research should address whether altered sAA reactivity is predictive of negative health outcomes in those with childhood adversity. PMID:27577885

MAR binding protein SMAR1 favors IL-10 mediated regulatory T cell function in acute colitis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mirlekar, Bhalchandra; Patil, Sachin; Bopanna, Ramanamurthy

2015-08-21

T{sub reg} cells are not only crucial for controlling immune responses to autoantigens but also prevent those directed towards commensal pathogens. Control of effector immune responses by T{sub reg} cells depend on their capacity to accumulate at inflammatory site and accordingly accommodate to inflammatory environment. Till date, the factors associated with maintaining these aspects of T{sub reg} phenotype is not understood properly. Here we have shown that a known nuclear matrix binding protein SMAR1 is selectively expressed more in colonic T{sub reg} cells and is required for their ability to accumulate at inflammatory site and to sustain high levels ofmore » Foxp3 and IL-10 expression during acute colitis. Elimination of anti-inflammatory subsets revealed a protective role for IL-10 producing T{sub reg} cells in SMAR1{sup −/−} mice. Moreover, a combined action of Foxp3 and SMAR1 restricts effector cytokine production and enhance the production of IL-10 by colonic T{sub reg} cells that controls acute colitis. This data highlights a critical role of SMAR1 in maintaining T{sub reg} physiology during inflammatory disorders. - Highlights: • SMAR1 is essential to sustain high level of Foxp3 and IL-10 in T{sub reg} cells. • SMAR1{sup −/−} T{sub reg} cells produce pro-inflammatory cytokine IL-17 leads to inflammation. • IL-10 administration can control the inflammation in SMAR1{sup −/−} mice. • Both Foxp3 and SMAR1 maintain T{sub reg} phenotype that controls colitis.« less

huJCAR014 CAR-T Cells in Treating Adult Patients With Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma or Acute Lymphoblastic Leukemia

ClinicalTrials.gov

2018-05-25

Adult B Acute Lymphoblastic Leukemia; BCL2 Gene Rearrangement; BCL6 Gene Rearrangement; CD19 Positive; Diffuse Large B-Cell Lymphoma, Not Otherwise Specified; MYC Gene Rearrangement; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent B-Cell Non-Hodgkin Lymphoma; Recurrent Diffuse Large B-Cell Lymphoma; Recurrent Mediastinal (Thymic) Large B-Cell Cell Lymphoma; Refractory Adult Acute Lymphoblastic Leukemia; Refractory B-Cell Non-Hodgkin Lymphoma; Refractory Diffuse Large B-Cell Lymphoma; Refractory Mediastinal (Thymic) Large B-Cell Cell Lymphoma; Transformed Recurrent Non-Hodgkin Lymphoma

Dynamics of the cytotoxic T cell response to a model of acute viral infection.

PubMed

DeWitt, William S; Emerson, Ryan O; Lindau, Paul; Vignali, Marissa; Snyder, Thomas M; Desmarais, Cindy; Sanders, Catherine; Utsugi, Heidi; Warren, Edus H; McElrath, Juliana; Makar, Karen W; Wald, Anna; Robins, Harlan S

2015-04-01

A detailed characterization of the dynamics and breadth of the immune response to an acute viral infection, as well as the determinants of recruitment to immunological memory, can greatly contribute to our basic understanding of the mechanics of the human immune system and can ultimately guide the design of effective vaccines. In addition to neutralizing antibodies, T cells have been shown to be critical for the effective resolution of acute viral infections. We report the first in-depth analysis of the dynamics of the CD8(+) T cell repertoire at the level of individual T cell clonal lineages upon vaccination of human volunteers with a single dose of YF-17D. This live attenuated yellow fever virus vaccine yields sterile, long-term immunity and has been previously used as a model to understand the immune response to a controlled acute viral infection. We identified and enumerated unique CD8(+) T cell clones specifically induced by this vaccine through a combined experimental and statistical approach that included high-throughput sequencing of the CDR3 variable region of the T cell receptor β-chain and an algorithm that detected significantly expanded T cell clones. This allowed us to establish that (i) on average, ∼ 2,000 CD8(+) T cell clones were induced by YF-17D, (ii) 5 to 6% of the responding clones were recruited to long-term memory 3 months postvaccination, (iii) the most highly expanded effector clones were preferentially recruited to the memory compartment, and (iv) a fraction of the YF-17D-induced clones could be identified from peripheral blood lymphocytes solely by measuring clonal expansion. The exhaustive investigation of pathogen-induced effector T cells is essential to accurately quantify the dynamics of the human immune response. The yellow fever vaccine (YFV) has been broadly used as a model to understand how a controlled, self-resolving acute viral infection induces an effective and long-term protective immune response. Here, we extend this previous work by reporting the identity of activated effector T cell clones that expand in response to the YFV 2 weeks postvaccination (as defined by their unique T cell receptor gene sequence) and by tracking clones that enter the memory compartment 3 months postvaccination. This is the first study to use high-throughput sequencing of immune cells to characterize the breadth of the antiviral effector cell response and to determine the contribution of unique virus-induced clones to the long-lived memory T cell repertoire. Thus, this study establishes a benchmark against which future vaccines can be compared to predict their efficacy. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Dynamics of the Cytotoxic T Cell Response to a Model of Acute Viral Infection

PubMed Central

DeWitt, William S.; Emerson, Ryan O.; Lindau, Paul; Vignali, Marissa; Snyder, Thomas M.; Desmarais, Cindy; Sanders, Catherine; Utsugi, Heidi; Warren, Edus H.; McElrath, Juliana; Makar, Karen W.; Wald, Anna

2015-01-01

ABSTRACT A detailed characterization of the dynamics and breadth of the immune response to an acute viral infection, as well as the determinants of recruitment to immunological memory, can greatly contribute to our basic understanding of the mechanics of the human immune system and can ultimately guide the design of effective vaccines. In addition to neutralizing antibodies, T cells have been shown to be critical for the effective resolution of acute viral infections. We report the first in-depth analysis of the dynamics of the CD8+ T cell repertoire at the level of individual T cell clonal lineages upon vaccination of human volunteers with a single dose of YF-17D. This live attenuated yellow fever virus vaccine yields sterile, long-term immunity and has been previously used as a model to understand the immune response to a controlled acute viral infection. We identified and enumerated unique CD8+ T cell clones specifically induced by this vaccine through a combined experimental and statistical approach that included high-throughput sequencing of the CDR3 variable region of the T cell receptor β-chain and an algorithm that detected significantly expanded T cell clones. This allowed us to establish that (i) on average, ∼2,000 CD8+ T cell clones were induced by YF-17D, (ii) 5 to 6% of the responding clones were recruited to long-term memory 3 months postvaccination, (iii) the most highly expanded effector clones were preferentially recruited to the memory compartment, and (iv) a fraction of the YF-17D-induced clones could be identified from peripheral blood lymphocytes solely by measuring clonal expansion. IMPORTANCE The exhaustive investigation of pathogen-induced effector T cells is essential to accurately quantify the dynamics of the human immune response. The yellow fever vaccine (YFV) has been broadly used as a model to understand how a controlled, self-resolving acute viral infection induces an effective and long-term protective immune response. Here, we extend this previous work by reporting the identity of activated effector T cell clones that expand in response to the YFV 2 weeks postvaccination (as defined by their unique T cell receptor gene sequence) and by tracking clones that enter the memory compartment 3 months postvaccination. This is the first study to use high-throughput sequencing of immune cells to characterize the breadth of the antiviral effector cell response and to determine the contribution of unique virus-induced clones to the long-lived memory T cell repertoire. Thus, this study establishes a benchmark against which future vaccines can be compared to predict their efficacy. PMID:25653453

AZD1775 sensitizes T cell acute lymphoblastic leukemia cells to cytarabine by promoting apoptosis over DNA repair.

PubMed

Ford, James B; Baturin, Dmitry; Burleson, Tamara M; Van Linden, Annemie A; Kim, Yong-Mi; Porter, Christopher C

2015-09-29

While some children with acute lymphoblastic leukemia (ALL) have excellent prognoses, the prognosis for adults and children with T cell ALL is more guarded. Treatment for T-ALL is heavily dependent upon antimetabolite chemotherapeutics, including cytarabine. Targeted inhibition of WEE1 with AZD1775 has emerged as a strategy to sensitize cancer cells to cytarabine and other chemotherapeutics. We sought to determine if this strategy would be effective for T-ALL with clinically relevant anti-leukemia agents. We found that AZD1775 sensitizes T-ALL cells to several traditional anti-leukemia agents, acting synergistically with cytarabine by enhancing DNA damage and apoptosis. In addition to increased phosphorylation of H2AX at serine 139 (γH2AX), AZD1775 led to increased phosphorylation of H2AX at tyrosine 142, a signaling event associated with promotion of apoptosis over DNA repair. In a xenograft model of T-ALL, the addition of AZD1775 to cytarabine slowed leukemia progression and prolonged survival. Inhibition of WEE1 with AZD1775 sensitizes T-ALL to several anti-leukemia agents, particularly cytarabine and that mechanistically, AZD1775 promotes apoptosis over DNA repair in cells treated with cytarabine. These data support the development of clinical trials including AZD1775 in combination with conventional chemotherapy for acute leukemia.

AZD1775 sensitizes T cell acute lymphoblastic leukemia cells to cytarabine by promoting apoptosis over DNA repair

PubMed Central

Burleson, Tamara M.; Van Linden, Annemie A.; Kim, Yong-Mi; Porter, Christopher C.

2015-01-01

While some children with acute lymphoblastic leukemia (ALL) have excellent prognoses, the prognosis for adults and children with T cell ALL is more guarded. Treatment for T-ALL is heavily dependent upon antimetabolite chemotherapeutics, including cytarabine. Targeted inhibition of WEE1 with AZD1775 has emerged as a strategy to sensitize cancer cells to cytarabine and other chemotherapeutics. We sought to determine if this strategy would be effective for T-ALL with clinically relevant anti-leukemia agents. We found that AZD1775 sensitizes T-ALL cells to several traditional anti-leukemia agents, acting synergistically with cytarabine by enhancing DNA damage and apoptosis. In addition to increased phosphorylation of H2AX at serine 139 (γH2AX), AZD1775 led to increased phosphorylation of H2AX at tyrosine 142, a signaling event associated with promotion of apoptosis over DNA repair. In a xenograft model of T-ALL, the addition of AZD1775 to cytarabine slowed leukemia progression and prolonged survival. Inhibition of WEE1 with AZD1775 sensitizes T-ALL to several anti-leukemia agents, particularly cytarabine. Mechanistically, AZD1775 promotes apoptosis over DNA repair in cells treated with cytarabine. These data support the development of clinical trials including AZD1775 in combination with conventional chemotherapy for acute leukemia. PMID:26334102

Management of Platelet Transfusion Therapy in Patients With Blood Cancer or Treatment-Induced Thrombocytopenia

ClinicalTrials.gov

2018-02-15

Acute Biphenotypic Leukemia; Acute Lymphoblastic Leukemia; Acute Myeloid Leukemia; B-Cell Non-Hodgkin Lymphoma; Chronic Lymphocytic Leukemia; Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Hematologic and Lymphocytic Disorder; Hematopoietic Cell Transplantation Recipient; Myelodysplastic Syndrome; Primary Myelofibrosis; Secondary Myelofibrosis; T-Cell Non-Hodgkin Lymphoma; Thrombocytopenia; Venous Thromboembolism

STAT4 and T-bet control follicular helper T cell development in viral infections.

PubMed

Weinstein, Jason S; Laidlaw, Brian J; Lu, Yisi; Wang, Jessica K; Schulz, Vincent P; Li, Ningcheng; Herman, Edward I; Kaech, Susan M; Gallagher, Patrick G; Craft, Joe

2018-01-02

Follicular helper T (Tfh) cells promote germinal center (GC) B cell survival and proliferation and guide their differentiation and immunoglobulin isotype switching by delivering contact-dependent and soluble factors, including IL-21, IL-4, IL-9, and IFN-γ. IL-21 and IFN-γ are coexpressed by Tfh cells during viral infections, but transcriptional regulation of these cytokines is not completely understood. In this study, we show that the T helper type 1 cell (Th1 cell) transcriptional regulators T-bet and STAT4 are coexpressed with Bcl6 in Tfh cells after acute viral infection, with a temporal decline in T-bet in the waning response. T-bet is important for Tfh cell production of IFN-γ, but not IL-21, and for a robust GC reaction. STAT4, phosphorylated in Tfh cells upon infection, is required for expression of T-bet and Bcl6 and for IFN-γ and IL-21. These data indicate that T-bet is expressed with Bcl6 in Tfh cells and is required alongside STAT4 to coordinate Tfh cell IL-21 and IFN-γ production and for promotion of the GC response after acute viral challenge. © 2018 Weinstein et al.

CD8+CD28+ T cells might mediate injury of cardiomyocytes in acute myocardial infarction.

PubMed

Zhang, Lili; Wang, Zhiyan; Wang, Di; Zhu, Jumo; Wang, Yi

2018-06-07

CD8 + T cells accumulate in the necrotic myocardium of acute myocardial infarction (AMI). It is unclear whether CD8 + CD28 + T cells, a specific subset of CD8 + T cells, contribute to myocardial injury. In this study, 92 consecutive patients with AMI and 28 healthy control subjects were enrolled. The frequency of CD8 + CD28 + T cells in peripheral blood samples was assayed by flow cytometry. Plasma cardiac troponin I (TNI) and left ventricular ejection fraction (LVEF) were determined. Long-term prognosis of the patients was evaluated by major adverse cardiac and cerebrovascular events (MACCE) over a 12-month follow-up period. Our findings indicated that patients with AMI who presented with high numbers of CD8 + CD28 + T cells had an increased infarction size and aggravated ventricular function. We proposed that cytotoxic CD8 + CD28 + T cell-mediated myocardial necrosis may act as a novel and alternative pathway of AMI. Copyright © 2018 Elsevier Ltd. All rights reserved.

PD-L1 Expression on Retrovirus-Infected Cells Mediates Immune Escape from CD8+ T Cell Killing.

PubMed

Akhmetzyanova, Ilseyar; Drabczyk, Malgorzata; Neff, C Preston; Gibbert, Kathrin; Dietze, Kirsten K; Werner, Tanja; Liu, Jia; Chen, Lieping; Lang, Karl S; Palmer, Brent E; Dittmer, Ulf; Zelinskyy, Gennadiy

2015-10-01

Cytotoxic CD8+ T Lymphocytes (CTL) efficiently control acute virus infections but can become exhausted when a chronic infection develops. Signaling of the inhibitory receptor PD-1 is an important mechanism for the development of virus-specific CD8+ T cell dysfunction. However, it has recently been shown that during the initial phase of infection virus-specific CD8+ T cells express high levels of PD-1, but are fully competent in producing cytokines and killing virus-infected target cells. To better understand the role of the PD-1 signaling pathway in CD8+ T cell cytotoxicity during acute viral infections we analyzed the expression of the ligand on retrovirus-infected cells targeted by CTLs. We observed increased levels of PD-L1 expression after infection of cells with the murine Friend retrovirus (FV) or with HIV. In FV infected mice, virus-specific CTLs efficiently eliminated infected target cells that expressed low levels of PD-L1 or that were deficient for PD-L1 but the population of PD-L1high cells escaped elimination and formed a reservoir for chronic FV replication. Infected cells with high PD-L1 expression mediated a negative feedback on CD8+ T cells and inhibited their expansion and cytotoxic functions. These findings provide evidence for a novel immune escape mechanism during acute retroviral infection based on PD-L1 expression levels on virus infected target cells.

Association of Childhood Chronic Physical Aggression with a DNA Methylation Signature in Adult Human T Cells

PubMed Central

Guillemin, Claire; Vitaro, Frank; Côté, Sylvana M.; Hallett, Michael; Tremblay, Richard E.; Szyf, Moshe

2014-01-01

Background Chronic physical aggression (CPA) is characterized by frequent use of physical aggression from early childhood to adolescence. Observed in approximately 5% of males, CPA is associated with early childhood adverse environments and long-term negative consequences. Alterations in DNA methylation, a covalent modification of DNA that regulates genome function, have been associated with early childhood adversity. Aims To test the hypothesis that a trajectory of chronic physical aggression during childhood is associated with a distinct DNA methylation profile during adulthood. Methods We analyzed genome-wide promoter DNA methylation profiles of T cells from two groups of adult males assessed annually for frequency of physical aggression between 6 and 15 years of age: a group with CPA and a control group. Methylation profiles covering the promoter regions of 20 000 genes and 400 microRNAs were generated using MeDIP followed by hybridization to microarrays. Results In total, 448 distinct gene promoters were differentially methylated in CPA. Functionally, many of these genes have previously been shown to play a role in aggression and were enriched in biological pathways affected by behavior. Their locations in the genome tended to form clusters spanning millions of bases in the genome. Conclusions This study provides evidence of clustered and genome-wide variation in promoter DNA methylation in young adults that associates with a history of chronic physical aggression from 6 to 15 years of age. However, longitudinal studies of methylation during early childhood will be necessary to determine if and how this methylation variation in T cells DNA plays a role in early development of chronic physical aggression. PMID:24691403

Transient mutism and pathologic laughter in the course of cerebellitis.

PubMed

Dimova, Petia S; Bojinova, Veneta S; Milanov, Ivan G

2009-07-01

The phenomenon of cerebellar mutism with subsequent dysarthria is most commonly described as a part of posterior fossa syndrome after surgery for neoplasms in childhood. Pathologic laughter, on the other hand, is observed primarily in various neurologic diseases in adults. In the present case, a child manifested transient mutism and pathologic laughter during a severe cerebellitis. Headache, vertigo, and impaired consciousness developed during an acute respiratory infection. Thereafter, severe ataxia, mutism, and involuntary laughter became the main clinical features, as well as pyramidal signs. Magnetic resonance imaging revealed cerebellar swelling and T(2) hyperintensity. During steroid treatment, a gradual vanishing of the pathologic laughter and improvement of the motor and speech functions occurred. Recovery was slow and incomplete, and follow-up magnetic resonance imaging showed cerebellar atrophy. This case confirms that mutism is a rare, but possible, manifestation in acute parainfectious cerebellitis and provides a novel example of pathologic laughter during this disease in childhood.

Fetal origins of the TEL-AML1 fusion gene in identical twins with leukemia

PubMed Central

Ford, Anthony M.; Bennett, Caroline A.; Price, Cathy M.; Bruin, M. C. A.; Van Wering, Elisabeth R.; Greaves, Mel

1998-01-01

The TEL (ETV6)−AML1 (CBFA2) gene fusion is the most common reciprocal chromosomal rearrangement in childhood cancer occurring in ≈25% of the most predominant subtype of leukemia— common acute lymphoblastic leukemia. The TEL-AML1 genomic sequence has been characterized in a pair of monozygotic twins diagnosed at ages 3 years, 6 months and 4 years, 10 months with common acute lymphoblastic leukemia. The twin leukemic DNA shared the same unique (or clonotypic) but nonconstitutive TEL-AML1 fusion sequence. The most plausible explanation for this finding is a single cell origin of the TEL-AML fusion in one fetus in utero, probably as a leukemia-initiating mutation, followed by intraplacental metastasis of clonal progeny to the other twin. Clonal identity is further supported by the finding that the leukemic cells in the two twins shared an identical rearranged IGH allele. These data have implications for the etiology and natural history of childhood leukemia. PMID:9539781

Blinatumomab and Nivolumab With or Without Ipilimumab in Treating Patients With Poor-Risk Relapsed or Refractory CD19+ Precursor B-Lymphoblastic Leukemia

ClinicalTrials.gov

2018-05-14

B Acute Lymphoblastic Leukemia; B Acute Lymphoblastic Leukemia With t(9;22)(q34.1;q11.2); BCR-ABL1; CD19-Positive Neoplastic Cells Present; Mixed Phenotype Acute Leukemia; Mixed Phenotype Acute Leukemia With t(9;22)(q34.1;q11.2); BCR-ABL1; Recurrent B Acute Lymphoblastic Leukemia; Refractory B Acute Lymphoblastic Leukemia

α4+β7hiCD4+ Memory T cells Harbor Most Th-17 cells and are Preferentially Infected During Acute SIV Infection

PubMed Central

Kader, Muhamuda; Wang, Xiaolei; Piatak, Michael; Lifson, Jeffrey; Roederer, Mario; Veazey, Ronald; Mattapallil, Joseph J.

2009-01-01

HIV/SIV are thought to infect minimally activated CD4+ T cells after viral entry. Not much is known about why SIV selectively targets these cells. Here we show that CD4+ T cells that express high levels of the α4β7 heterodimer are preferentially infected very early during the course of SIV infection. At day 2–4 post infection, α4+β7hiCD4+ T cells had ∼ 5x more SIV-gag DNA than β7−CD4+ T cells. α4+β7hiCD4+ T cells displayed a predominantly central memory (CD45RA−CD28+CCR7+) and resting (CD25−CD69−HLA-DR−Ki-67−) phenotype. Though the expression of detectable CCR5 was variable on α4+β7hi and β7−CD4+ T cells, both CCR5+ and CCR5− subsets of α4+β7hi and β7−CD4+ T cells were found to express sufficient levels of CCR5 mRNA suggesting that both these subsets could be efficiently infected by SIV. In line with this, we found similar levels of SIV infection in β7−CD4+CCR5+ and β7−CD4+CCR5− T cells. α4β7hiCD4+ T cells were found to harbor most Th-17 cells that were significantly depleted during acute SIV infection. Taken together, our results show that resting memory α4+β7hiCD4+ T cells in blood are preferentially depleted during acute SIV infection, and the loss of these cells alters the balance between Th-17 and Th-1 responses thereby contributing to disease pathogenesis. PMID:19571800

RUNX1 promotes cell growth in human T-cell acute lymphoblastic leukemia by transcriptional regulation of key target genes.

PubMed

Jenkins, Catherine E; Gusscott, Samuel; Wong, Rachel J; Shevchuk, Olena O; Rana, Gurneet; Giambra, Vincenzo; Tyshchenko, Kateryna; Islam, Rashedul; Hirst, Martin; Weng, Andrew P

2018-05-04

RUNX1 is frequently mutated in T-cell acute lymphoblastic leukemia (T-ALL). The spectrum of RUNX1 mutations has led to the notion that it acts as a tumor suppressor in this context; however, other studies have placed RUNX1 along with transcription factors TAL1 and NOTCH1 as core drivers of an oncogenic transcriptional program. To reconcile these divergent roles, we knocked down RUNX1 in human T-ALL cell lines and deleted Runx1 or Cbfb in primary mouse T-cell leukemias. RUNX1 depletion consistently resulted in reduced cell proliferation and increased apoptosis. RUNX1 upregulated variable sets of target genes in each cell line, but consistently included a core set of oncogenic effectors including IGF1R and NRAS. Our results support the conclusion that RUNX1 has a net positive effect on cell growth in the context of established T-ALL. Copyright © 2018. Published by Elsevier Inc.

Rapid selection of escape mutants by the first CD8 T cell responses in acute HIV-1 infection

DOE Office of Scientific and Technical Information (OSTI.GOV)

Korber, Bette Tina Marie

2008-01-01

The recent failure of a vaccine that primes T cell responses to control primary HIV-1 infection has raised doubts about the role of CD8+ T cells in early HIV-1 infection. We studied four patients who were identified shortly after HIV-1 infection and before seroconversion. In each patient there was very rapid selection of multiple HIV-1 escape mutants in the transmitted virus by CD8 T cells, including examples of complete fixation of non-synonymous substitutions within 2 weeks. Sequencing by single genome amplification suggested that the high rate of virus replication in acute infection gave a selective advantage to virus molecules thatmore » contained simultaneous and gained sequential T cell escape mutations. These observations show that whilst early HIV-1 specific CD8 T cells can act against virus, rapid escape means that these T cell responses are unlikely to benefit the patient and may in part explain why current HIV-1 T cell vaccines may not be protective.« less

Busulfan, Fludarabine Phosphate, and Anti-Thymocyte Globulin Followed By Donor Stem Cell Transplant and Azacitidine in Treating Patients With High-Risk Myelodysplastic Syndrome and Older Patients With Acute Myeloid Leukemia

ClinicalTrials.gov

2018-03-05

Acute Myeloid Leukemia; Adult Acute Megakaryoblastic Leukemia; Adult Acute Monoblastic Leukemia; Adult Acute Monocytic Leukemia; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With Maturation; Adult Acute Myeloid Leukemia With Minimal Differentiation; Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With t(8;21); (q22; q22.1); RUNX1-RUNX1T1; Adult Acute Myeloid Leukemia With t(9;11)(p22.3;q23.3); MLLT3-KMT2A; Adult Acute Myeloid Leukemia Without Maturation; Adult Acute Myelomonocytic Leukemia; Adult Erythroleukemia; Adult Pure Erythroid Leukemia; Alkylating Agent-Related Acute Myeloid Leukemia; de Novo Myelodysplastic Syndrome; Myelodysplastic Syndrome; Myelodysplastic Syndrome With Excess Blasts; Previously Treated Myelodysplastic Syndrome; Recurrent Adult Acute Myeloid Leukemia; Secondary Myelodysplastic Syndrome; Untreated Adult Acute Myeloid Leukemia

The effect of RFC G80A polymorphism in Cretan children with acute lymphoblastic leukemia and its interaction with MTHFR C677T and A1298C polymorphisms.

PubMed

Karathanasis, N V; Stiakaki, E; Goulielmos, G Ν; Kalmanti, M

2014-08-01

The association between the risk of acute lymphoblastic leukemia (ALL) in children and enzymes involved in the folate metabolism has been under investigation lately. The reduced folate carrier gene (RFC) encodes reduced folate carrier, a protein that transports into the cell both folate and methotrexate, a commonly used chemotherapeutic drug, has been proved polymorphic at position 80 (G→A). The role of this polymorphism in childhood ALL and its interaction with other enzymes of the folate metabolic pathway, including MTHFR, has been examined in different populations with diverse results. In the present case-control study, 35 children with ALL and 48 healthy adult blood donors, all originating from the island of Crete (Greece), were screened for the presence of the RFC G80A polymorphism, using PCR/RFLP techniques. The effect on ALL risk and methotrexate-induced toxicities, along with the role of gene-gene interactions in our population, were examined. No significant association was observed between the RFC G80A genotypes and either the development of ALL or the presence of adverse events. However, a significant association was detected between the MTHFR A1298C/ RFC G80A genotype and a nonpredisposition for ALL (P = 0.035). This study suggests that gene-gene interactions in childhood ALL may be of prognostic value in our population. © 2013 John Wiley & Sons Ltd.

Molecular characterization of acute lymphoblastic leukemia with high CRLF2 gene expression in childhood.

PubMed

Schmäh, Juliane; Fedders, Birthe; Panzer-Grümayer, Renate; Fischer, Susanna; Zimmermann, Martin; Dagdan, Elif; Bens, Susanne; Schewe, Denis; Moericke, Anja; Alten, Julia; Bleckmann, Kirsten; Siebert, Reiner; Schrappe, Martin; Stanulla, Martin; Cario, Gunnar

2017-10-01

A high-level expression of the CRLF2 gene is frequent in precursor B-cell acute lymphoblastic leukemia (pB-ALL) and can be caused by different genetic aberrations. The presence of the most frequent alteration, the P2RY8/CRLF2 fusion, was shown to be associated with a high relapse incidence in children treated according to ALL-Berlin-Frankfurt-Münster (BFM) protocols, which is poorly understood. Moreover, the frequency of other alterations has not been systematically analyzed yet. CRLF2 mRNA expression and potential genetic aberrations causing a CRLF2 high expression were prospectively assessed in 1,105 patients treated according to the Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP)-BFM ALL 2009 protocol. Additionally, we determined copy number alterations in selected B-cell differentiation genes for all CRLF2 high-expressing pB-ALL cases, as well as JAK2 and CRLF2 mutations. A CRLF2 high expression was detected in 26/178 (15%) T-cell acute lymphoblastic leukemia (T-ALL) cases, 21 of them (81%) had been stratified as high-risk patients by treatment response. In pB-ALL, a CRLF2 high expression was determined in 91/927 (10%) cases; the P2RY8/CRLF2 rearrangement in 44/91 (48%) of them, supernumerary copies of CRLF2 in 18/91 (20%), and, notably, the IGH/CRLF2 translocation was detected in 16/91 (18%). Remarkably, 7 of 16 (44%) patients with IGH/CRLF2 translocation had already relapsed. P2RY8/CRLF2- and IGH/CRLF2-positive samples (70 and 94%, respectively) were characterized by a high frequency of additional deletions in B-cell differentiation genes such as IKZF1 or PAX5. Our data suggest that this high frequency of genetic aberrations in the context of a high CRLF2 expression could contribute to the high risk of relapse in P2RY8/CRLF2- and IGH/CRLF2-positive ALL. © 2017 Wiley Periodicals, Inc.

Positive and negative regulation of T cell responses by fibroblastic reticular cells within paracortical regions of lymph nodes

PubMed Central

Siegert, Stefanie; Luther, Sanjiv A.

2012-01-01

Fibroblastic reticular cells (FRC) form the structural backbone of the T cell rich zones in secondary lymphoid organs (SLO), but also actively influence the adaptive immune response. They provide a guidance path for immigrating T lymphocytes and dendritic cells (DC) and are the main local source of the cytokines CCL19, CCL21, and IL-7, all of which are thought to positively regulate T cell homeostasis and T cell interactions with DC. Recently, FRC in lymph nodes (LN) were also described to negatively regulate T cell responses in two distinct ways. During homeostasis they express and present a range of peripheral tissue antigens, thereby participating in peripheral tolerance induction of self-reactive CD8+ T cells. During acute inflammation T cells responding to foreign antigens presented on DC very quickly release pro-inflammatory cytokines such as interferon γ. These cytokines are sensed by FRC which transiently produce nitric oxide (NO) gas dampening the proliferation of neighboring T cells in a non-cognate fashion. In summary, we propose a model in which FRC engage in a bidirectional crosstalk with both DC and T cells to increase the efficiency of the T cell response. However, during an acute response, FRC limit excessive expansion and inflammatory activity of antigen-specific T cells. This negative feedback loop may help to maintain tissue integrity and function during rapid organ growth. PMID:22973278

Apoptosome activation, an important molecular instigator in 6-mercaptopurine induced Leydig cell death

PubMed Central

Morgan, Jessica A.; Lynch, John; Panetta, John C.; Wang, Yao; Frase, Sharon; Bao, Ju; Zheng, Jie; Opferman, Joseph T.; Janke, Laura; Green, Daniel M.; Chemaitilly, Wassim; Schuetz, John D.

2015-01-01

Leydig cells are crucial to the production of testosterone in males. It is unknown if the cancer chemotherapeutic drug, 6-mercaptopurine (6 MP), produces Leydig cell failure among adult survivors of childhood acute lymphoblastic leukemia. Moreover, it is not known whether Leydig cell failure is due to either a loss of cells or an impairment in their function. Herein, we show, in a subset of childhood cancer survivors, that Leydig cell failure is related to the dose of 6 MP. This was extended, in a murine model, to demonstrate that 6 MP exposure induced caspase 3 activation, and the loss of Leydig cells was independent of Bak and Bax activation. The death of these non-proliferating cells was triggered by 6 MP metabolism, requiring formation of both cytosolic reactive oxygen species and thiopurine nucleotide triphosphates. The thiopurine nucleotide triphosphates (with physiological amounts of dATP) uniquely activated the apoptosome. An ABC transporter (Abcc4/Mrp4) reduced the amount of thiopurines, thereby providing protection for Leydig cells. The studies reported here demonstrate that the apoptosome is uniquely activated by thiopurine nucleotides and suggest that 6 MP induced Leydig cell death is likely a cause of Leydig cell failure in some survivors of childhood cancer. PMID:26576726

Apoptosome activation, an important molecular instigator in 6-mercaptopurine induced Leydig cell death.

PubMed

Morgan, Jessica A; Lynch, John; Panetta, John C; Wang, Yao; Frase, Sharon; Bao, Ju; Zheng, Jie; Opferman, Joseph T; Janke, Laura; Green, Daniel M; Chemaitilly, Wassim; Schuetz, John D

2015-11-18

Leydig cells are crucial to the production of testosterone in males. It is unknown if the cancer chemotherapeutic drug, 6-mercaptopurine (6 MP), produces Leydig cell failure among adult survivors of childhood acute lymphoblastic leukemia. Moreover, it is not known whether Leydig cell failure is due to either a loss of cells or an impairment in their function. Herein, we show, in a subset of childhood cancer survivors, that Leydig cell failure is related to the dose of 6 MP. This was extended, in a murine model, to demonstrate that 6 MP exposure induced caspase 3 activation, and the loss of Leydig cells was independent of Bak and Bax activation. The death of these non-proliferating cells was triggered by 6 MP metabolism, requiring formation of both cytosolic reactive oxygen species and thiopurine nucleotide triphosphates. The thiopurine nucleotide triphosphates (with physiological amounts of dATP) uniquely activated the apoptosome. An ABC transporter (Abcc4/Mrp4) reduced the amount of thiopurines, thereby providing protection for Leydig cells. The studies reported here demonstrate that the apoptosome is uniquely activated by thiopurine nucleotides and suggest that 6 MP induced Leydig cell death is likely a cause of Leydig cell failure in some survivors of childhood cancer.

In Vitro Pre-Clinical Validation of Suicide Gene Modified Anti-CD33 Redirected Chimeric Antigen Receptor T-Cells for Acute Myeloid Leukemia

PubMed Central

Minagawa, Kentaro; Jamil, Muhammad O.; AL-Obaidi, Mustafa; Pereboeva, Larisa; Salzman, Donna; Erba, Harry P.; Lamb, Lawrence S.; Bhatia, Ravi; Mineishi, Shin

2016-01-01

Background Approximately fifty percent of patients with acute myeloid leukemia can be cured with current therapeutic strategies which include, standard dose chemotherapy for patients at standard risk of relapse as assessed by cytogenetic and molecular analysis, or high-dose chemotherapy with allogeneic hematopoietic stem cell transplant for high-risk patients. Despite allogeneic hematopoietic stem cell transplant about 25% of patients still succumb to disease relapse, therefore, novel strategies are needed to improve the outcome of patients with acute myeloid leukemia. Methods and findings We developed an immunotherapeutic strategy targeting the CD33 myeloid antigen, expressed in ~ 85–90% of patients with acute myeloid leukemia, using chimeric antigen receptor redirected T-cells. Considering that administration of CAR T-cells has been associated with cytokine release syndrome and other potential off-tumor effects in patients, safety measures were here investigated and reported. We genetically modified human activated T-cells from healthy donors or patients with acute myeloid leukemia with retroviral supernatant encoding the inducible Caspase9 suicide gene, a ΔCD19 selectable marker, and a humanized third generation chimeric antigen receptor recognizing human CD33. ΔCD19 selected inducible Caspase9-CAR.CD33 T-cells had a 75±3.8% (average ± standard error of the mean) chimeric antigen receptor expression, were able to specifically lyse CD33+ targets in vitro, including freshly isolated leukemic blasts from patients, produce significant amount of tumor-necrosis-factor-alpha and interferon-gamma, express the CD107a degranulation marker, and proliferate upon antigen specific stimulation. Challenging ΔCD19 selected inducible Caspase9-CAR.CD33 T-cells with programmed-death-ligand-1 enriched leukemia blasts resulted in significant killing like observed for the programmed-death-ligand-1 negative leukemic blasts fraction. Since the administration of 10 nanomolar of a non-therapeutic dimerizer to activate the suicide gene resulted in the elimination of only 76.4±2.0% gene modified cells in vitro, we found that co-administration of the dimerizer with either the BCL-2 inhibitor ABT-199, the pan-BCL inhibitor ABT-737, or mafosfamide, resulted in an additive effect up to complete cell elimination. Conclusions This strategy could be investigated for the safety of CAR T-cell applications, and targeting CD33 could be used as a ‘bridge” therapy for patients coming to allogeneic hematopoietic stem cell transplant, as anti-leukemia activity from infusing CAR.CD33 T-cells has been demonstrated in an ongoing clinical trial. Albeit never performed in the clinical setting, our future plan is to investigate the utility of iC9-CAR.CD33 T-cells as part of the conditioning therapy for an allogeneic hematopoietic stem cell transplant for acute myeloid leukemia, together with other myelosuppressive agents, whilst the activation of the inducible Caspase9 suicide gene would grant elimination of the infused gene modified T-cells prior to stem cell infusion to reduce the risk of engraftment failure as the CD33 is also expressed on a proportion of the donor stem cell graft. PMID:27907031

Adoptive immunotherapy for hematological malignancies: Current status and new insights in chimeric antigen receptor T cells.

PubMed

Allegra, Alessandro; Innao, Vanessa; Gerace, Demetrio; Vaddinelli, Doriana; Musolino, Caterina

2016-11-01

Hematological malignancies frequently express cancer-associated antigens that are shared with normal cells. Such tumor cells elude the host immune system because several T cells targeted against self-antigens are removed during thymic development, and those that persist are eliminated by a regulatory population of T cells. Chimeric antigen receptor-modified T cells (CAR-Ts) have emerged as a novel modality for tumor immunotherapy due to their powerful efficacy against tumor cells. These cells are created by transducing genes-coding fusion proteins of tumor antigen-recognition single-chain Fv connected to the intracellular signaling domains of T cell receptors, and are classed as first-, second- and third-generation, differing on the intracellular signaling domain number of T cell receptors. CAR-T treatment has emerged as a promising approach for patients with hematological malignancies, and there are several works reporting clinical trials of the use of CAR-modified T-cells in acute lymphoblastic leukemia, chronic lymphoblastic leukemia, multiple myeloma, lymphoma, and in acute myeloid leukemia by targeting different antigens. This review reports the history of adoptive immunotherapy using CAR-Ts, the CAR-T manufacturing process, and T cell therapies in development for hematological malignancies. Copyright © 2016 Elsevier Inc. All rights reserved.

Can Exposure to Environmental Chemicals Increase the Risk of Diabetes Type 1 Development?

PubMed Central

Stene, Lars Christian

2015-01-01

Type 1 diabetes mellitus (T1DM) is an autoimmune disease, where destruction of beta-cells causes insulin deficiency. The incidence of T1DM has increased in the last decades and cannot entirely be explained by genetic predisposition. Several environmental factors are suggested to promote T1DM, like early childhood enteroviral infections and nutritional factors, but the evidence is inconclusive. Prenatal and early life exposure to environmental pollutants like phthalates, bisphenol A, perfluorinated compounds, PCBs, dioxins, toxicants, and air pollutants can have negative effects on the developing immune system, resulting in asthma-like symptoms and increased susceptibility to childhood infections. In this review the associations between environmental chemical exposure and T1DM development is summarized. Although information on environmental chemicals as possible triggers for T1DM is sparse, we conclude that it is plausible that environmental chemicals can contribute to T1DM development via impaired pancreatic beta-cell and immune-cell functions and immunomodulation. Several environmental factors and chemicals could act together to trigger T1DM development in genetically susceptible individuals, possibly via hormonal or epigenetic alterations. Further observational T1DM cohort studies and animal exposure experiments are encouraged. PMID:25883945

Can exposure to environmental chemicals increase the risk of diabetes type 1 development?

PubMed

Bodin, Johanna; Stene, Lars Christian; Nygaard, Unni Cecilie

2015-01-01

Type 1 diabetes mellitus (T1DM) is an autoimmune disease, where destruction of beta-cells causes insulin deficiency. The incidence of T1DM has increased in the last decades and cannot entirely be explained by genetic predisposition. Several environmental factors are suggested to promote T1DM, like early childhood enteroviral infections and nutritional factors, but the evidence is inconclusive. Prenatal and early life exposure to environmental pollutants like phthalates, bisphenol A, perfluorinated compounds, PCBs, dioxins, toxicants, and air pollutants can have negative effects on the developing immune system, resulting in asthma-like symptoms and increased susceptibility to childhood infections. In this review the associations between environmental chemical exposure and T1DM development is summarized. Although information on environmental chemicals as possible triggers for T1DM is sparse, we conclude that it is plausible that environmental chemicals can contribute to T1DM development via impaired pancreatic beta-cell and immune-cell functions and immunomodulation. Several environmental factors and chemicals could act together to trigger T1DM development in genetically susceptible individuals, possibly via hormonal or epigenetic alterations. Further observational T1DM cohort studies and animal exposure experiments are encouraged.

Laboratory Treated T Cells in Treating Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia, Non-Hodgkin Lymphoma, or Acute Lymphoblastic Leukemia

ClinicalTrials.gov

2017-10-24

CD19-Positive Neoplastic Cells Present; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Chronic Lymphocytic Leukemia; Recurrent Diffuse Large B-Cell Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Non-Hodgkin Lymphoma; Recurrent Small Lymphocytic Lymphoma; Refractory Acute Lymphoblastic Leukemia; Refractory Chronic Lymphocytic Leukemia; Refractory Diffuse Large B-Cell Lymphoma; Refractory Mantle Cell Lymphoma; Refractory Non-Hodgkin Lymphoma; Refractory Small Lymphocytic Lymphoma

Symptom Severity Predicts Degree of T Cell Activation In Adult Women Following Childhood Maltreatment

PubMed Central

Lemieux, Andrine; Coe, Christopher L.; Carnes, Molly

2008-01-01

Although depression is often associated with a reduction in cellular immune responses, other types of emotional disturbance and psychopathology can activate certain aspects of immunity. Activation markers on T cells, in particular, have been found to be elevated in post-traumatic stress states. However, little is known about the relationship between the severity of PTSD symptoms and the degree of change in T cell phenotypes, or about the potential role of neuroendocrine factors in mediating the association. Twenty-four women with a history of sexual trauma during childhood, including 11 who met diagnostic criteria for PTSD, were compared to 12 age-matched, healthy women without a history of maltreatment. The women provided fasted blood samples for enumeration of cell subsets by immunofluorescence and 24-hour urine samples for analysis of catecholamine and cortisol levels. The percent of T cells expressing CD45RA, an early activation marker, was higher in the PTSD diagnosed women, and the levels correlated positively with intrusive symptoms and negatively with avoidant symptoms. These alterations in cell surface markers did not appear to be mediated by norepinephrine (NE) or cortisol, making them a distinctive and independent biomarker of arousal and disturbance in PTSD. PMID:18396007

Outcome after failure of allogeneic hematopoietic stem cell transplantation in children with acute leukemia: a study by the société Francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC).

PubMed

Roux, C; Tifratene, K; Socié, G; Galambrun, C; Bertrand, Y; Rialland, F; Jubert, C; Pochon, C; Paillard, C; Sirvent, A; Nelken, B; Vannier, J P; Freycon, C; Beguin, Y; Raus, N; Yakoub-Agha, I; Mohty, M; Dalle, J-H; Michel, G; Pradier, C; Peffault de Latour, R; Rohrlich, P-S

2017-05-01

Allogeneic hematopoietic stem cell transplantation (SCT) contributes to improved outcome in childhood acute leukemia (AL). However, therapeutic options are poorly defined in the case of post-transplantation relapse. We aimed to compare treatment strategies in 334 consecutive children with acute leukemia relapse or progression after SCT in a recent 10-year period. Data could be analyzed in 288 patients (157 ALL, 123 AML and 8 biphenotypic AL) with a median age of 8.16 years at transplantation. The median delay from first SCT to relapse or progression was 182 days. The treatment consisted of chemotherapy alone (n=108), chemotherapy followed by second SCT (n=70), supportive/palliative care (n=67), combination of chemotherapy and donor lymphocyte infusion (DLI; n=30), or isolated reinfusion of donor lymphocytes (DLI; n=13). The median OS duration after relapse was 164 days and differed according to therapy: DLI after chemotherapy=385 days, second allograft=391 days, chemotherapy=174 days, DLI alone=140 days, palliative care=43 days. A second SCT or a combination of chemotherapy and DLI yielded similar outcome (hazard ratio (HR)=0.85, P=0.53) unlike chemotherapy alone (HR=1.43 P=0.04), palliative care (HR=4.24, P<0.0001) or isolated DLI (HR=1,94, P<0.04). Despite limitations in this retrospective setting, strategies including immunointervention appear superior to other approaches, mostly in AML.

General Information about Childhood Acute Lymphoblastic Leukemia

MedlinePlus

... Acute Lymphoblastic Leukemia Treatment (PDQ®)–Patient Version General Information About Childhood Acute Lymphoblastic Leukemia Go to Health ... the PDQ Pediatric Treatment Editorial Board . Clinical Trial Information A clinical trial is a study to answer ...

T-cell acute lymphoblastic leukemia associated with complex karyotype and SET-NUP214 rearrangement: a case study and review of the literature.

PubMed

Lee, Sang-Guk; Park, Tae Sung; Cho, Sun Young; Lim, Gayoung; Park, Gwang Jin; Oh, Seung Hwan; Cho, Eun Hae; Chong, So Young; Huh, Ji Young

2011-01-01

SET-NUP214 rearrangements have been rarely reported in T-cell acute lymphoblastic leukemia (T-ALL), acute undifferentiated leukemia, and acute myeloid leukemia, and most documented cases have been associated with normal karyotypes in conventional cytogenetic analyses. Here, we describe a novel case of T-ALL associated with a mediastinal mass and a SET-NUP214 rearrangement, which was masked by a complex karyotype at the time of initial diagnosis. Using multiplex reverse transcriptase-polymerase chain reaction analysis, we detected a cryptic SET-NUP214 rearrangement in our patient. As only 11 cases (including the present study) of T-ALL with SET-NUP214 rearrangement have been reported, the clinical features and treatment outcomes have not been fully determined. Further studies are necessary to evaluate the incidence of SET-NUP214 rearrangement in T-ALL patients and the treatment responses as well as prognosis of these patients.

Rituximab in Preventing Acute Graft-Versus-Host Disease in Patients Undergoing a Donor Stem Cell Transplant for Hematologic Cancer

ClinicalTrials.gov

2017-09-29

Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Nasal Type Extranodal NK/T-cell Lymphoma; Blastic Phase Chronic Myelogenous Leukemia; Contiguous Stage II Adult Burkitt Lymphoma; Contiguous Stage II Adult Diffuse Large Cell Lymphoma; Contiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Contiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Contiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Contiguous Stage II Adult Lymphoblastic Lymphoma; Contiguous Stage II Grade 1 Follicular Lymphoma; Contiguous Stage II Grade 2 Follicular Lymphoma; Contiguous Stage II Grade 3 Follicular Lymphoma; Contiguous Stage II Mantle Cell Lymphoma; Contiguous Stage II Marginal Zone Lymphoma; Contiguous Stage II Small Lymphocytic Lymphoma; de Novo Myelodysplastic Syndromes; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Graft Versus Host Disease; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Burkitt Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Noncontiguous Stage II Adult Lymphoblastic Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Relapsing Chronic Myelogenous Leukemia; Secondary Myelodysplastic Syndromes; Splenic Marginal Zone Lymphoma; Stage I Adult Burkitt Lymphoma; Stage I Adult Diffuse Large Cell Lymphoma; Stage I Adult Diffuse Mixed Cell Lymphoma; Stage I Adult Diffuse Small Cleaved Cell Lymphoma; Stage I Adult Immunoblastic Large Cell Lymphoma; Stage I Adult Lymphoblastic Lymphoma; Stage I Adult T-cell Leukemia/Lymphoma; Stage I Chronic Lymphocytic Leukemia; Stage I Cutaneous T-cell Non-Hodgkin Lymphoma; Stage I Grade 1 Follicular Lymphoma; Stage I Grade 2 Follicular Lymphoma; Stage I Grade 3 Follicular Lymphoma; Stage I Mantle Cell Lymphoma; Stage I Marginal Zone Lymphoma; Stage I Mycosis Fungoides/Sezary Syndrome; Stage I Small Lymphocytic Lymphoma; Stage II Adult T-cell Leukemia/Lymphoma; Stage II Chronic Lymphocytic Leukemia; Stage II Cutaneous T-cell Non-Hodgkin Lymphoma; Stage II Mycosis Fungoides/Sezary Syndrome; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Adult T-cell Leukemia/Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Cutaneous T-cell Non-Hodgkin Lymphoma; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Mycosis Fungoides/Sezary Syndrome; Stage III Small Lymphocytic Lymphoma; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Adult T-cell Leukemia/Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Mycosis Fungoides/Sezary Syndrome; Stage IV Small Lymphocytic Lymphoma; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Adult Acute Myeloid Leukemia; Waldenström Macroglobulinemia

MTHFR gene polymorphism in acute lymphoblastic leukemia among North Indian children: a case-control study and meta-analysis updated from 2011.

PubMed

Roy Moulik, Nirmalya; Parveen, Farah; Kumar, Archana; Awasthi, Shally; Agrawal, Suraksha

2014-07-01

Studies on the association of methylenetetrahydrofolate reductase (MTHFR) genotype in childhood acute lymphoblastic leukemia (ALL) have yielded conflicting results. The present study examines this association in north Indian children with ALL and includes an updated meta-analysis. MTHFR (677 and 1298) genotype of children with ALL and healthy adult controls were done by the PCR-restriction fragment length polymorphism (PCR-RFLP) method and were compared using various models of inheritance. A total of 150 patients and 300 controls were included. The 677T allele was found protective (odds ratio (OR) 0.21, 95% confidence interval (CI) 0.04-0.94), whereas 1298C allele led to an increase in risk (OR 4.44, 95% CI 2.19-8.99) of childhood ALL. Meta-analysis included 31 and 27 studies examining the association of 677 and 1298 genotypes, respectively. The 677 C -> T polymorphism was protective (OR 0.90, 95% CI 0.82-0.99). Protection was more pronounced in folate-sufficient populations as compared with those not covered by folate fortification guidelines. The 1298A->C polymorphism was associated with a marginal increase in risk (OR 1.19, 95% CI 1.01-1.40).

Is the gut the major source of virus in early simian immunodeficiency virus infection?

PubMed

Lay, Matthew D H; Petravic, Janka; Gordon, Shari N; Engram, Jessica; Silvestri, Guido; Davenport, Miles P

2009-08-01

The acute phases of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infection are characterized by rapid and profound depletion of CD4+ T cells from the guts of infected individuals. The large number of CD4+ T cells in the gut (a large fraction of which are activated and express the HIV/SIV coreceptor CCR5), the high level of infection of these cells, and the temporal coincidence of this CD4+ T-cell depletion with the peak of virus in plasma in acute infection suggest that the intestinal mucosa may be the major source of virus driving the peak viral load. Here, we used data on CD4+ T-cell proportions in the lamina propria of the rectums of SIV-infected rhesus macaques (which progress to AIDS) and sooty mangabeys (which do not progress) to show that in both species, the depletion of CD4+ T cells from this mucosal site and its maximum loss rate are often observed several days before the peak in viral load, with few CD4+ T cells remaining in the rectum by the time of peak viral load. In contrast, the maximum loss rate of CD4+ T cells from bronchoalveolar lavage specimens and lymph nodes coincides with the peak in virus. Analysis of the kinetics of depletion suggests that, in both rhesus macaques and sooty mangabeys, CD4+ T cells in the intestinal mucosa are a highly susceptible population for infection but not a major source of plasma virus in acute SIV infection.

Is the Gut the Major Source of Virus in Early Simian Immunodeficiency Virus Infection? ▿

PubMed Central

Lay, Matthew D. H.; Petravic, Janka; Gordon, Shari N.; Engram, Jessica; Silvestri, Guido; Davenport, Miles P.

2009-01-01

The acute phases of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infection are characterized by rapid and profound depletion of CD4+ T cells from the guts of infected individuals. The large number of CD4+ T cells in the gut (a large fraction of which are activated and express the HIV/SIV coreceptor CCR5), the high level of infection of these cells, and the temporal coincidence of this CD4+ T-cell depletion with the peak of virus in plasma in acute infection suggest that the intestinal mucosa may be the major source of virus driving the peak viral load. Here, we used data on CD4+ T-cell proportions in the lamina propria of the rectums of SIV-infected rhesus macaques (which progress to AIDS) and sooty mangabeys (which do not progress) to show that in both species, the depletion of CD4+ T cells from this mucosal site and its maximum loss rate are often observed several days before the peak in viral load, with few CD4+ T cells remaining in the rectum by the time of peak viral load. In contrast, the maximum loss rate of CD4+ T cells from bronchoalveolar lavage specimens and lymph nodes coincides with the peak in virus. Analysis of the kinetics of depletion suggests that, in both rhesus macaques and sooty mangabeys, CD4+ T cells in the intestinal mucosa are a highly susceptible population for infection but not a major source of plasma virus in acute SIV infection. PMID:19458001

Distinct activation phenotype of a highly conserved novel HLA-B57-restricted epitope during dengue virus infection

PubMed Central

Townsley, Elizabeth; Woda, Marcia; Thomas, Stephen J; Kalayanarooj, Siripen; Gibbons, Robert V; Nisalak, Ananda; Srikiatkhachorn, Anon; Green, Sharone; Stephens, Henry AF; Rothman, Alan L; Mathew, Anuja

2014-01-01

Variation in the sequence of T-cell epitopes between dengue virus (DENV) serotypes is believed to alter memory T-cell responses during second heterologous infections. We identified a highly conserved, novel, HLA-B57-restricted epitope on the DENV NS1 protein. We predicted higher frequencies of B57-NS126–34-specific CD8+ T cells in peripheral blood mononuclear cells from individuals undergoing secondary rather than primary DENV infection. However, high tetramer-positive T-cell frequencies during acute infection were seen in only one of nine subjects with secondary infection. B57-NS126–34-specific and other DENV epitope-specific CD8+ T cells, as well as total CD8+ T cells, expressed an activated phenotype (CD69+ and/or CD38+) during acute infection. In contrast, expression of CD71 was largely limited to DENV epitope-specific CD8+ T cells. In vitro stimulation of cell lines indicated that CD71 expression was differentially sensitive to stimulation by homologous and heterologous variant peptides. CD71 may represent a useful marker of antigen-specific T-cell activation. PMID:23941420

Distinct activation phenotype of a highly conserved novel HLA-B57-restricted epitope during dengue virus infection.

PubMed

Townsley, Elizabeth; Woda, Marcia; Thomas, Stephen J; Kalayanarooj, Siripen; Gibbons, Robert V; Nisalak, Ananda; Srikiatkhachorn, Anon; Green, Sharone; Stephens, Henry A F; Rothman, Alan L; Mathew, Anuja

2014-01-01

Variation in the sequence of T-cell epitopes between dengue virus (DENV) serotypes is believed to alter memory T-cell responses during second heterologous infections. We identified a highly conserved, novel, HLA-B57-restricted epitope on the DENV NS1 protein. We predicted higher frequencies of B57-NS1(26-34) -specific CD8(+) T cells in peripheral blood mononuclear cells from individuals undergoing secondary rather than primary DENV infection. However, high tetramer-positive T-cell frequencies during acute infection were seen in only one of nine subjects with secondary infection. B57-NS1(26-34) -specific and other DENV epitope-specific CD8(+) T cells, as well as total CD8(+) T cells, expressed an activated phenotype (CD69(+) and/or CD38(+)) during acute infection. In contrast, expression of CD71 was largely limited to DENV epitope-specific CD8(+) T cells. In vitro stimulation of cell lines indicated that CD71 expression was differentially sensitive to stimulation by homologous and heterologous variant peptides. CD71 may represent a useful marker of antigen-specific T-cell activation. © 2013 John Wiley & Sons Ltd.

Clinical significance of HOX11L2 expression linked to t(5;14)(q35;q32), of HOX11 expression, and of SIL-TAL fusion in childhood T-cell malignancies: results of EORTC studies 58881 and 58951.

PubMed

Cavé, Hélène; Suciu, Stefan; Preudhomme, Claude; Poppe, Bruce; Robert, Alain; Uyttebroeck, Anne; Malet, Michèle; Boutard, Patrick; Benoit, Yves; Mauvieux, Laurent; Lutz, Patrick; Méchinaud, Françoise; Grardel, Nathalie; Mazingue, Francoise; Dupont, Madeleine; Margueritte, Geneviève; Pages, Marie-Pierre; Bertrand, Yves; Plouvier, Emmanuel; Brunie, Ghislaine; Bastard, Christian; Plantaz, Dominique; Vande Velde, Isabel; Hagemeijer, Anne; Speleman, Frank; Lessard, Michel; Otten, Jacques; Vilmer, Etienne; Dastugue, Nicole

2004-01-15

In a series of 153 children with T-cell malignancies enrolled in 2 consecutive European Organization for Research and Treatment of Cancer (EORTC) trials, we assessed the HOX11L2 expression and/or the presence of a t(5;14)(q35;q32). Additionally, in 138 of these patients, HOX11 expression and SIL-TAL rearrangement were also assessed. These alterations were mutually exclusive, and their frequency was 23% (n = 35), 7% (n = 10), and 12% (n = 17), respectively. HOX11L2/t(5;14) positivity was more frequent in acute lymphoblastic leukemia (ALL) with cortical T immunophenotype and in children aged between 6 and 9 years. In contrast with previously reported data, patients positive and negative for HOX11L2/t(5;14) were comparable with regard to clinical outcome as well as to the response to a 7-day prephase treatment or to residual disease at completion of induction therapy. The 3-year event-free survival (EFS) rate (+/- SE percentage) for patients positive and negative for HOX11L2/t(5;14) was 75.5% (+/- 8.1%) and 68.3% (+/- 5.0%), respectively; the hazard ratio was 0.84 (95% confidence interval, 0.40-1.80). Patients with HOX11-high expression and those with SIL-TAL fusion had low levels of residual disease at the end of induction and a favorable prognosis: the 3-year EFS rate was 83.3% (+/- 8.5%) and 75.3% (+/- 12.6%), respectively. The results obtained in HOX11L2/t(5;14) patients in this study do not confirm the unfavorable prognosis reported in previous studies.

Leukoencephalopathy and long-term neurobehavioural, neurocognitive, and brain imaging outcomes in survivors of childhood acute lymphoblastic leukaemia treated with chemotherapy: a longitudinal analysis.

PubMed

Cheung, Yin Ting; Sabin, Noah D; Reddick, Wilburn E; Bhojwani, Deepa; Liu, Wei; Brinkman, Tara M; Glass, John O; Hwang, Scott N; Srivastava, Deokumar; Pui, Ching-Hon; Robison, Leslie L; Hudson, Melissa M; Krull, Kevin R

2016-10-01

Leukoencephalopathy is observed in some children undergoing chemotherapy for acute lymphoblastic leukaemia, although its effects on long-term outcomes is unknown. This study examines the associations between acute leukoencephalopathy and neurobehavioural, neurocognitive, and brain white matter imaging outcomes in long-term survivors of childhood acute lymphoblastic leukaemia treated with chemotherapy without cranial radiation. In this longitudinal analysis, we used data of children with acute lymphoblastic leukaemia at St Jude Children's Research Hospital (Memphis, TN, USA) who had been treated between June 1, 2000, and Oct 31, 2010. Eligible patients were diagnosed with non-B-cell acute lymphoblastic leukaemia, aged at least 8 years, and survivors with at least 5 years since their initial diagnosis. Brain MRIs obtained during active therapy were systematically coded for leukoencephalopathy using Common Terminology Criteria for Adverse Event version 4. At least 5 years after their diagnosis, survivors completed neurocognitive testing, another brain MRI, and their parents completed neurobehavioural ratings of their child (Behavior Rating Inventory of Executive Function [BRIEF]). Follow-up MRI included diffusion tensor imaging to assess white matter integrity, with indices of fractional anisotropy, axial diffusivity, and radial diffusivity from frontal lobes, parietal lobes, and in the frontostriatal tract. The neuroradiologist, who assessed abnormal MRIs, was masked to both group assignment of survivors and the neurobehavioural and neurocognitive outcomes. The primary outcomes were neurobehavioural function, assessed from completed BRIEF, and neurocognitive performance, measured by direct neurocognitive tests (Delis-Kaplan Executive Function System, Wechsler Intelligence Scale for Children-IV/Wechsler Adult Intelligence Scale-III, Rey-Osterrieth Complex Figure Test, and Lafayette Grooved Pegboard Test). This study had completed enrolment in October, 2014, and is registered as an observational study at ClinicalTrials.gov, number NCT01014195. Between Feb 18, 2010, and Oct 22, 2014, 210 (70%) of 301 eligible survivors participated in our study of whom 190 were evaluable, 162 had an MRI. 56 participants had quantitative brain imaging data and were included in evaluable population analyses. 51 (27%) of the 190 evaluable participants had acute leukoencephalopathy. Compared with population norms, survivors were reported to have more neurobehavioural problems with working memory, organisation, initiation, and planning (p<0·001 for all). Survivors had worse scores than the general population on direct measures of memory span, processing speed, and executive function (p<0·05 for all). Survivors with a history of acute leukoencephalopathy had more neurobehavioural problems than survivors with no history of leukoencephalopathy on organisation (adjusted T-score 56·2 [95% CI 53·3-59·1] vs 52·2 [50·4-53·9], p=0·020) and initiation (55·5 [52·7-58·3] vs 52·1 [50·4-53·8], p=0·045). Survivors with acute leukoencephalopathy also had reduced white matter integrity in the frontostriatal tract at follow-up: lower fractional anisotropy (p=0·069), higher axial diffusivity (p=0·020), and higher radial diffusivity (p=0·0077). A one-unit change in the radial diffusivity index corresponded with a 15·0 increase in raw score points on initiation, 30·3 on planning, and 28·0 on working memory (p<0·05 for all). Acute leukoencephalopathy during chemotherapy treatment, without cranial radiation, for childhood acute lymphoblastic leukaemia predicted higher risk for long-term neurobehavioural problems and reduced white matter integrity in frontal brain regions. Survivors of childhood acute lymphoblastic leukaemia might benefit from preventive cognitive or behavioural interventions, particularly those who develop acute leukoencephalopathy. National Institute of Mental Health, National Cancer Institute, American Lebanese Syrian Associated Charities. Copyright © 2016 Elsevier Ltd. All rights reserved.

Radiation-induced leukemia: Comparative studies in mouse and man

DOE Office of Scientific and Technical Information (OSTI.GOV)

Haas, M.

1991-01-01

We now have a clear understanding of the mechanism by which radiation-induced (T-cell) leukemia occurs. In irradiated mice (radiation-induced thymic leukemia) and in man (acute lymphoblastic T-cell leukemia, T-ALL) the mechanism of leukemogenesis is surprisingly similar. Expressed in the most elementary terms, T-cell leukemia occurs when T-cell differentiation is inhibited by a mutation, and pre-T cells attempt but fail to differentiate in the thymus. Instead of leaving the thymus for the periphery as functional T-cells they continue to proliferate in the thymus. The proliferating pre- (pro-) T-cells constitute the (early) acute T-cell leukemia (A-TCL). This model for the mechanism ofmore » T-cell leukemogenesis accounts for all the properties of both murine and human A-TCL. Important support for the model has recently come from work by Ilan Kirsch and others, who have shown that mutations/deletions in the genes SCL (TAL), SIL, and LCK constitute primary events in the development of T-ALL, by inhibiting differentiation of thymic pre- (pro-) T-cells. This mechanism of T-cell leukemogenesis brings several specific questions into focus: How do early A-TCL cells progress to become potently tumorigenic and poorly treatable Is it feasible to genetically suppress early and/or progressed A-TCL cells What is the mechanism by which the differentiation-inhibited (leukemic) pre-T cells proliferate During the first grant year we have worked on aspects of all three questions.« less

Global Characteristics of Childhood Acute Promyelocytic Leukemia

PubMed Central

Zhang, L; Samad, A; Pombo-de-Oliveira, MS; Scelo, G; Smith, MT; Feusner, J; Wiemels, JL; Metayer, C

2014-01-01

Acute promyelocytic leukemia (APL) comprises approximately 5–10% of childhood acute myeloid leukemia (AML) cases in the US. While variation in this percentage among other populations was noted previously, global patterns of childhood APL have not been thoroughly characterized. In this comprehensive review of childhood APL, we examined its geographic pattern and the potential contribution of environmental factors to observed variation. In 142 studies (spanning >60 countries) identified, variation was apparent—de novo APL represented from 2% (Switzerland) to >50% (Nicaragua) of childhood AML in different geographic regions. Because a limited number of previous studies addressed specific environmental exposures that potentially underlie childhood APL development, we gathered 28 childhood cases of therapy-related APL, which exemplified associations between prior exposures to chemotherapeutic drugs/radiation and APL diagnosis. Future population-based studies examining childhood APL patterns and the potential association with specific environmental exposures and other risk factors are needed. PMID:25445717

Radon and leukemia in the Danish study: another source of dose.

PubMed

Harley, Naomi H; Robbins, Edith S

2009-10-01

An epidemiologic study of childhood leukemia in Denmark (2,400 cases; 6,697 controls) from 1968 to 1994 suggested a weak, but statistically significant, association of residential radon exposure and acute childhood lymphoblastic leukemia (ALL). The Danish study estimated a relative risk (RR) = 1.56 (95% CI, 1.05-2.30) for a cumulative exposure of 1,000 Bq m-3 y. For an exposure duration of 10 y their RR corresponds to a radon concentration of 100 Bq m-3. There are two dose pathways of interest where alpha particles could damage potential stem cells for ALL. One is the alpha dose to bone marrow, and two is the dose to bronchial mucosa where an abundance of circulating lymphocytes is found. Compared with an exposure of about 1 mSv y-1 from natural external background, radon and decay products contribute an additional 10 to 60% to the bone marrow equivalent dose. The other pathway for exposure of T (or B) lymphocytes is within the tracheobronchial epithelium (BE). Inhaled radon decay products deposit on the relatively small area of airway surfaces and deliver a significant dose to the nearby basal or mucous cells implicated in human lung cancer. Lymphocytes are co-located with basal cells and are half as abundant. Using a 10-y exposure to 100 Bq m-3, our dose estimates suggest that the equivalent dose to these lymphocytes could approach 1 Sv. The relatively high dose estimate to lymphocytes circulating through the BE, potential precursor cells for ALL, provides a dose pathway for an association.

Veliparib and Topotecan With or Without Carboplatin in Treating Patients With Relapsed or Refractory Acute Leukemia, High-Risk Myelodysplasia, or Aggressive Myeloproliferative Disorders

ClinicalTrials.gov

2018-04-20

Adult Acute Megakaryoblastic Leukemia; Adult Acute Monoblastic Leukemia; Adult Acute Monocytic Leukemia; Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With Maturation; Adult Acute Myeloid Leukemia With Minimal Differentiation; Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With t(8;21); (q22; q22.1); RUNX1-RUNX1T1; Adult Acute Myeloid Leukemia With t(9;11)(p22.3;q23.3); MLLT3-KMT2A; Adult Acute Myeloid Leukemia Without Maturation; Adult Acute Myelomonocytic Leukemia; Adult Erythroleukemia; Adult Pure Erythroid Leukemia; Chronic Myelomonocytic Leukemia; de Novo Myelodysplastic Syndrome; Essential Thrombocythemia; Hematopoietic and Lymphoid Cell Neoplasm; Myelodysplastic Syndrome; Philadelphia Chromosome Negative, BCR-ABL1 Positive Chronic Myelogenous Leukemia; Polycythemia Vera; Previously Treated Myelodysplastic Syndrome; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Disease; Secondary Myelodysplastic Syndrome

Characteristics and Outcomes of Second Malignant Neoplasms after Childhood Cancer Treatment: Multi-Center Retrospective Survey.

PubMed

Koh, Kyung-Nam; Yoo, Keon Hee; Im, Ho Joon; Sung, Ki Woong; Koo, Hong Hoe; Kim, Hyo Sun; Han, Jung Woo; Yoon, Jong Hyung; Park, Hyeon Jin; Park, Byung-Kiu; Baek, Hee Jo; Kook, Hoon; Lee, Jun Ah; Lee, Jae Min; Lee, Kwang Chul; Kim, Soon Ki; Park, Meerim; Lee, Young-Ho; Lyu, Chuhl Joo; Seo, Jong Jin

2016-08-01

This retrospective study investigated the clinical characteristics and outcomes of second malignant neoplasms (SMNs) in survivors of childhood cancer from multiple institutions in Korea. A total of 102 patients from 11 institutions who developed SMN after childhood cancer treatment between 1998 and 2011 were retrospectively enrolled. The most common primary malignant neoplasms (PMNs) were central nervous system (CNS) tumors (n = 17), followed by acute lymphoblastic leukemia (n = 16), non-Hodgkin lymphoma (n = 13), and osteosarcoma (n = 12). The most common SMNs were therapy-related myeloid neoplasms (t-MNs; acute myeloid leukemia [AML], 29 cases; myelodysplastic syndrome [MDS], 12 cases), followed by thyroid carcinomas (n = 15) and CNS tumors (n = 10). The median latency period was 4.9 years (range, 0.5-18.5 years). Among 45 patients with solid tumors defined as an SMN, 15 (33%) developed the lesion in a field previously subjected to radiation. The 5-year overall survival (OS) rate of patients with an SMN was 45% with a median follow-up time of 8.6 years. Patients with AML, MDS, and CNS tumors exhibited the poorest outcomes with 5-year OS rates of 18%, 33%, and 32%, respectively, whereas those with second osteosarcoma showed comparable outcomes (64%) to patients with primary counterpart and those with second thyroid carcinoma had a 100% OS rate. Further therapeutic efforts are recommended to improve the survival outcomes in patients with SMNs, especially in cases with t-MNs and CNS tumors.

Regulatory T cells inhibit acute IFN-γ synthesis without blocking T-helper cell type 1 (Th1) differentiation via a compartmentalized requirement for IL-10

PubMed Central

Sojka, Dorothy K.; Fowell, Deborah J.

2011-01-01

CD4+CD25+Forkhead box P3 (Foxp3)+ regulatory T cells (Tregs) control immune responses to self and foreign antigens in secondary lymphoid organs and at tissue sites of inflammation. Tregs can modify the function of many immune cells and have been proposed to block early proliferation, differentiation, and effector function. Acute ablation of Tregs has revealed rapid cytokine production immediately after Treg removal, suggesting that Tregs may regulate effector function acutely rather than regulating the programming for immune function. We developed in vitro and in vivo models that enabled the direct test of Treg regulation of T-helper cell type 1 (Th1) differentiation. CD28 signaling is known to abrogate Treg suppression of IL-2 secretion and proliferation, but our studies show that Treg suppression of IFN-γ during Th1 priming proceeds despite enhanced CD28 signaling. Importantly, during Th1 differentiation, Tregs inhibited early IFN-γ transcription without disrupting expression of Th1-specific T-box transcription factor (Tbet) and Th1 programming. Acute shutoff of effector cytokine production by Tregs was selective for IFN-γ but not TNF-α and was independent of TGF-β and Epstein-Barr virus-induced gene 3. In vivo, Tregs potently controlled CD4 IFN-γ and CD4 effector cell expansion in the lymph node (four- to fivefold reduction) but not Th1 programming, independent of IL-10. Tregs additionally reduced CD4 IFN-γ in the inflamed dermis (twofold reduction) dependent on their production of IL-10. We propose a model for Treg inhibition of effector function based on acute cytokine regulation. Interestingly, Tregs used different regulatory mechanisms to regulate IFN-γ (IL-10–dependent or –independent) subject to the target T-cell stage of activation and its tissue location. PMID:22025707

Vγ1+γδT, early cardiac infiltrated innate population dominantly producing IL-4, protect mice against CVB3 myocarditis by modulating IFNγ+ T response.

PubMed

Wan, Fangfang; Yan, Kepeng; Xu, Dan; Qian, Qian; Liu, Hui; Li, Min; Xu, Wei

2017-01-01

Viral myocarditis (VMC) is an inflammation of the myocardium closely associated with Coxsackievirus B3 (CVB3) infection. Vγ1 + γδT cells, one of early cardiac infiltrated innate population, were reported to protect CVB3 myocarditis while the precise mechanism not fully addressed. To explore cytokine profiles and kinetics of Vγ1 + γδT and mechanism of protection against VMC, flow cytometry was conducted on cardiac Vγ1 cells in C57BL/6 mice following CVB3 infection. The level of cardiac inflammation, transthoracic echocardiography and viral replication were evaluated after monoclonal antibody depletion of Vγ1γδT. We found that Vγ1 + γδT cells infiltration peaked in the heart at day3 post CVB3 infection and constituted a minor source of IFN-γ but major producers for early IL-4. Vγ1γδT cells were activated earlier holding a higher IL-4-producing efficiency than CD4 + Th cells in the heart. Depletion of Vγ1 + γδT resulted in a significantly exacerbated cardiac infiltration, increased T, macrophage and neutrophil population in heart homogenates and worse cardiomyopathy; which was accompanied by a significant expansion of peripheral IFNγ + CD4+ and CD8+T cells. Neutralization of IL-4 in mice resulted in an exacerbated acute myocarditis confirming the IL-4-mediated protective mechanism of Vγ1. Our findings identify a unique property of Vγ1 + γδT cells as one dominant early producers of IL-4 upon CVB3 acute infection which is a key mediator to protect mice against acute myocarditis by modulating IFNγ-secreting T response. Copyright © 2016 Elsevier Ltd. All rights reserved.

[Effects of birth order, maternal abortion and mode of delivery on childhood acute leukemia risk: a meta-analysis].

PubMed

Zou, Guobin; Sha, Xia

2014-03-01

To evaluate the associations between birth order, maternal abortion and mode of delivery and childhood acute leukemia risk. Multiple electronic databases were searched to identify relevant studies up to March 2013 using the search terms "childhood leukemia", "acute lymphoblastic leukemia", "acute myeloid leukemia","birth order", "abortion", "miscarriage", "cesarean", "birth characteristics" and "prenatal risk factor". Data from cohort and case-control studies were analyzed using the Stata software. Twenty-three studies were included in this meta-analysis according to the selection criteria. No significant associations were identified for birth order and mode of delivery (birth order = 2: OR = 0.97, 95%CI: 0.89-1.05; birth order = 3: OR = 1.00, 95%CI: 0.91-1.11; birth order ≥ 4: OR = 1.02, 95%CI: 0.87-1.20; mode of delivery: OR = 1.05, 95%CI: 0.96-1.15). However, there was a significant association between maternal abortion and childhood acute leukemia risk (spontaneous abortion: OR = 1.21, 95%CI: 1.05-1.41; induced abortion: OR = 1.23, 95%CI: 1.07-1.43). Furthermore, the stratified analysis by disease subtypes showed that spontaneous and induced abortions were significantly associated with the risks of childhood acute myeloid leukemia (OR = 1.71, 95%CI: 1.09-2.70) and acute lymphoblastic leukemia (OR = 1.23, 95%CI: 1.05-1.42), respectively. This meta-analysis revealed that maternal abortion might contribute to the childhood acute leukemia risk.

Scrutinizing the Expression and Blockade of Inhibitory Molecules Expressed on T Cells from Acute Myeloid Leukemia Patients.

PubMed

Abdolmaleki, Mohsen; Mojtabavi, Nazanin; Zavvar, Mahdi; Vaezi, Mohammad; Noorbakhsh, Farshid; Nicknam, Mohammad Hossein

2018-06-01

T cell exhaustion is an immunosuppressive mechanism which occurs in chronic viral infections, solid tumors and hematologic malignancies. Exhausted T cell has increased the expression of inhibitory receptors, and functional impairment. In this study, we investigated the expression from some of those inhibitory receptors being Programmed death 1 (PD-1), T cell immunoglobulin and mucin domain containing molecules 3 (TIM-3) and CD244 on T cells from Iranian acute myeloid leukemia (AML) patients. Peripheral blood samples were collected from Iranian newly diagnosed AML patients and flow cytometric analysis was accomplished for cell surface expression of PD-1, TIM-3, and CD244 on T lymphocytes. Functionality and proliferation assay were done in the presence of anti-PD-1 and anti-CD244 blocking antibodies. Immunophenotyping of T cells showed a significant increase of PD-1 and CD244 expression on CD4+ and CD8+ T cells of AML patients. Whereas blockade of PD1 and CD244 increased the proliferation of CD4+ and CD8+ T lymphocytes of AML patients but IFN-γ production was not significantly increased. In conclusion, our data indicate that CD4+ and CD8+ T cells from AML patients appeared to be exhausted and blockade of some immune checkpoints can improve the proliferation of those cells.

Differential cellular targets of Epstein-Barr virus (EBV) infection between acute EBV-associated hemophagocytic lymphohistiocytosis and chronic active EBV infection.

PubMed

Kasahara, Y; Yachie, A; Takei, K; Kanegane, C; Okada, K; Ohta, K; Seki, H; Igarashi, N; Maruhashi, K; Katayama, K; Katoh, E; Terao, G; Sakiyama, Y; Koizumi, S

2001-09-15

Unusual Epstein-Barr virus (EBV) infection into T or natural killer cells plays a pivotal role in the pathogenesis of acute EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH) and chronic active EBV infection (CAEBV). The precise frequency and localization of EBV genome in lymphocyte subpopulations especially within T-cell subpopulations are unclear in these EBV-related disorders. This study analyzed the frequency of EBV-infected cells in circulating lymphocyte subpopulations from 4 patients with acute EBV-HLH and 4 with CAEBV. EBV- encoded small RNA-1 in situ hybridization examination of peripheral blood lymphocytes showed a significantly higher frequency of EBV-infected cells of 1.0% to 13.4% in EBV-HLH and 1.6% to 25.6% in CAEBV, respectively. The patterns of EBV infection in lymphocyte subpopulations were quite different between acute EBV-HLH and CAEBV. EBV infection was predominant in CD8(+) T cells in all EBV-HLH patients, whereas the dominant EBV-infected cell populations were non-CD8(+) lymphocyte subpopulations in CAEBV patients. Phenotypical analysis revealed that EBV-infected cell populations from both EBV-HLH and CAEBV were activated. There was no predominance of any EBV substrain of latent membrane protein-1, EBV-associated nuclear antigen (EBNA)-1, and EBNA-2 genes between the 2 abnormal EBV-associated disorders, and self-limited acute infectious mononucleosis. These results showing differential virus-cell interactions between acute EBV-HLH and CAEBV indicated different pathogenic mechanisms against EBV infection between the 2 EBV-associated diseases, which accounts for the difference in clinical manifestations between the 2 diseases.

Lineage Switching in Acute Leukemias: A Consequence of Stem Cell Plasticity?

PubMed Central

Dorantes-Acosta, Elisa; Pelayo, Rosana

2012-01-01

Acute leukemias are the most common cancer in childhood and characterized by the uncontrolled production of hematopoietic precursor cells of the lymphoid or myeloid series within the bone marrow. Even when a relatively high efficiency of therapeutic agents has increased the overall survival rates in the last years, factors such as cell lineage switching and the rise of mixed lineages at relapses often change the prognosis of the illness. During lineage switching, conversions from lymphoblastic leukemia to myeloid leukemia, or vice versa, are recorded. The central mechanisms involved in these phenomena remain undefined, but recent studies suggest that lineage commitment of plastic hematopoietic progenitors may be multidirectional and reversible upon specific signals provided by both intrinsic and environmental cues. In this paper, we focus on the current knowledge about cell heterogeneity and the lineage switch resulting from leukemic cells plasticity. A number of hypothetical mechanisms that may inspire changes in cell fate decisions are highlighted. Understanding the plasticity of leukemia initiating cells might be fundamental to unravel the pathogenesis of lineage switch in acute leukemias and will illuminate the importance of a flexible hematopoietic development. PMID:22852088

7-Hydroxystaurosporine and Perifosine in Treating Patients With Relapsed or Refractory Acute Leukemia, Chronic Myelogenous Leukemia or High Risk Myelodysplastic Syndromes

ClinicalTrials.gov

2013-09-27

Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Acute Promyelocytic Leukemia (M3); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Blastic Phase Chronic Myelogenous Leukemia; Myelodysplastic/Myeloproliferative Neoplasms; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; T-cell Adult Acute Lymphoblastic Leukemia; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Adult Acute Myeloid Leukemia

[Immunophenotype of lymphoblastic leukaemia in children in relation to clinical symptoms and laboratory tests, preceding its diagnosis].

PubMed

Zapolska, Beata; Krawczuk-Rybak, Maryna; Łuczyński, Włodzimierz; Zak, Janusz; Leszczyńska, Elzbieta

2004-01-01

The aim of study was to compare the clinical picture and results of laboratory tests according to the acute lymphoblastic leukaemia (ALL) immunophenotype. The observation was carried out on a group of 67 patients treated in the IIIrd Department of Paediatrics and Department of Children Oncology in the Medical Academy of Białystok from January 1994 to April 2001. This group consists of 4 children with pro-B acute lymphoblastic leukaemia, 52 children with pre-B cell ALL, 1 child with B-cell acute lymphoblastic leukaemia and 9 children with T-cell acute lymphoblastic leukaemia. Haemorrhagic diathesis. splenomegaly, enlargement of peripheral lymph nodes as well as higher values of white blood cells count, blasts count, haemoglobin concentration, haematocrit and LDH activity were observed more frequently in patients with T-cell leukaemia than in others.

Human T Lymphocytes Are Permissive for Dengue Virus Replication.

PubMed

Silveira, Guilherme F; Wowk, Pryscilla F; Cataneo, Allan H D; Dos Santos, Paula F; Delgobo, Murilo; Stimamiglio, Marco A; Lo Sarzi, Maria; Thomazelli, Ana Paula F S; Conchon-Costa, Ivete; Pavanelli, Wander R; Antonelli, Lis R V; Báfica, André; Mansur, Daniel S; Dos Santos, Claudia N Duarte; Bordignon, Juliano

2018-05-15

Dengue virus (DV) infection can cause either a self-limiting flu-like disease or a threatening hemorrhage that may evolve to shock and death. A variety of cell types, such as dendritic cells, monocytes, and B cells, can be infected by DV. However, despite the role of T lymphocytes in the control of DV replication, there remains a paucity of information on possible DV-T cell interactions during the disease course. In the present study, we have demonstrated that primary human naive CD4 + and CD8 + T cells are permissive for DV infection. Importantly, both T cell subtypes support viral replication and secrete viable virus particles. DV infection triggers the activation of both CD4 + and CD8 + T lymphocytes, but preactivation of T cells reduces the susceptibility of T cells to DV infection. Interestingly, the cytotoxicity-inducing protein granzyme A is highly secreted by human CD4 + but not CD8 + T cells after exposure to DV in vitro Additionally, using annexin V and polycaspase assays, we have demonstrated that T lymphocytes, in contrast to monocytes, are resistant to DV-induced apoptosis. Strikingly, both CD4 + and CD8 + T cells were found to be infected with DV in acutely infected dengue patients. Together, these results show that T cells are permissive for DV infection in vitro and in vivo , suggesting that this cell population may be a viral reservoir during the acute phase of the disease. IMPORTANCE Infection by dengue virus (DV) causes a flu-like disease that can evolve to severe hemorrhaging and death. T lymphocytes are important cells that regulate antibody secretion by B cells and trigger the death of infected cells. However, little is known about the direct interaction between DV and T lymphocytes. Here, we show that T lymphocytes from healthy donors are susceptible to infection by DV, leading to cell activation. Additionally, T cells seem to be resistant to DV-induced apoptosis, suggesting a potential role as a viral reservoir in humans. Finally, we show that both CD4 + and CD8 + T lymphocytes from acutely infected DV patients are infected by DV. Our results raise new questions about DV pathogenesis and vaccine development. Copyright © 2018 American Society for Microbiology.

Impaired circulating CD4+ LAP+ regulatory T cells in patients with acute coronary syndrome and its mechanistic study.

PubMed

Zhu, Zheng-Feng; Meng, Kai; Zhong, Yu-Cheng; Qi, Liang; Mao, Xiao-Bo; Yu, Kun-Wu; Zhang, Wei; Zhu, Peng-Fei; Ren, Ze-Peng; Wu, Bang-Wei; Ji, Qin-Wei; Wang, Xiang; Zeng, Qiu-Tang

2014-01-01

CD4(+) latency-associated peptide (LAP)(+) regulatory T cells (Tregs) are a newly discovered T cell subset in humans and the role of these cells in patients with acute coronary syndrome (ACS) has not been explored. We designed to investigate whether circulating frequency and function of CD4(+)LAP(+) Tregs are defective in ACS. One hundred eleven ACS patients (acute myocardial infarction and unstable angina) and 117 control patients were enrolled in the study. The control patients consisted of chronic stable angina (CSA) and chest pain syndrome (CPS). The frequencies of circulating CD4(+)LAP(+) Tregs and the expression of the transmembrane protein glycoprotein-A repetitions predominant (GARP) on CD4(+) T cells were determined by flow cytometry. The function of CD4(+)LAP(+) Tregs was detected using thymidine uptake. Serum interleukin-10 (IL-10) and transforming growth factor-β protein (TGF-β) levels were detected using ELISA and expression of GARP mRNA in peripheral blood mononuclear cells (PBMCs) was measured by real time-polymerase chain reaction. We found ACS patients had a significantly lower frequency of circulating CD4(+)LAP(+) Tregs, and the function of these cells was reduced compared to controls. The expression of GARP in CD4(+) T cells and the serum levels of TGF-β in ACS patients were lower than those of control patients. The serum levels of IL-10 were similar between the two cohorts. A novel regulatory T cell subset, defined as CD4(+)LAP(+) T cells is defective in ACS patients.

Acute leukemias of ambiguous lineage.

PubMed

Béné, Marie C; Porwit, Anna

2012-02-01

The 2008 edition of the WHO Classification of Tumors of Haematopoietic and Lymphoid Tissues recognizes a special category called "leukemias of ambiguous lineage." The vast majority of these rare leukemias are classified as mixed phenotype acute leukemia (MPAL), although acute undifferentiated leukemias and natural killer lymphoblastic leukemias are also included. The major immunophenotypic markers used by the WHO 2008 to determine the lineage for these proliferations are myeloperoxidase, CD19, and cytoplasmic CD3. However, extensive immunophenotyping is necessary to confirm that the cells indeed belong to 2 different lineages or coexpress differentiation antigens of more than 1 lineage. Specific subsets of MPAL are defined by chromosomal anomalies such as the t(9;22) Philadelphia chromosome BCR-ABL1 or involvement of the MLL gene on chromosome 11q23. Other MPAL are divided into B/myeloid NOS, T/myeloid NOS, B/T NOS, and B/T/myeloid NOS. MPAL are usually of dire prognosis, respond variably to chemotherapy of acute lymphoblastic or acute myeloblastic type, and benefit most from rapid allogeneic hematopoietic stem cell transplantation.

Early Gag Immunodominance of the HIV-Specific T-Cell Response during Acute/Early Infection Is Associated with Higher CD8+ T-Cell Antiviral Activity and Correlates with Preservation of the CD4+ T-Cell Compartment

PubMed Central

Ghiglione, Yanina; Falivene, Juliana; Socias, María Eugenia; Laufer, Natalia; Coloccini, Romina Soledad; Rodriguez, Ana María; Ruiz, María Julia; Pando, María Ángeles; Giavedoni, Luis David; Cahn, Pedro; Sued, Omar; Salomon, Horacio; Gherardi, María Magdalena

2013-01-01

The important role of the CD8+ T-cell response on HIV control is well established. Moreover, the acute phase of infection represents a proper scenario to delineate the antiviral cellular functions that best correlate with control. Here, multiple functional aspects (specificity, ex vivo viral inhibitory activity [VIA] and polyfunctionality) of the HIV-specific CD8+ T-cell subset arising early after infection, and their association with disease progression markers, were examined. Blood samples from 44 subjects recruited within 6 months from infection (primary HIV infection [PHI] group), 16 chronically infected subjects, 11 elite controllers (EC), and 10 healthy donors were obtained. Results indicated that, although Nef dominated the anti-HIV response during acute/early infection, a higher proportion of early anti-Gag T cells correlated with delayed progression. Polyfunctional HIV-specific CD8+ T cells were detected at early time points but did not associate with virus control. Conversely, higher CD4+ T-cell set points were observed in PHI subjects with higher HIV-specific CD8+ T-cell VIA at baseline. Importantly, VIA levels correlated with the magnitude of the anti-Gag cellular response. The advantage of Gag-specific cells may result from their enhanced ability to mediate lysis of infected cells (evidenced by a higher capacity to degranulate and to mediate VIA) and to simultaneously produce IFN-γ. Finally, Gag immunodominance was associated with elevated plasma levels of interleukin 2 (IL-2) and macrophage inflammatory protein 1β (MIP-1β). All together, this study underscores the importance of CD8+ T-cell specificity in the improved control of disease progression, which was related to the capacity of Gag-specific cells to mediate both lytic and nonlytic antiviral mechanisms at early time points postinfection. PMID:23616666

Expansion of highly activated invariant natural killer T cells with altered phenotype in acute dengue infection

PubMed Central

Kamaladasa, A.; Wickramasinghe, N.; Adikari, T. N.; Gomes, L.; Shyamali, N. L. A.; Salio, M.; Cerundolo, V.; Ogg, G. S.

2016-01-01

Summary Invariant natural killer T (iNKT) cells are capable of rapid activation and production of cytokines upon recognition of antigenic lipids presented by CD1d molecules. They have been shown to play a significant role in many viral infections and were observed to be highly activated in patients with acute dengue infection. In order to characterize further their role in dengue infection, we investigated the proportion of iNKT cells and their phenotype in adult patients with acute dengue infection. The functionality of iNKT cells in patients was investigated by both interferon (IFN)‐γ and interleukin (IL)−4 ex‐vivo enzyme‐linked immunospot (ELISPOT) assays following stimulation with alpha‐galactosyl‐ceramide (αGalCer). We found that circulating iNKT cell proportions were significantly higher (P = 0·03) in patients with acute dengue when compared to healthy individuals and were predominantly of the CD4+ subset. iNKT cells of patients with acute dengue had reduced proportions expressing CD8α and CD161 when compared to healthy individuals. The iNKT cells of patients were highly activated and iNKT activation correlated significantly with dengue virus‐specific immunoglobulin (Ig)G antibody levels. iNKT cells expressing Bcl‐6 (P = 0·0003) and both Bcl‐6 and inducible T cell co‐stimulator (ICOS) (P = 0·006) were increased significantly in patients when compared to healthy individuals. Therefore, our data suggest that in acute dengue infection there is an expansion of highly activated CD4+ iNKT cells, with reduced expression of CD161 markers. PMID:26874822

Longitudinal characterization of dysfunctional T cell-activation during human acute Ebola infection

PubMed Central

Agrati, C; Castilletti, C; Casetti, R; Sacchi, A; Falasca, L; Turchi, F; Tumino, N; Bordoni, V; Cimini, E; Viola, D; Lalle, E; Bordi, L; Lanini, S; Martini, F; Nicastri, E; Petrosillo, N; Puro, V; Piacentini, M; Di Caro, A; Kobinger, G P; Zumla, A; Ippolito, G; Capobianchi, M R

2016-01-01

Data on immune responses during human Ebola virus disease (EVD) are scanty, due to limitations imposed by biosafety requirements and logistics. A sustained activation of T-cells was recently described but functional studies during the acute phase of human EVD are still missing. Aim of this work was to evaluate the kinetics and functionality of T-cell subsets, as well as the expression of activation, autophagy, apoptosis and exhaustion markers during the acute phase of EVD until recovery. Two EVD patients admitted to the Italian National Institute for Infectious Diseases, Lazzaro Spallanzani, were sampled sequentially from soon after symptom onset until recovery and analyzed by flow cytometry and ELISpot assay. An early and sustained decrease of CD4 T-cells was seen in both patients, with an inversion of the CD4/CD8 ratio that was reverted during the recovery period. In parallel with the CD4 T-cell depletion, a massive T-cell activation occurred and was associated with autophagic/apoptotic phenotype, enhanced expression of the exhaustion marker PD-1 and impaired IFN-gamma production. The immunological impairment was accompanied by EBV reactivation. The association of an early and sustained dysfunctional T-cell activation in parallel to an overall CD4 T-cell decline may represent a previously unknown critical point of Ebola virus (EBOV)-induced immune subversion. The recent observation of late occurrence of EBOV-associated neurological disease highlights the importance to monitor the immuno-competence recovery at discharge as a tool to evaluate the risk of late sequelae associated with resumption of EBOV replication. Further studies are required to define the molecular mechanisms of EVD-driven activation/exhaustion and depletion of T-cells. PMID:27031961

Longitudinal characterization of dysfunctional T cell-activation during human acute Ebola infection.

PubMed

Agrati, C; Castilletti, C; Casetti, R; Sacchi, A; Falasca, L; Turchi, F; Tumino, N; Bordoni, V; Cimini, E; Viola, D; Lalle, E; Bordi, L; Lanini, S; Martini, F; Nicastri, E; Petrosillo, N; Puro, V; Piacentini, M; Di Caro, A; Kobinger, G P; Zumla, A; Ippolito, G; Capobianchi, M R

2016-03-31

Data on immune responses during human Ebola virus disease (EVD) are scanty, due to limitations imposed by biosafety requirements and logistics. A sustained activation of T-cells was recently described but functional studies during the acute phase of human EVD are still missing. Aim of this work was to evaluate the kinetics and functionality of T-cell subsets, as well as the expression of activation, autophagy, apoptosis and exhaustion markers during the acute phase of EVD until recovery. Two EVD patients admitted to the Italian National Institute for Infectious Diseases, Lazzaro Spallanzani, were sampled sequentially from soon after symptom onset until recovery and analyzed by flow cytometry and ELISpot assay. An early and sustained decrease of CD4 T-cells was seen in both patients, with an inversion of the CD4/CD8 ratio that was reverted during the recovery period. In parallel with the CD4 T-cell depletion, a massive T-cell activation occurred and was associated with autophagic/apoptotic phenotype, enhanced expression of the exhaustion marker PD-1 and impaired IFN-gamma production. The immunological impairment was accompanied by EBV reactivation. The association of an early and sustained dysfunctional T-cell activation in parallel to an overall CD4 T-cell decline may represent a previously unknown critical point of Ebola virus (EBOV)-induced immune subversion. The recent observation of late occurrence of EBOV-associated neurological disease highlights the importance to monitor the immuno-competence recovery at discharge as a tool to evaluate the risk of late sequelae associated with resumption of EBOV replication. Further studies are required to define the molecular mechanisms of EVD-driven activation/exhaustion and depletion of T-cells.

Talazoparib and Temozolomide in Treating Younger Patients With Refractory or Recurrent Malignancies

ClinicalTrials.gov

2018-03-02

Adult Solid Neoplasm; Childhood Solid Neoplasm; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Central Nervous System Neoplasm; Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Recurrent Malignant Solid Neoplasm; Refractory Central Nervous System Neoplasm

Methylenetetrahydrofolate reductase C677T and A1298C polymorphism and susceptibility to acute lymphoblastic leukemia in a cohort of Egyptian children.

PubMed

Mosaad, Youssef M; Abousamra, Nashwa K; Elashery, Rasha; Fawzy, Iman M; Eldein, Omar A Sharaf; Sherief, Doaa M; El Azab, Hend M M

2015-01-01

This case-control study was planned to investigate the possible role of methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms as a risk factor for the development of acute lymphoblastic leukemia (ALL) in a cohort of Egyptian children. Typing of MTHFR C677T and A1298C polymorphisms was done using restriction fragment length polymorphism (RFLP) for 100 children with ALL and 100 age- and sex-matched healthy controls. No significant differences were found between patients with ALL and controls for the frequency of MTHFR C677T and A1298C alleles, genotypes, combined genotypes or haplotypes. The C677T and A1298C genotype frequency was different from that in Korean and Chinese populations (p < 0.5) and was similar to that in British, French-Canadian and German-Caucasian populations (p > 0.5). Our findings suggest that MTHFR C677T and A1298C polymorphisms are unlikely to affect the development of childhood ALL in an Egyptian population from Delta.

Zinc induces long-term upregulation of T-type calcium current in hippocampal neurons in vivo.

PubMed

Ekstein, Dana; Benninger, Felix; Daninos, Moshe; Pitsch, Julika; van Loo, Karen M J; Becker, Albert J; Yaari, Yoel

2012-11-15

Extracellular zinc can induce numerous acute and persistent physiological and toxic effects in neurons by acting at their plasma membrane or intracellularly following permeation or uptake into them. Zinc acutely and reversibly blocks T-type voltage-gated calcium current (I(CaT)), but the long-term effect of zinc on this current has not been studied. Because chemically induced status epilepticus (SE) results in the release of zinc into the extracellular space, as well as in a long-lasting increase in I(CaT) in CA1 pyramidal cells, we hypothesized that zinc may play a causative role in I(CaT) upregulation. We tested this hypothesis by monitoring for 18 days the effects of zinc and ibotenic acid (a neurotoxic agent serving as control for zinc), injected into the right lateral ventricle, on I(CaT) in rat CA1 pyramidal cells. Both zinc and ibotenic acid caused marked hippocampal lesions on the side of injection, but only minor damage to contralateral hippocampi. Zinc, but not ibotenic acid, caused upregulation of a nickel-sensitive I(CaT) in a subset of contralateral CA1 pyramidal cells, appearing 2 days after injection and lasting for about 2 weeks thereafter. In contrast, acute application of zinc to CA1 pyramidal cells promptly blocked I(CaT). These data indicate that extracellular zinc has a dual effect on I(CaT), blocking it acutely while causing its long-term upregulation. Through the latter effect, zinc may regulate the intrinsic excitability of principal neurons, particularly in pathological conditions associated with enhanced release of zinc, such as SE.

Towards an understanding of the biology and targeted treatment of paediatric relapsed acute lymphoblastic leukaemia.

PubMed

Irving, Julie A E

2016-03-01

Acute lymphoblastic leukaemia is the most common childhood cancer and for those children who relapse, prognosis is poor and new therapeutic strategies are needed. Recurrent pathways implicated in relapse include RAS, JAK STAT, cell cycle, epigenetic regulation, B cell development, glucocorticoid response, nucleotide metabolism and DNA repair. Targeting these pathways is a rational therapeutic strategy and may deliver novel, targeted therapies into the clinic. Relapse often stems from a minor clone present at diagnosis and thus analysis of persisting leukaemia during upfront therapy may allow targeted drug intervention to prevent relapse. © 2015 John Wiley & Sons Ltd.

Single-cell immunofluorescence assay for terminal transferase: human leukaemic and non-leukaemic cells.

PubMed

Okamura, S; Crane, F; Jamal, N; Messner, H A; Mak, T W

1980-02-01

The characteristics of a single-cell immunofluorescence assay for terminal deoxynucleotidyl transferase (terminal transferase, TdT) is described. The data indicate that the single-cell immunofluorescence assay is highly efficient and specific for the detection of cells containing TdT. Using this assay, we have examined 124 marrow or peripheral-blood samples from 104 patients with or without haematological malignancies. Results indicate that TdT(+) cells from 6% to 100% were found in the following patients: 34/40 samples from patients with ALL at the time of diagnosis or during relapse; 2/3 patients with acute undifferentiated leukaemia; 2/3 patients with acute myelomonocytic leukaemia; 1/24 patients with acute myeloblastic leukaemia; 1/5 patients with chronic myelocytic leukaemia (CML) in blastic crisis; and 2/2 patients with diffuse lymphoblastic lymphoma. In contrast less than 1% of TdT(+) cells were found in 20 marrow or peripheral-blood samples from ALL patients in complete remission; 8 patients with CML in chronic phase; 2 patients with myeloma; 1 sample from a patient with Hodgkin's disease, peripheral-blood samples from 7 normal donors and marrow samples from 6 patients without haematological malignancies. TdT(+) cells were also found in association with cells with lymphoblast morphology. The TdT(+) cells in marrow were shown to be directly correlated with the percentage of morphological lymphoblasts, with a Spearman rank coefficient of 0·81, significant at a 0·001 level. In 2 longitudinal studies of 2 ALL patients with TdT(+) cells at diagnosis, the percentage TdT(+) cells also changed in parallel with the proportion of lymphoblasts. However, studies of 2 other patients with morphologically diagnosed ALL with < 1% TdT(+) cells at diagnosis also showed < 1% TdT(+) cells throughout the period studied, indicating a stable phenotype of blast cells in these patients. The single-cell immunofluorescence assay for TdT, which requires < 0·1% of the cells used in a conventional biochemical assay, is highly specific, and could provide a technically more efficient alternative for use in clinics as well as in experimental investigations of subpopulations of leukaemic and normal marrow cells.

Methylenetetrahydrofolate reductase polymorphisms, serum methylenetetrahydrofolate reductase levels, and risk of childhood acute lymphoblastic leukemia in a Chinese population.

PubMed

Tong, Na; Fang, Yongjun; Li, Jie; Wang, Meilin; Lu, Qin; Wang, Shizhi; Tian, Yuanyuan; Rong, Liucheng; Sun, Jielin; Xu, Jianfeng; Zhang, Zhengdong

2010-03-01

Methylenetetrahydrofolate reductase (MTHFR), involved in DNA methylation and nucleotide synthesis, is thought to be associated with a decreased risk of adult and childhood acute lymphoblastic leukemia (ALL). Accumulating evidence has indicated that two common genetic variants, C677T and A1298C, are associated with cancer risk. We hypothesized that these two variants were associated with childhood ALL susceptibility and influence serum MTHFR levels. We genotyped these two polymorphisms and detected MTHFR levels in a case-control study of 361 cases and 508 controls. Compared with the 677CC and 677CC/CT genotypes, the 677TT genotype was associated with a statistically significantly decreased risk of childhood ALL (odds ratio = 0.53, 95% confidence interval = 0.32-0.88, and odds ratio = 0.55, 95% confidence interval = 0.35-0.88, respectively). In addition, a pronounced reduced risk of ALL was observed among low-risk ALL and B-phenotype ALL. Moreover, the mean serum MTHFR level was 8.01 ng/mL (+/-4.38) in cases and 9.27 ng/mL (+/-4.80) in controls (P < 0.001). MTHFR levels in subjects with 677TT genotype was significantly higher than those with 677CC genotype (P = 0.010) or 677CT genotype (P = 0.043) in controls. In conclusion, our results provide evidence that the MTHFR polymorphisms might contribute to reduced childhood ALL risk in this population.

Mechanical Stimulation in Preventing Bone Density Loss in Patients Undergoing Donor Stem Cell Transplant

ClinicalTrials.gov

2012-07-05

Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative; Blastic Phase Chronic Myelogenous Leukemia; Chronic Eosinophilic Leukemia; Chronic Myelomonocytic Leukemia; Chronic Neutrophilic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; de Novo Myelodysplastic Syndromes; Disseminated Neuroblastoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Burkitt Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Noncontiguous Stage II Adult Lymphoblastic Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Plasma Cell Neoplasm; Poor Prognosis Metastatic Gestational Trophoblastic Tumor; Previously Treated Myelodysplastic Syndromes; Primary Myelofibrosis; Prolymphocytic Leukemia; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Malignant Testicular Germ Cell Tumor; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Neuroblastoma; Recurrent Ovarian Epithelial Cancer; Recurrent Ovarian Germ Cell Tumor; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Splenic Marginal Zone Lymphoma; Stage II Ovarian Epithelial Cancer; Stage II Ovarian Germ Cell Tumor; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Hodgkin Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Malignant Testicular Germ Cell Tumor; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Ovarian Epithelial Cancer; Stage III Ovarian Germ Cell Tumor; Stage III Small Lymphocytic Lymphoma; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Hodgkin Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Breast Cancer; Stage IV Chronic Lymphocytic Leukemia; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Ovarian Epithelial Cancer; Stage IV Ovarian Germ Cell Tumor; Stage IV Small Lymphocytic Lymphoma

Safety and Efficacy of Pentostatin and Low Dose TBI With Allogenic Peripheral Blood Stem Cell Transplant

ClinicalTrials.gov

2018-01-22

Acute Myelogenous Leukemia; Acute Lymphocytic Leukemia; Chronic Myelogenous Leukemia; Chronic Lymphocytic Leukemia; Myelodysplastic Syndromes; Multiple Myeloma; Non-Hodgkins Lymphoma; Hodgkins Disease; Peripheral T-cell Lymphoma

Characterization of CD31 expression on murine and human neonatal T lymphocytes during development and activation

PubMed Central

Fike, Adam J.; Nguyen, Linda T.; Kumova, Ogan K.; Carey, Alison J.

2017-01-01

Background CD31, expressed by the majority of the neonatal T cell pool, is involved in modulation of T-cell Receptor signalling by increasing the threshold for T cell activation. Therefore, CD31 could modulate neonatal tolerance and adaptive immune responses. Methods Lymphocytes were harvested from murine neonates at different ages, human late preterm and term cord blood, and adult peripheral blood. Human samples were activated over a five-day period to simulate acute inflammation. Mice were infected with influenza; lungs and spleens were harvested at days 6 and 9 post-infection and analyzed by flow cytometry. Results CD31 expressing neonatal murine CD4+ and CD8a+ T cells increase over the first week of life. Upon in vitro stimulation, human infants’ CD4+ and CD8a+ T cells shed CD31 faster in comparison to adults. In the context of acute infection, mice infected at 3-days old have an increased number of naive and activated CD31+ T lymphocytes at the site of infection at day 6 and 9 post-infection, as compared to 7-days old; however, the opposite is true in the periphery. Conclusion Differences in trafficking of CD31+ Cytotoxic T Lymphocytes (CTLs) during acute influenza infection could modulate tolerance and contribute to a dampened adaptive immune response in neonates. PMID:28355204

[T-cell pediatric acute lymphoblastic leukemia: analysis of survival and prognostic factors in 4 consecutive protocols of the Spanish cooperative study group SHOP].

PubMed

Rives, Susana; Estella, Jesús; Camós, Mireia; García-Miguel, Purificación; Verdeguer, Amparo; Couselo, José Miguel; Tasso, María; Molina, Javier; Gómez, Pedro; Fernández-Delgado, Rafael; Navajas, Aurora; Badell, Isabel

2012-07-07

Acute lymphoblastic leukemia (ALL) is the most frequent cancer in childhood, with cure rates of 80-85%. In T-cell ALL (15% of ALL), prognostic factors are ill defined. We aimed to describe the event-free survival (EFS) and analyze clinical prognostic factors in a series of pediatric T-ALL of 4 consecutive clinical trials. Children with T-ALL aged 1-18 years treated in 37 institutions in Spain were enrolled in 4 consecutive trials from February-1989 to November-2009. A total of 218 T-ALL patients out of 1,652 pediatric ALL were evaluable during the study period (SHOP/ALL-89: 35, ALL-94: 63, ALL-99: 62, ALL-2005: 58). There were 164 boys (75%). Median age (years) was 7.8 range (1.3-18.6). Median leukocytes (10(9)/L) was 78.2, range 0.8-930. Fifteen (6.8%) children had central nervous system (CNS) involvement at diagnosis. Regarding response to induction treatment, 150 (75%) patients had less than 5% blasts on day-14 bone marrow and 199 achieved complete remission at the end of induction. Overall survival (OS) at 60 months for SHOP/ALL-89, ALL-94, ALL-99 was 48 (8), 49 (6), 70 (6) %, respectively, and at 48 months for SHOP/ALL-2005 (ongoing protocol) was 74 (8) %. Median follow-up (months) was 206, 152, 74 and 17 respectively. Analysis of prognostic factors revealed no statistical differences regarding sex or age. Leukocyte count over 200×10(9)/l (P=.024), CNS infiltration at diagnosis (P<.006) and treatment response had prognostic significance (end-induction complete remission) (P=.0000), day 14-bone marrow (P=.005). Results for the SHOP/ALL-89 and ALL-94 protocols were inferior to other contemporary protocols but there has been an improvement in survival in the 2 last trials. In line with other T-ALL series, response to treatment had the strongest prognostic impact. Copyright © 2011 Elsevier España, S.L. All rights reserved.

Plerixafor and Filgrastim For Mobilization of Donor Peripheral Blood Stem Cells Before A Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Hematologic Malignancies

ClinicalTrials.gov

2017-06-26

Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Atypical Chronic Myeloid Leukemia, BCR-ABL Negative; Blastic Phase Chronic Myelogenous Leukemia; Chronic Phase Chronic Myelogenous Leukemia; de Novo Myelodysplastic Syndromes; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Burkitt Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Noncontiguous Stage II Adult Lymphoblastic Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Refractory Multiple Myeloma; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Splenic Marginal Zone Lymphoma; Stage I Multiple Myeloma; Stage II Multiple Myeloma; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Hodgkin Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Multiple Myeloma; Stage III Small Lymphocytic Lymphoma; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Hodgkin Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Small Lymphocytic Lymphoma

UCB Transplant for Hematological Diseases Using a Non Myeloablative Prep

ClinicalTrials.gov

2017-12-03

Acute Leukemia; Acute Myeloid Leukemia; Acute Lymphoblastic Leukemia/Lymphoma; Burkitt's Lymphoma; Natural Killer Cell Malignancies; Chronic Myelogenous Leukemia; Myelodysplastic Syndrome; Large-cell Lymphoma; Hodgkin Lymphoma; Multiple Myeloma; Relapsed Chronic Lymphocytic Leukemia; Relapsed Small Lymphocytic Lymphoma; Marginal Zone B-cell Lymphoma; Follicular Lymphoma; Lymphoplasmacytic Lymphoma; Mantle-cell Lymphoma; Prolymphocytic Leukemia; Bone Marrow Failure Syndromes; Myeloproliferative Neoplasms/Myelofibrosis; Biphenotypic/Undifferentiated/Prolymphocytic Leukemias; MRD Positive Leukemia; Leukemia or MDS in Aplasia; Relapsed T-Cell Lymphoma; Relapsed Multiple Myeloma; Plasma Cell Leukemia

Deferasirox for Treating Patients Who Have Undergone Allogeneic Stem Cell Transplant and Have Iron Overload

ClinicalTrials.gov

2017-11-07

Iron Overload; Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Atypical Chronic Myeloid Leukemia, BCR-ABL Negative; Blastic Phase Chronic Myelogenous Leukemia; Chronic Eosinophilic Leukemia; Chronic Myelomonocytic Leukemia; Chronic Neutrophilic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; de Novo Myelodysplastic Syndromes; Disseminated Neuroblastoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Burkitt Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Noncontiguous Stage II Adult Lymphoblastic Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Poor Prognosis Metastatic Gestational Trophoblastic Tumor; Previously Treated Myelodysplastic Syndromes; Primary Myelofibrosis; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Malignant Testicular Germ Cell Tumor; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Neuroblastoma; Recurrent Ovarian Epithelial Cancer; Recurrent Ovarian Germ Cell Tumor; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Splenic Marginal Zone Lymphoma; Stage I Multiple Myeloma; Stage II Multiple Myeloma; Stage II Ovarian Epithelial Cancer; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Hodgkin Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Malignant Testicular Germ Cell Tumor; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Multiple Myeloma; Stage III Ovarian Epithelial Cancer; Stage III Small Lymphocytic Lymphoma; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Hodgkin Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Breast Cancer; Stage IV Chronic Lymphocytic Leukemia; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Ovarian Epithelial Cancer; Stage IV Small Lymphocytic Lymphoma

Molecular targeting in childhood malignancies using nanoparticles

NASA Astrophysics Data System (ADS)

Satake, Noriko; Barisone, Gustavo; Diaz, Elva; Nitin, Nitin; Nolta, Jan; Lam, Kit

2012-06-01

The goal of our project is to develop a new therapy for childhood malignancies using nanoformulated siRNA targeting Mxd3, a molecule in the Sonic Hedgehog signaling pathway, which we believe is important for cell survival. We plan to use cancer-specific ligands and superparamagnetic iron oxide nanoparticles (SPIO NPs) to carry siRNA. This delivery system will be tested in mouse xenograft models that we developed with primary cancer tissues. Our current focus is acute lymphoblastic leukemia (ALL), the most common cancer in children. We report our progress to date.

Specificity in the immunosuppression induced by avian reticuloendotheliosis virus.

PubMed Central

Walker, M H; Rup, B J; Rubin, A S; Bose, H R

1983-01-01

Several parameters of the cellular and humoral immune responses of chickens infected with reticuloendotheliosis virus (REV-T), an avian defective acute leukemia virus, or with its helper virus, reticuloendotheliosis-associated virus (REV-A), were evaluated. Spleen cells from chickens infected with REV-T (REV-A) or REV-A exhibited depressed mixed lymphocyte and mitogen responses in vitro. Allograft rejection was delayed by 6 to 14 days in birds infected with REV-A. The specific antitumor cell immune response was also studied by a 51Cr-release cytotoxicity assay. Lymphocytes from chickens infected with low numbers of the REV-T-transformed cells exhibited significant levels of cytolytic reactivity against the 51Cr-labeled REV-T tumor cells in vitro. The mitogen response of lymphocytes from these injected birds was similar to that of uninjected chickens. In contrast, lymphocytes from chickens injected with higher numbers of REV-T-transformed cells exhibited suppressed mitogen reactivity and failed to develop detectable levels of cytotoxic activity directed against the REV-T tumor cells. These results suggest that the general depression of cellular immune competence which occurs during REV-T (REV-A) infection could contribute to the development of this acute leukemia by inhibiting the proliferation of cytotoxic cells directed against the tumor cell antigens. The cytotoxic effect observed after the injection of chickens with non-immunosuppressive levels of REV-T-transformed cells appears to be specific for the REV-T tumor cell antigens since cells transformed by Marek's disease virus or avian erythroblastosis virus were not lysed. In marked contrast, birds whose cellular immune responses were suppressed by infection with REV-A were capable of producing a humoral immune response to viral antigens. Detectable levels of viral antibody, however, did not appear until 12 to 15 days after REV-A infection. Since REV-T (REV-A) induced an acute leukemia resulting in death within 7 to 14 days, it appears unlikely that the ability of chickens to make antiviral antibody influences the development of lethal reticuloendotheliosis. Images PMID:6187691

PD-1 is a marker for abnormal distribution of naïve/memory T cell subsets in HIV-1 infection

PubMed Central

Breton, Gaëlle; Chomont, Nicolas; Takata, Hiroshi; Fromentin, Rémi; Ahlers, Jeffrey; Filali-Mouhim, Abdelali; Riou, Catherine; Boulassel, Mohamed-Rachid; Routy, Jean-Pierre; Yassine-Diab, Bader; Sékaly, Rafick-Pierre

2013-01-01

Chronic activation of T cells is a hallmark of HIV-1 infection and plays an important role in disease progression. We previously showed that the engagement of the inhibitory receptor PD-1 on HIV-1 specific CD4+ and CD8+ T cells leads to their functional exhaustion in vitro. However, little is known about the impact of PD-1 expression on the turnover and maturation status of T cells during the course of the disease. Here, we show that PD-1 is up regulated on all T cell subsets including naïve, central memory and transitional memory T cells in HIV-1 infected subjects. PD-1 is expressed at similar levels on most CD4+ T cells during the acute and the chronic phase of disease and identifies cells that have recently entered the cell cycle. In contrast, PD-1 expression dramatically increased in CD8+ T cells during the transition from acute to chronic infection and this was associated with reduced levels of cell proliferation. The failure to down regulate expression of PD-1 in most T cells during chronic HIV-1 infection was associated to persistent alterations in the distribution of T cell subsets and was associated with impaired responses to IL-7. Our findings identify PD-1 as a marker for aberrant distribution of T cell subsets in HIV-1 infection. PMID:23918986

Haploidentical Allogeneic Transplant With Post-transplant Infusion of Regulatory T-cells

ClinicalTrials.gov

2018-06-01

Leukemia, Acute; Chronic Myelogenous Leukemia (CML); Myelodysplastic Syndrome (MDS); Non-Hodgkin Lymphoma (NHL); Chronic Lymphocytic Leukemia (CLL); Acute Myelogenous Leukemia (AML); Acute Lymphoblastic Leukemia (ALL)

CREBBP knockdown enhances RAS/RAF/MEK/ERK signaling in Ras pathway mutated acute lymphoblastic leukemia but does not modulate chemotherapeutic response.

PubMed

Dixon, Zach A; Nicholson, Lindsay; Zeppetzauer, Martin; Matheson, Elizabeth; Sinclair, Paul; Harrison, Christine J; Irving, Julie A E

2017-04-01

Relapsed acute lymphoblastic leukemia is the most common cause of cancer-related mortality in young people and new therapeutic strategies are needed to improve outcome. Recent studies have shown that heterozygous inactivating mutations in the histone acetyl transferase, CREBBP , are particularly frequent in relapsed childhood acute lymphoblastic leukemia and associated with a hyperdiploid karyotype and KRAS mutations. To study the functional impact of CREBBP haploinsufficiency in acute lymphoblastic leukemia, RNA interference was used to knock down expression of CREBBP in acute lymphoblastic leukemia cell lines and various primagraft acute lymphoblastic leukemia cells. We demonstrate that attenuation of CREBBP results in reduced acetylation of histone 3 lysine 18, but has no significant impact on cAMP-dependent target gene expression. Impaired induction of glucocorticoid receptor targets was only seen in 1 of 4 CREBBP knockdown models, and there was no significant difference in glucocorticoid-induced apoptosis, sensitivity to other acute lymphoblastic leukemia chemotherapeutics or histone deacetylase inhibitors. Importantly, we show that CREBBP directly acetylates KRAS and that CREBBP knockdown enhances signaling of the RAS/RAF/MEK/ERK pathway in Ras pathway mutated acute lymphoblastic leukemia cells, which are still sensitive to MEK inhibitors. Thus, CREBBP mutations might assist in enhancing oncogenic RAS signaling in acute lymphoblastic leukemia but do not alter response to MEK inhibitors. Copyright© Ferrata Storti Foundation.

Radiation-induced leukemia: Comparative studies in mouse and man. Annual performance report, June 1, 1991--October 31, 1991

DOE Office of Scientific and Technical Information (OSTI.GOV)

Haas, M.

1991-12-31

We now have a clear understanding of the mechanism by which radiation-induced (T-cell) leukemia occurs. In irradiated mice (radiation-induced thymic leukemia) and in man (acute lymphoblastic T-cell leukemia, T-ALL) the mechanism of leukemogenesis is surprisingly similar. Expressed in the most elementary terms, T-cell leukemia occurs when T-cell differentiation is inhibited by a mutation, and pre-T cells attempt but fail to differentiate in the thymus. Instead of leaving the thymus for the periphery as functional T-cells they continue to proliferate in the thymus. The proliferating pre- (pro-) T-cells constitute the (early) acute T-cell leukemia (A-TCL). This model for the mechanism ofmore » T-cell leukemogenesis accounts for all the properties of both murine and human A-TCL. Important support for the model has recently come from work by Ilan Kirsch and others, who have shown that mutations/deletions in the genes SCL (TAL), SIL, and LCK constitute primary events in the development of T-ALL, by inhibiting differentiation of thymic pre- (pro-) T-cells. This mechanism of T-cell leukemogenesis brings several specific questions into focus: How do early A-TCL cells progress to become potently tumorigenic and poorly treatable? Is it feasible to genetically suppress early and/or progressed A-TCL cells? What is the mechanism by which the differentiation-inhibited (leukemic) pre-T cells proliferate? During the first grant year we have worked on aspects of all three questions.« less

In utero and acute exposure to benzene: investigation of DNA double-strand breaks and DNA recombination in mice.

PubMed

Lau, Annette; Belanger, Christine Lea; Winn, Louise M

2009-05-31

Benzene, a ubiquitous pollutant, has been identified as a human leukemogen and early exposure to environmental carcinogens such as benzene has been linked to childhood leukemia. It is known that genotoxic agents can increase the frequency of DNA double-strand breaks (DSBs), which can initiate DNA recombinational repair mechanisms. In this study we investigated the induction of micronuclei, the formation of gamma-H2A.X as a marker of DNA DSBs, and the induction of somatic DNA recombination events in hematopoietic tissue from pKZ1 transgenic mice exposed acutely or in utero to benzene. Adult male C57Bl/6N mice were treated with a single i.p. injection of benzene, and timed-pregnant females pKZ1 were treated with daily i.p. injections of 200 mg/kg or 400 mg/kg benzene through gestational days 7-15. Acute exposure to 400 mg/kg benzene resulted in a statistically significant increase in the percentage of micronucleated cells in adult male bone marrow cells and in fetal liver and post-natal day 9 bone marrow cells of mice exposed in utero. Immunoblotting techniques did not detect benzene-induced increases in the formation of gamma-H2A.X in bone marrow cells of adult male mice and in maternal bone marrow, fetal liver, and post-natal bone marrow cells after specific time-point exposures. Finally, no recombination events were detected in adult pKZ1 mouse tissue; however, in post-natal day 9 pups in utero exposure to 400 mg/kg of benzene caused a trend towards increasing recombination frequency although this did not reach statistical significance. These results demonstrate that in utero exposure increases the frequency of micronuclei and DNA recombination events in hematopoietic tissue of fetal and post-natal mice and may be an initiating event in the etiology of childhood leukemias. Further investigations into different types of DNA damage and repair pathways are warranted to fully elucidate the role of genotoxic mechanisms in the etiology of benzene-induced childhood leukemias.

Palifermin in Preventing Chronic Graft-Versus-Host Disease in Patients Who Have Undergone Donor Stem Cell Transplant for Hematologic Cancer

ClinicalTrials.gov

2014-02-19

Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative; Blastic Phase Chronic Myelogenous Leukemia; Chronic Eosinophilic Leukemia; Chronic Myelomonocytic Leukemia; Chronic Neutrophilic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; de Novo Myelodysplastic Syndromes; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Graft Versus Host Disease; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Burkitt Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Noncontiguous Stage II Adult Lymphoblastic Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Previously Treated Myelodysplastic Syndromes; Primary Myelofibrosis; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Refractory Multiple Myeloma; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Splenic Marginal Zone Lymphoma; Stage I Multiple Myeloma; Stage II Multiple Myeloma; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Hodgkin Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Multiple Myeloma; Stage III Small Lymphocytic Lymphoma; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Hodgkin Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Small Lymphocytic Lymphoma

Textural characteristics of bone marrow blast nucleus images with different variants of acute lymphoblastic leukemia

NASA Astrophysics Data System (ADS)

Nikitaev, V. G.; Pronichev, A. N.; Polyakov, E. V.; Mozhenkova, A. V.; Tupitsin, N. N.; Frenkel, M. A.

2018-01-01

The paper describes the method of recognition of T - and B - variants of acute lymphoblastic leukemia in microscopic images of blood cells. The method is based on the use of texture characteristics of images. Experimental recognition accuracy evaluation is obtained from the sample of 38 patients (17 with T-ALL and 21 with B-ALL variants of acute lymphoblastic leukemia). The obtained results show the possibility of applying of the proposed approach to the differential diagnosis of T- and B- variants of acute lymphoblastic leukemia.

Phenotypic Characteristics of PD-1 and CTLA-4 Expression in Symptomatic Acute Hepatitis A.

PubMed

Cho, Hyosun; Kang, Hyojeung; Kim, Chang Wook; Kim, Hee Yeon; Jang, Jeong Won; Yoon, Seung Kew; Lee, Chang Don

2016-03-01

The immunoregulatory molecules programmed death 1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) are associated with the dysfunction of antiviral effector T-cells, which leads to T-cell exhaustion and persistent viral infection in patients with chronic hepatitis C and chronic hepatitis B. Little is known about the role of PD-1 and CTLA-4 in patients with symptomatic acute hepatitis A (AHA). Peripheral blood mononuclear cells were isolated from seven patients with AHA and from six patients with nonviral acute toxic hepatitis (ATH) during the symptomatic and convalescent phases of the respective diseases; five healthy subjects acted as controls. The expression of PD-1 and CTLA-4 on T-cells was measured by flow cytometry. PD-1 and CTLA-4 expression during the symptomatic phase was significantly higher in the T-cells of AHA patients than in those of ATH patients or healthy controls (PD-1 18.3% vs 3.7% vs 1.6%, respectively, p<0.05; CTLA-4 23.5% vs 6.1% vs 5.9%, respectively, p<0.05). The levels of both molecules decreased dramatically during the convalescent phase of AHA, whereas a similar pattern was not seen in ATH. Our findings are consistent with a viral-protective effect of PD-1 and CTLA-4 as inhibitory molecules that suppress cytotoxic T-cells and thereby prevent the destruction of virus-infected hepatocytes in AHA.

Peripheral Frequency of CD4+ CD28− Cells in Acute Ischemic Stroke

PubMed Central

Tuttolomondo, Antonino; Pecoraro, Rosaria; Casuccio, Alessandra; Di Raimondo, Domenico; Buttà, Carmelo; Clemente, Giuseppe; Corte, Vittoriano della; Guggino, Giuliana; Arnao, Valentina; Maida, Carlo; Simonetta, Irene; Maugeri, Rosario; Squatrito, Rosario; Pinto, Antonio

2015-01-01

Abstract CD4+ CD28− T cells also called CD28 null cells have been reported as increased in the clinical setting of acute coronary syndrome. Only 2 studies previously analyzed peripheral frequency of CD28 null cells in subjects with acute ischemic stroke but, to our knowledge, peripheral frequency of CD28 null cells in each TOAST subtype of ischemic stroke has never been evaluated. We hypothesized that CD4+ cells and, in particular, the CD28 null cell subset could show a different degree of peripheral percentage in subjects with acute ischemic stroke in relation to clinical subtype and severity of ischemic stroke. The aim of our study was to analyze peripheral frequency of CD28 null cells in subjects with acute ischemic stroke in relation to TOAST diagnostic subtype, and to evaluate their relationship with scores of clinical severity of acute ischemic stroke, and their predictive role in the diagnosis of acute ischemic stroke and diagnostic subtype We enrolled 98 consecutive subjects admitted to our recruitment wards with a diagnosis of ischemic stroke. As controls we enrolled 66 hospitalized patients without a diagnosis of acute ischemic stroke. Peripheral frequency of CD4+ and CD28 null cells has been evaluated with a FACS Calibur flow cytometer. Subjects with acute ischemic stroke had a significantly higher peripheral frequency of CD4+ cells and CD28 null cells compared to control subjects without acute ischemic stroke. Subjects with cardioembolic stroke had a significantly higher peripheral frequency of CD4+ cells and CD28 null cells compared to subjects with other TOAST subtypes. We observed a significant relationship between CD28 null cells peripheral percentage and Scandinavian Stroke Scale and NIHSS scores. ROC curve analysis showed that CD28 null cell percentage may be useful to differentiate between stroke subtypes. These findings seem suggest a possible role for a T-cell component also in acute ischemic stroke clinical setting showing a different peripheral frequency of CD28 null cells in relation of each TOAST subtype of stroke. PMID:25997053

Stages of Childhood Non-Hodgkin Lymphoma

MedlinePlus

... Common Cancer Types Recurrent Cancer Common Cancer Types Bladder Cancer Breast Cancer Colorectal Cancer Kidney (Renal Cell) Cancer ... Patients with anaplastic large cell lymphoma have a receptor , called CD30, on the surface of their T ...

Burn-injury affects gut-associated lymphoid tissues derived CD4+ T cells.

PubMed

Fazal, Nadeem; Shelip, Alla; Alzahrani, Alhusain J

2013-01-01

After scald burn-injury, the intestinal immune system responds to maintain immune balance. In this regard CD4+T cells in Gut-Associated Lymphoid Tissues (GALT), like mesenteric lymph nodes (MLN) and Peyer's patches (PP) respond to avoid immune suppression following major injury such as burn. Therefore, we hypothesized that the gut CD4+T cells become dysfunctional and turn the immune homeostasis towards depression of CD4+ T cell-mediated adaptive immune responses. In the current study we show down regulation of mucosal CD4+ T cell proliferation, IL-2 production and cell surface marker expression of mucosal CD4+ T cells moving towards suppressive-type. Acute burn-injury lead to up-regulation of regulatory marker (CD25+), down regulation of adhesion (CD62L, CD11a) and homing receptor (CD49d) expression, and up-regulation of negative co-stimulatory (CTLA-4) molecule. Moreover, CD4+CD25+ T cells of intestinal origin showed resistance to spontaneous as well as induced apoptosis that may contribute to suppression of effector CD4+ T cells. Furthermore, gut CD4+CD25+ T cells obtained from burn-injured animals were able to down-regulate naïve CD4+ T cell proliferation following adoptive transfer of burn-injured CD4+CD25+ T cells into sham control animals, without any significant effect on cell surface activation markers. Together, these data demonstrate that the intestinal CD4+ T cells evolve a strategy to promote suppressive CD4+ T cell effector responses, as evidenced by enhanced CD4+CD25+ T cells, up-regulated CTLA-4 expression, reduced IL-2 production, tendency towards diminished apoptosis of suppressive CD4+ T cells, and thus lose their natural ability to regulate immune homeostasis following acute burn-injury and prevent immune paralysis.

Leukemia diagnosis and testing of complement-fixing antibodies for bone marrow purging in acute lymphoid leukemia.

PubMed

Campana, D; Janossy, G

1986-12-01

In this paper a microplate method is described for diagnosing acute leukemia and for investigating the reactivity of monoclonal antibodies (MoAbs) against membrane antigens in combination with rabbit or murine antibodies to nuclear terminal transferase (TdT). The speed of this method facilitates the investigation of fresh leukemic cells from individual patients and assesses the cytolytic efficacy of the relevant MoAbs in the presence of complement (C'). Lymphoblasts (TdT+) are mixed in equal proportions with known numbers of "inert" cells, eg, RBC or nonleukemic bone marrow (BM). Following incubation with MoAbs and C' the ratio of residual TdT+ cells and inert cells is determined on cytospin preparations. Initially, percentages of TdT+ cells are counted in a unit volume of 5,000 inert cells, followed by the scanning of greater than 2 X 10(4) inert cells on entire slides. With this method more than 4 log cytoreduction of TdT + cells is detected. The method is also applicable for studying the cytolysis of malignant B cells by using mostly monoclonal lg expression rather than TdT for the identification of residual B cells. Ten representative patients selected from a group of greater than 100 are reported. In some cases cytoreduction of greater than 4 log with no identifiable residual TdT + cells is achieved by a single C'-fixing MoAb: anti-CD10 (RFAL3) in common acute lymphoid leukemia (ALL) and anti-CD7 (RFT2) in T cell ALL (T-ALL). Other cases require cocktails of anti-CD10, anti-CD19, and anti-CD24 in common ALL or anti-CD7 and anti-CD8 in T-ALL. In T-ALL a few TdT + cells remain that exhibit the features of normal TdT + BM cells (CD7-, HLA-DR+). This is particularly noticeable when patients are studied in partial remission or if nonleukemic BM is used as a source of inert cells. The methods described here contribute to establishing a range of MoAbs (ie, of IgM class) and techniques for efficient purging and to comparing the efficacy of "clean-up," in remission, of common ALL, T-ALL, and B cell malignancies.

Multi-Agent Simulations of the Immune Response to Hiv during the Acute Stage of Infection

NASA Astrophysics Data System (ADS)

Walshe, R.; Ruskin, H. J.; Callaghan, A.

Results of multi-agent based simulations of the immune response to HIV during the acute phase of infection are presented here. The model successfully recreates the viral dynamics associated with the acute phase of infection, i.e., a rapid rise in viral load followed by a sharp decline to what is often referred to as a "set point", a result of T-cell response and emergence of HIV neutralizing antibodies. The results indicate that sufficient T Killer cell response is the key factor in controlling viral growth during this phase with antibody levels of critical importance only in the absence of a sufficient T Killer response.

T Cell Depletion for Recipients of HLA Haploidentical Related Donor Stem Cell Grafts

ClinicalTrials.gov

2017-08-29

Acute Lymphoblastic Leukemia; Non Hodgkins Lymphoma; Myelodysplastic Syndrome; Acute Myeloid Leukemia; Chronic Myelogenous Leukemia; Hemophagocytic Lymphohistiocytosis (HLH); Familial Hemophagocytic Lymphohistiocytosis (FLH); Viral-associated Hemophagocytic Syndrome (VAHS); X-linked Lymphoproliferative Disease (XLP)

MicroRNA Expression Patterns of CD8+ T Cells in Acute and Chronic Brucellosis

PubMed Central

Budak, Ferah; Bal, S. Haldun; Tezcan, Gulcin; Guvenc, Furkan; Akalin, E. Halis; Goral, Guher; Deniz, Gunnur

2016-01-01

Although our knowledge about Brucella virulence factors and the host response increase rapidly, the mechanisms of immune evasion by the pathogen and causes of chronic disease are still unknown. Here, we aimed to investigate the immunological factors which belong to CD8+ T cells and their roles in the transition of brucellosis from acute to chronic infection. Using miRNA microarray, more than 2000 miRNAs were screened in CD8+ T cells of patients with acute or chronic brucellosis and healthy controls that were sorted from peripheral blood with flow cytometry and validated through qRT-PCR. Findings were evaluated using GeneSpring GX (Agilent) 13.0 software and KEGG pathway analysis. Expression of two miRNAs were determined to display a significant fold change in chronic group when compared with acute or control groups. Both miRNAs (miR-126-5p and miR-4753-3p) were decreased (p <0.05 or fold change > 2). These miRNAs have the potential to be the regulators of CD8+ T cell-related marker genes for chronic brucellosis infections. The differentially expressed miRNAs and their predicted target genes are involved in MAPK signaling pathway, cytokine-cytokine receptor interactions, endocytosis, regulation of actin cytoskeleton, and focal adhesion indicating their potential roles in chronic brucellosis and its progression. It is the first study of miRNA expression analysis of human CD8+ T cells to clarify the mechanism of inveteracy in brucellosis. PMID:27824867

Partial regulatory T cell depletion prior to acute feline immunodeficiency virus infection does not alter disease pathogenesis.

PubMed

Mikkelsen, S Rochelle; Long, Julie M; Zhang, Lin; Galemore, Erin R; VandeWoude, Sue; Dean, Gregg A

2011-02-25

Feline immunodeficiency virus (FIV) infection in cats follows a disease course similar to HIV-1, including a short acute phase characterized by high viremia, and a prolonged asymptomatic phase characterized by low viremia and generalized immune dysfunction. CD4(+)CD25(hi)FoxP3(+) immunosuppressive regulatory T (Treg) cells have been implicated as a possible cause of immune dysfunction during FIV and HIV-1 infection, as they are capable of modulating virus-specific and inflammatory immune responses. Additionally, the immunosuppressive capacity of feline Treg cells has been shown to be increased during FIV infection. We have previously shown that transient in vivo Treg cell depletion during asymptomatic FIV infection reveals FIV-specific immune responses suppressed by Treg cells. In this study, we sought to determine the immunological influence of Treg cells during acute FIV infection. We asked whether Treg cell depletion prior to infection with the highly pathogenic molecular clone FIV-C36 in cats could alter FIV pathogenesis. We report here that partial Treg cell depletion prior to FIV infection does not significantly change provirus, viremia, or CD4(+) T cell levels in blood and lymphoid tissues during the acute phase of disease. The effects of anti-CD25 mAb treatment are truncated in cats acutely infected with FIV-C36 as compared to chronically infected cats or FIV-naïve cats, as Treg cell levels were heightened in all treatment groups included in the study within two weeks post-FIV infection. Our findings suggest that the influence of Treg cell suppression during FIV pathogenesis is most prominent after Treg cells are activated in the environment of established FIV infection.

The anti-caspase inhibitor Q-VD-OPH prevents AIDS disease progression in SIV-infected rhesus macaques.

PubMed

Laforge, Mireille; Silvestre, Ricardo; Rodrigues, Vasco; Garibal, Julie; Campillo-Gimenez, Laure; Mouhamad, Shahul; Monceaux, Valérie; Cumont, Marie-Christine; Rabezanahary, Henintsoa; Pruvost, Alain; Cordeiro-da-Silva, Anabela; Hurtrel, Bruno; Silvestri, Guido; Senik, Anna; Estaquier, Jérôme

2018-04-02

Apoptosis has been proposed as a key mechanism responsible for CD4+ T cell depletion and immune dysfunction during HIV infection. We demonstrated that Q-VD-OPH, a caspase inhibitor, inhibits spontaneous and activation-induced death of T cells from SIV-infected rhesus macaques (RMs). When administered during the acute phase of infection, Q-VD-OPH was associated with (a) reduced levels of T cell death, (b) preservation of CD4+/CD8+ T cell ratio in lymphoid organs and in the gut, (c) maintenance of memory CD4+ T cells, and (d) increased specific CD4+ T cell response associated with the expression of cytotoxic molecules. Although therapy was limited to the acute phase of infection, Q-VD-OPH-treated RMs showed lower levels of both viral load and cell-associated SIV DNA as compared with control SIV-infected RMs throughout the chronic phase of infection, and prevented the development of AIDS. Overall, our data demonstrate that Q-VD-OPH injection in SIV-infected RMs may represent an adjunctive therapeutic agent to control HIV infection and delaying disease progression to AIDS.

Co-infusion of haplo-identical CD19-chimeric antigen receptor T cells and stem cells achieved full donor engraftment in refractory acute lymphoblastic leukemia.

PubMed

Cai, Bo; Guo, Mei; Wang, Yao; Zhang, Yajing; Yang, Jun; Guo, Yelei; Dai, Hanren; Yu, Changlin; Sun, Qiyun; Qiao, Jianhui; Hu, Kaixun; Zuo, Hongli; Dong, Zheng; Zhang, Zechuan; Feng, Mingxing; Li, Bingxia; Sun, Yujing; Liu, Tieqiang; Liu, Zhiqing; Wang, Yi; Huang, Yajing; Yao, Bo; Han, Weidong; Ai, Huisheng

2016-11-25

Elderly patients with relapsed and refractory acute lymphoblastic leukemia (ALL) have poor prognosis. Autologous CD19 chimeric antigen receptor-modified T (CAR-T) cells have potentials to cure patients with B cell ALL; however, safety and efficacy of allogeneic CD19 CAR-T cells are still undetermined. We treated a 71-year-old female with relapsed and refractory ALL who received co-infusion of haplo-identical donor-derived CD19-directed CAR-T cells and mobilized peripheral blood stem cells (PBSC) following induction chemotherapy. Undetectable minimal residual disease by flow cytometry was achieved, and full donor cell engraftment was established. The transient release of cytokines and mild fever were detected. Significantly elevated serum lactate dehydrogenase, alanine transaminase, bilirubin and glutamic-oxalacetic transaminase were observed from days 14 to 18, all of which were reversible after immunosuppressive therapy. Our preliminary results suggest that co-infusion of haplo-identical donor-derived CAR-T cells and mobilized PBSCs may induce full donor engraftment in relapsed and refractory ALL including elderly patients, but complications related to donor cell infusions should still be cautioned. Allogeneic CART-19 for Elderly Relapsed/Refractory CD19+ ALL. NCT02799550.

A novel 2,6-diisopropylphenyl-docosahexaenoamide conjugate induces apoptosis in T cell acute lymphoblastic leukemia cell lines

DOE Office of Scientific and Technical Information (OSTI.GOV)

Altenburg, Jeffrey D.; Harvey, Kevin A.; McCray, Sharon

2011-07-29

Highlights: {yields} 2,6-Diisopropylphenyl-docosahexaenoamide conjugates (DIP-DHA) inhibits the proliferation of T-cell leukemic cell lines. {yields} DIP-DHA resulted in increased activation of caspase-3, and caspase-7. {yields} DIP-DHA significantly downregulated CXCR4 surface expression. -- Abstract: We have previously characterized the effects of 2,6-diisopropylphenyl-docosahexaenoamide (DIP-DHA) conjugates and their analogs on the proliferation and progression of breast cancer cell lines. For this study, we investigated the effects of the DIP-DHA conjugate on 2 representative T cell acute lymphoblastic leukemia (T-ALL) cell lines: CEM and Jurkat. Treatment of both cell lines with DIP-DHA resulted in significantly greater inhibition of proliferation and induction of apoptosis than thatmore » of parent compounds, 2,6-diisopropylphenol (DIP) or docosahexaenoate (DHA). Treatment of the cells with DIP-DHA resulted in increased activation of caspase-3, and caspase-7. Furthermore, induction of apoptosis in both cell lines was reversed in the presence of a caspase family inhibitor. Treatment with DIP-DHA reduced mitochondrial membrane potential. These observations suggest that the effects are driven by intrinsic apoptotic pathways. DIP-DHA treatment also downregulated surface CXCR4 expression, an important chemokine receptor involved in cancer metastasis that is highly expressed in both CEM and Jurkat cells. In conclusion, our data suggest that the DIP-DHA conjugate exhibits significantly more potent effects on CEM and Jurkat cells than that of DIP or DHA alone. These conjugates have potential use for treatment of patients with T cell acute lymphoblastic leukemia.« less

Stem cell mobilization with G-CSF analogs: a rational approach to separate GVHD and GVL?

PubMed

Morris, Edward S; MacDonald, Kelli P A; Hill, Geoffrey R

2006-05-01

The separation of graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) remains the "holy grail" of allogeneic stem cell transplantation, and improvements are urgently needed to allow more effective therapy of malignant disease. The use of G-CSF-mobilized peripheral blood as a clinical stem cell source is associated with enhanced GVL effects without amplification of significant acute GVHD. Preclinical studies have demonstrated that G-CSF modulates donor T cell function before transplantation, promoting T(H)2 differentiation and regulatory T cell function. In addition, the expansion of immature antigen-presenting cells (APCs) and plasmacytoid dendritic cells (DCs) favors the maintenance of this pattern of T cell differentiation after transplantation. Although these patterns of T cell differentiation attenuate acute GVHD, they do not have an impact on the cytolytic pathways of the CD8(+) T cells that are critical for effective GVL. Recently, it has been demonstrated that modification of G-CSF, either by pegylation of the native cytokine or conjugation to Flt-3L, results in the expansion and activation of donor iNKT cells, which significantly augment CD8(+) T cell-mediated cytotoxicity and GVL effects after transplantation. Given that these cytokines also enhance the expansion of regulatory T cells and APCs, they further separate GVHD and GVL, offering potential clinical advantages for the transplant recipient.

Blimp-1 represses CD8 T cell expression of PD-1 using a feed-forward transcriptional circuit during acute viral infection

PubMed Central

Lu, Peiyuan; Youngblood, Benjamin A.; Austin, James W.; Rasheed Mohammed, Ata Ur; Butler, Royce; Ahmed, Rafi

2014-01-01

Programmed cell death 1 (PD-1) is an inhibitory immune receptor that regulates T cell function, yet the molecular events that control its expression are largely unknown. We show here that B lymphocyte–induced maturation protein 1 (Blimp-1)–deficient CD8 T cells fail to repress PD-1 during the early stages of CD8 T cell differentiation after acute infection with lymphocytic choriomeningitis virus (LCMV) strain Armstrong. Blimp-1 represses PD-1 through a feed-forward repressive circuit by regulating PD-1 directly and by repressing NFATc1 expression, an activator of PD-1 expression. Blimp-1 binding induces a repressive chromatin structure at the PD-1 locus, leading to the eviction of NFATc1 from its site. These data place Blimp-1 at an important phase of the CD8 T cell effector response and provide a molecular mechanism for its repression of PD-1. PMID:24590765

Application of FTIR microspectroscopy for the follow-up of childhood leukemia chemotherapy

NASA Astrophysics Data System (ADS)

Mordechai, Shaul; Mordehai, J.; Ramesh, Jagannathan; Levi, C.; Huleihal, Mahmud; Erukhimovitch, Vitaly; Moser, A.; Kapelushnik, J.

2001-11-01

Acute Lymphoblastic Leukemia (ALL) accounts for majority of the childhood leukemia. Outcome of children with ALL treatment has improved dramatically. Sensitive techniques are available today for detection of minimal residual disease in children with ALL, which provide insight into the effective cytotoxic treatment. Here, we present a case study, where lymphocytes isolated from two children before and after the treatment were characterized using microscopic Fourier Transform Infrared spectroscopy. Significant changes in the absorbance and spectral pattern in the wavenumber region between 800-1800 cm-1 were found after the treatment. Preliminary analysis of the spectra revealed that the protein content decreased in the T-lymphoma patient before the treatment in comparison to the age matched controls. The chemotherapy treatment resulted in decreased nucleic acids, total carbohydrates and cholesterol contents to a remarkable extent in both B and T lymphoma patients.

Optimized depletion of chimeric antigen receptor T cells in murine xenograft models of human acute myeloid leukemia

PubMed Central

Kenderian, Saad S.; Shen, Feng; Ruella, Marco; Shestova, Olga; Kozlowski, Miroslaw; Li, Yong; Schrank-Hacker, April; Morrissette, Jennifer J. D.; Carroll, Martin; June, Carl H.; Grupp, Stephan A.; Gill, Saar

2017-01-01

We and others previously reported potent antileukemia efficacy of CD123-redirected chimeric antigen receptor (CAR) T cells in preclinical human acute myeloid leukemia (AML) models at the cost of severe hematologic toxicity. This observation raises concern for potential myeloablation in patients with AML treated with CD123-redirected CAR T cells and mandates novel approaches for toxicity mitigation. We hypothesized that CAR T-cell depletion with optimal timing after AML eradication would preserve leukemia remission and allow subsequent hematopoietic stem cell transplantation. To test this hypothesis, we compared 3 CAR T-cell termination strategies: (1) transiently active anti-CD123 messenger RNA–electroporated CART (RNA-CART123); (2) T-cell ablation with alemtuzumab after treatment with lentivirally transduced anti–CD123-4-1BB-CD3ζ T cells (CART123); and (3) T-cell ablation with rituximab after treatment with CD20-coexpressing CART123 (CART123-CD20). All approaches led to rapid leukemia elimination in murine xenograft models of human AML. Subsequent antibody-mediated depletion of CART123 or CART123-CD20 did not impair leukemia remission. Time-course studies demonstrated that durable leukemia remission required CAR T-cell persistence for 4 weeks prior to ablation. Upon CAR T-cell termination, we further demonstrated successful hematopoietic engraftment with a normal human donor to model allogeneic stem cell rescue. Results from these studies will facilitate development of T-cell depletion strategies to augment the feasibility of CAR T-cell therapy for patients with AML. PMID:28246194

Clinical value of pre-transplant minimal residual disease in childhood lymphoblastic leukaemia: the results of the French minimal residual disease-guided protocol.

PubMed

Gandemer, Virginie; Pochon, Cécile; Oger, Emmanuel; Dalle, Jean-Hugues H; Michel, Gérard; Schmitt, Claudine; de Berranger, Eva; Galambrun, Claire; Cavé, Hélène; Cayuela, Jean-Michel; Grardel, Nathalie; Macintyre, Elizabeth; Margueritte, Geneviève; Méchinaud, Françoise; Rorhlich, Pierre; Lutz, Patrick; Demeocq, François; Schneider, Pascale; Plantaz, Dominique; Poirée, Marilyne; Bordigoni, Pierre

2014-05-01

Minimal residual disease (MRD) is a major predictive factor of the cure rate of acute lymphoblastic leukaemia (ALL). Haematopoietic cell transplantation is a treatment option for patients at high risk of relapse. Between 2005 and 2008, we conducted a prospective study evaluating the feasibility and efficacy of the reduction of immunosuppressive medication shortly after a non-ex vivo T depleted myeloablative transplantation. Immunoglobulin (Ig)H/T-cell receptor MRD 30 d before transplant could be obtained in 122 of the 133 cases of high-risk paediatric ALL enrolled. There were no significant demographic differences except remission status (first or second complete remission) between the 95 children with MRD <10(-3) and the 27 with MRD ≥10(-3) . Multivariate analysis identified sex match and MRD as being significantly associated with 5-year survival. MRD ≥10(-3) compromised the 5-year cumulative incidence of relapse (43·6 vs. 16·7%). Complete remission status and stem cell source did not modify the relationship between MRD and prognosis. Thus, pre-transplant MRD is still a major predictor of outcome for ALL. The MRD-guided strategy resulted in survival for 72·3% of patients with MRD<10(-3) and 40·4% of those with MRD ≥10(-3). © 2014 John Wiley & Sons Ltd.

Ethnic differences in the frequency of subtypes of childhood acute lymphoblastic leukemia: results of the Malaysia-Singapore Leukemia Study Group.

PubMed

Ariffin, Hany; Chen, Siew-Peng; Kwok, Cecilia S; Quah, Thuan-Chong; Lin, Hai-Peng; Yeoh, Allen E J

2007-01-01

Childhood acute lymphoblastic leukemia (ALL) is clinically heterogeneous with prognostically and biologically distinct subtypes. Although racial differences in frequency of different types of childhood ALL have been reported, many are confounded by selected or limited population samples. The Malaysia-Singapore (MA-SPORE) Leukemia Study Group provided a unique platform for the study of the frequency of major subgroups of childhood ALL in a large cohort of unselected multiethnic Asian children. Screening for the prognostically important chromosome abnormalities (TEL-AML1, BCR-ABL, E2A-PBX1, and MLL) using multiplex reverse-transcription polymerase chain reaction was performed on 299 consecutive patients with ALL at 3 study centers (236 de novo, 63 at relapse), with the ethnic composition predominantly Chinese (51.8%) and Malay (34.8%). Reverse-transcription polymerase chain reaction was successful in 278 (93%) of cases screened. The commonest fusion transcript was TEL-AML1 (19.1%) followed by BCR-ABL (7.8%), MLL rearrangements (4.2%), and E2A-PBX1 (3.1%). Chinese have a significantly lower frequency of TEL-AML1 (13.3% in de novo patients) compared with Malays (22.2%) and Indians (21.7%) (P=0.04). Malays have a lower frequency of T-ALL (6.2%) compared with the Chinese and Indians (9.8%). Both Malays (7.4%) and Chinese (5.0%) have significantly higher frequency of BCR-ABL compared with the Indian population (P<0.05) despite a similar median age at presentation. Our study suggests that there are indeed significant and important racial differences in the frequency of subtypes of childhood ALL. Comprehensive subgrouping of childhood ALL may reveal interesting population frequency differences of the various subtypes, their risk factors and hopefully, its etiology.

Is there a stronger graft-versus-leukemia effect using HLA-haploidentical donors compared with HLA-identical siblings?

PubMed

Ringdén, O; Labopin, M; Ciceri, F; Velardi, A; Bacigalupo, A; Arcese, W; Ghavamzadeh, A; Hamladji, R M; Schmid, C; Nagler, A; Mohty, M

2016-02-01

Haploidentical hematopoietic stem cell transplants (HSCTs) are increasingly used, but it is unknown whether they have a stronger graft-versus-leukemia (GVL) effect. We analyzed 10 679 acute leukemia patients who underwent HSCT from an HLA-matched sibling donor (MSD, n=9815) or a haploidentical donor (⩾2 HLA-antigen disparity, n=864) between 2007 and 2012, reported to the European Group for Blood and Marrow Transplantation. In a Cox regression model, acute and chronic graft-versus-host disease (GVHD) was added as time-dependent variables. There was no difference in probability of relapse between recipients of haploidentical and MSD grafts. Factors of importance for relapse after T-cell-replete grafts included remission status at HSCT, Karnofsky score ⩽80, acute GVHD of grade II or higher and chronic GVHD (P<10(-5)). Patients with post-transplant cyclophosphamide (n=194) had similar outcome as other T-cell-replete haploidentical transplants (n=369). Non-relapse mortality was significantly higher in the haploidentical group compared with that in MSD patients (P<10(-5)). Leukemia-free survival was superior in the MSD patients receiving T-cell-replete (P<10(-5)) or T-cell-depleted grafts (P=0.0006). The risk of relapse was the same in acute leukemia patients who received haploidentical donor grafts as in those given MSD transplants, suggesting a similar GVL effect.

Oral or parenteral administration of curcumin does not prevent the growth of high-risk t(4;11) acute lymphoblastic leukemia cells engrafted into a NOD/SCID mouse model

USDA-ARS?s Scientific Manuscript database

The efficacy of orally and parenterally administered curcumin was evaluated in NOD.CB17-Prkdcscid/J mice engrafted with the human t(4;11) acute lymphoblastic leukemia line SEM. SEM cells were injected into the tail vein and engraftment was monitored by flow cytometry. Once engraftment was observed...

CAR-T cells targeting CLL-1 as an approach to treat acute myeloid leukemia.

PubMed

Wang, Jinghua; Chen, Siyu; Xiao, Wei; Li, Wende; Wang, Liang; Yang, Shuo; Wang, Weida; Xu, Liping; Liao, Shuangye; Liu, Wenjian; Wang, Yang; Liu, Nawei; Zhang, Jianeng; Xia, Xiaojun; Kang, Tiebang; Chen, Gong; Cai, Xiuyu; Yang, Han; Zhang, Xing; Lu, Yue; Zhou, Penghui

2018-01-10

Acute myeloid leukemia (AML) is one of the most common types of adult acute leukemia. Standard chemotherapies can induce complete remission in selected patients; however, a majority of patients eventually relapse and succumb to the disease. Thus, the development of novel therapeutics for AML is urgently needed. Human C-type lectin-like molecule-1 (CLL-1) is a type II transmembrane glycoprotein, and its expression is restricted to myeloid cells and the majority of AML blasts. Moreover, CLL-1 is expressed in leukemia stem cells (LSCs), but absent in hematopoietic stem cells (HSCs), which may provide a potential therapeutic target for AML treatment. We tested the expression of CLL-1 antigen on peripheral blood cells and bone marrow cells in healthy donor and AML patients. Then, we developed a chimeric antigen receptor (CAR) containing a CLL1-specific single-chain variable fragment, in combination with CD28, 4-1BB costimulatory domains, and CD3-ζ signaling domain. We further investigate the function of CLL-1 CAR-T cells. The CLL-1 CAR-T cells specifically lysed CLL-1 + cell lines as well as primary AML patient samples in vitro. Strong anti-leukemic activity was observed in vivo by using a xenograft model of disseminated AML. Importantly, CLL-1 + myeloid progenitor cells and mature myeloid cells were specifically eliminated by CLL-1 CAR-T cells, while normal HSCs were not targeted due to the lack of CLL-1 expression. CLL-1 CAR-T represents a promising immunotherapy for the treatment of AML.

AML Therapy With Irradiated Allogeneic Cells

ClinicalTrials.gov

2017-02-01

Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Recurrent Adult Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

Tetherin/BST-2 promotes dendritic cell activation and function during acute retrovirus infection.

PubMed

Li, Sam X; Barrett, Bradley S; Guo, Kejun; Kassiotis, George; Hasenkrug, Kim J; Dittmer, Ulf; Gibbert, Kathrin; Santiago, Mario L

2016-02-05

Tetherin/BST-2 is a host restriction factor that inhibits retrovirus release from infected cells in vitro by tethering nascent virions to the plasma membrane. However, contradictory data exists on whether Tetherin inhibits acute retrovirus infection in vivo. Previously, we reported that Tetherin-mediated inhibition of Friend retrovirus (FV) replication at 2 weeks post-infection correlated with stronger natural killer, CD4+ T and CD8+ T cell responses. Here, we further investigated the role of Tetherin in counteracting retrovirus replication in vivo. FV infection levels were similar between wild-type (WT) and Tetherin KO mice at 3 to 7 days post-infection despite removal of a potent restriction factor, Apobec3/Rfv3. However, during this phase of acute infection, Tetherin enhanced myeloid dendritic cell (DC) function. DCs from infected, but not uninfected, WT mice expressed significantly higher MHC class II and the co-stimulatory molecule CD80 compared to Tetherin KO DCs. Tetherin-associated DC activation during acute FV infection correlated with stronger NK cell responses. Furthermore, Tetherin+ DCs from FV-infected mice more strongly stimulated FV-specific CD4+ T cells ex vivo compared to Tetherin KO DCs. The results link the antiretroviral and immunomodulatory activity of Tetherin in vivo to improved DC activation and MHC class II antigen presentation.

Tetherin/BST-2 promotes dendritic cell activation and function during acute retrovirus infection

PubMed Central

Li, Sam X.; Barrett, Bradley S.; Guo, Kejun; Kassiotis, George; Hasenkrug, Kim J.; Dittmer, Ulf; Gibbert, Kathrin; Santiago, Mario L.

2016-01-01

Tetherin/BST-2 is a host restriction factor that inhibits retrovirus release from infected cells in vitro by tethering nascent virions to the plasma membrane. However, contradictory data exists on whether Tetherin inhibits acute retrovirus infection in vivo. Previously, we reported that Tetherin-mediated inhibition of Friend retrovirus (FV) replication at 2 weeks post-infection correlated with stronger natural killer, CD4+ T and CD8+ T cell responses. Here, we further investigated the role of Tetherin in counteracting retrovirus replication in vivo. FV infection levels were similar between wild-type (WT) and Tetherin KO mice at 3 to 7 days post-infection despite removal of a potent restriction factor, Apobec3/Rfv3. However, during this phase of acute infection, Tetherin enhanced myeloid dendritic cell (DC) function. DCs from infected, but not uninfected, WT mice expressed significantly higher MHC class II and the co-stimulatory molecule CD80 compared to Tetherin KO DCs. Tetherin-associated DC activation during acute FV infection correlated with stronger NK cell responses. Furthermore, Tetherin+ DCs from FV-infected mice more strongly stimulated FV-specific CD4+ T cells ex vivo compared to Tetherin KO DCs. The results link the antiretroviral and immunomodulatory activity of Tetherin in vivo to improved DC activation and MHC class II antigen presentation. PMID:26846717

Adult T-cell leukaemia/lymphoma can mimic other lymphomas in a non-endemic area: dilemmas in diagnosis and treatment.

PubMed

Huang, C-T; Lee, Y-H; Chow, K-C; Yang, C-F; Chen, P C-H; Hsiao, L-T; Gau, J-P; Tzeng, C-H; Liu, C-Y; Chiou, T-J

2014-04-01

The diagnosis of Adult T-cell leukaemia/lymphoma (ATL) in non-endemic regions is challenging. This study analyses the clinicopathologic features and diagnostic processes of ATL patients in Taiwan. ATL patients diagnosed and treated at Taipei Veterans General Hospital from 1998 through 2010 were retrospectively identified. The diagnosis of ATL was confirmed by in situ detection of human T-cell leukaemia virus type 1 (HTLV-1) when necessary. Patients' data were reviewed and analysed. Fourteen ATL patients were identified, among whom six (42.9%) had an antecedent diagnosis of other malignant lymphomas before the ATL diagnosis, including two diagnosed with Hodgkin disease (HD), one with peripheral T-cell lymphoma, two with chronic lymphocytic leukaemia and one with angioimmunoblastic T-cell lymphoma. Of the 14 patients, eight (57%) were subclassified as the acute type, three (21.4%) as the lymphoma type, and three (21.4%) as the chronic type ATL. Five of six (83.3%) patients with initial non-ATL misdiagnosis were diagnosed with non-acute type ATL. In particular, a patient with an antecedent diagnosis of HD presented with typical Reed-Sternberg (RS)-like cells harbouring Epstein-Barr virus genomes in affected lymph nodes. The patient progressed to acute type ATL 3 years after the initial diagnosis, and HTLV-1 genomes were identified in the previous RS-like cells. In non-endemic areas, such as Taiwan, ATL, particularly the non-acute type, may mimic other lymphomas and easily be misdiagnosed. HTLV-1 serology should be routinely screened in all malignant lymphoma patients. In situ detection of HTLV-1 is helpful in cases with diagnostic dilemmas. © 2014 The Authors; Internal Medicine Journal © 2014 Royal Australasian College of Physicians.

Non-tumour bone marrow lymphocytes correlate with improved overall survival in childhood acute lymphoblastic leukaemia.

PubMed

Edwin, Claire; Dean, Joanne; Bonnett, Laura; Phillips, Kate; Keenan, Russell

2016-10-01

Composition of tumour immune cell infiltrates correlates with response to treatment and overall survival (OS) in several cancer settings. We retrospectively examined immune cells present in diagnostic bone marrow aspirates from paediatric patients with B-cell acute lymphoblastic leukaemia. Our analysis identified a sub-group (∼30% of patients) with >2.37% CD20 and >6.05% CD7 expression, which had 100% OS, and a sub-group (∼30% of patients) with ≤2.37% CD20 and ≤6.05% CD7 expression at increased risk of treatment failure (66.7% OS, P < 0.05). Immune cell infiltrate at diagnosis may predict treatment response and could provide a means to enhance immediate treatment risk stratification. © 2016 The Authors. Pediatric Blood & Cancer, published by Wiley Periodicals, Inc.

Transient immune deficiency in patients with acute Epstein-Barr virus infection.

PubMed

Junker, A K; Ochs, H D; Clark, E A; Puterman, M L; Wedgwood, R J

1986-09-01

To study the effect of primary Epstein-Barr virus (EBV) infection on antigen-specific antibody production, we immunized 17 college students who had developed acute infectious mononucleosis with the T-cell dependent neoantigen bacteriophage phi X174. During the early phase of infectious mononucleosis, the proportion of peripheral blood lymphocytes displaying Ia and T8 (CD8) phenotypes was increased and the T helper/suppressor (T4/T8) ratio was decreased (less than 1). These abnormalities disappeared during the convalescent phase. Correlating with EBV-induced changes in T lymphocytes, we demonstrated depressed humoral immune responses to bacteriophage phi X174 both in vivo and in vitro. In vitro coculture experiments indicated that the Ia+ suppressor T cells could inhibit antibody production and isotype switch. Removal of T8+ lymphocytes from patient T cells normalized in vitro antibody synthesis. In addition, impaired B-cell function was shown to be in part responsible for deficient antibody production. These studies demonstrate that infection with EBV affects both B and T lymphocytes and causes a broad-based transient immune deficiency in patients with uncomplicated infectious mononucleosis.

Endothelial health in childhood acute lymphoid leukemia survivors: pilot evaluation with peripheral artery tonometry.

PubMed

Ruble, Kathy; Davis, Catherine L; Han, Hae-Ra

2015-03-01

Childhood cancer survivors are a growing population at risk for poor cardiac outcomes. Acute lymphoid leukemia (ALL) survivors are among those at increased risk of cardiovascular complications. Early identification of impaired vascular health may allow for interventions to improve these outcomes. The purpose of this study was to evaluate vascular health using peripheral artery tonometry in ALL survivors and compare results with healthy siblings. Sixteen ALL survivor, healthy sibling pairs, aged 8 to 20 years, were evaluated for vascular health and cardiovascular risk factors (body mass index, central adiposity, blood pressure, and fitness). One-tailed paired t test was used to compare the groups. Survivors were similar to siblings in cardiovascular risk measures but had poorer vascular health as measured by reactive hyperemia index (survivor RHI 1.54 vs. sibling 1.77; P=0.0474). This study reveals that even among survivors who are comparable to their healthy siblings in other traditional cardiovascular risks, there is evidence of poorer vascular health.

Stem Cell Modeling of Core Binding Factor Acute Myeloid Leukemia

PubMed Central

Mosna, Federico

2016-01-01

Even though clonally originated from a single cell, acute leukemia loses its homogeneity soon and presents at clinical diagnosis as a hierarchy of cells endowed with different functions, of which only a minority possesses the ability to recapitulate the disease. Due to their analogy to hematopoietic stem cells, these cells have been named “leukemia stem cells,” and are thought to be chiefly responsible for disease relapse and ultimate survival after chemotherapy. Core Binding Factor (CBF) Acute Myeloid Leukemia (AML) is cytogenetically characterized by either the t(8;21) or the inv(16)/t(16;16) chromosomal abnormalities, which, although being pathognomonic, are not sufficient per se to induce overt leukemia but rather determine a preclinical phase of disease when preleukemic subclones compete until the acquisition of clonal dominance by one of them. In this review we summarize the concepts regarding the application of the “leukemia stem cell” theory to the development of CBF AML; we will analyze the studies investigating the leukemogenetic role of t(8;21) and inv(16)/t(16;16), the proposed theories of its clonal evolution, and the role played by the hematopoietic niches in preserving the disease. Finally, we will discuss the clinical implications of stem cell modeling of CBF AML for the therapy of the disease. PMID:26880987

The Effect of Chronic Kidney Disease on T Cell Alloimmunity

PubMed Central

Winterberg, Pamela D.; Ford, Mandy L.

2017-01-01

Purpose of review Altered differentiation and activation of T cell subsets occur in patients with CKD, but the impact on graft rejection and protective immunity during transplantation are not fully understood. Recent findings Patients with CKD have decreased frequency of naïve T cells, accumulation of activated, terminally differentiated memory cells, and skewed regulatory versus T helper 17 ratio. Naïve and memory T cell subsets do not appear to improve following kidney transplantation. Retained thymic output is associated with acute rejection, while naïve lymphopenia and accumulation of CD8+TEMRA cells correlate with long-term graft dysfunction. CD28null memory cells accumulate during CKD and appear to confer protection against acute rejection under standard immunosuppression and possibly co-stimulation blockade. T cells bearing CD57 are also increased in patients with CKD and may underlie rejection during co-stimulation blockade. Summary The mechanisms by which CKD alters the differentiation and activation status of T cell subsets is poorly understood. Further research is also needed to understand which cell populations mediate rejection under various immunosuppressive regimens. To date, there is little use of animal models of organ failure in transplant immunology research. CKD mouse models may help identify novel pathways and targets to better control alloimmunity in post-transplant. PMID:27926546

Profound CD4+/CCR5+ T cell expansion is induced by CD8+ lymphocyte depletion but does not account for accelerated SIV pathogenesis

PubMed Central

Okoye, Afam; Park, Haesun; Rohankhedkar, Mukta; Coyne-Johnson, Lia; Lum, Richard; Walker, Joshua M.; Planer, Shannon L.; Legasse, Alfred W.; Sylwester, Andrew W.; Piatak, Michael; Lifson, Jeffrey D.; Sodora, Donald L.; Villinger, Francois; Axthelm, Michael K.; Schmitz, Joern E.

2009-01-01

Depletion of CD8+ lymphocytes during acute simian immunodeficiency virus (SIV) infection of rhesus macaques (RMs) results in irreversible prolongation of peak-level viral replication and rapid disease progression, consistent with a major role for CD8+ lymphocytes in determining postacute-phase viral replication set points. However, we report that CD8+ lymphocyte depletion is also associated with a dramatic induction of proliferation among CD4+ effector memory T (TEM) cells and, to a lesser extent, transitional memory T (TTrM) cells, raising the question of whether an increased availability of optimal (activated/proliferating), CD4+/CCR5+ SIV “target” cells contributes to this accelerated pathogenesis. In keeping with this, depletion of CD8+ lymphocytes in SIV− RMs led to a sustained increase in the number of potential CD4+ SIV targets, whereas such depletion in acute SIV infection led to increased target cell consumption. However, we found that the excess CD4+ TEM cell proliferation of CD8+ lymphocyte–depleted, acutely SIV-infected RMs was completely inhibited by interleukin (IL)-15 neutralization, and that this inhibition did not abrogate the rapidly progressive infection in these RMs. Moreover, although administration of IL-15 during acute infection induced robust CD4+ TEM and TTrM cell proliferation, it did not recapitulate the viral dynamics of CD8+ lymphocyte depletion. These data suggest that CD8+ lymphocyte function has a larger impact on the outcome of acute SIV infection than the number and/or activation status of target cells available for infection and viral production. PMID:19546246

VpreB gene expression in hematopoietic malignancies: a lineage- and stage-restricted marker for B-cell precursor leukemias.

PubMed

Bauer, S R; Kubagawa, H; Maclennan, I; Melchers, F

1991-09-15

We show here that analysis of VpreB gene transcription can be a specific way to identify acute leukemias of cells at very early stages of B-cell development. Northern blot analysis of RNAs from 63 leukemia samples showed that VpreB RNA was present in malignancies of precursor B cells, the expression being a feature of both common acute lymphoblastic leukemia (ALL) (CD10+) and null ALL (CD10-). It was absent from malignancies of mature B cells (surface Ig positive), from acute leukemias of the T-cell lineage and granulocyte-macrophage lineages, and from normal tonsil B and T lymphocytes. Chronic myeloid leukemia blast crises of the B-precursor-cell type expressed the VpreB gene while myeloid blast crises did not. VpreB RNA was also expressed in the neoplastic cells of one of three patients with acute undifferentiated leukemias. These data show that VpreB RNA expression is a marker of the malignant forms of precursor B cells, and that it appears at least as early as cytoplasmic CD22 and CD19 in tumors of the B-cell lineage.

Internet-Based Program With or Without Telephone-Based Problem-Solving Training in Helping Long-Term Survivors of Hematopoietic Stem Cell Transplant Cope With Late Complications

ClinicalTrials.gov

2012-03-05

Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Atypical Chronic Myeloid Leukemia, BCR-ABL Negative; Blastic Phase Chronic Myelogenous Leukemia; Cancer Survivor; Chronic Eosinophilic Leukemia; Chronic Myelomonocytic Leukemia; Chronic Neutrophilic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; de Novo Myelodysplastic Syndromes; Depression; Disseminated Neuroblastoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Fatigue; Long-term Effects Secondary to Cancer Therapy in Adults; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Burkitt Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Noncontiguous Stage II Adult Lymphoblastic Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Previously Treated Myelodysplastic Syndromes; Primary Myelofibrosis; Psychosocial Effects of Cancer and Its Treatment; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Refractory Multiple Myeloma; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Splenic Marginal Zone Lymphoma; Stage I Multiple Myeloma; Stage II Multiple Myeloma; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Hodgkin Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Multiple Myeloma; Stage III Small Lymphocytic Lymphoma; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Hodgkin Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Small Lymphocytic Lymphoma

CD4+ αβ T cell infiltration into the leptomeninges of lumbar dorsal roots contributes to the transition from acute to chronic mechanical allodynia after adult rat tibial nerve injuries.

PubMed

Du, Bin; Ding, You-Quan; Xiao, Xia; Ren, Hong-Yi; Su, Bing-Yin; Qi, Jian-Guo

2018-03-15

Antigen-specific and MHCII-restricted CD4+ αβ T cells have been shown or suggested to play an important role in the transition from acute to chronic mechanical allodynia after peripheral nerve injuries. However, it is still largely unknown where these T cells infiltrate along the somatosensory pathways transmitting mechanical allodynia to initiate the development of chronic mechanical allodynia after nerve injuries. Therefore, the purpose of this study was to ascertain the definite neuroimmune interface for these T cells to initiate the development of chronic mechanical allodynia after peripheral nerve injuries. First, we utilized both chromogenic and fluorescent immunohistochemistry (IHC) to map αβ T cells along the somatosensory pathways for the transmission of mechanical allodynia after modified spared nerve injuries (mSNIs), i.e., tibial nerve injuries, in adult male Sprague-Dawley rats. We further characterized the molecular identity of these αβ T cells selectively infiltrating into the leptomeninges of L4 dorsal roots (DRs). Second, we identified the specific origins in lumbar lymph nodes (LLNs) for CD4+ αβ T cells selectively present in the leptomeninges of L4 DRs by two experiments: (1) chromogenic IHC in these lymph nodes for CD4+ αβ T cell responses after mSNIs and (2) fluorescent IHC for temporal dynamics of CD4+ αβ T cell infiltration into the L4 DR leptomeninges after mSNIs in prior lymphadenectomized or sham-operated animals to LLNs. Finally, following mSNIs, we evaluated the effects of region-specific targeting of these T cells through prior lymphadenectomy to LLNs and chronic intrathecal application of the suppressive anti-αβTCR antibodies on the development of mechanical allodynia by von Frey hair test and spinal glial or neuronal activation by fluorescent IHC. Our results showed that during the sub-acute phase after mSNIs, αβ T cells selectively infiltrate into the leptomeninges of the lumbar DRs along the somatosensory pathways responsible for transmitting mechanical allodynia. Almost all these αβ T cells are CD4 positive. Moreover, the temporal dynamics of CD4+ αβ T cell infiltration into the lumbar DR leptomeninges are specifically determined by LLNs after mSNIs. Prior lymphadenectomy to LLNs specifically reduces the development of mSNI-induced chronic mechanical allodynia. More importantly, intrathecal application of the suppressive anti-αβTCR antibodies reduces the development of mSNI-induced chronic mechanical allodynia. In addition, prior lymphadenectomy to LLNs attenuates mSNI-induced spinal activation of glial cells and PKCγ + excitatory interneurons. The noteworthy results here provide the first evidence that CD4+ αβ T cells selectively infiltrate into the DR leptomeninges of the somatosensory pathways transmitting mechanical allodynia and contribute to the transition from acute to chronic mechanical allodynia after peripheral nerve injuries.

Reconstitution of lymphocyte subpopulations after hematopoietic stem cell transplantation: comparison of hematologic malignancies and donor types in event-free patients.

PubMed

Park, Borae G; Park, Chan-Jeoung; Jang, Seongsoo; Chi, Hyun-Sook; Kim, Dae-Young; Lee, Jung-Hee; Lee, Je-Hwan; Lee, Kyoo-Hyung

2015-12-01

The reconstitution of different immunocyte subsets after hematopoietic stem cell transplantation (HSCT), follows different timelines. We prospectively investigated changes in lymphocyte subsets after HSCT and their associations with primary diagnosis, conditioning regimen, and HSCT type in event-free patients. A total of 95 patients (48 with acute myeloid leukemia, 22 with acute lymphoid leukemia, and 25 with myelodysplastic syndrome) who underwent allogeneic HSCT (34 sibling matched, 37 unrelated matched, and 24 haploidentical HSCT) but did not experience any events such as relapse or death were enrolled in this study. Lymphocyte subpopulations (T cells, helper/inducer T cells, cytotoxic/suppressor T cells, memory T cells, regulatory T cells, natural killer (NK) cells, NK-T cells, and B cells) were quantified by flow cytometry of peripheral blood from recipients 7 days before and 1, 2, 3, 6, and 12 months after HSCT. Leukocyte counts recovered within 1 month after HSCT. However, the number of T and B lymphocytes recovered at 2 months after HSCT. NK cell counts recovered shortly after haploidentical HSCT. However, T lymphocytes and their subpopulations showed delayed recovery after haploidentical HSCT. Lymphocyte subsets showed different sequential patterns according to HSCT type but no differences were seen according to primary diagnosis or conditioning regimen. Copyright © 2015 Elsevier Ltd. All rights reserved.

The reliability of cytoplasmic CD3 and CD22 antigen expression in the immunodiagnosis of acute leukemia: a study of 500 cases.

PubMed

Janossy, G; Coustan-Smith, E; Campana, D

1989-03-01

Current views about the origin of acute lymphoid leukemia (ALL) emphasize the importance of maturation arrest at a precursor cell level. Recently, the CD22 antigen has been identified in the cytoplasm of normal bone marrow-borne immature B lineage cells, while the CD3 antigen (epsilon chain) has been detected within normal immature thymic blasts. In the first part our study performed on 100 cases of known acute leukemias, the expression of such cytoplasmic molecules, referred to as cCD22 and cCD3, was analyzed together with their appearance in the leukemic cells' membrane (mCD22 and mCD3). The presence of cCD22 in B-lineage ALL and that of cCD3 in T-ALL has indeed fully confirmed the diagnosis reached by other markers, and mCD22 and mCD3 were expressed on only a few cases of B- and T-lineage ALL, also revealing a degree of developmental asynchrony within leukemic blasts. In the subsequent analysis both cCD22 and cCD3 have been included in a standard panel of diagnostic reagents applied on 500 consecutive cases of acute leukemia. Here the aim was to analyze both the diagnostic precision of individual markers and the heterogeneity of various leukemic types in terms of the expression of membrane and intracellular antigens and their cytochemical features (Sudan Black B and esterases). It has been found that cCD22 and cCD3 are exquisitely specific for B-precursor ALL (TdT+, CD19+) and T-ALL (TdT+, CD7+), respectively, while both markers are absent in acute myeloblastic leukemia (AML) and acute myelomonocytic and monocytic leukemia (AMML/AMoL). These observations contrast the findings which demonstrate that 31% of cases among nonlymphoid acute leukemia (including AML and AMML) express CD7 and/or TdT. The study of myeloid antigens detected by CD13, CD33, and CD14 is also informative and complementary, both in diagnosing and subdividing the AML and AMML/AMoL groups. The peculiar main observation of this study is that only with the combined use of these markers in a microplate assay for membrane antigens, followed by double staining for intracellular antigens such as terminal deoxynucleotidyl transferase, cCD3, cCD22, c mu heavy chain, and T cell receptor beta, it is possible to safely establish the lineage affiliation and subgrouping of virtually all acute leukemias. Among these cases are those with aberrant combinations of markers, including 14% of B-lineage ALL (cCD22+,CD19+,TdT+) and a single case T-ALL (cCD3+,CD7+,TdT+), which exhibit CD13 and/or CD33 antigens, cases with mixtures of ALL and AML blasts, and 1.2% of acute leukemias which lack lineage affiliation and can be regarded as acute undifferentiated leukemia.

miR-664 negatively regulates PLP2 and promotes cell proliferation and invasion in T-cell acute lymphoblastic leukaemia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhu, Hong; Miao, Mei-hua; Ji, Xue-qiang

2015-04-03

MicroRNAs (miRNAs) play important roles in the pathogenesis of many types of cancers by negatively regulating gene expression at posttranscriptional level. However, the role of microRNAs in leukaemia, particularly T-cell acute lymphoblastic leukaemia (T-ALL), has remained elusive. Here, we identified miR-664 and its predicted target gene PLP2 were differentially expressed in T-ALL using bioinformatics methods. In T-ALL cell lines, CCK-8 proliferation assay indicated that the cell proliferation was promoted by miR-664, while miR-664 inhibitor could significantly inhibited the proliferation. Moreover, migration and invasion assay showed that overexpression of miR-664 could significantly promoted the migration and invasion of T-ALL cells, whereasmore » miR-664 inhibitor could reduce cell migration and invasion. luciferase assays confirmed that miR-664 directly bound to the 3'untranslated region of PLP2, and western blotting showed that miR-664 suppressed the expression of PLP2 at the protein levels. This study indicated that miR-664 negatively regulates PLP2 and promotes proliferation and invasion of T-ALL cell lines. Thus, miR-664 may represent a potential therapeutic target for T-ALL intervention. - Highlights: • miR-664 mimics promote the proliferation and invasion of T-ALL cells. • miR-664 inhibitors inhibit the proliferation and invasion of T-ALL cells. • miR-664 targets 3′ UTR of PLP2 in T-ALL cells. • miR-664 negatively regulates PLP2 in T-ALL cells.« less

Emergence of dendritic cells in the myocardium after acute myocardial infarction - implications for inflammatory myocardial damage.

PubMed

Yilmaz, Atilla; Dietel, Barbara; Cicha, Iwona; Schubert, Katja; Hausmann, Roland; Daniel, Werner G; Garlichs, Christoph D; Stumpf, Christian

2010-03-01

Dendritic cells (DC) are crucial for T cell mediated immune responses. Recently, we observed a significant decrease in circulating myeloid DC precursors in patients with acute myocardial infarction (AMI). The aim of the present study was to investigate whether myeloid DC are present in infarcted myocardium. Myocardial specimens of 10 patients with AMI and 7 accident victims (controls) were collected after autopsy. In immunostainings the presence of DC (CD209(+), fascin(+)), T cells (CD3(+)), macrophages (CD68(+)), and HLA-DR expression was analyzed. Significantly higher numbers of CD209(+)-DC (97 vs. 44 cells/0.25 mm(2), p=0.03), fascin(+)-DC (54 vs. 8 cells/0.25 mm(2), p=0.02), T cells (27 vs. 6 cells/0.25 mm(2), p=0.02), and macrophages (44 vs. 6 cells/0.25 mm(2), p=0.01) associated with high HLA-DR expression were detected in infarcted myocardium. Frequent colocalizations of DC and T cells were observed. In occluded coronary arteries numerous DC, T cells, macrophages and high HLA-DR expression were found. We show that DC are present in infarcted myocardium after AMI. High HLA-DR expression and the colocalization with T cells suggest that they might trigger an immune response leading to further myocardial damage.

Radiolabeled Monoclonal Antibody Therapy, Fludarabine Phosphate, and Low-Dose Total-Body Irradiation Followed by Donor Stem Cell Transplant and Immunosuppression Therapy in Treating Older Patients With Advanced Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndromes

ClinicalTrials.gov

2017-11-06

Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Chronic Myelomonocytic Leukemia; de Novo Myelodysplastic Syndromes; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Myeloid Leukemia; Refractory Anemia With Excess Blasts; Refractory Anemia With Excess Blasts in Transformation; Refractory Anemia With Ringed Sideroblasts; Refractory Cytopenia With Multilineage Dysplasia; Secondary Myelodysplastic Syndromes; Untreated Adult Acute Myeloid Leukemia

Production and first-in-man use of T cells engineered to express a HSVTK-CD34 sort-suicide gene.

PubMed

Zhan, Hong; Gilmour, Kimberly; Chan, Lucas; Farzaneh, Farzin; McNicol, Anne Marie; Xu, Jin-Hua; Adams, Stuart; Fehse, Boris; Veys, Paul; Thrasher, Adrian; Gaspar, Hubert; Qasim, Waseem

2013-01-01

Suicide gene modified donor T cells can improve immune reconstitution after allogeneic haematopoietic stem cell transplantation (SCT), but can be eliminated in the event of graft versus host disease (GVHD) through the administration of prodrug. Here we report the production and first-in-man use of mismatched donor T cells modified with a gamma-retroviral vector expressing a herpes simplex thymidine kinase (HSVTK):truncated CD34 (tCD34) suicide gene/magnetic selection marker protein. A stable packaging cell line was established to produce clinical grade vector pseudotyped with the Gibbon Ape Leukaemia Virus (GALV). T cells were transduced in a closed bag system following activation with anti-CD3/CD28 beads, and enriched on the basis of CD34 expression. Engineered cells were administered in two escalating doses to three children receiving T-depleted, CD34 stem cell selected, mismatched allogeneic grafts. All patients had pre-existing viral infections and received chemotherapy conditioning without serotherapy. In all three subjects cell therapy was tolerated without acute toxicity or the development of acute GVHD. Circulating gene modified T cells were detectable by flow cytometry and by molecular tracking in all three subjects. There was resolution of virus infections, concordant with detectable antigen-specific T cell responses and gene modified cells persisted for over 12 months. These findings highlight the suitability of tCD34 as a GMP compliant selection marker and demonstrate the feasibility, safety and immunological potential of HSVTK-tCD34 suicide gene modified donor T cells. ClinicalTrials.gov NCT01204502

The cancer-immunity cycle as rational design for synthetic cancer drugs: Novel DC vaccines and CAR T-cells.

PubMed

Ramachandran, Mohanraj; Dimberg, Anna; Essand, Magnus

2017-08-01

Cell therapy is an advanced form of cancer immunotherapy that has had remarkable clinical progress in the past decade in the search for cure of cancer. Most success has been achieved for chimeric antigen receptor (CAR) T-cells where CAR T-cells targeting CD19 show very high complete response rates for patients with refractory acute B-cell acute lymphoblastic leukemia (ALL) and are close to approval for this indication. CD19 CAR T-cells are also effective against B-cell chronic lymphoblastic leukemia (CLL) and B-cell lymphomas. Although encouraging, CAR T-cells have not yet proven clinically effective for solid tumors. This is mainly due to the lack of specific and homogenously expressed targets to direct the T-cells against and a hostile immunosuppressive tumor microenvironment in solid tumors. Cancer vaccines based on dendritic cells (DC) are also making progress although clinical efficacy is still lacking. The likelihood of success is however increasing now when individual tumors can be sequences and patient-specific neoepitopes identified. Neoepitopes and/or neoantigens can then be included in patient-based DC vaccines. This review discusses recent advancements of DC vaccines and CAR T-cells with emphasis on the cancer-immunity cycle, and current efforts to design novel cell therapies. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Phloridzin docosahexaenoate, a novel flavonoid derivative, suppresses growth and induces apoptosis in T-cell acute lymphoblastic leukemia cells.

PubMed

Arumuggam, Niroshaathevi; Melong, Nicole; Too, Catherine Kl; Berman, Jason N; Rupasinghe, Hp Vasantha

2017-01-01

The overall clinical outcome in T-cell acute lymphoblastic leukemia (T-ALL) can be improved by minimizing risk for treatment failure using effective pharmacological adjuvants. Phloridzin (PZ), a flavonoid precursor found in apple peels, was acylated with docosahexaenoic acid (DHA) yielding a novel ester known as phloridzin docosahexaenoate (PZ-DHA). Here, we have studied the cytotoxic effects of PZ-DHA on human leukemia cells using in vitro and in vivo models. The inhibitory effects of PZ-DHA were tested on human Jurkat T-ALL cells in comparison to K562 chronic myeloid leukemia (CML) cells and non-malignant murine T-cells. PZ-DHA, not PZ or DHA alone, reduced cell viability and ATP levels, increased intracellular LDH release, and caused extensive morphological alterations in both Jurkat and K562 cells. PZ-DHA also inhibited cell proliferation, and selectively induced apoptosis in Jurkat and K562 cells while sparing normal murine T-cells. The cytotoxic effects of PZ-DHA on Jurkat cells were associated with caspase activation, DNA fragmentation, and selective down-regulation of STAT3 phosphorylation. PZ-DHA significantly inhibited Jurkat cell proliferation in zebrafish larvae; however, the proliferation of K562 cells was not affected in vivo . We propose that PZ-DHA-induced cytotoxic response is selective towards T-ALL in the presence of a tumor-stromal microenvironment. Prospective studies evaluating the combinatorial effects of PZ-DHA with conventional chemotherapy for T-ALL are underway.

Phloridzin docosahexaenoate, a novel flavonoid derivative, suppresses growth and induces apoptosis in T-cell acute lymphoblastic leukemia cells

PubMed Central

Arumuggam, Niroshaathevi; Melong, Nicole; Too, Catherine KL; Berman, Jason N; Rupasinghe, HP Vasantha

2017-01-01

The overall clinical outcome in T-cell acute lymphoblastic leukemia (T-ALL) can be improved by minimizing risk for treatment failure using effective pharmacological adjuvants. Phloridzin (PZ), a flavonoid precursor found in apple peels, was acylated with docosahexaenoic acid (DHA) yielding a novel ester known as phloridzin docosahexaenoate (PZ-DHA). Here, we have studied the cytotoxic effects of PZ-DHA on human leukemia cells using in vitro and in vivo models. The inhibitory effects of PZ-DHA were tested on human Jurkat T-ALL cells in comparison to K562 chronic myeloid leukemia (CML) cells and non-malignant murine T-cells. PZ-DHA, not PZ or DHA alone, reduced cell viability and ATP levels, increased intracellular LDH release, and caused extensive morphological alterations in both Jurkat and K562 cells. PZ-DHA also inhibited cell proliferation, and selectively induced apoptosis in Jurkat and K562 cells while sparing normal murine T-cells. The cytotoxic effects of PZ-DHA on Jurkat cells were associated with caspase activation, DNA fragmentation, and selective down-regulation of STAT3 phosphorylation. PZ-DHA significantly inhibited Jurkat cell proliferation in zebrafish larvae; however, the proliferation of K562 cells was not affected in vivo. We propose that PZ-DHA-induced cytotoxic response is selective towards T-ALL in the presence of a tumor-stromal microenvironment. Prospective studies evaluating the combinatorial effects of PZ-DHA with conventional chemotherapy for T-ALL are underway. PMID:29312799

Attenuation of acute lung inflammation induced by cigarette smoke in CXCR3 knockout mice.

PubMed

Nie, Li; Xiang, Ruolan; Zhou, Weixun; Lu, Bao; Cheng, Deyun; Gao, Jinming

2008-12-16

CD8+ T cells may participate in cigarette smoke (CS) induced-lung inflammation in mice. CXCL10/IP-10 (IFNgamma-inducible protein 10) and CXCL9/Mig (monokine induced by IFN-gamma) are up-regulated in CS-induced lung injury and may attract T-cell recruitment to the lung. These chemokines together with CXCL11/ITAC (IFN-inducible T-cell alpha chemoattractant) are ligands for the chemokine receptor CXCR3 which is preferentially expressed chiefly in activated CD8+ T cells. The purpose of this investigation was to study the contribution of CXCR3 to acute lung inflammation induced by CS using CXCR3 knockout (KO) mice. Mice (n = 8 per group) were placed in a closed plastic box connected to a smoke generator and were exposed whole body to the tobacco smoke of five cigarettes four times a day for three days. Lung pathological changes, expression of inflammatory mediators in bronchoalveolar lavage (BAL) fluid and lungs at mRNA and protein levels, and lung infiltration of CD8+ T cells were compared between CXCR3-/- mice and wild type (WT) mice. Compared with the WT littermates, CXCR3 KO mice showed less CS-induced lung inflammation as evidenced by less infiltration of inflammatory cells in airways and lung tissue, particularly fewer CD8+ T cells, lower levels of IFNgamma and CXCR3 ligands (particularly CXCL10). Our findings show that CXCR3 is important in promoting CD8+ T cell recruitment and in initiating IFNgamma and CXCL10 release following CS exposure. CXCR3 may represent a promising therapeutic target for acute lung inflammation induced by CS.

Attenuation of acute lung inflammation induced by cigarette smoke in CXCR3 knockout mice

PubMed Central

Nie, Li; Xiang, Ruolan; Zhou, Weixun; Lu, Bao; Cheng, Deyun; Gao, Jinming

2008-01-01

Background CD8+ T cells may participate in cigarette smoke (CS) induced-lung inflammation in mice. CXCL10/IP-10 (IFNγ-inducible protein 10) and CXCL9/Mig (monokine induced by IFN-γ) are up-regulated in CS-induced lung injury and may attract T-cell recruitment to the lung. These chemokines together with CXCL11/ITAC (IFN-inducible T-cell alpha chemoattractant) are ligands for the chemokine receptor CXCR3 which is preferentially expressed chiefly in activated CD8+ T cells. The purpose of this investigation was to study the contribution of CXCR3 to acute lung inflammation induced by CS using CXCR3 knockout (KO) mice. Methods Mice (n = 8 per group) were placed in a closed plastic box connected to a smoke generator and were exposed whole body to the tobacco smoke of five cigarettes four times a day for three days. Lung pathological changes, expression of inflammatory mediators in bronchoalveolar lavage (BAL) fluid and lungs at mRNA and protein levels, and lung infiltration of CD8+ T cells were compared between CXCR3-/- mice and wild type (WT) mice. Results Compared with the WT littermates, CXCR3 KO mice showed less CS-induced lung inflammation as evidenced by less infiltration of inflammatory cells in airways and lung tissue, particularly fewer CD8+ T cells, lower levels of IFNγ and CXCR3 ligands (particularly CXCL10). Conclusion Our findings show that CXCR3 is important in promoting CD8+ T cell recruitment and in initiating IFNγ and CXCL10 release following CS exposure. CXCR3 may represent a promising therapeutic target for acute lung inflammation induced by CS. PMID:19087279

MicroRNA-155 Modulates Acute Graft-versus-Host Disease by Impacting T Cell Expansion, Migration, and Effector Function.

PubMed

Zitzer, Nina C; Snyder, Katiri; Meng, Xiamoei; Taylor, Patricia A; Efebera, Yvonne A; Devine, Steven M; Blazar, Bruce R; Garzon, Ramiro; Ranganathan, Parvathi

2018-06-15

MicroRNA-155 (miR-155) is a small noncoding RNA critical for the regulation of inflammation as well as innate and adaptive immune responses. MiR-155 has been shown to be dysregulated in both donor and recipient immune cells during acute graft-versus-host disease (aGVHD). We previously reported that miR-155 is upregulated in donor T cells of mice and humans with aGVHD and that mice receiving miR-155-deficient (miR155 -/- ) splenocytes had markedly reduced aGVHD. However, molecular mechanisms by which miR-155 modulates T cell function in aGVHD have not been fully investigated. We identify that miR-155 expression in both donor CD8 + T cells and conventional CD4 + CD25 - T cells is pivotal for aGVHD pathogenesis. Using murine aGVHD transplant experiments, we show that miR-155 strongly impacts alloreactive T cell expansion through multiple distinct mechanisms, modulating proliferation in CD8 + donor T cells and promoting exhaustion in donor CD4 + T cells in both the spleen and colon. Additionally, miR-155 drives a proinflammatory Th1 phenotype in donor T cells in these two sites, and miR-155 -/- donor T cells are polarized toward an IL-4-producing Th2 phenotype. We further demonstrate that miR-155 expression in donor T cells regulates CCR5 and CXCR4 chemokine-dependent migration. Notably, we show that miR-155 expression is crucial for donor T cell infiltration into multiple target organs. These findings provide further understanding of the role of miR-155 in modulating aGVHD through T cell expansion, effector cytokine production, and migration. Copyright © 2018 by The American Association of Immunologists, Inc.

CD4 T cell subsets in the Mucosa are CD28+Ki-67−HLA-DR−CD69+ but show differential infection based on α4β7 receptor expression during acute SIV infection

PubMed Central

Kader, Muhamuda; Bixler, Sandra; Roederer, Mario; Veazey, Ronald; Mattapallil, Joseph J.

2009-01-01

Background CD4 T cell depletion in the mucosa has been well documented during acute HIV and SIV infections. The demonstration the HIV/SIV can use the α4β7 receptor for viral entry suggests that these viruses selectively target CD4 T cells in the mucosa that express high levels of α4β7 receptor. Methods Mucosal samples obtained from SIV infected rhesus macaques during the early phase of infection were used for immunophenotypic analysis. CD4 T cell subsets were sorted based on the expression of β7 and CD95 to quantify the level of SIV infection in different subsets of CD4 T cells. Changes in IL-17, IL-21, IL-23 and TGFβ mRNA expression was determined using Taqman PCR. Results CD4 T cells in the mucosa were found to harbor two major population of cells; ~25% of CD4 T cells expressed the α4+β7hi phenotype, whereas the rest of the 75% expressed an α4+β7int phenotype. Both the subsets were predominantly CD28+Ki-67− HLA-DR− but CD69+, and expressed detectable levels of CCR5 on their surface. Interestingly, however, α4+β7hiCD4 T cells were found to harbor more SIV than the α4+β7int subsets at day 10 pi. Early infection was associated with a dramatic increase in the expression of IL-17, and IL-17 promoting cytokines IL-21, IL-23, and TGFβ that stayed high even after the loss of mucosal CD4 T cells. Conclusions Our results suggest that the differential expression of the α4β7 receptor contributes to the differences in the extent of infection in CD4 T cell subsets in the mucosa. Early infection associated dysregulation of the IL-17 network in mucosal tissues involves other non-Th-17 cells that likely contributes to the pro-inflammatory environment in the mucosa during acute stages of SIV infection. PMID:19863675

T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial.

PubMed

Lee, Daniel W; Kochenderfer, James N; Stetler-Stevenson, Maryalice; Cui, Yongzhi K; Delbrook, Cindy; Feldman, Steven A; Fry, Terry J; Orentas, Rimas; Sabatino, Marianna; Shah, Nirali N; Steinberg, Seth M; Stroncek, Dave; Tschernia, Nick; Yuan, Constance; Zhang, Hua; Zhang, Ling; Rosenberg, Steven A; Wayne, Alan S; Mackall, Crystal L

2015-02-07

Chimeric antigen receptor (CAR) modified T cells targeting CD19 have shown activity in case series of patients with acute and chronic lymphocytic leukaemia and B-cell lymphomas, but feasibility, toxicity, and response rates of consecutively enrolled patients treated with a consistent regimen and assessed on an intention-to-treat basis have not been reported. We aimed to define feasibility, toxicity, maximum tolerated dose, response rate, and biological correlates of response in children and young adults with refractory B-cell malignancies treated with CD19-CAR T cells. This phase 1, dose-escalation trial consecutively enrolled children and young adults (aged 1-30 years) with relapsed or refractory acute lymphoblastic leukaemia or non-Hodgkin lymphoma. Autologous T cells were engineered via an 11-day manufacturing process to express a CD19-CAR incorporating an anti-CD19 single-chain variable fragment plus TCR zeta and CD28 signalling domains. All patients received fludarabine and cyclophosphamide before a single infusion of CD19-CAR T cells. Using a standard 3 + 3 design to establish the maximum tolerated dose, patients received either 1 × 10(6) CAR-transduced T cells per kg (dose 1), 3 × 10(6) CAR-transduced T cells per kg (dose 2), or the entire CAR T-cell product if sufficient numbers of cells to meet the assigned dose were not generated. After the dose-escalation phase, an expansion cohort was treated at the maximum tolerated dose. The trial is registered with ClinicalTrials.gov, number NCT01593696. Between July 2, 2012, and June 20, 2014, 21 patients (including eight who had previously undergone allogeneic haematopoietic stem-cell transplantation) were enrolled and infused with CD19-CAR T cells. 19 received the prescribed dose of CD19-CAR T cells, whereas the assigned dose concentration could not be generated for two patients (90% feasible). All patients enrolled were assessed for response. The maximum tolerated dose was defined as 1 × 10(6) CD19-CAR T cells per kg. All toxicities were fully reversible, with the most severe being grade 4 cytokine release syndrome that occurred in three (14%) of 21 patients (95% CI 3·0-36·3). The most common non-haematological grade 3 adverse events were fever (nine [43%] of 21 patients), hypokalaemia (nine [43%] of 21 patients), fever and neutropenia (eight [38%] of 21 patients), and cytokine release syndrome (three [14%) of 21 patients). CD19-CAR T cell therapy is feasible, safe, and mediates potent anti-leukaemic activity in children and young adults with chemotherapy-resistant B-precursor acute lymphoblastic leukaemia. All toxicities were reversible and prolonged B-cell aplasia did not occur. National Institutes of Health Intramural funds and St Baldrick's Foundation. Copyright © 2015 Elsevier Ltd. All rights reserved.

Gain-of-function mutations in interleukin-7 receptor-α (IL7R) in childhood acute lymphoblastic leukemias

PubMed Central

Shochat, Chen; Tal, Noa; Bandapalli, Obul R.; Palmi, Chiara; Ganmore, Ithamar; te Kronnie, Geertruy; Cario, Gunnar; Cazzaniga, Giovanni; Kulozik, Andreas E.; Stanulla, Martin; Schrappe, Martin; Biondi, Andrea; Basso, Giuseppe; Bercovich, Dani; Muckenthaler, Martina U.

2011-01-01

Interleukin-7 receptor α (IL7R) is required for normal lymphoid development. Loss-of-function mutations in this gene cause autosomal recessive severe combined immune deficiency. Here, we describe somatic gain-of-function mutations in IL7R in pediatric B and T acute lymphoblastic leukemias. The mutations cause either a serine-to-cysteine substitution at amino acid 185 in the extracellular domain (4 patients) or in-frame insertions and deletions in the transmembrane domain (35 patients). In B cell precursor leukemias, the mutations were associated with the aberrant expression of cytokine receptor-like factor 2 (CRLF2), and the mutant IL-7R proteins formed a functional receptor with CRLF2 for thymic stromal lymphopoietin (TSLP). Biochemical and functional assays reveal that these IL7R mutations are activating mutations conferring cytokine-independent growth of progenitor lymphoid cells. A cysteine, included in all but three of the mutated IL-7R alleles, is essential for the constitutive activation of the receptor. This is the first demonstration of gain-of-function mutations of IL7R. Our current and recent observations of mutations in IL7R and CRLF2, respectively suggest that the addition of cysteine to the juxtamembranous domains is a general mechanism for mutational activation of type I cytokine receptors in leukemia. PMID:21536738

Adoptive immunotherapy for acute leukemia: New insights in chimeric antigen receptors

PubMed Central

Heiblig, Maël; Elhamri, Mohamed; Michallet, Mauricette; Thomas, Xavier

2015-01-01

Relapses remain a major concern in acute leukemia. It is well known that leukemia stem cells (LSCs) hide in hematopoietic niches and escape to the immune system surveillance through the outgrowth of poorly immunogenic tumor-cell variants and the suppression of the active immune response. Despite the introduction of new reagents and new therapeutic approaches, no treatment strategies have been able to definitively eradicate LSCs. However, recent adoptive immunotherapy in cancer is expected to revolutionize our way to fight against this disease, by redirecting the immune system in order to eliminate relapse issues. Initially described at the onset of the 90’s, chimeric antigen receptors (CARs) are recombinant receptors transferred in various T cell subsets, providing specific antigens binding in a non-major histocompatibility complex restricted manner, and effective on a large variety of human leukocyte antigen-divers cell populations. Once transferred, engineered T cells act like an expanding “living drug” specifically targeting the tumor-associated antigen, and ensure long-term anti-tumor memory. Over the last decades, substantial improvements have been made in CARs design. CAR T cells have finally reached the clinical practice and first clinical trials have shown promising results. In acute lymphoblastic leukemia, high rate of complete and prolonged clinical responses have been observed after anti-CD19 CAR T cell therapy, with specific but manageable adverse events. In this review, our goal was to describe CAR structures and functions, and to summarize recent data regarding pre-clinical studies and clinical trials in acute leukemia. PMID:26328018

Advances in therapy for Philadelphia-positive acute lymphoblastic leukaemia of childhood and adolescence.

PubMed

Bleckmann, Kirsten; Schrappe, Martin

2016-03-01

The presence of the BCR/ABL1 fusion gene in childhood acute lymphoblastic leukaemia (ALL) is a rare finding and has been an adverse prognostic factor associated with a high risk of therapeutic failure. The current key components of treatment are intensive polychemotherapy and a BCR/ABL1 kinase domain inhibitor. This treatment approach has been applied in a few clinical trials by paediatric leukaemia study groups. Thus, this subtype of ALL serves as the first model system for truly targeted treatment. The role of haematopoietic stem cell transplantation (HSCT) is increasingly called into question, at least in a favourable, though not yet clearly defined, subset of patients. Currently, the choice of the most effective tyrosine kinase inhibitor is not yet settled, in particular, in view of potential reduction of overall treatment intensity. © 2016 John Wiley & Sons Ltd.

Adoptive immunotherapy for B-cell malignancies using CD19-targeted chimeric antigen receptor T-cells: A systematic review of efficacy and safety.

PubMed

Hao, Lu; Li, Tongtong; Chang, Lung-Ji; Chen, Xiaochuan

2017-08-01

Adoptive infusion of chimeric antigen receptor transduced T-cells (CAR-T) is a powerful tool of immunotherapy for hematological malignancies, as evidenced by recently published and unpublished clinical results. In this report, we performed a meta-analysis to evaluate the efficacy and side effects of CAR-T on relapsed B-cell malignancies, including leukemia and lymphoma. Clinical studies investigating efficacy and safety of CAR-T in acute and chronic lymphocytic leukemia and lymphoma were identified by searching PubMed and EMBASE. Outcomes of efficacy subjected to analysis were the rates of complete remission (CR) and partial remission (PR). The safety parameters were the prevalence of adverse effects including fever, hypotension, and acute renal failure. Meta analyses were performed using R software. Weighted hazard ratio (HR) with 95% confidence intervals was calculated for each outcome. Fixed or random-effects models were employed depending on the heterogeneity across the included studies. Nineteen published clinical studies, with a total of 391 patients were included for the meta-analysis. The pooled rate of complete remission was 55% (95% CI 41%-69%); the pooled rate of partial remission was 25% (95% CI: 19%-33%). The prevalence of fever was 62% (95% CI: 41%-79%); the hypotension was 22% (95% CI: 15%-31%); acute renal failure was 24% (95% CI: 16%-34%). All adverse effects were manageable and no death was reported due to toxicity. CD19-targeted CAR-T is an effective modality in treating refractory B-cell malignancies including acute and chronic lymphatic leukemia, Hodjkin's and non-Hodjkin's lymphoma. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Regulation of inflammatory chemokine receptors on blood T cells associated to the circulating versus liver chemokines in dengue fever.

PubMed

de-Oliveira-Pinto, Luzia Maria; Marinho, Cíntia Ferreira; Povoa, Tiago Fajardo; de Azeredo, Elzinandes Leal; de Souza, Luiza Assed; Barbosa, Luiza Damian Ribeiro; Motta-Castro, Ana Rita C; Alves, Ada M B; Ávila, Carlos André Lins; de Souza, Luiz José; da Cunha, Rivaldo Venâncio; Damasco, Paulo Vieira; Paes, Marciano Viana; Kubelka, Claire Fernandes

2012-01-01

Little is known about the role of chemokines/chemokines receptors on T cells in natural DENV infection. Patients from DENV-2 and -3- outbreaks were studied prospectively during the acute or convalescent phases. Expression of chemokine receptor and activation markers on lymphocyte subpopulations were determined by flow cytometry analysis, plasma chemokine ligands concentrations were measured by ELISA and quantification of CCL5/RANTES(+) cells in liver tissues from fatal dengue cases was performed by immunochemistry. In the acute DENV-infection, T-helper/T-cytotoxic type-1 cell (Th1/Tc1)-related CCR5 is significantly higher expressed on both CD4 and CD8 T cells. The Th1-related CXCR3 is up-regulated among CD4 T cells and Tc2-related CCR4 is up-regulated among CD8 T cells. In the convalescent phase, all chemokine receptor or chemokine ligand expression tends to reestablish control healthy levels. Increased CCL2/MCP-1 and CCL4/MIP-1β but decreased CCL5/RANTES levels were observed in DENV-patients during acute infection. Moreover, we showed an increased CD107a expression on CCR5 or CXCR3-expressing T cells and higher expression of CD29, CD44(HIGH) and CD127(LOW) markers on CCR4-expressing CD8 T cells in DENV-patients when compared to controls. Finally, liver from dengue fatal patients showed increased number of cells expressing CCL5/RANTES in three out of four cases compared to three death from a non-dengue patient. In conclusion, both Th1-related CCR5 and CXCR3 among CD4 T cells have a potential ability to exert cytotoxicity function. Moreover, Tc1-related CCR5 and Tc2-related CCR4 among CD8 T cells have a potential ability to exert effector function and migration based on cell markers evaluated. The CCR5 expression would be promoting an enhanced T cell recruitment into liver, a hypothesis that is corroborated by the CCL5/RANTES increase detected in hepatic tissue from dengue fatal cases. The balance between protective and pathogenic immune response mediated by chemokines during dengue fever will be discussed.

Regulation of Inflammatory Chemokine Receptors on Blood T Cells Associated to the Circulating Versus Liver Chemokines in Dengue Fever

PubMed Central

Povoa, Tiago Fajardo; de Azeredo, Elzinandes Leal; de Souza, Luiza Assed; Barbosa, Luiza Damian Ribeiro; Motta-Castro, Ana Rita C.; Alves, Ada M. B.; Ávila, Carlos André Lins; de Souza, Luiz José; da Cunha, Rivaldo Venâncio; Damasco, Paulo Vieira; Paes, Marciano Viana; Kubelka, Claire Fernandes

2012-01-01

Little is known about the role of chemokines/chemokines receptors on T cells in natural DENV infection. Patients from DENV-2 and -3- outbreaks were studied prospectively during the acute or convalescent phases. Expression of chemokine receptor and activation markers on lymphocyte subpopulations were determined by flow cytometry analysis, plasma chemokine ligands concentrations were measured by ELISA and quantification of CCL5/RANTES+ cells in liver tissues from fatal dengue cases was performed by immunochemistry. In the acute DENV-infection, T-helper/T-cytotoxic type-1 cell (Th1/Tc1)-related CCR5 is significantly higher expressed on both CD4 and CD8 T cells. The Th1-related CXCR3 is up-regulated among CD4 T cells and Tc2-related CCR4 is up-regulated among CD8 T cells. In the convalescent phase, all chemokine receptor or chemokine ligand expression tends to reestablish control healthy levels. Increased CCL2/MCP-1 and CCL4/MIP-1β but decreased CCL5/RANTES levels were observed in DENV-patients during acute infection. Moreover, we showed an increased CD107a expression on CCR5 or CXCR3-expressing T cells and higher expression of CD29, CD44HIGH and CD127LOW markers on CCR4-expressing CD8 T cells in DENV-patients when compared to controls. Finally, liver from dengue fatal patients showed increased number of cells expressing CCL5/RANTES in three out of four cases compared to three death from a non-dengue patient. In conclusion, both Th1-related CCR5 and CXCR3 among CD4 T cells have a potential ability to exert cytotoxicity function. Moreover, Tc1-related CCR5 and Tc2-related CCR4 among CD8 T cells have a potential ability to exert effector function and migration based on cell markers evaluated. The CCR5 expression would be promoting an enhanced T cell recruitment into liver, a hypothesis that is corroborated by the CCL5/RANTES increase detected in hepatic tissue from dengue fatal cases. The balance between protective and pathogenic immune response mediated by chemokines during dengue fever will be discussed. PMID:22815692

Arctigenin protects against liver injury from acute hepatitis by suppressing immune cells in mice.

PubMed

Cheng, Xixi; Wang, Huafeng; Yang, Jinlai; Cheng, Yingnan; Wang, Dan; Yang, Fengrui; Li, Yan; Zhou, Dongmei; Wang, Yanxia; Xue, Zhenyi; Zhang, Lijuan; Zhang, Qi; Yang, Luhong; Zhang, Rongxin; Da, Yurong

2018-06-01

As a phenylpropanoid and dibenzylbutyrolactone lignan present in medical plants, such as those used in traditional Chinese herbal medicine, including Arctium lappa (Niubang), arctigenin exhibits antimicrobial, anti-inflammatory, and anticancer activities. In this study, we investigated the protective role of arctigenin in Concanavalin A (ConA)-induced acute hepatitis in mice. Arctigenin remarkably reduced the congestion and necroinflammation of livers, and improved hepatic function (ALT and AST) in ConA-induced acute hepatitis in vivo. The infiltration of CD4 T, NKT and macrophages into the livers was found to be reduced with arctigenin treatment. Arctigenin suppressed ConA-induced T lymphocyte proliferations that might have resulted from enhanced IL-10 production by macrophages and CD4 T cells. These results suggested that arctigenin could be a powerful drug candidate for acute hepatitis through immune suppression. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

The Usher Syndrome Type IIIB Histidyl-tRNA Synthetase Mutation Confers Temperature Sensitivity.

PubMed

Abbott, Jamie A; Guth, Ethan; Kim, Cindy; Regan, Cathy; Siu, Victoria M; Rupar, C Anthony; Demeler, Borries; Francklyn, Christopher S; Robey-Bond, Susan M

2017-07-18

Histidyl-tRNA synthetase (HARS) is a highly conserved translation factor that plays an essential role in protein synthesis. HARS has been implicated in the human syndromes Charcot-Marie-Tooth (CMT) Type 2W and Type IIIB Usher (USH3B). The USH3B mutation, which encodes a Y454S substitution in HARS, is inherited in an autosomal recessive fashion and associated with childhood deafness, blindness, and episodic hallucinations during acute illness. The biochemical basis of the pathophysiologies linked to USH3B is currently unknown. Here, we present a detailed functional comparison of wild-type (WT) and Y454S HARS enzymes. Kinetic parameters for enzymes and canonical substrates were determined using both steady state and rapid kinetics. Enzyme stability was examined using differential scanning fluorimetry. Finally, enzyme functionality in a primary cell culture was assessed. Our results demonstrate that the Y454S substitution leaves HARS amino acid activation, aminoacylation, and tRNA His binding functions largely intact compared with those of WT HARS, and the mutant enzyme dimerizes like the wild type does. Interestingly, during our investigation, it was revealed that the kinetics of amino acid activation differs from that of the previously characterized bacterial HisRS. Despite the similar kinetics, differential scanning fluorimetry revealed that Y454S is less thermally stable than WT HARS, and cells from Y454S patients grown at elevated temperatures demonstrate diminished levels of protein synthesis compared to those of WT cells. The thermal sensitivity associated with the Y454S mutation represents a biochemical basis for understanding USH3B.