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Sample records for childhood leukemia relapse

  1. Late relapsing childhood lymphoblastic leukemia.

    PubMed

    Vora, A; Frost, L; Goodeve, A; Wilson, G; Ireland, R M; Lilleyman, J; Eden, T; Peake, I; Richards, S

    1998-10-01

    Childhood lymphoblastic leukemia (ALL) is usually assumed to have been permanently eradicated in patients in long-term remission, but occasionally can recur after many years. To learn more about the problem, we studied a group of children whose leukemia had been in remission for 10 or more years before relapse and tried to determine whether they had true recurrences or second malignancies. We studied children treated on Medical Research Council ALL protocols between 1970 and 1984 and followed up by the Clinical Trial Service Unit in Oxford. Detailed clinical and laboratory data was collected from the centers concerned on all who were reported to have had a recurrence of their leukemia after 10 or more years from the time of achieving first complete remission (CR1). To prove that the relapse was a true recurrence rather than a second or secondary leukemia, DNA extracted from archived marrow smears was subjected to polymerase chain reaction (PCR) analysis for the presence of an identical Ig heavy chain (IgH) or T-cell receptor (TCR) gene rearrangement at initial diagnosis and subsequent relapse. A total of 1,134 of 2,746 children had survived 10 years or more (range, 10 to 24 years) in CR1 and of those, 12 (approximately 1%) had subsequently relapsed. Relapse blast cells were shown to express the common ALL antigen (CD 10) in all cases and an identical clonal IgH or TCR gene rearrangement was found on PCR analysis of DNA from diagnosis and relapse in all eight cases where DNA extraction was successful. A further program of therapy was successful in inducing a second CR in all patients, four of whom have succumbed to a second relapse after 12 to 27 months. The remaining eight are in continuing CR2 at a follow-up of 12 to 108 months (median, 52) from relapse. Although the risk of relapse of childhood ALL after 10 years in remission appears to be small (around 1%), it persists. This raises questions about how blasts can survive quiescent for so long and when we can

  2. Outcome following late marrow relapse in childhood acute lymphoblastic leukemia

    SciTech Connect

    Chessells, J.; Leiper, A.; Rogers, D.

    1984-10-01

    Thirty-four children with acute lymphoblastic leukemia, who developed bone marrow relapse after treatment was electively stopped, received reinduction, consolidation, continuing therapy, and intrathecal (IT) methotrexate (MTX). Sixteen children who relapsed within six months of stopping treatment had a median second-remission duration of 26 weeks; all next relapses occurred in the bone marrow. In 18 children who relapsed later, the median duration of second remission was in excess of two years, but after a minimum of four years follow-up, 16 patients have so far relapsed again (six in the CNS). CNS relapse occurred as a next event in four of 17 children who received five IT MTX injections only and in two of 14 children who received additional regular IT MTX. Although children with late marrow relapses may achieve long second remissions, their long-term out-look is poor, and regular IT MTX does not afford adequate CNS prophylaxis. It remains to be seen whether more intensive chemotherapy, including high-dose chemoradiotherapy and bone marrow transplantation, will improve the prognosis in this group of patients.

  3. Minimal residual disease analysis by eight-color flow cytometry in relapsed childhood acute lymphoblastic leukemia

    PubMed Central

    Karawajew, Leonid; Dworzak, Michael; Ratei, Richard; Rhein, Peter; Gaipa, Giuseppe; Buldini, Barbara; Basso, Giuseppe; Hrusak, Ondrej; Ludwig, Wolf-Dieter; Henze, Günter; Seeger, Karl; von Stackelberg, Arend; Mejstrikova, Ester; Eckert, Cornelia

    2015-01-01

    Multiparametric flow cytometry is an alternative approach to the polymerase chain reaction method for evaluating minimal residual disease in treatment protocols for primary acute lymphoblastic leukemia. Given considerable differences between primary and relapsed acute lymphoblastic leukemia treatment regimens, flow cytometric assessment of minimal residual disease in relapsed leukemia requires an independent comprehensive investigation. In the present study we addressed evaluation of minimal residual disease by flow cytometry in the clinical trial for childhood relapsed acute lymphoblastic leukemia using eight-color flow cytometry. The major challenge of the study was to reliably identify low amounts of residual leukemic cells against the complex background of regeneration, characteristic of follow-up samples during relapse treatment. In a prospective study of 263 follow-up bone marrow samples from 122 patients with B-cell precursor acute lymphoblastic leukemia, we tested various B-cell markers, adapted the antibody panel to the treatment protocol, and evaluated its performance by a blinded parallel comparison with the polymerase chain reaction data. The resulting eight-color single-tube panel showed a consistently high overall concordance (P<0.001) and, under optimal conditions, sensitivity similar to that of the reference polymerase chain reaction method. Overall, evaluation of minimal residual disease by flow cytometry can be successfully integrated into the clinical management of relapsed childhood acute lymphoblastic leukemia either as complementary to the polymerase chain reaction or as an independent risk stratification tool. ALL-REZ BFM 2002 clinical trial information: NCT00114348 PMID:26001791

  4. Deletion analysis of p16(INKa) and p15(INKb) in relapsed childhood acute lymphoblastic leukemia.

    PubMed

    Graf Einsiedel, Hagen; Taube, Tillmann; Hartmann, Reinhard; Wellmann, Sven; Seifert, Georg; Henze, Günter; Seeger, Karl

    2002-06-15

    This study aimed at determining the prevalence of INK4 deletions and their impact on outcome in 125 children with acute lymphoblastic leukemia (ALL) at first relapse using real-time quantitative polymerase chain reaction. Patients were enrolled into relapse trials ALL-REZ BFM (ALL-Relapse Berlin-Frankfurt-Münster) 90 and 96. The prevalence of p16(INK4a) and p15(INK4b) homozygous deletions was 35% (44 of 125) and 30% (38 of 125), respectively. A highly significant association of both gene deletions was found with the 2 major adverse prognostic factors known for relapsed childhood ALL: T-cell immunophenotype and first remission duration. There was no correlation between INK4 deletions and probability of event-free survival. These findings argue against an independent prognostic role of INK4 deletions in relapsed childhood ALL. PMID:12036898

  5. Childhood Leukemia

    MedlinePlus

    Leukemia is cancer of the white blood cells. It is the most common type of childhood cancer. ... blood cells help your body fight infection. In leukemia, the bone marrow produces abnormal white blood cells. ...

  6. KRAS and CREBBP mutations: a relapse-linked malicious liaison in childhood high hyperdiploid acute lymphoblastic leukemia

    PubMed Central

    Malinowska-Ozdowy, K; Frech, C; Schönegger, A; Eckert, C; Cazzaniga, G; Stanulla, M; zur Stadt, U; Mecklenbräuker, A; Schuster, M; Kneidinger, D; von Stackelberg, A; Locatelli, F; Schrappe, M; Horstmann, M A; Attarbaschi, A; Bock, C; Mann, G; Haas, O A; Panzer-Grümayer, R

    2015-01-01

    High hyperdiploidy defines the largest genetic entity of childhood acute lymphoblastic leukemia (ALL). Despite its relatively low recurrence risk, this subgroup generates a high proportion of relapses. The cause and origin of these relapses remains obscure. We therefore explored the mutational landscape in high hyperdiploid (HD) ALL with whole-exome (n=19) and subsequent targeted deep sequencing of 60 genes in 100 relapsing and 51 non-relapsing cases. We identified multiple clones at diagnosis that were primarily defined by a variety of mutations in receptor tyrosine kinase (RTK)/Ras pathway and chromatin-modifying genes. The relapse clones consisted of reappearing as well as new mutations, and overall contained more mutations. Although RTK/Ras pathway mutations were similarly frequent between diagnosis and relapse, both intergenic and intragenic heterogeneity was essentially lost at relapse. CREBBP mutations, however, increased from initially 18–30% at relapse, then commonly co-occurred with KRAS mutations (P<0.001) and these relapses appeared primarily early (P=0.012). Our results confirm the exceptional susceptibility of HD ALL to RTK/Ras pathway and CREBBP mutations, but, more importantly, suggest that mutant KRAS and CREBBP might cooperate and equip cells with the necessary capacity to evolve into a relapse-generating clone. PMID:25917266

  7. KRAS and CREBBP mutations: a relapse-linked malicious liaison in childhood high hyperdiploid acute lymphoblastic leukemia.

    PubMed

    Malinowska-Ozdowy, K; Frech, C; Schönegger, A; Eckert, C; Cazzaniga, G; Stanulla, M; zur Stadt, U; Mecklenbräuker, A; Schuster, M; Kneidinger, D; von Stackelberg, A; Locatelli, F; Schrappe, M; Horstmann, M A; Attarbaschi, A; Bock, C; Mann, G; Haas, O A; Panzer-Grümayer, R

    2015-08-01

    High hyperdiploidy defines the largest genetic entity of childhood acute lymphoblastic leukemia (ALL). Despite its relatively low recurrence risk, this subgroup generates a high proportion of relapses. The cause and origin of these relapses remains obscure. We therefore explored the mutational landscape in high hyperdiploid (HD) ALL with whole-exome (n=19) and subsequent targeted deep sequencing of 60 genes in 100 relapsing and 51 non-relapsing cases. We identified multiple clones at diagnosis that were primarily defined by a variety of mutations in receptor tyrosine kinase (RTK)/Ras pathway and chromatin-modifying genes. The relapse clones consisted of reappearing as well as new mutations, and overall contained more mutations. Although RTK/Ras pathway mutations were similarly frequent between diagnosis and relapse, both intergenic and intragenic heterogeneity was essentially lost at relapse. CREBBP mutations, however, increased from initially 18-30% at relapse, then commonly co-occurred with KRAS mutations (P<0.001) and these relapses appeared primarily early (P=0.012). Our results confirm the exceptional susceptibility of HD ALL to RTK/Ras pathway and CREBBP mutations, but, more importantly, suggest that mutant KRAS and CREBBP might cooperate and equip cells with the necessary capacity to evolve into a relapse-generating clone. PMID:25917266

  8. Childhood Leukemia

    MedlinePlus

    ... acute types. Symptoms include Infections Fever Loss of appetite Tiredness Easy bruising or bleeding Swollen lymph nodes Night sweats Shortness of breath Pain in the bones or joints Risk factors for childhood leukemia include having a brother ...

  9. Clofarabine-based combination chemotherapy for relapse and refractory childhood acute lymphoblastic leukemia.

    PubMed

    Arakawa, Yuki; Koh, Katsuyoshi; Aoki, Takahiro; Kubota, Yasuo; Oyama, Ryo; Mori, Makiko; Hayashi, Mayumi; Hanada, Ryoji

    2014-11-01

    Clofarabine, one of the key treatment agents for refractory and relapsed acute lymphoblastic leukemia (ALL), achieves a remission rate of approximately 30% with single-agent clofarabine induction chemotherapy. However, a remission rate of approximately 50% was reported with a combination chemotherapy regimen consisting of clofarabine, etoposide, and cyclophosphamide. We treated two cases with refractory and relapsed ALL with combination chemotherapy including clofarabine; one was an induction failure but the other achieved remission. Both cases developed an infectious complication (NCI-CTCAE grade 3) and body pain with infusion. Prophylactic antibiotic and opioid infusions facilitated avoiding septic shock and pain. Further investigation of such cases is required. PMID:25501414

  10. What Is Childhood Leukemia?

    MedlinePlus

    ... key statistics for childhood leukemia? What is childhood leukemia? Cancer starts when cells start to grow out ... start making antibodies to fight them. Types of leukemia in children Leukemia is often described as being ...

  11. 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

  12. Inherited GATA3 variants are associated with Ph-like childhood acute lymphoblastic leukemia and risk of relapse

    PubMed Central

    Perez-Andreu, Virginia; Roberts, Kathryn G.; Harvey, Richard C.; Yang, Wenjian; Cheng, Cheng; Pei, Deqing; Xu, Heng; Gastier-Foster, Julie; Shuyu, E; Yew-Suang Lim, Joshua; Chen, I-Ming; Fan, Yiping; Devidsa, Meenakshi; Borowitz, Michael J.; Smith, Colton; Neale, Geoffrey; Burchard, Esteban G.; Torgerson, Dara G.; Klussmann, Federico Antillon; Villagran, Cesar Rolando Najera; Winick, Naomi J.; Camitta, Bruce M.; Raetz, Elizabeth; Wood, Brent; Yue, Feng; Carroll, William L.; Larsen, Eric; Bowman, W. Paul; Loh, Mignon L.; Dean, Michael; Bhojwani, Deepa; Pui, Ching-Hon; Evans, William E.; Relling, Mary V.; Hunger, Stephen P.; Willman, Cheryl L.; Mullighan, Charles G.; Yang, Jun J.

    2014-01-01

    Recent genomic profiling of childhood acute lymphoblastic leukemia (ALL) identified a novel high-risk subtype with a gene expression signature resembling Philadelphia chromosome-positive ALL and a poor prognosis (Ph-like ALL). However, the role of inherited genetic variation in Ph-like ALL pathogenesis remains unknown. In a genome-wide association study (GWAS) of 511 ALL cases and 6,661 non-ALL controls, we identified a single susceptibility locus for Ph-like ALL (GATA3, rs3824662, P=2.17×10−14, odds ratio [OR]=3.85, for Ph-like ALL vs. non-ALL; P=1.05×10−8, OR=3.25, for Ph-like ALL vs. non-Ph-like ALL) that was independently validated. The rs3824662 risk allele was associated with somatic lesions underlying Ph-like ALL (i.e., CRLF2 rearrangement, JAK mutation, and IKZF1 deletion) and directly influenced GATA3 transcription. Finally, GATA3 SNP genotype was also associated with early treatment response and the risk of ALL relapse. Our results provide insights into interactions between host and tumor genomes and their importance in ALL pathogenesis and prognosis. PMID:24141364

  13. CD7 aberrant expression led to a lineage switch at relapsed childhood acute pre-B lymphoblastic leukemia.

    PubMed

    Fallah Azad, Vahid; Hedayati Asl, Amir Abbas; Tashvighi, Maryam; Niktoreh Mofrad, Naghmeh; Haghighi, Mansoureh; Mehrvar, Azim

    2016-03-01

    Immunophenotypic changes and lineage switch between diagnosis and relapse in acute lymphoblastic leukemia are uncommon and accompanied by poor outcomes. In this report, a 12-year-old boy with diagnosis of pre-B ALL with an aberrant expression of CD 7 is described. Patient was treated with the ALL-BFM 2000 protocol and suffered an episode of relapse with a lineage switch from pre-B ALL to T cell ALL. This report concludes that presence of aberrant expression of CD7 at diagnosis of pre-B ALL can have prognostic value of lineage switch to T cell ALL at relapse. PMID:26242204

  14. Immunophenotype of adult and childhood acute lymphoblastic leukemia: changes at first relapse and clinico-prognostic implications.

    PubMed

    Guglielmi, C; Cordone, I; Boecklin, F; Masi, S; Valentini, T; Vegna, M L; Ferrari, A; Testi, A M; Foa, R

    1997-09-01

    The immunologic features of leukemic cells at the time of 1st hematologic relapse were compared to those obtained at initial diagnosis in 128 patients (69 children and 59 adults) with acute lymphoblastic leukemia (ALL) treated at a single institution. An immunophenotypic change was observed in 59 cases (46%), more frequently in T (20/25) than in B (39/103) lineage ALL (80 vs 38%, P=0.0008), but with a similar incidence in adults and children. Of these cases, 34 (24 B- and 10 T-ALL) changed at relapse their intralineage subgroup affiliation, although no complete shift from B to T lineage ALL, or vice versa, was observed. The myeloid antigens CD13 and/or CD33 were frequently lost (2/5 cases) or acquired (12/123 cases) at relapse. In 21 cases, the immunophenotype at relapse was more undifferentiated than at diagnosis, while it was more differentiated in 13 cases. Initial treatment intensity or preceding treatment with teniposide did not affect the phenotypic profile at relapse. Complete response (CR) rate to salvage therapy and event-free survival were not influenced by the immunophenotypic shifts, nor by the presence, at relapse, of leukemic cells expressing the myeloid antigens CD13 and/or CD33. Univariate analysis suggested that prognosis after relapse was dependent on the duration of 1st CR, patients' age and immunophenotype at the time of diagnosis, with a worse outcome for patients with T lineage ALL and for patients with the less differentiated subgroup of B lineage ALL (CD19+ and CD10-). Multivariate analysis showed that only two factors, duration of 1st CR and grade of immunologic differentiation at diagnosis, have independent prognostic value in relapsed ALL. PMID:9305605

  15. Genetically Modified T-cell Immunotherapy in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

    ClinicalTrials.gov

    2016-08-10

    Adult Acute Myeloid Leukemia in Remission; Donor; Early Relapse of Acute Myeloid Leukemia; Late Relapse of Acute Myeloid Leukemia; Recurrent Adult Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia

  16. Obatoclax Mesylate, Vincristine Sulfate, Doxorubicin Hydrochloride, and Dexrazoxane Hydrochloride in Treating Young Patients With Relapsed or Refractory Solid Tumors, Lymphoma, or Leukemia

    ClinicalTrials.gov

    2014-04-30

    Acute Leukemias of Ambiguous Lineage; Acute Undifferentiated Leukemia; Angioimmunoblastic T-cell Lymphoma; Blastic Phase Chronic Myelogenous Leukemia; 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; Cutaneous B-cell Non-Hodgkin Lymphoma; Hepatosplenic T-cell Lymphoma; Intraocular Lymphoma; Noncutaneous Extranodal Lymphoma; Peripheral T-cell 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 Mycosis Fungoides/Sezary Syndrome; Recurrent/Refractory Childhood Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Relapsing Chronic Myelogenous Leukemia; Small Intestine Lymphoma; Unspecified Childhood Solid Tumor, Protocol Specific

  17. Combination Chemotherapy and Imatinib Mesylate in Treating Children With Relapsed Acute Lymphoblastic Leukemia

    ClinicalTrials.gov

    2013-10-07

    L1 Childhood Acute Lymphoblastic Leukemia; L2 Childhood Acute Lymphoblastic Leukemia; Non-T, Non-B Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; T-cell Childhood Acute Lymphoblastic Leukemia

  18. Integration of genetic and clinical risk factors improves prognostication in relapsed childhood B-cell precursor acute lymphoblastic leukemia.

    PubMed

    Irving, Julie A E; Enshaei, Amir; Parker, Catriona A; Sutton, Rosemary; Kuiper, Roland P; Erhorn, Amy; Minto, Lynne; Venn, Nicola C; Law, Tamara; Yu, Jiangyan; Schwab, Claire; Davies, Rosanna; Matheson, Elizabeth; Davies, Alysia; Sonneveld, Edwin; den Boer, Monique L; Love, Sharon B; Harrison, Christine J; Hoogerbrugge, Peter M; Revesz, Tamas; Saha, Vaskar; Moorman, Anthony V

    2016-08-18

    Somatic genetic abnormalities are initiators and drivers of disease and have proven clinical utility at initial diagnosis. However, the genetic landscape and its clinical utility at relapse are less well understood and have not been studied comprehensively. We analyzed cytogenetic data from 427 children with relapsed B-cell precursor ALL treated on the international trial, ALLR3. Also we screened 238 patients with a marrow relapse for selected copy number alterations (CNAs) and mutations. Cytogenetic risk groups were predictive of outcome postrelapse and survival rates at 5 years for patients with good, intermediate-, and high-risk cytogenetics were 68%, 47%, and 26%, respectively (P < .001). TP53 alterations and NR3C1/BTG1 deletions were associated with a higher risk of progression: hazard ratio 2.36 (95% confidence interval, 1.51-3.70, P < .001) and 2.15 (1.32-3.48, P = .002). NRAS mutations were associated with an increased risk of progression among standard-risk patients with high hyperdiploidy: 3.17 (1.15-8.71, P = .026). Patients classified clinically as standard and high risk had distinct genetic profiles. The outcome of clinical standard-risk patients with high-risk cytogenetics was equivalent to clinical high-risk patients. Screening patients at relapse for key genetic abnormalities will enable the integration of genetic and clinical risk factors to improve patient stratification and outcome. This study is registered at www.clinicaltrials.org as #ISCRTN45724312. PMID:27229005

  19. Immunotoxin Therapy for Relapsed Hairy Cell Leukemia

    Cancer.gov

    In this trial, patients with hairy cell leukemia who have relapsed multiple times or not responded to prior chemotherapy will be treated with an experimental immunotoxin called moxetumomab pasudotox given intravenously on days 1, 3, and 5 of 28-day cycles

  20. Novel Therapies for Relapsed Acute Lymphoblastic Leukemia

    PubMed Central

    Fullmer, Amber; O’Brien, Susan; Kantarjian, Hagop; Jabbour, Elias

    2015-01-01

    The outcome of salvage therapy for relapsed acute lymphoblastic leukemia (ALL) remains poor. Salvage therapy mimics regimens with activity in newly diagnosed ALL. Novel strategies under investigation as monotherapy or in combination with chemotherapy improve the treatment of relapsed disease. For some ALL subsets, specific therapies are indicated. The addition of targeted therapy in Philadelphia chromosome–positive ALL has improved responses in relapsed patients without resistance to available tyrosine kinase inhibitors. Nelarabine demonstrates activity as monotherapy in T-cell ALL and is approved by the US Food and Drug Administration. Clofarabine, a second-generation purine analogue approved in pediatric leukemia, has shown activity in adult acute leukemias including ALL and acute myeloid leukemia. The role of pegaspargase in adult ALL requires further investigation. The benefit of matched related-donor allogeneic stem cell transplantation is significant for standard-risk ALL but not for high-risk ALL. Development of new drugs and agents tailored to subset-specific cytogenetic-molecular characteristics remains vital to success in treating adult ALL. PMID:20425428

  1. 8-Chloro-Adenosine in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

    ClinicalTrials.gov

    2016-05-11

    Recurrent Adult Acute Myeloid Leukemia; Relapsed Adult Acute Myeloid Leukemia; Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome; Acute Myeloid Leukemia Arising From Previous Myeloproliferative Disorder

  2. Flavopiridol and Vorinostat in Treating Patients With Relapsed or Refractory Acute Leukemia or Chronic Myelogenous Leukemia or Refractory Anemia

    ClinicalTrials.gov

    2013-04-01

    Blastic Phase Chronic Myelogenous Leukemia; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Refractory Anemia With Excess Blasts; Relapsing Chronic Myelogenous Leukemia; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Adult Acute Myeloid Leukemia

  3. Nilotinib and Imatinib Mesylate After Donor Stem Cell Transplant in Treating Patients With Acute Lymphoblastic Leukemia or Chronic Myelogenous Leukemia

    ClinicalTrials.gov

    2014-12-09

    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 Chromosome Positive Adult Precursor Acute Lymphoblastic Leukemia; Philadelphia Chromosome Positive Childhood Precursor 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

  4. Developmental Outcome of Childhood Leukemia.

    ERIC Educational Resources Information Center

    Coniglio, Susan J.; Blackman, James A.

    1995-01-01

    Literature on developmental and psychosocial outcomes of childhood leukemia is reviewed, focusing on preschool-age children. Studies are categorized in terms of outcome measures: intelligence/achievement, neuropsychological, memory/attention, and psychosocial tests. Evidence suggests that preschool children with leukemia are at high risk for…

  5. 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

  6. Ancestry and pharmacogenomics of relapse in acute lymphoblastic leukemia.

    PubMed

    Yang, Jun J; Cheng, Cheng; Devidas, Meenakshi; Cao, Xueyuan; Fan, Yiping; Campana, Dario; Yang, Wenjian; Neale, Geoff; Cox, Nancy J; Scheet, Paul; Borowitz, Michael J; Winick, Naomi J; Martin, Paul L; Willman, Cheryl L; Bowman, W Paul; Camitta, Bruce M; Carroll, Andrew; Reaman, Gregory H; Carroll, William L; Loh, Mignon; Hunger, Stephen P; Pui, Ching-Hon; Evans, William E; Relling, Mary V

    2011-03-01

    Although five-year survival rates for childhood acute lymphoblastic leukemia (ALL) are now over 80% in most industrialized countries, not all children have benefited equally from this progress. Ethnic differences in survival after childhood ALL have been reported in many clinical studies, with poorer survival observed among African Americans or those with Hispanic ethnicity when compared with European Americans or Asians. The causes of ethnic differences remain uncertain, although both genetic and non-genetic factors are likely important. Interrogating genome-wide germline SNP genotypes in an unselected large cohort of children with ALL, we observed that the component of genomic variation that co-segregated with Native American ancestry was associated with risk of relapse (P = 0.0029) even after adjusting for known prognostic factors (P = 0.017). Ancestry-related differences in relapse risk were abrogated by the addition of a single extra phase of chemotherapy, indicating that modifications to therapy can mitigate the ancestry-related risk of relapse. PMID:21297632

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

    ClinicalTrials.gov

    2016-05-19

    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 Adult Acute Lymphoblastic Leukemia; Refractory Childhood Acute Lymphoblastic Leukemia

  8. Signs and Symptoms of Childhood Leukemia

    MedlinePlus

    ... early? Next Topic How is childhood leukemia diagnosed? Signs and symptoms of childhood leukemia Many of the ... blood cells do. Fever is often the main sign of infection. But some children might have a ...

  9. Gemtuzumab Ozogamicin in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia or Acute Promyelocytic Leukemia

    ClinicalTrials.gov

    2015-07-27

    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); Childhood Acute Promyelocytic Leukemia (M3); Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Myeloid Leukemia

  10. Nivolumab and Dasatinib in Treating Patients With Relapsed or Refractory Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia

    ClinicalTrials.gov

    2016-06-28

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

  11. The Childhood Leukemia International Consortium

    PubMed Central

    Metayer, Catherine; Milne, Elizabeth; Clavel, Jacqueline; Infante-Rivard, Claire; Petridou, Eleni; Taylor, Malcolm; Schüz, Joachim; Spector, Logan G.; Dockerty, John D.; Magnani, Corrado; Pombo-de-Oliveira, Maria S.; Sinnett, Daniel; Murphy, Michael; Roman, Eve; Monge, Patricia; Ezzat, Sameera; Mueller, Beth A.; Scheurer, Michael E.; Armstrong, Bruce K.; Birch, Jill; Kaatsch, Peter; Koifman, Sergio; Lightfoot, Tracy; Bhatti, Parveen; Bondy, Melissa L.; Rudant, Jérémie; O’Neill, Kate; Miligi, Lucia; Dessypris, Nick; Kang, Alice Y.; Buffler, Patricia A.

    2013-01-01

    Background Acute leukemia is the most common cancer in children under 15 years of age; 80% are acute lymphoblastic leukemia (ALL) and 17% are acute myeloid leukemia (AML). Childhood leukemia shows further diversity based on cytogenetic and molecular characteristics, which may relate to distinct etiologies. Case–control studies conducted worldwide, particularly of ALL, have collected a wealth of data on potential risk factors and in some studies, biospecimens. There is growing evidence for the role of infectious/immunologic factors, fetal growth, and several environmental factors in the etiology of childhood ALL. The risk of childhood leukemia, like other complex diseases, is likely to be influenced both by independent and interactive effects of genes and environmental exposures. While some studies have analyzed the role of genetic variants, few have been sufficiently powered to investigate gene–environment interactions. Objectives The Childhood Leukemia International Consortium (CLIC) was established in 2007 to promote investigations of rarer exposures, gene–environment interactions and subtype-specific associations through the pooling of data from independent studies. Methods By September 2012, CLIC included 22 studies (recruitment period: 1962–present) from 12 countries, totaling approximately 31 000 cases and 50 000 controls. Of these, 19 case–control studies have collected detailed epidemiologic data, and DNA samples have been collected from children and child–parent trios in 15 and 13 of these studies, respectively. Two registry-based studies and one study comprising hospital records routinely obtained at birth and/or diagnosis have limited interview data or biospecimens. Conclusions CLIC provides a unique opportunity to fill gaps in knowledge about the role of environmental and genetic risk factors, critical windows of exposure, the effects of gene–environment interactions and associations among specific leukemia subtypes in different ethnic

  12. Clinical and In Vitro Studies on Impact of High-Dose Etoposide Pharmacokinetics Prior Allogeneic Hematopoietic Stem Cell Transplantation for Childhood Acute Lymphoblastic Leukemia on the Risk of Post-Transplant Leukemia Relapse.

    PubMed

    Sobiak, Joanna; Kazimierczak, Urszula; Kowalczyk, Dariusz W; Chrzanowska, Maria; Styczyński, Jan; Wysocki, Mariusz; Szpecht, Dawid; Wachowiak, Jacek

    2015-10-01

    The impact of etoposide (VP-16) plasma concentrations on the day of allogeneic hematopoietic stem cell transplantation (allo-HSCT) on leukemia-free survival in children with acute lymphoblastic leukemia (ALL) was studied. In addition, the in vitro effects of VP-16 on the lymphocytes proliferation, cytotoxic activity and on Th1/Th2 cytokine responses were assessed. In 31 children undergoing allo-HSCT, VP-16 plasma concentrations were determined up to 120 h after the infusion using the HPLC-UV method. For mentioned in vitro studies, VP-16 plasma concentrations observed on allo-HSCT day were used. In 84 % of children, VP-16 plasma concentrations (0.1-1.5 μg/mL) were quantifiable 72 h after the end of the drug infusion, i.e. when allo-HSCT should be performed. In 20 (65 %) children allo-HSCT was performed 4 days after the end of the drug infusion, and VP-16 was still detectable (0.1-0.9 μg/mL) in plasma of 12 (39 %) of them. Post-transplant ALL relapse occurred in four children, in all of them VP-16 was detectable in plasma (0.1-0.8 μg/mL) on allo-HSCT day, while there was no relapse in children with undetectable VP-16. In in vitro studies, VP-16 demonstrated impact on the proliferation activity of stimulated lymphocytes depending on its concentration and exposition time. The presence of VP-16 in plasma on allo-HSCT day may demonstrate an adverse effect on graft-versus-leukemia (GvL) reaction and increase the risk of post-transplant ALL relapse. Therefore, if 72 h after VP-16 administration its plasma concentration is still above 0.1 μg/mL then the postponement of transplantation for next 24 h should be considered to protect GvL effector cells from transplant material. PMID:26040247

  13. Bortezomib and Combination Chemotherapy in Treating Young Patients With Relapsed Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma

    ClinicalTrials.gov

    2014-09-30

    B-cell Adult Acute Lymphoblastic Leukemia; B-cell Childhood Acute Lymphoblastic Leukemia; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Lymphoblastic Lymphoma; T-cell Adult Acute Lymphoblastic Leukemia; T-cell Childhood Acute Lymphoblastic Leukemia

  14. 5T4 oncofetal antigen is expressed in high risk of relapse childhood pre-B acute lymphoblastic leukemia and is associated with a more invasive and chemotactic phenotype.

    PubMed

    Castro, F V; McGinn, O J; Krishnan, S; Marinov, G; Li, J; Rutkowski, A J; Elkord, E; Burt, D J; Holland, M; Vaghjiani, R; Gallego, A; Saha, V; Stern, P L

    2012-07-01

    Although the overall prognosis in childhood acute lymphoblastic leukemia (ALL) is good, outcome after relapse is poor. Recurrence is frequently characterized by the occurrence of disease at extramedullary sites, such as the central nervous system and testes. Subpopulations of blasts able to migrate to such areas may have a survival advantage and give rise to disease recurrence. Gene expression profiling of 85 diagnostic pre-B-ALL bone marrow samples revealed higher 5T4 oncofetal antigen transcript levels in cytogenetic high-risk subgroups of patients (P<0.001). Flow cytometric analysis determined that bone marrow from relapse patients have a significantly higher percentage of 5T4-positive leukemic blasts than healthy donors (P=0.005). The high-risk Sup-B15 pre-B-ALL line showed heterogeneity in 5T4 expression, and the derived, 5T4(+) (Sup5T4) and 5T4(-) (Sup) subline cells, displayed differential spread to the omentum and ovaries following intraperitoneal inoculation of immunocompromised mice. Consistent with this, Sup5T4 compared with Sup cells show increased invasion in vitro concordant with increased LFA-1 and VLA-4 integrin expression, adhesion to extracellular matrix and secretion of matrix metalloproteases (MMP-2/-9). We also show that 5T4-positive Sup-B15 cells are susceptible to 5T4-specific superantigen antibody-dependent cellular toxicity providing support for targeted immunotherapy in high-risk pre-B-ALL. PMID:22266911

  15. Phase I Trial of the Selective Inhibitor of Nuclear Export, KPT-330, in Relapsed Childhood ALL and AML

    ClinicalTrials.gov

    2016-08-03

    Relapsed Acute Lymphoblastic Leukemia (ALL); Refractory Acute Lymphoblastic Leukemia (ALL); Relapsed Acute Myelogenous Leukemia (AML); Refractory Acute Myelogenous Leukemia (AML); Relapsed Mixed Lineage Leukemia; Refractory Mixed Lineage Leukemia; Relapsed Biphenotypic Leukemia; Refractory Biphenotypic Leukemia; Chronic Myelogenous Leukemia (CML) in Blast Crisis

  16. Treating Multiply Relapsed or Refractory Hairy Cell Leukemia

    Cancer.gov

    In this trial, patients with hairy cell leukemia who have not responded or relapsed after initial chemotherapy will be randomly assigned to receive rituximab combined with either pentostatin or bendamustine.

  17. 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 ...

  18. Fludarabine Phosphate and Total-Body Irradiation Followed by Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Acute Lymphoblastic Leukemia or Chronic Myelogenous Leukemia That Has Responded to Treatment With Imatinib Mesylate, Dasatinib, or Nilotinib

    ClinicalTrials.gov

    2016-07-18

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

  19. Treatment Option Overview (Childhood Acute Lymphoblastic Leukemia)

    MedlinePlus

    ... recovery) and treatment options. Childhood acute lymphoblastic leukemia (ALL) is a type of cancer in which the ... genetic conditions affect the risk of having childhood ALL. Anything that increases your risk of getting a ...

  20. Risk Groups for Childhood Acute Lymphoblastic Leukemia

    MedlinePlus

    ... recovery) and treatment options. Childhood acute lymphoblastic leukemia (ALL) is a type of cancer in which the ... genetic conditions affect the risk of having childhood ALL. Anything that increases your risk of getting a ...

  1. Treatment Options for Childhood Acute Lymphoblastic Leukemia

    MedlinePlus

    ... recovery) and treatment options. Childhood acute lymphoblastic leukemia (ALL) is a type of cancer in which the ... genetic conditions affect the risk of having childhood ALL. Anything that increases your risk of getting a ...

  2. Maternal immunoglobulin E and childhood leukemia.

    PubMed

    Chang, Jeffrey S; Buffler, Patricia A; Metayer, Catherine; Chokkalingam, Anand P; Patoka, Joe; Kronish, Daniel; Wiemels, Joseph L

    2009-08-01

    Childhood leukemia, particularly acute lymphoblastic leukemia (ALL), has long been hypothesized to be affected by abnormal immune responses to microbial challenges stemming from a lack of immune modulation in early childhood. Studies of allergies suggest that a child's immune development may be modulated by maternal immune status. We conducted a study to explore the relationship between maternal immunoglobulin E (IgE) and childhood leukemia and to investigate whether maternal immune status can influence childhood leukemia risk. Serum total and specific IgE (respiratory and food) were measured in biological mothers of 352 children (193 healthy controls and 159 leukemia cases, including 139 ALL cases) ages <8 years who were enrolled in the Northern California Childhood Leukemia Study. Odds ratios associated with maternal IgE were calculated using unconditional logistic regression adjusted for child's age, sex, race/ethnicity, and annual household income. A positive association between childhood leukemia or ALL and elevated levels of maternal serum total IgE was observed, especially among Hispanics. In addition, a positive association was observed between childhood leukemia or ALL and maternal respiratory or food IgE status. These results suggest that maternal immune function may play a crucial role in the etiology of childhood leukemia, although additional studies need to be conducted to confirm the results of this study and provide a perspective on mechanisms. PMID:19622720

  3. 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

  4. Genomic characterization of childhood acute lymphoblastic leukemia

    PubMed Central

    Mullighan, Charles G.

    2013-01-01

    Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy and a leading case of childhood cancer death. The last decade has witnessed a transformation in our understanding of the genetic basis of ALL due to detailed integrative genomic profiling of large cohorts of childhood ALL. Initially using microarray based approaches, and more recently with next-generation sequencing, these studies have enabled more precise sub-classification of ALL, and have shown that each ALL entity is characterized by constellations of structural and sequence mutations that typically perturb key cellular pathways including lymphoid development, cell cycle regulation, tumor suppression, Ras- and tyrosine kinase driven signaling, and epigenetic regulation. Importantly, several of the newly identified genetic alterations have entered the clinic to improve diagnosis and risk stratification, and are being pursued as new targets for therapeutic intervention. Studies of ALL have also led the way in dissecting the subclonal heterogeneity of cancer, and have shown that individual patients commonly harbor multiple related but genetically distinct subclones, and that this genetically determined clonal heterogeneity is an important determinant of relapse. In addition, genome-wide profiling has identified inherited genetic variants that influence ALL risk. Ongoing studies are deploying detailed integrative genetic transcriptomic and epigenetic sequencing to comprehensively define the genomic landscape of ALL. This review describes the recent advances in our understanding of the genetics of ALL, with an emphasis on those alterations of key pathogenic or therapeutic importance. PMID:24246699

  5. Genomic characterization of childhood acute lymphoblastic leukemia.

    PubMed

    Mullighan, Charles G

    2013-10-01

    Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy and a leading case of childhood cancer death. The last decade has witnessed a transformation in our understanding of the genetic basis of ALL due to detailed integrative genomic profiling of large cohorts of childhood ALL. Initially using microarray based approaches, and more recently with next-generation sequencing, these studies have enabled more precise subclassification of ALL, and have shown that each ALL entity is characterized by constellations of structural and sequence mutations that typically perturb key cellular pathways including lymphoid development, cell cycle regulation, tumor suppression, Ras- and tyrosine kinase-driven signaling, and epigenetic regulation. Importantly, several of the newly identified genetic alterations have entered the clinic to improve diagnosis and risk stratification, and are being pursued as new targets for therapeutic intervention. Studies of ALL have also led the way in dissecting the subclonal heterogeneity of cancer, and have shown that individual patients commonly harbor multiple related but genetically distinct subclones, and that this genetically determined clonal heterogeneity is an important determinant of relapse. In addition, genome-wide profiling has identified inherited genetic variants that influence ALL risk. Ongoing studies are deploying detailed integrative genetic transcriptomic and epigenetic sequencing to comprehensively define the genomic landscape of ALL. This review describes the recent advances in our understanding of the genetics of ALL, with an emphasis on those alterations of key pathogenic or therapeutic importance. PMID:24246699

  6. 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

  7. What Are the Key Statistics for Childhood Leukemia?

    MedlinePlus

    ... factors for childhood leukemia? What are the key statistics for childhood leukemia? Leukemia is the most common ... about 2. Visit the American Cancer Society’s Cancer Statistics Center for more key statistics. Survival statistics for ...

  8. Prognostic Factors in Childhood Leukemia (ALL or AML)

    MedlinePlus

    ... for childhood leukemias Prognostic factors in childhood leukemia (ALL or AML) Certain factors that can affect a ... myelogenous leukemia (AML). Prognostic factors for children with ALL Children with ALL are often divided into risk ...

  9. Aggressive chemotherapy for acute leukemia relapsed after transplantation.

    PubMed

    Sica, S; Salutari, P; Di Mario, A; D'Onofrio, G; Etuk, B; Leone, G

    1994-09-01

    Bone marrow transplantation procedure has emerged as an effective treatment for hematological malignancies. However, recurrence of leukemia is still the major cause of treatment failure. Subsequent treatment in this category of patients, generally considered incurable, has not been yet standardized. At our institution, 13 patients, 7 with acute non lymphoid leukemia (ANLL) and 6 with acute lymphoid leukemia (ALL), were treated at relapse after bone marrow transplantation either autologous or allogeneic (AuBMT 8, ABMT 4) performed in complete remission (CR). The interval between BMT and relapse was less than 9 months in 6 patients (2 ABMT and 4 AuBMT) and more than 9 months in 7 patients. Early relapsed patients showed no response to treatment and died at a median of 5.5 months (range 1-13) after relapse. Late relapse after BMT was characterized by a high percentage of response (5 CR and 1 PR), particularly after intensive chemotherapy and by a longer survival (median 14 months; range 2-36). Chemotherapy after transplantation should be carefully evaluated in patients relapsed after BMT in order to select a population that can achieve long term disease free survival. PMID:7858490

  10. RALLE pilot: response-guided therapy for marrow relapse in acute lymphoblastic leukemia in children.

    PubMed

    Saarinen-Pihkala, Ulla M; Parto, Katriina; Riikonen, Pekka; Lähteenmäki, Päivi M; Békàssy, Albert N; Glomstein, Anders; Möttönen, Merja

    2012-05-01

    Despite improved treatment results of childhood acute lymphoblastic leukemia (ALL), 20% to 30% have a relapse, and then the outcome is very poor. We studied 40 children with ALL marrow relapse piloting an ALL relapse protocol with well-known drugs and drug combinations by using a concept of response-guided design. We also measured response in logarithmic fashion. Our primary end points were achievement of M1 marrow status, minimal residual disease status below 10, and second remission. The remission induction rate was 90% with 10% induction mortality. After the A blocks (dexamethasone, vincristine, idarubicin and pegylated L-asparaginase), 85% had M1 status, 39% had minimal residual disease ≤1×10, and 66% had 2 to 3 log response. After B1 block (cyclo, VP-16) the figures were 92%, 58%, and 83%, respectively. Twenty-five of 40 patients received allogeneic stem cell transplantation. Three-year event-free survival of the whole cohort was 37%, and the relapse rate was 38%. Three-year event-free survival by risk group was 53% for late, 34% for early, and 21% for very early relapses. An ALL marrow relapse nonresponsive to steroids, vincristine, asparaginase, anthracyclines, and alkylating agents is uncommon, and these classic drugs can still be advocated for induction of ALL relapse. The problems lie in creating a consolidation capable of preventing particularly posttransplant relapses. PMID:22246158

  11. Comprehensive mutational analysis of primary and relapse acute promyelocytic leukemia

    PubMed Central

    Madan, V; Shyamsunder, P; Han, L; Mayakonda, A; Nagata, Y; Sundaresan, J; Kanojia, D; Yoshida, K; Ganesan, S; Hattori, N; Fulton, N; Tan, K-T; Alpermann, T; Kuo, M-C; Rostami, S; Matthews, J; Sanada, M; Liu, L-Z; Shiraishi, Y; Miyano, S; Chendamarai, E; Hou, H-A; Malnassy, G; Ma, T; Garg, M; Ding, L-W; Sun, Q-Y; Chien, W; Ikezoe, T; Lill, M; Biondi, A; Larson, R A; Powell, B L; Lübbert, M; Chng, W J; Tien, H-F; Heuser, M; Ganser, A; Koren-Michowitz, M; Kornblau, S M; Kantarjian, H M; Nowak, D; Hofmann, W-K; Yang, H; Stock, W; Ghavamzadeh, A; Alimoghaddam, K; Haferlach, T; Ogawa, S; Shih, L-Y; Mathews, V; Koeffler, H P

    2016-01-01

    Acute promyelocytic leukemia (APL) is a subtype of myeloid leukemia characterized by differentiation block at the promyelocyte stage. Besides the presence of chromosomal rearrangement t(15;17), leading to the formation of PML-RARA (promyelocytic leukemia-retinoic acid receptor alpha) fusion, other genetic alterations have also been implicated in APL. Here, we performed comprehensive mutational analysis of primary and relapse APL to identify somatic alterations, which cooperate with PML-RARA in the pathogenesis of APL. We explored the mutational landscape using whole-exome (n=12) and subsequent targeted sequencing of 398 genes in 153 primary and 69 relapse APL. Both primary and relapse APL harbored an average of eight non-silent somatic mutations per exome. We observed recurrent alterations of FLT3, WT1, NRAS and KRAS in the newly diagnosed APL, whereas mutations in other genes commonly mutated in myeloid leukemia were rarely detected. The molecular signature of APL relapse was characterized by emergence of frequent mutations in PML and RARA genes. Our sequencing data also demonstrates incidence of loss-of-function mutations in previously unidentified genes, ARID1B and ARID1A, both of which encode for key components of the SWI/SNF complex. We show that knockdown of ARID1B in APL cell line, NB4, results in large-scale activation of gene expression and reduced in vitro differentiation potential. PMID:27063598

  12. Comprehensive mutational analysis of primary and relapse acute promyelocytic leukemia.

    PubMed

    Madan, V; Shyamsunder, P; Han, L; Mayakonda, A; Nagata, Y; Sundaresan, J; Kanojia, D; Yoshida, K; Ganesan, S; Hattori, N; Fulton, N; Tan, K-T; Alpermann, T; Kuo, M-C; Rostami, S; Matthews, J; Sanada, M; Liu, L-Z; Shiraishi, Y; Miyano, S; Chendamarai, E; Hou, H-A; Malnassy, G; Ma, T; Garg, M; Ding, L-W; Sun, Q-Y; Chien, W; Ikezoe, T; Lill, M; Biondi, A; Larson, R A; Powell, B L; Lübbert, M; Chng, W J; Tien, H-F; Heuser, M; Ganser, A; Koren-Michowitz, M; Kornblau, S M; Kantarjian, H M; Nowak, D; Hofmann, W-K; Yang, H; Stock, W; Ghavamzadeh, A; Alimoghaddam, K; Haferlach, T; Ogawa, S; Shih, L-Y; Mathews, V; Koeffler, H P

    2016-08-01

    Acute promyelocytic leukemia (APL) is a subtype of myeloid leukemia characterized by differentiation block at the promyelocyte stage. Besides the presence of chromosomal rearrangement t(15;17), leading to the formation of PML-RARA (promyelocytic leukemia-retinoic acid receptor alpha) fusion, other genetic alterations have also been implicated in APL. Here, we performed comprehensive mutational analysis of primary and relapse APL to identify somatic alterations, which cooperate with PML-RARA in the pathogenesis of APL. We explored the mutational landscape using whole-exome (n=12) and subsequent targeted sequencing of 398 genes in 153 primary and 69 relapse APL. Both primary and relapse APL harbored an average of eight non-silent somatic mutations per exome. We observed recurrent alterations of FLT3, WT1, NRAS and KRAS in the newly diagnosed APL, whereas mutations in other genes commonly mutated in myeloid leukemia were rarely detected. The molecular signature of APL relapse was characterized by emergence of frequent mutations in PML and RARA genes. Our sequencing data also demonstrates incidence of loss-of-function mutations in previously unidentified genes, ARID1B and ARID1A, both of which encode for key components of the SWI/SNF complex. We show that knockdown of ARID1B in APL cell line, NB4, results in large-scale activation of gene expression and reduced in vitro differentiation potential. PMID:27063598

  13. Vorinostat and Idarubicin in Treating Patients With Relapsed or Refractory Leukemia or Myelodysplastic Syndromes

    ClinicalTrials.gov

    2013-09-27

    Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome; 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 Promyelocytic Leukemia (M3); Blastic Phase Chronic Myelogenous Leukemia; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes

  14. 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

  15. Tanespimycin and Cytarabine in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, Chronic Myelogenous Leukemia, Chronic Myelomonocytic Leukemia, or Myelodysplastic Syndromes

    ClinicalTrials.gov

    2013-09-27

    Accelerated Phase Chronic Myelogenous Leukemia; 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); Blastic Phase Chronic Myelogenous Leukemia; Chronic Myelomonocytic Leukemia; de Novo Myelodysplastic Syndromes; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Refractory Anemia With Excess Blasts in Transformation; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes

  16. Perspectives on the Causes of Childhood Leukemia

    PubMed Central

    Wiemels, Joseph

    2013-01-01

    Acute leukemia is the most common cancer in children but the causes of the disease in the majority of cases are not known. About 80% are precursor-B cell in origin (CD19+, CD10+), and this immunophenotype has increased in incidence over the past several decades in the Western world. Part of this increase may be due to the introduction of new chemical exposures into the child's environment including parental smoking, pesticides, traffic fumes, paint and household chemicals. However, much of the increase in leukemia rates is likely linked to altered patterns of infection during early childhood development, mirroring causal pathways responsible for a similarly increased incidence of other childhood-diagnosed immune-related illnesses including allergy, asthma, and type 1 diabetes. Factors linked to childhood leukemia that are likely surrogates for immune stimulation include exposure to childcare settings, parity status and birth order, vaccination history, and population mixing. In case-control studies, acute lymphoblastic leukemia (ALL) is consistently inversely associated with greater exposure to infections, via daycare and later birth order. New evidence suggests also that children who contract leukemia may harbor a congenital defect in immune responder status, as indicated by lower levels of the immunosuppressive cytokine IL-10 at birth in children who grow up to contract leukemia, as well as higher need for clinical care for infections within the first year of life despite having lower levels of exposure to infections. One manifestation of this phenomenon may be leukemia clusters which tend to appear as a leukemia “outbreak” among populations with low herd immunity to a new infection. Critical answers to the etiology of childhood leukemia will require incorporating new tools into traditional epidemiologic approaches – including the classification of leukemia at a molecular scale, better exposure assessments at all points in a child's life, a comprehensive

  17. Rebeccamycin Analog in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia, Myelodysplastic Syndrome, Acute Lymphoblastic Leukemia, or Chronic Myelogenous Leukemia

    ClinicalTrials.gov

    2013-01-22

    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); Blastic Phase Chronic Myelogenous Leukemia; Chronic Myelomonocytic Leukemia; de Novo Myelodysplastic Syndromes; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Refractory Anemia With Excess Blasts; Refractory Anemia With Excess Blasts in Transformation; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes

  18. CCI-779 in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, Myelodysplastic Syndromes, or Chronic Myelogenous Leukemia in Blastic Phase

    ClinicalTrials.gov

    2013-01-22

    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); Blastic Phase Chronic Myelogenous Leukemia; Chronic Myelomonocytic Leukemia; de Novo Myelodysplastic Syndromes; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Refractory Anemia With Excess Blasts; Refractory Anemia With Excess Blasts in Transformation; Relapsing Chronic Myelogenous Leukemia; Secondary Myelodysplastic Syndromes

  19. A Case of T-cell Acute Lymphoblastic Leukemia Relapsed As Myeloid Acute Leukemia.

    PubMed

    Paganin, Maddalena; Buldini, Barbara; Germano, Giuseppe; Seganfreddo, Elena; Meglio, Annamaria di; Magrin, Elisa; Grillo, Francesca; Pigazzi, Martina; Rizzari, Carmelo; Cazzaniga, Giovanni; Khiabanian, Hossein; Palomero, Teresa; Rabadan, Raul; Ferrando, Adolfo A; Basso, Giuseppe

    2016-09-01

    A 4-year-old male with the diagnosis of T-cell acute lymphoblastic leukemia (T-ALL) relapsed after 19 months with an acute myeloid leukemia (AML). Immunoglobulin and T-cell receptor gene rearrangements analyses reveal that both leukemias were rearranged with a clonal relationship between them. Comparative genomic hybridization (Array-CGH) and whole-exome sequencing analyses of both samples suggest that this leukemia may have originated from a common T/myeloid progenitor. The presence of homozygous deletion of p16/INK4A, p14/ARF, p15/INK4B, and heterozygous deletion of WT1 locus remained stable in the leukemia throughout phenotypic switch, revealing that this AML can be genetically associated to T-ALL. PMID:27149388

  20. Mutations in epigenetic regulators are involved in acute lymphoblastic leukemia relapse following allogeneic hematopoietic stem cell transplantation

    PubMed Central

    Lai, Xiaoyu; Li, Caihua; Shi, Jimin; Tan, Yamin; Fu, Shan; Wang, Yebo; Zhu, Ni; He, Jingsong; Zheng, Weiyan; Yu, Xiaohong; Cai, Zhen; Huang, He

    2016-01-01

    Although steady improvements to chemotherapeutic treatments has helped cure 80% of childhood acute lymphoblastic leukemia (ALL) cases, chemotherapy has proven to be less effective in treating the majority of adult patients, leaving allogeneic hematopoietic stem cell transplantation (allo-HSCT) as the primary adult treatment option. Nevertheless relapse are the leading cause of death following allo-HSCT. The genetic pathogenesis of relapse following allo-HSCT in Philadelphia chromosome- negative ALL (Ph− ALL) remains unexplored. We performed longitudinal whole-exome sequencing analysis in three adult patients with Ph− B-cell ALL (Ph− B-ALL) on samples collected from diagnosis to relapse after allo-HSCT. Based on these data, we performed target gene sequencing on 23 selected genes in 58 adult patients undergoing allo-HSCT with Ph− B-ALL. Our results revealed a significant enrichment of mutations in epigenetic regulators from relapsed samples, with recurrent somatic mutations in SETD2, CREBBP, KDM6A and NR3C1. The relapsed samples were also enriched in signaling factor mutations, including KRAS, PTPN21, MYC and USP54. Furthermore, we are the first to reveal the clonal evolution patterns during leukemia relapse after allo-HSCT. Cells present in relapsed specimens were genetically related to the diagnosed tumor, these cells therefore arose from either an existing subclone that was not eradicated by allo-HSCT therapy, or from the same progenitor that acquired new mutations. In some cases, however, it is possible that leukemia recurrence following allo-HSCT could result from a secondary malignancy with a distinct set of mutations. We identified novel genetic causes of leukemia relapse after allo-HSCT using the largest generated data set to date from adult patients with Ph− B-ALL. PMID:26527318

  1. Dasatinib in Treating Young Patients With Recurrent or Refractory Solid Tumors or Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia or Chronic Myelogenous Leukemia That Did Not Respond to Imatinib Mesylate

    ClinicalTrials.gov

    2013-02-04

    Accelerated Phase Chronic Myelogenous Leukemia; Blastic Phase Chronic Myelogenous Leukemia; Childhood Chronic Myelogenous Leukemia; Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Meningeal Chronic Myelogenous Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Relapsing Chronic Myelogenous Leukemia; Unspecified Childhood Solid Tumor, Protocol Specific

  2. 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

  3. How Is Childhood Leukemia Classified?

    MedlinePlus

    ... in immature forms of cells that make platelets. World Health Organization (WHO) classification of AML The FAB ... phases, but a common system (proposed by the World Health Organization) is described below. If the leukemia ...

  4. Negative feedback-defective PRPS1 mutants drive thiopurine resistance in relapsed childhood ALL.

    PubMed

    Li, Benshang; Li, Hui; Bai, Yun; Kirschner-Schwabe, Renate; Yang, Jun J; Chen, Yao; Lu, Gang; Tzoneva, Gannie; Ma, Xiaotu; Wu, Tongmin; Li, Wenjing; Lu, Haisong; Ding, Lixia; Liang, Huanhuan; Huang, Xiaohang; Yang, Minjun; Jin, Lei; Kang, Hui; Chen, Shuting; Du, Alicia; Shen, Shuhong; Ding, Jianping; Chen, Hongzhuan; Chen, Jing; von Stackelberg, Arend; Gu, Longjun; Zhang, Jinghui; Ferrando, Adolfo; Tang, Jingyan; Wang, Shengyue; Zhou, Bin-Bing S

    2015-06-01

    Relapse is the leading cause of mortality in children with acute lymphoblastic leukemia (ALL). Among chemotherapeutics, thiopurines are key drugs in ALL combination therapy. Using whole-exome sequencing, we identified relapse-specific mutations in the phosphoribosyl pyrophosphate synthetase 1 gene (PRPS1), which encodes a rate-limiting purine biosynthesis enzyme, in 24/358 (6.7%) relapsed childhood B cell ALL (B-ALL) cases. All individuals who harbored PRPS1 mutations relapsed early during treatment, and mutated ALL clones expanded exponentially before clinical relapse. Our functional analyses of PRPS1 mutants uncovered a new chemotherapy-resistance mechanism involving reduced feedback inhibition of de novo purine biosynthesis and competitive inhibition of thiopurine activation. Notably, the de novo purine synthesis inhibitor lometrexol effectively abrogated PRPS1 mutant-driven drug resistance. These results highlight the importance of constitutive activation of the de novo purine synthesis pathway in thiopurine resistance, and they offer therapeutic strategies for the treatment of relapsed and thiopurine-resistant ALL. PMID:25962120

  5. GTI-2040 in Treating Patients With Relapsed, Refractory, or High-Risk Acute Leukemia, High-Grade Myelodysplastic Syndromes, or Refractory or Blastic Phase Chronic Myelogenous Leukemia

    ClinicalTrials.gov

    2015-12-03

    Acute Undifferentiated Leukemia; 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); Blastic Phase Chronic Myelogenous Leukemia; de Novo Myelodysplastic Syndromes; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Adult Acute Myeloid Leukemia

  6. A revised definition for cure of childhood acute lymphoblastic leukemia.

    PubMed

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

    2014-12-01

    With improved contemporary therapy, we reassess long-term outcome in patients completing treatment for childhood acute lymphoblastic leukemia (ALL) to determine when cure can be declared with a high degree of confidence. In six successive clinical trials between 1984 and 2007, 1291 (84.5%) patients completed all therapies in continuous complete remission. The post-therapy cumulative risk of relapse or development of a second neoplasm and the event-free survival rate and overall survival were analyzed according to the presenting features and the three treatment periods defined by relative outcome. Over the three treatment periods, there has been progressive increase in the rate of event-free survival (65.2% vs 74.8% vs 85.1% (P<0.001)) and overall survival (76.5% vs 81.1% vs 91.7% (P<0.001)) at 10 years. The most important predictor of outcome after completion of therapy was the type of treatment. In the most recent treatment period, which omitted the use of prophylactic cranial irradiation, the post-treatment cumulative risk of relapse was 6.4%, death in remission 1.5% and development of a second neoplasm 2.3% at 10 years, with all relapses except one occurring within 4 years of therapy. None of the 106 patients with the t(9;22)/BCR-ABL1, t(1;19)/TCF3-PBX1 or t(4;11)/MLL-AFF1 had relapsed after 2 years from completion of therapy. These findings demonstrate that with contemporary effective therapy that excludes cranial irradiation, approximately 6% of children with ALL may relapse after completion of treatment, and those who remain in remission at 4 years post treatment may be considered cured (that is, less than 1% chance of relapse). PMID:24781017

  7. Early childhood leukemia incidence trends in Brazil.

    PubMed

    Reis, Rejane de Souza; Santos, Marceli de Oliveira; de Camargo, Beatriz; Oliveira, Julio Fernando Pinto; Thuler, Luiz Claudio Santos; Pombo-de-Oliveira, Maria S

    2016-03-01

    Incidence rates of childhood leukemia vary between different regions of the world. The objective of this study was to test possible trends in incidence rate of early childhood leukemia (children <5 years old at the diagnosis) in Brazil. Data from 18 population-based cancer registries (PBCRs) were analyzed (period 1999-2010). The analysis consisted of frequencies, age-adjusted incidence rates, and joinpoint regression results, including annual average percent change (AAPC) in incidence rates and 95% confidence intervals (CIs). The median age-adjusted incidence rate (AAIR) of overall early childhood leukemia was 61 per million. The AAIR for acute lymphoid leukemia (ALL) was 44 per million and nonlymphoid acute leukemia (NLAL) was 14 per million. The median ALL/NLAL ratio was 3.0, suggesting higher incidence rate of NLAL in these settings. The joinpoint analysis demonstrated increased leukemia incidence rate in João Pessoa (AAPC = 20; 95% CI: 3.5, 39.4) and Salvador (AAPC = 8.68; 95% CI: 1.0, 16.9), respectively, whereas incidence rate in São Paulo PBCR decreased (AAPC = -4.02%; 95% CI: -6.1%, -1.9%). Correlation between ALL AAIR and selected variables of socioeconomic (SES) factors was not observed. Increased AAIR regionally overtime was observed. However, the interpretation for such phenomenon should be cautious because it might reflect the access to health care, diagnosis procedures, and improvement of PBCR´s quality. The observed trend supports the necessity of further ecological studies. PMID:26925506

  8. Epidemiology of childhood acute myelogenous leukemia.

    PubMed

    Bhatia, S; Neglia, J P

    1995-05-01

    Acute myelogenous leukemia (AML) is the second most common leukemia in children, with approximately 400 new cases occurring annually in the United States. Worldwide, the highest rates of childhood AML occur in Asia and the lowest rates are reported from India and South America. Numerous genetic risk factors for childhood AML have been defined, including Down syndrome, neurofibromatosis, and Fanconi anemia. Research into environmental risk factors has been limited by the rarity of this disease; however, studies of AML in adults have implicated ionizing radiation, solvents, and petroleum products as potential etiologic agents. The largest analytic study of childhood AML found that occupational exposures of either parent to pesticides, paternal exposure to petroleum products, and postnatal exposures to pesticides are increased in children with AML. In addition, maternal use of marijuana during pregnancy was associated with an increased risk of AML, especially the monocytic subtypes. Further study of childhood AML, including occurrence of the disease as a second malignancy, is needed in order to confirm these findings and to increase our understanding of this leukemia. PMID:7749772

  9. Aggressive chemotherapy for acute leukemia relapsed after bone marrow transplantation: a second chance?

    PubMed

    Sica, S; Di Mario, A; Pagano, L; Etuk, B; Salutari, P; Leone, G

    1992-01-01

    Eight patients, 5 with acute non lymphoid leukemia and 3 with lymphoid leukemia, were treated at relapse after bone marrow transplantation (BMT; 4 autologous BMT and 4 allogeneic BMT). Of these, 2 relapsed within 3 months after BMT (2 allogeneic BMT) and 6 (2 allogeneic and 4 autologous BMT) after more than 9 months after BMT. The 2 patients relapsing early showed no response to treatment and died. Five out of 6 patients relapsing late achieved complete remission (4 of them with intensive chemotherapy). Four patients are currently alive. Aggressive combination chemotherapy can produce long-term survival in selected patients relapsed after BMT. PMID:1519431

  10. Temsirolimus, Dexamethasone, Mitoxantrone Hydrochloride, Vincristine Sulfate, and Pegaspargase in Treating Young Patients With Relapsed Acute Lymphoblastic Leukemia or Non-Hodgkin Lymphoma

    ClinicalTrials.gov

    2015-07-09

    Childhood B Acute Lymphoblastic Leukemia; Childhood T Acute Lymphoblastic Leukemia; Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Lymphoblastic Lymphoma

  11. Arsenic trioxide-based therapy of relapsed acute promyelocytic leukemia: registry results from the European LeukemiaNet.

    PubMed

    Lengfelder, E; Lo-Coco, F; Ades, L; Montesinos, P; Grimwade, D; Kishore, B; Ramadan, S M; Pagoni, M; Breccia, M; Huerta, A J G; Nloga, A M; González-Sanmiguel, J D; Schmidt, A; Lambert, J-F; Lehmann, S; Di Bona, E; Cassinat, B; Hofmann, W-K; Görlich, D; Sauerland, M-C; Fenaux, P; Sanz, M

    2015-05-01

    In 2008, a European registry of relapsed acute promyelocytic leukemia was established by the European LeukemiaNet. Outcome data were available for 155 patients treated with arsenic trioxide in first relapse. In hematological relapse (n=104), 91% of the patients entered complete hematological remission (CR), 7% had induction death and 2% resistance, 27% developed differentiation syndrome and 39% leukocytosis, whereas no death or side effects occurred in patients treated in molecular relapse (n=40). The rate of molecular (m)CR was 74% in hematological and 62% in molecular relapse (P=0.3). All patients with extramedullary relapse (n=11) entered clinical and mCR. After 3.2 years median follow-up, the 3-year overall survival (OS) and cumulative incidence of second relapse were 68% and 41% in hematological relapse, 66% and 48% in molecular relapse and 90 and 11% in extramedullary relapse, respectively. After allogeneic or autologous transplantation in second CR (n=93), the 3-year OS was 80% compared with 59% without transplantation (n=55) (P=0.03). Multivariable analysis demonstrated the favorable prognostic impact of first remission duration ⩾1.5 years, achievement of mCR and allogeneic or autologous transplantation on OS of patients alive after induction (P=0.03, P=0.01, P=0.01) and on leukemia-free survival (P=0.006, P<0.0001, P=0.003), respectively. PMID:25627637

  12. Cauda equina involvement in acute myeloid leukemia relapse.

    PubMed

    Buakhao, Jitsuda; Tansawet, Amarate

    2011-10-01

    Although central nervous system (CNS) involvement in acute myeloid leukemia has been described in about 2 to 4%, it still represents a major therapeutic problem, particularly cauda eqina involvement that is clinically significant and unusual. Here, a 22-year-old man, with underlying AML (M2-Subtype, FAB classification) and cytogenetic analysis resulted in 45, x, -y, t(8;21) (q22;q22)[15] whose presenting symptoms of low back pain and incontinence, 10 months after first remission, was reported. This was followed by peripheral and bone marrow relapse. The magnetic resonance image (MRI) findings revealed leukemic infiltration at S1-S5 of the spinal cord canal with associated soft tissue component at presacral area encasing bilateral S1-S5 exiting root with heterogeneous enhancement in bone marrow of S2-S4. The therapeutic and prognosis implications of spinal cord involvement by leukemia were discussed. Because of severe morbidity, the patient developed bone marrow failure and died from sepsis. PMID:22145515

  13. Minimal Residual Disease Evaluation in Childhood Acute Lymphoblastic Leukemia: A Clinical Evidence Review

    PubMed Central

    2016-01-01

    Background Leukemia accounts for nearly a third of childhood cancers in Canada, with acute lymphoblastic leukemia (ALL) comprising nearly 80% of cases. Identification of prognostic factors that allow risk stratification and tailored treatment have improved overall survival. However, nearly a quarter of patients considered standard risk on the basis of conventional prognostic factors still relapse, and relapse is associated with increased morbidity and mortality. Relapse is thought to result from extremely low levels of leukemic cells left over once complete remission is reached, termed minimal residual disease (MRD). Poor event-free survival (EFS) as well as overall survival for those who are classified as MRD-positive have been substantiated in seminal studies demonstrating the prognostic value of MRD for EFS in the past few decades. This review sought to further elucidate the relationship between MRD and EFS by looking at relapse, the primary determinant of EFS and the biological mechanism through which MRD is thought to act. This evidence review aimed to ascertain whether MRD is an independent prognostic factor for relapse and to assess the effect of MRD-directed treatment on patient-important outcomes in childhood ALL. Methods Large prospective cohort studies with a priori multivariable analysis that includes potential confounders are required to draw confirmatory conclusions about the independence of a prognostic factor. Data on the prognostic value of MRD for relapse measured by molecular methods (polymerase chain reaction [PCR] of immunoglobulin or T-cell receptor rearrangements) or flow cytometry for leukemia-associated immunophenotypes or difference-from-normal approach were abstracted from included studies. Relevant data on relapse, EFS, and overall survival were abstracted from randomized controlled trials (RCTs) evaluating the effect of MRD-directed treatment. Results A total of 2,832 citations were reviewed, of which 12 studies were included in this

  14. Survival and risk of relapse of acute lymphoblastic leukemia in a Mexican population is affected by dihydrofolate reductase gene polymorphisms

    PubMed Central

    GÓMEZ-GÓMEZ, YAZMÍN; ORGANISTA-NAVA, JORGE; SAAVEDRA-HERRERA, MÓNICA VIRGINIA; RIVERA-RAMÍREZ, ANA BERTHA; TERÁN-PORCAYO, MARCO ANTONIO; DEL CARMEN ALARCÓN-ROMERO, LUZ; ILLADES-AGUIAR, BERENICE; LEYVA-VÁZQUEZ, MARCO ANTONIO

    2012-01-01

    Dihydrofolate reductase (DHFR) is the major target of methotrexate, a key component in childhood acute lymphoblastic leukemia (ALL) treatment. Polymorphisms in the gene coding for DHFR have been associated with adverse event treatment. This study evaluated the effect of the -A317G and C829T polymorphisms in the DHFR gene on survival and risk of relapse of ALL. Seventy patients with ALL and 100 healthy individuals were genotyped by the polymerase chain reaction-restriction fragment length polymorphism method. An association between the polymorphisms and the risk of relapse was found (p<0.05); patients with the -317G/G genotype were found to have an 8.55 (95% CI 1.84–39.70) higher chance of relapse and carriers of the 829T/T genotype had a 14.0 (95% CI 1.13–172.63) higher chance of relapse. Other variables, such as age and leukocyte count, were associated (p<0.05) with the risk of relapse of the disease. Individuals with the G/G and T/T genotype of the -A317G and C829T polymorphisms had poorer survival compared to other genotype groups (log-rank test; p<0.05). Although preliminary, these data seem to suggest a role for the DHFR polymorphisms in the risk of relapse of ALL and the mortality risk in these patients. PMID:22969948

  15. Residential Traffic Density and Childhood Leukemia Risk

    PubMed Central

    Von Behren, Julie; Reynolds, Peggy; Gunier, Robert B.; Rull, Rudolph P.; Hertz, Andrew; Urayama, Kevin Y.; Kronish, Daniel; Buffler, Patricia A.

    2009-01-01

    Background Exposures to carcinogenic compounds from vehicle exhaust may increase childhood leukemia risk, and the timing of this exposure may be important. Methods We examined the association between traffic density and childhood leukemia risk for three time periods: birth, time of diagnosis, and lifetime average, based on complete residential history in a case-control study. Cases were rapidly ascertained from participating hospitals in northern and central California between 1995 and 2002. Controls were selected from birth records, individually matched on age, sex, race, and Hispanic ethnicity. Traffic density was calculated by estimating total vehicle miles traveled per square mile within a 500-foot (152 meter) radius area around each address. We used conditional logistic regression analyses to account for matching factors and to adjust for household income. Results We included 310 cases of acute lymphocytic leukemias (ALL) and 396 controls in our analysis. The odds ratio for ALL and residential traffic density above the 75th percentile, compared with subjects with zero traffic density, was 1.17 [95% confidence interval (95% CI), 0.76–1.81) for residence at diagnosis and 1.11 (95% CI, 0.70–1.78) for the residence at birth. For average lifetime traffic density, the odds ratio was 1.24 (95% CI, 0.74–2.08) for the highest exposure category. Conclusions Living in areas of high traffic density during any of the exposure time periods was not associated with increased risk of childhood ALL in this study. PMID:18768496

  16. Idelalisib and Rituximab in Relapsed Chronic Lymphocytic Leukemia

    PubMed Central

    Cheson, Bruce D.; Pagel, John M.; Hillmen, Peter; Barrientos, Jacqueline C.; Zelenetz, Andrew D.; Kipps, Thomas J.; Flinn, Ian; Ghia, Paolo; Eradat, Herbert; Ervin, Thomas; Lamanna, Nicole; Coiffier, Bertrand; Pettitt, Andrew R.; Ma, Shuo; Stilgenbauer, Stephan; Cramer, Paula; Aiello, Maria; Johnson, Dave M.; Miller, Langdon L.; Li, Daniel; Jahn, Thomas M.; Dansey, Roger D.; Hallek, Michael; O’Brien, Susan M.

    2014-01-01

    BACKGROUND Patients with relapsed chronic lymphocytic leukemia (CLL) who have clinically significant coexisting medical conditions are less able to undergo standard chemo-therapy. Effective therapies with acceptable side-effect profiles are needed for this patient population. METHODS In this multicenter, randomized, double-blind, placebo-controlled, phase 3 study, we assessed the efficacy and safety of idelalisib, an oral inhibitor of the delta iso-form of phosphatidylinositol 3-kinase, in combination with rituximab versus rituximab plus placebo. We randomly assigned 220 patients with decreased renal function, previous therapy-induced myelosuppression, or major coexisting illnesses to receive rituximab and either idelalisib (at a dose of 150 mg) or placebo twice daily. The primary end point was progression-free survival. At the first prespecified interim analysis, the study was stopped early on the recommendation of the data and safety monitoring board owing to overwhelming efficacy. RESULTS The median progression-free survival was 5.5 months in the placebo group and was not reached in the idelalisib group (hazard ratio for progression or death in the idelalisib group, 0.15; P<0.001). Patients receiving idelalisib versus those receiving placebo had improved rates of overall response (81% vs. 13%; odds ratio, 29.92; P<0.001) and overall survival at 12 months (92% vs. 80%; hazard ratio for death, 0.28; P = 0.02). Serious adverse events occurred in 40% of the patients receiving idelalisib and rituximab and in 35% of those receiving placebo and rituximab. CONCLUSIONS The combination of idelalisib and rituximab, as compared with placebo and rituximab, significantly improved progression-free survival, response rate, and overall survival among patients with relapsed CLL who were less able to undergo chemo-therapy. (Funded by Gilead; ClinicalTrials.gov number, NCT01539512.) PMID:24450857

  17. Targeted Therapy in Treating Patients With Relapsed or Refractory Acute Lymphoblastic Leukemia or Acute Myelogenous Leukemia

    ClinicalTrials.gov

    2016-07-28

    Chronic Myelomonocytic Leukemia; Myelodysplastic Syndrome; Recurrent Acute Myeloid Leukemia With Myelodysplasia-Related Changes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Refractory Adult Acute Lymphoblastic Leukemia

  18. Pediatric T-cell lymphoblastic leukemia evolves into relapse by clonal selection, acquisition of mutations and promoter hypomethylation

    PubMed Central

    Kunz, Joachim B.; Rausch, Tobias; Bandapalli, Obul R.; Eilers, Juliane; Pechanska, Paulina; Schuessele, Stephanie; Assenov, Yassen; Stütz, Adrian M.; Kirschner-Schwabe, Renate; Hof, Jana; Eckert, Cornelia; von Stackelberg, Arend; Schrappe, Martin; Stanulla, Martin; Koehler, Rolf; Avigad, Smadar; Elitzur, Sarah; Handgretinger, Rupert; Benes, Vladimir; Weischenfeldt, Joachim; Korbel, Jan O.; Muckenthaler, Martina U.; Kulozik, Andreas E.

    2015-01-01

    Relapsed precursor T-cell acute lymphoblastic leukemia is characterized by resistance against chemotherapy and is frequently fatal. We aimed at understanding the molecular mechanisms resulting in relapse of T-cell acute lymphoblastic leukemia and analyzed 13 patients at first diagnosis, remission and relapse by whole exome sequencing, targeted ultra-deep sequencing, multiplex ligation dependent probe amplification and DNA methylation array. Compared to primary T-cell acute lymphoblastic leukemia, in relapse the number of single nucleotide variants and small insertions and deletions approximately doubled from 11.5 to 26. Targeted ultra-deep sequencing sensitively detected subclones that were selected for in relapse. The mutational pattern defined two types of relapses. While both are characterized by selection of subclones and acquisition of novel mutations, ‘type 1’ relapse derives from the primary leukemia whereas ‘type 2’ relapse originates from a common pre-leukemic ancestor. Relapse-specific changes included activation of the nucleotidase NT5C2 resulting in resistance to chemotherapy and mutations of epigenetic modulators, exemplified by SUZ12, WHSC1 and SMARCA4. While mutations present in primary leukemia and in relapse were enriched for known drivers of leukemia, relapse-specific changes revealed an association with general cancer-promoting mechanisms. This study thus identifies mechanisms that drive progression of pediatric T-cell acute lymphoblastic leukemia to relapse and may explain the characteristic treatment resistance of this condition. PMID:26294725

  19. Pediatric T-cell lymphoblastic leukemia evolves into relapse by clonal selection, acquisition of mutations and promoter hypomethylation.

    PubMed

    Kunz, Joachim B; Rausch, Tobias; Bandapalli, Obul R; Eilers, Juliane; Pechanska, Paulina; Schuessele, Stephanie; Assenov, Yassen; Stütz, Adrian M; Kirschner-Schwabe, Renate; Hof, Jana; Eckert, Cornelia; von Stackelberg, Arend; Schrappe, Martin; Stanulla, Martin; Koehler, Rolf; Avigad, Smadar; Elitzur, Sarah; Handgretinger, Rupert; Benes, Vladimir; Weischenfeldt, Joachim; Korbel, Jan O; Muckenthaler, Martina U; Kulozik, Andreas E

    2015-11-01

    Relapsed precursor T-cell acute lymphoblastic leukemia is characterized by resistance against chemotherapy and is frequently fatal. We aimed at understanding the molecular mechanisms resulting in relapse of T-cell acute lymphoblastic leukemia and analyzed 13 patients at first diagnosis, remission and relapse by whole exome sequencing, targeted ultra-deep sequencing, multiplex ligation dependent probe amplification and DNA methylation array. Compared to primary T-cell acute lymphoblastic leukemia, in relapse the number of single nucleotide variants and small insertions and deletions approximately doubled from 11.5 to 26. Targeted ultra-deep sequencing sensitively detected subclones that were selected for in relapse. The mutational pattern defined two types of relapses. While both are characterized by selection of subclones and acquisition of novel mutations, 'type 1' relapse derives from the primary leukemia whereas 'type 2' relapse originates from a common pre-leukemic ancestor. Relapse-specific changes included activation of the nucleotidase NT5C2 resulting in resistance to chemotherapy and mutations of epigenetic modulators, exemplified by SUZ12, WHSC1 and SMARCA4. While mutations present in primary leukemia and in relapse were enriched for known drivers of leukemia, relapse-specific changes revealed an association with general cancer-promoting mechanisms. This study thus identifies mechanisms that drive progression of pediatric T-cell acute lymphoblastic leukemia to relapse and may explain the characteristic treatment resistance of this condition. PMID:26294725

  20. Genomic Profiling of Pediatric Acute Myeloid Leukemia Reveals a Changing Mutational Landscape from Disease Diagnosis to Relapse.

    PubMed

    Farrar, Jason E; Schuback, Heather L; Ries, Rhonda E; Wai, Daniel; Hampton, Oliver A; Trevino, Lisa R; Alonzo, Todd A; Guidry Auvil, Jaime M; Davidsen, Tanja M; Gesuwan, Patee; Hermida, Leandro; Muzny, Donna M; Dewal, Ninad; Rustagi, Navin; Lewis, Lora R; Gamis, Alan S; Wheeler, David A; Smith, Malcolm A; Gerhard, Daniela S; Meshinchi, Soheil

    2016-04-15

    The genomic and clinical information used to develop and implement therapeutic approaches for acute myelogenous leukemia (AML) originated primarily from adult patients and has been generalized to patients with pediatric AML. However, age-specific molecular alterations are becoming more evident and may signify the need to age-stratify treatment regimens. The NCI/COG TARGET-AML initiative used whole exome capture sequencing (WXS) to interrogate the genomic landscape of matched trios representing specimens collected upon diagnosis, remission, and relapse from 20 cases of de novo childhood AML. One hundred forty-five somatic variants at diagnosis (median 6 mutations/patient) and 149 variants at relapse (median 6.5 mutations) were identified and verified by orthogonal methodologies. Recurrent somatic variants [in (greater than or equal to) 2 patients] were identified for 10 genes (FLT3, NRAS, PTPN11, WT1, TET2, DHX15, DHX30, KIT, ETV6, KRAS), with variable persistence at relapse. The variant allele fraction (VAF), used to measure the prevalence of somatic mutations, varied widely at diagnosis. Mutations that persisted from diagnosis to relapse had a significantly higher diagnostic VAF compared with those that resolved at relapse (median VAF 0.43 vs. 0.24, P < 0.001). Further analysis revealed that 90% of the diagnostic variants with VAF >0.4 persisted to relapse compared with 28% with VAF <0.2 (P < 0.001). This study demonstrates significant variability in the mutational profile and clonal evolution of pediatric AML from diagnosis to relapse. Furthermore, mutations with high VAF at diagnosis, representing variants shared across a leukemic clonal structure, may constrain the genomic landscape at relapse and help to define key pathways for therapeutic targeting. Cancer Res; 76(8); 2197-205. ©2016 AACR. PMID:26941285

  1. Risk factors for relapse after allogeneic transplantation in acute myeloid leukemia

    PubMed Central

    Ossenkoppele, Gert J.; Janssen, Jeroen J.W.M.; van de Loosdrecht, Arjan A.

    2016-01-01

    Acute myeloid leukemia is a clonal neoplasm derived from myeloid progenitor cells with a varying outcome. The initial goal of treatment is the achievement of complete remission, defined for over 40 years by morphology. However, without additional post-remission treatment the majority of patients relapse. In many cases of acute myeloid leukemia, allogeneic stem cell transplantation offers the best prospects of cure. In 2013, 5608 stem cell transplantations in acute myeloid leukemia were performed in Europe (5228 allogeneic and 380 autologous stem cell transplantations). Most stem cell transplantations are performed in first complete remission. However, despite a considerable reduction in the chance of relapse, in most studies, overall survival benefit of allogeneic stem cell transplantation is modest due to substantial non-relapse mortality. Here we discuss the many factors related to the risk of relapse after allogeneic stem cell transplantation. PMID:26721801

  2. Prognosis of patients with core binding factor acute myeloid leukemia after first relapse

    PubMed Central

    Kurosawa, Saiko; Miyawaki, Shuichi; Yamaguchi, Takuhiro; Kanamori, Heiwa; Sakura, Toru; Moriuchi, Yukiyoshi; Sano, Fumiaki; Kobayashi, Takeshi; Yasumoto, Atsushi; Hatanaka, Kazuo; Yanada, Masamitsu; Nawa, Yuichiro; Takeuchi, Jin; Nakamura, Yukinori; Fujisawa, Shin; Shibayama, Hirohiko; Miura, Ikuo; Fukuda, Takahiro

    2013-01-01

    Core binding factor acute myeloid leukemia is known to have a favorable prognosis, however, there have been no detailed analyses on prognostic factors after first relapse. Using a nationwide database, we retrospectively analyzed core binding factor acute myeloid leukemia patients who relapsed after being treated with chemotherapy alone during their first complete remission. Of a total of 397 patients who were diagnosed with core binding factor acute myeloid leukemia, 208 experienced a first relapse, and analyses were performed in 139 patients for whom additional data were available. In the entire cohort, the overall survival rate after relapse was 48% at 3 years. By multivariate analysis, younger age at diagnosis, a longer interval before relapse, and inv(16) were shown to be independently associated with better survival after relapse. Although there was no significant difference in survival after relapse between patients who underwent allogeneic hematopoietic cell transplantation and those who did not in the overall series of relapsed patients, we found that transplantation significantly improved survival among patients who had t(8;21) (54% versus 26% at 3 years, P=0.002). In addition, among patients with t(8;21), those who had different cytogenetics at relapse had a significantly improved survival after transplantation, while those who had same cytogenetics did not. We showed that the prognosis differs significantly and optimal treatment strategies may vary between groups of patients with core binding factor acute myeloid leukemia with different cytogenetic profiles at relapse. These findings may help to guide therapeutic decisions after first relapse. PMID:23716553

  3. The contributions of the European Medicines Agency and its pediatric committee to the fight against childhood leukemia

    PubMed Central

    Rose, Klaus; Walson, Philip D

    2015-01-01

    Background Although the diagnosis of childhood leukemia is no longer a death sentence, too many patients still die, more with acute myeloid leukemia than with acute lymphoblastic leukemia. The European Union pediatric legislation was introduced to improve pharmaceutical treatment of children, but some question whether the European Medicines Agency (EMA) approach is helping children with leukemia. Some have even suggested that the decisions of EMA pediatric committee (PDCO) are counterproductive. This study was designed to investigate the impact of PDCO-issued pediatric investigation plans (PIPs) for leukemia drugs. Methods All PIPs listed under “oncology” were downloaded from the EMA website. Non-leukemia decisions including misclassifications, waivers (no PIP), and solid tumors were discarded. The leukemia decisions were analyzed, compared to pediatric leukemia trials in the database http://www.clinicaltrials.gov, and discussed in the light of current literature. Results The PDCO leukemia decisions demand clinical trials in pediatric leukemia for all new adult drugs without prioritization. However, because leukemia in children is different and much rarer than in adults, these decisions have resulted in proposed studies that are scientifically and ethically questionable. They are also unnecessary, since once promising new compounds are approved for adults, more appropriate, prioritized pediatric leukemia trials are initiated worldwide without PDCO involvement. Conclusion EMA/PDCO leukemia PIPs do little to advance the treatment of childhood leukemia. The unintended negative effects of the flawed EMA/PDCO’s standardized requesting of non-prioritized testing of every new adult leukemia drug in children with relapsed or refractory disease expose these children to questionable trials, and could undermine public trust in pediatric clinical research. Institutions, investigators, and ethics committees/institutional review boards need to be skeptical of trials

  4. Improving Access To Novel Agents For Childhood Leukemia

    PubMed Central

    Sun, Weili; Gaynon, Paul S.; Sposto, Richard; Wayne, Alan S.

    2015-01-01

    Leukemia is the most common pediatric cancer. Despite great progress in the development of curative therapy, leukemia remains a leading cause of death from disease in childhood and survivors are at life-long risk of complications of treatment. New agents are needed to further increase cure rates and decrease treatment-associated toxicities. The complex biology and aggressive nature of childhood leukemia, coupled with the relatively small patient population available for study, pose specific challenges to the development of new therapies. In this review, we discuss strategies and initiatives designed to improve access to new agents in the treatment of pediatric leukemia. PMID:25678105

  5. Concurrent hypopituitarism and leukemic retinopathy in a child with B-precursor acute lymphoblastic leukemia and isolated central nervous system relapse

    PubMed Central

    Wu, K.H.; Wu, H.P.; Lin, H.J.; Wang, C.H.; Chen, H.Y.; Weng, T.; Peng, C.T.; Chao, Y.H.

    2016-01-01

    Hypopituitarism in leukemia is very rare. In addition, central nervous system (cns) relapse and leukemic retinopathy in childhood acute lymphoblastic leukemia (all) have declined with the use of modern systemic chemotherapy that includes cns prophylaxis. Here, we report the case of a 4-year-old girl who received chemotherapy and intrathecal therapy without cns radiation after a diagnosis of B-precursor all without cns involvement. Three months after chemotherapy completion, she presented with lower-extremity weakness and was diagnosed with an isolated cns relapse. Concurrent hypopituitarism and leukemic retinopathy were also found. After receiving craniospinal radiotherapy and systemic chemotherapy, her retinopathy and vision improved. She is now in complete remission, and she is still on chemotherapy according to the guideline from the Pediatric Oncology Group. Although rare, hypopituitarism and leukemic retinopathy should be taken into consideration in patients with cns involvement by leukemia. PMID:27536191

  6. Biological Therapy in Treating Patients With Advanced Myelodysplastic Syndrome, Acute or Chronic Myeloid Leukemia, or Acute Lymphoblastic Leukemia Who Are Undergoing Stem Cell Transplantation

    ClinicalTrials.gov

    2013-07-03

    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); B-cell Adult Acute Lymphoblastic Leukemia; B-cell Childhood Acute Lymphoblastic Leukemia; Childhood Chronic Myelogenous Leukemia; Childhood Myelodysplastic Syndromes; Chronic Myelomonocytic Leukemia; Essential Thrombocythemia; Polycythemia Vera; 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; Secondary Acute Myeloid Leukemia; T-cell Adult Acute Lymphoblastic Leukemia; T-cell Childhood Acute Lymphoblastic Leukemia

  7. 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

  8. 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

  9. Longitudinal pancreaticojejunostomy in chronic relapsing pancreatitis with onset in childhood.

    PubMed Central

    Scott, H W; Neblett, W W; O'Neill, J A; Sawyers, J L; Avant, G S; Starnes, V A

    1984-01-01

    Despite the rarity of chronic relapsing pancreatitis in children, in the last 15 years at Vanderbilt University Medical Center and its Children's Hospital we have used longitudinal pancreaticojejunostomy in treatment of eight patients whose symptoms began in childhood. Duration of symptoms ranged from 2 to 36 years. Seven of the eight patients had hereditary pancreatitis. Recurrent epigastric pain was characteristic and serum amylase was elevated in all patients on admission or shortly thereafter. Demonstration of an obstructed dilated pancreatic duct in all and stones in seven of eight patients by operative pancreatography in three early patients and by endoscopic retrograde cholangiopancreatography (ERCP) in five others established the therapeutic problem and facilitated treatment by removal of stones and longitudinal pancreaticojejunostomy. Results were uniformly excellent, both in the early postoperative period and in long-range follow-ups. Early diagnosis and early surgical drainage of the obstructed pancreatic duct by longitudinal pancreaticojejunostomy are desirable objectives in chronic relapsing pancreatitis with onset in childhood. Images Fig. 6. Fig. 7. Fig. 8. PMID:6721610

  10. Molecular relapse in chronic myelogenous leukemia patients after bone marrow transplantation detected by polymerase chain reaction

    SciTech Connect

    Sawyers, C.L.; Timson, L.; Clark, S.S.; Witte, O.N.; Champlin, R. ); Kawasaki, E.S. )

    1990-01-01

    Relapse of chronic myelogenous leukemia after bone marrow transplantation can be detected by using clinical, cytogenetic, or molecular tools. A modification of the polymerase chain reaction can be used in patients to detect low levels of the BCR-ABL-encoded mRNA transcript, a specific marker for chronic myelogenous leukemia. Early detection of relapse after bone marrow transplantation could potentially alter treatment decisions. The authors prospectively evaluated 19 patients for evidence of molecular relapse, cytogenetic relapse, and clinical relapse after bone marrow transplantation. They used the polymerase chain reaction to detect residual BCR-ABL mRNA in patients followed up to 45 months after treatment and found 4 patients with BCR-ABL mRNA expression following bone marrow transplantation. Fifteen patients did not express detectable BCR-ABL mRNA. All 19 patients remain in clinical remission. In this prospective study of chronic myelogenous leukemia patients treated with bone marrow transplantation, molecular relapse preceded cytogenetic relapse in those patients who persistently express BCR-ABL mRNA. They recommend using standard clinical and cytogenetic testing to make patient care decisions until further follow-up determines the clinical outcome of those patients with residual BCR-ABL mRNA transcripts detected by polymerase chain reaction.

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

    ClinicalTrials.gov

    2011-07-12

    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

  12. Impact of childhood trauma on risk of relapse requiring psychiatric hospital admission for psychosis.

    PubMed

    Petros, N; Foglia, E; Klamerus, E; Beards, S; Murray, R M; Bhattacharyya, S

    2016-08-01

    Relapse in psychosis typically necessitates admission to hospital placing a significant financial burden on the health service. Exposure to childhood trauma is associated with an increased risk of psychosis, however, the extent to which this influences relapse is unclear. This report summarises current research investigating the influence of childhood trauma on relapse requiring psychiatric hospital admission for psychosis. Seven studies were included; two revealed a positive association between childhood trauma and relapse admission, two studies found a negative relationship and three found no significant difference. Inconsistent current evidence suggests a need for further research in this area. PMID:27151070

  13. [Molecular remission induced by gemtuzumab ozogamicin in an elderly patient with relapsed acute promyelocytic leukemia].

    PubMed

    Yago, Kazuhiro; Aono, Maki; Shimada, Hideto

    2010-04-01

    A 79-year-old female with acute promyelocytic leukemia (APL) presented with second hematological relapse. She had been treated previously with modified AIDA protocol as the front-line therapy and had achieved complete remission. During ATRA maintenance therapy, the first hematological relapse occurred and she was treated with arsenic trioxide (ATO), achieving the second complete remission. After four courses of consolidation therapy of ATO, the second hematological relapse occurred. At this time, except for a transient effect of tamibarotene, neither arsenic trioxide nor combination chemotherapy was effective. The patient was then treated with two courses of gemtuzumab ozogamicin (GO) and achieved the third complete remission. At present, she is maintaining molecular remission more than one year after GO treatment. GO is considered to be a promising agent for elderly patients with relapsed acute promyelocytic leukemia resistant to arsenic trioxide. PMID:20467227

  14. 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…

  15. Sorafenib in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, or Chronic Myelogenous Leukemia

    ClinicalTrials.gov

    2013-01-08

    Adult Acute Basophilic Leukemia; Adult Acute Eosinophilic Leukemia; Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); 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 Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia

  16. Evaluation of D-dimer and lactate dehydrogenase plasma levels in patients with relapsed acute leukemia

    PubMed Central

    HU, WANGQIANG; WANG, XIAOXIA; YANG, RONGRONG

    2016-01-01

    Despite the outstanding advances made over the past decade regarding our knowledge of acute leukemia (AL), relapsed AL remains to be associated with a dismal prognosis. A better understanding of AL relapse and monitoring of the D-dimer and lactate dehydrogenase (LDH) plasma levels following chemotherapy may aid clinicians in determining whether relapse may occur in the subsequent phases of the disease. The present study evaluated D-dimer and LDH levels in 204 patients with relapsed AL. Data were collected at the initial onset of AL, at complete remission (CR) and in patients with relapsed AL. D-dimer plasma levels were significantly increased in patients with initial AL and in patients with relapsed AL (P=0.005 and P=0.007, respectively) but not in those with CR. LDH levels were significantly increased in AL patients at the initial onset of disease and at relapse compared with patients achieving CR, irrespective of cell type. Plasma prothrombin time, activated partial thromboplastin time and fibrinogen levels were not significantly different across patients (with the exception of acute promyelocytic leukemia patients) at the initial onset, relapsed AL or CR. Routine hematological parameters (white blood cell count, hemoglobin, platelet count) were significantly different at the initial onset of AL (P=0.002, P<0.001 and P=0.001, respectively) and during relapsed AL (P=0.009, P=0.003 and P<0.001, respectively) compared with patients achieving CR, suggesting an association between D-dimer, LDH and relapsed AL. These results also indicate that determination of D-dimer and LDH levels may be useful for predicting the probability of relapse during chemotherapy, but should also be combined with routine hematological parameters. PMID:27347185

  17. Laboratory-Treated T Cells in Treating Patients With High-Risk Relapsed Acute Myeloid Leukemia, Myelodysplastic Syndrome, or Chronic Myelogenous Leukemia Previously Treated With Donor Stem Cell Transplant

    ClinicalTrials.gov

    2016-08-08

    Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome; Adult Myelodysplastic Syndrome; Childhood Myelodysplastic Syndrome; Previously Treated Myelodysplastic Syndrome; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Secondary Acute Myeloid Leukemia; Therapy-Related Acute Myeloid Leukemia

  18. Trends in Childhood Leukemia in Basrah, Iraq, 1993–2007

    PubMed Central

    Lafta, Riyadh; Hassan, Jenan; Davis, Scott; Mirick, Dana; Takaro, Tim

    2010-01-01

    Objectives. Through a sister-university relationship between the University of Basrah and the University of Washington, we analyzed Ibn Ghazwan Hospital's leukemia registry data to evaluate trends in childhood leukemia since 1993. Methods. We documented leukemia cases among children aged 0 to 14 years for each of the last 15 years. Population data were obtained from a 1997 census and various subsequent estimates to calculate rates. Results. We observed 698 cases of childhood leukemia between 1993 and 2007, ranging between 15 cases (2.6 per 100 000 annual rate) in the first year and 56 cases (6.9 per 100 000 annual rate) in the final year, reaching a peak of 97 cases in 2006 (12.2 per 100 000 annual rate). Conclusions. Childhood leukemia rates in Basrah more than doubled over a 15-year period. The test for trend was significant (P = .03). Basrah's childhood leukemia rate compared unfavorably with neighboring Kuwait and nearby Oman, as well as the United States, the European Union, and other countries. PMID:20167894

  19. Childhood Acute Lymphoblastic Leukemia and Indicators of Early Immune Stimulation: A Childhood Leukemia International Consortium Study

    PubMed Central

    Rudant, Jérémie; Lightfoot, Tracy; Urayama, Kevin Y.; Petridou, Eleni; Dockerty, John D.; Magnani, Corrado; Milne, Elizabeth; Spector, Logan G.; Ashton, Lesley J.; Dessypris, Nikolaos; Kang, Alice Y.; Miller, Margaret; Rondelli, Roberto; Simpson, Jill; Stiakaki, Eftichia; Orsi, Laurent; Roman, Eve; Metayer, Catherine; Infante-Rivard, Claire; Clavel, Jacqueline

    2015-01-01

    The associations between childhood acute lymphoblastic leukemia (ALL) and several proxies of early stimulation of the immune system, that is, day-care center attendance, birth order, maternally reported common infections in infancy, and breastfeeding, were investigated by using data from 11 case-control studies participating in the Childhood Leukemia International Consortium (enrollment period: 1980–2010). The sample included 7,399 ALL cases and 11,181 controls aged 2–14 years. The data were collected by questionnaires administered to the parents. Pooled odds ratios and 95% confidence intervals were estimated by unconditional logistic regression adjusted for age, sex, study, maternal education, and maternal age. Day-care center attendance in the first year of life was associated with a reduced risk of ALL (odds ratio = 0.77, 95% confidence interval: 0.71, 0.84), with a marked inverse trend with earlier age at start (P < 0.0001). An inverse association was also observed with breastfeeding duration of 6 months or more (odds ratio = 0.86, 95% confidence interval: 0.79, 0.94). No significant relationship with a history of common infections in infancy was observed even though the odds ratio was less than 1 for more than 3 infections. The findings of this large pooled analysis reinforce the hypothesis that day-care center attendance in infancy and prolonged breastfeeding are associated with a decreased risk of ALL. PMID:25731888

  20. Risk for childhood leukemia associated with maternal and paternal age.

    PubMed

    Sergentanis, Theodoros N; Thomopoulos, Thomas P; Gialamas, Spyros P; Karalexi, Maria A; Biniaris-Georgallis, Stylianos-Iason; Kontogeorgi, Evangelia; Papathoma, Paraskevi; Tsilimidos, Gerasimos; Skalkidou, Alkistis; Iliadou, Anastasia N; Petridou, Eleni T

    2015-12-01

    The role of reproductive factors, such as parental age, in the pathogenesis of childhood leukemias is being intensively examined; the results of individual studies are controversial. This meta-analysis aims to quantitatively synthesize the published data on the association between parental age and risk of two major distinct childhood leukemia types in the offspring. Eligible studies were identified and pooled relative risk (RR) estimates were calculated using random-effects models, separately for childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Subgroup analyses were performed by study design, geographical region, adjustment factors; sensitivity analyses and meta-regression analyses were also undertaken. 77 studies (69 case-control and eight cohort) were deemed eligible. Older maternal and paternal age were associated with increased risk for childhood ALL (pooled RR = 1.05, 95 % CI 1.01-1.10; pooled RR = 1.04, 95 % CI 1.00-1.08, per 5 year increments, respectively). The association between maternal age and risk of childhood AML showed a U-shaped pattern, with symmetrically associated increased risk in the oldest (pooled RR = 1.23, 95 % CI 1.06-1.43) and the youngest (pooled RR = 1.23, 95 % CI 1.07-1.40) extremes. Lastly, only younger fathers were at increased risk of having a child with AML (pooled RR = 1.28, 95 % CI 1.04-1.59). In conclusion, maternal and paternal age represents a meaningful risk factor for childhood leukemia, albeit of different effect size by leukemia subtype. Genetic and socio-economic factors may underlie the observed associations. Well-adjusted studies, scheduled by large consortia, are anticipated to satisfactorily address methodological issues, whereas the potential underlying genetic mechanisms should be elucidated by basic research studies. PMID:26537708

  1. Socioeconomic Status and Childhood Leukemia Incidence in Switzerland

    PubMed Central

    Adam, Martin; Kuehni, Claudia E.; Spoerri, Adrian; Schmidlin, Kurt; Gumy-Pause, Fabienne; Brazzola, Pierluigi; Probst-Hensch, Nicole; Zwahlen, Marcel

    2015-01-01

    Socioeconomic status (SES) discrepancies exist for child and adult cancer morbidity and are a major public health concern. In this Swiss population-based matched case–control study on the etiology of childhood leukemia, we selected the cases from the Swiss Childhood Cancer Registry diagnosed since 1991 and the controls randomly from census. We assigned eight controls per case from the 1990 and 2000 census and matched them by the year of birth and gender. SES information for both cases and controls was obtained from census records by probabilistic record linkage. We investigated the association of SES with childhood leukemia in Switzerland, and explored whether it varied with different definitions of socioeconomic status (parental education, living condition, area-based SES), time period, and age. In conditional logistic regression analyses of 565 leukemia cases and 4433 controls, we found no consistent evidence for an association between SES and childhood leukemia. The odds ratio comparing the highest with the lowest SES category ranged from 0.95 (95% CI: 0.71–1.26; Ptrend = 0.73) for paternal education to 1.37 (1.00–1.89; Ptrend = 0.064) for maternal education. No effect modification was found for time period and age at diagnosis. Based on this population-based study, which avoided participation and reporting bias, we assume the potential association of socioeconomic status and childhood leukemia if existing to be small. This study did not find evidence that socioeconomic status, of Switzerland or comparable countries, is a relevant risk factor or strong confounder in etiological investigations on childhood leukemia. PMID:26175964

  2. 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

  3. Microbiome interaction with sugar plays an important role in relapse of childhood caries.

    PubMed

    Tian, Jing; Qin, Man; Ma, Wenli; Xia, Bin; Xu, He; Zhang, Qian; Chen, Feng

    Childhood caries have a high relapse rate after full mouth therapy. This study aimed to elucidate the relationship between the microbiome, sugar, and the relapse of childhood caries after therapy. A total of 24 children aged 2-4 years who underwent one caries treatment session participated in this study. Supragingival plaque was collected before therapy and 1 and 7 months after therapy, then sequenced using the 16S rRNA high-throughput approach. We found 11 phyla, 140 genera, and 444 species in 72 samples. The children were divided into relapse-free (n = 13) and relapse (n = 11) groups according to whether they relapsed 7 months after therapy. The bacterial community richness, diversity, structure, and relative abundance of bacterial taxa were significantly different between the two groups 7 months after therapy. The two groups also differed in the relative abundance of bacterial taxa, both before and 1 month after therapy. Bacterial community richness and diversity were lower in the relapse-free group 1 month after therapy. Using different operational taxonomic units between the relapse-free and relapse groups 1 month after therapy, a relapse-risk assessment model was built with 75% accuracy, 0.1905 out-of-bag error, and 66.67% validation accuracy. Patients in the relapse group had higher sugar intake frequencies than those in the relapse-free group during follow-up. Interactions between the microbiome and sugar intake frequency were found through co-occurrence networks. We conclude that the microbiome is significantly different between the relapse-free and relapse groups at the time of relapse. Supragingival plaque collected immediately after therapy can be used to predict the risk of relapse. Furthermore, the correlation between sugar intake frequency and microbiome is associated with the relapse. PMID:26505801

  4. Molecular epidemiology of childhood leukemia with emphasis on chemical exposures

    SciTech Connect

    Buffler, P.A.; Smith, M.T.; Wood, S.; Reynolds, P.

    1996-12-31

    Developing markets in the Pacific Basin depend heavily on the production and export of consumer goods. The generation of hazardous waste as a by-product of industrial production can be linked to adverse health outcomes, such as childhood leukemia, in ways that are presently unknown. In California, exposures resulting from hazardous waste disposal are of concern in the etiology of childhood cancer. Approximately 63% of the 57 hazardous waste sites that the U.S. Environmental Protection Agency (USEPA) included in the national priority list under the Comprehensive Environmental Response, Compensation and Liability Act (CERCLA) statute were in the six-county San Francisco Bay area. This area includes California`s Silicon Valley, where a disproportionate majority of these sites are located. Although only one study links hazardous waste disposal to childhood leukemia evidence is accumulating that in utero and maternal pesticide exposures as well as chemical exposures during childhood are important in the etiology of childhood leukemia. This study investigates whether children with leukemia have common genetic changes, whether children with genetic changes experience common chemical exposures, and whether the occurrences of these genetic changes correspond to the same temporal sequence as exposure. The purpose of this paper is to describe the study design and report on the status of research activity. 10 refs., 1 fig., 3 tabs.

  5. Leukemia after therapy with alkylating agents for childhood cancer

    SciTech Connect

    Tucker, M.A.; Meadows, A.T.; Boice, J.D. Jr.; Stovall, M.; Oberlin, O.; Stone, B.J.; Birch, J.; Voute, P.A.; Hoover, R.N.; Fraumeni, J.F. Jr.

    1987-03-01

    The risk of leukemia was evaluated in 9,170 2-or-more-year survivors of childhood cancer in the 13 institutions of the Late Effects Study Group. Secondary leukemia occurred in 22 nonreferred individuals compared to 1.52 expected, based on general population rates (relative risk (RR) = 14; 95% confidence interval (CI), 9-22). The influence of therapy for the first cancer on subsequent leukemia risk was determined by a case-control study conducted on 25 cases and 90 matched controls. Treatment with alkylating agents was associated with a significantly elevated risk of leukemia (RR = 4.8; 95% CI, 1.2-18.9). A strong dose-response relationship was also observed between leukemia risk and total dose of alkylating agents, estimated by an alkylator score. The RR of leukemia reached 23 in the highest dose category. Radiation therapy, however, did not increase risk. Although doxorubicin was also identified as a possible risk factor, the excess risk of leukemia following treatment for childhood cancer appears almost entirely due to alkylating agents.

  6. Breastfeeding, Other Early Life Exposures and Childhood Leukemia and Lymphoma.

    PubMed

    Amitay, Efrat Lev; Dubnov Raz, Gal; Keinan-Boker, Lital

    2016-01-01

    Childhood cancer incidence increases and although rare, it is a leading cause of mortality. Leukemia and lymphoma comprise 40% of all cancers in children but little is known of their etiology. In this study, we examined the associations of breastfeeding and other early life exposures with childhood leukemia and lymphoma. A population-based case-control study carried out in 2011-2013 comprised mothers of 190 incidents (2005-2013) of leukemia/lymphoma cases aged 1-19 yr at diagnosis and 384 population-based controls. Interviews based on a computerized structured questionnaire were conducted with the mothers. Multivariate logistic regression models adjusted for potential confounders assessed the association between breastfeeding patterns and childhood leukemia/lymphoma. Ever breastfeeding category was associated with a 64% decreased risk for childhood leukemia/lymphoma lsqb;odds ratio (OR) = 0.36, 95% confidence interval (CI): 0.22, 0.60lrqb; and similar trends, with a dose-response effect, were observed for any breastfeeding (exclusive and/or partial) category for 6, 12, and 18+ mo. Other infant exposures associated with cancer risk were child iron supplementation (OR = 0.39, 95% CI: 0.26, 0.59), pet ownership (OR = 0.50, 95% CI: 0.33, 0.78), paternal smoking (OR = 1.93, 95% CI: 1.18, 3.15), and having older siblings (OR = 1.18, 95% CI: 1.05, 1.33). Breastfeeding-a controllable and modifiable exposure-is inversely associated with risk for childhood leukemia and lymphoma with a dose-response effect. PMID:27352124

  7. Bone mineral density in survivors of childhood acute lymphoblastic leukemia.

    PubMed

    Athanassiadou, Fani; Tragiannidis, Athanassios; Rousso, Israel; Katsos, Georgios; Sidi, Vassiliki; Papageorgiou, Theodotis; Papastergiou, Christos; Tsituridis, Ioannis; Koliouskas, Dimitrios

    2006-01-01

    The aim of our study was to evaluate bone metabolism with measurement of bone mineral density (BMD) after management (chemo-, radiotherapy) for childhood acute lymphoblastic leukemia (ALL). Bone mineral density (g/cm2) of lumbar spine was measured by dual energy X-ray absorptiometry (Norland bone densitometer) in 18 children with ALL and a median of 34 months' post-diagnosis with no history of relapse, secondary malignancy, or transplantation. In addition, patients' BMDs were correlated with particular attention to age, sex and time (years) from completion of chemotherapy. The results were compared with healthy age- and sex-matched controls of the same population and expressed as standard deviation scores (SDS). Mean age of children was 9.8 +/- 3.7 years. Of 18 children (10 boys and 8 girls), 13 were grouped as standard and 5 as high-risk, respectively. Based on z-score values, 9 were classified as normal (z-score <1 SD), 7 as osteopenic (z-score 1-2.5 SD) and 2 as osteoporotic (z-score >2.5 SD). Children with ALL had reduced lumbar BMDs (z score -0.99) in comparison to healthy controls (z score -0.14) (p=0.011), which is indicative of relative osteopenia. Moreover, the reduced BMD was associated with patient age (z score -0.14 and -1.52 for ages <10 and >10 years, respectively, p=0.016). Reduced BMD was not correlated with time from completion of chemotherapy (p=0.33), risk group (p=0.9) and sex (p=0.3). We conclude that children's BMDs are reduced after completion of chemotherapy for ALL. The causes are multifactorial and mainly related to antineoplastic treatments, such as corticosteroids and methotrexate, physical inactivity and cranial irradiation. We suggest that further studies are needed to evaluate the long-term effect on BMD in these children and to prevent pathological fractures later in life. PMID:16848106

  8. Hematologic Response to Vorinostat Treatment in Relapsed Myeloid Leukemia of Down Syndrome.

    PubMed

    Scheer, Carina; Kratz, Christian; Witt, Olaf; Creutzig, Ursula; Reinhardt, Dirk; Klusmann, Jan-Henning

    2016-09-01

    Children with Down syndrome are at high risk to develop myeloid leukemia (ML-DS). Despite their excellent prognosis, children with ML-DS particularly suffer from severe therapy-related toxicities and for relapsed ML-DS the cure rates are very poor. Here we report the clinical course of one child with ML-DS treated with the histone deacetylase (HDAC) inhibitor vorinostat (suberoylanilide hydroxamic acid) after second relapse. The child had previously received conventional chemotherapy and stem cell transplantation, yet showed a remarkable clinical and hematologic response. Thus, HDAC inhibitor may represent an effective class of drugs for the treatment of ML-DS. PMID:27191354

  9. Strategies to Reduce Relapse after Allogeneic Hematopoietic Cell Transplantation in Acute Myeloid Leukemia

    PubMed Central

    Mawad, Raya; Lionberger, Jack M.; Pagel, John M.

    2013-01-01

    The incidence of acute myeloid leukemia (AML) is expected to increase in conjunction with our ageing population. Although it is proving to be a heterogeneous disease process, the only treatment with proven survival benefit for poor risk AML remains allogeneic hematopoietic cell transplant. Although this is presumed to be a curative strategy, many patients relapse after transplant, prompting us to examine various ways that we can improve outcomes. These efforts involve every step of AML diagnostics and therapy, including the intricate processes of conditioning, graft manipulation and immunomodulation. The hope is that improvement in these steps will ultimately improve survival and decrease relapse rates for AML patients after transplant. PMID:23456518

  10. Childhood leukemia and residential proximity to industrial and urban sites

    SciTech Connect

    García-Pérez, Javier; López-Abente, Gonzalo; Gómez-Barroso, Diana; Morales-Piga, Antonio; Pardo Romaguera, Elena; Tamayo, Ibon; Fernández-Navarro, Pablo; and others

    2015-07-15

    Background: Few risk factors for the childhood leukemia are well established. While a small fraction of cases of childhood leukemia might be partially attributable to some diseases or ionizing radiation exposure, the role of industrial and urban pollution also needs to be assessed. Objectives: To ascertain the possible effect of residential proximity to both industrial and urban areas on childhood leukemia, taking into account industrial groups and toxic substances released. Methods: We conducted a population-based case–control study of childhood leukemia in Spain, covering 638 incident cases gathered from the Spanish Registry of Childhood Tumors and for those Autonomous Regions with 100% coverage (period 1990-2011), and 13,188 controls, individually matched by year of birth, sex, and autonomous region of residence. Distances were computed from the respective subject’s residences to the 1068 industries and the 157 urban areas with ≥10,000 inhabitants, located in the study area. Using logistic regression, odds ratios (ORs) and 95% confidence intervals (95%CIs) for categories of distance to industrial and urban pollution sources were calculated, with adjustment for matching variables. Results: Excess risk of childhood leukemia was observed for children living near (≤2.5 km) industries (OR=1.31; 95%CI=1.03–1.67) – particularly glass and mineral fibers (OR=2.42; 95%CI=1.49–3.92), surface treatment using organic solvents (OR=1.87; 95%CI=1.24–2.83), galvanization (OR=1.86; 95%CI=1.07–3.21), production and processing of metals (OR=1.69; 95%CI=1.22–2.34), and surface treatment of metals (OR=1.62; 95%CI=1.22–2.15) – , and urban areas (OR=1.36; 95%CI=1.02–1.80). Conclusions: Our study furnishes some evidence that living in the proximity of industrial and urban sites may be a risk factor for childhood leukemia. - Highlights: • We studied proximity to both industrial and urban sites on childhood leukemia. • We conducted a case–control study in

  11. The association of glutathione S-transferase gene mutations (including GSTT1 and GSTM1) with the prognostic factors and relapse in acute lymphoblastic leukemia.

    PubMed

    Zareifar, Soheila; Monabati, Ahmad; Saeed, Amir; Fakhraee, Farzaneh; Cohan, Nader

    2013-09-01

    Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. It accounts for one fourth of all childhood cancers and approximately 75% of all childhood leukemias. Some prognostic factors determine the outcome of therapy [e.g. age, sex, initial white blood cell count (WBC), etc.]; however, it is believed that other mechanisms such as glutathione S-transferase (GST) gene mutation, the expression of lung resistance protein (LRP), and multidrug resistance-associated protein (MRP) also plays a role in treatment failure. In this study, GST gene mutations including GSTM1 and GSTT1 were evaluated in patients with leukemia. Thirty newly diagnosed ALL patients younger than 15 years of age participated in the present study. Bone marrow aspiration and biopsy were evaluated for immune phenotyping and DNA was extracted for GST genotyping. All data plus sex, age, initial WBC count, central nervous system (CNS) or testicular involvement, immune phenotype, and outcome (relapse or not) were analyzed statistically. Genotyping showed that 46% were double null, 50% were M1 null and 93.3% were T1 null for GST mutations. There was no statistically significant relationship between GSTT1 and GSTM1 mutations, or between double null status, prognostic factors and relapse (P > .05). So, although the results of GST mutations were consistent, it seems that these mutations are not statistically significant. PMID:23444902

  12. Negative feedback-defective PRPS1 mutants drive thiopurine resistance in relapsed childhood ALL

    PubMed Central

    Li, Benshang; Li, Hui; Bai, Yun; Kirschner-Schwabe, Renate; Yang, Jun J; Chen, Yao; Lu, Gang; Tzoneva, Gannie; Ma, Xiaotu; Wu, Tongmin; Li, Wenjing; Lu, Haisong; Ding, Lixia; Liang, Huanhuan; Huang, Xiaohang; Yang, Minjun; Jin, Lei; Kang, Hui; Chen, Shuting; Du, Alicia; Shen, Shuhong; Ding, Jianping; Chen, Hongzhuan; Chen, Jing; von Stackelberg, Arend; Gu, Longjun; Zhang, Jinghui; Ferrando, Adolfo; Tang, Jingyan; Wang, Shengyue; Zhou, Bin-Bing S.

    2015-01-01

    Relapse is the leading cause of mortality in children with acute lymphoblastic leukemia (ALL). Among chemotherapeutics, thiopurines are key drugs in the backbone of ALL combination therapy. Using whole-exome sequencing, we identified relapse-specific mutations in phosphoribosyl pyrophosphate synthetase 1 (PRPS1), a rate-limiting purine biosynthesis enzyme, in 24/358 (6.7%) relapse B-ALL cases. All individuals who harbored PRPS1 mutations relapsed early on-treatment, and mutated ALL clones expanded exponentially prior to clinical relapse. Our functional analyses of PRPS1 mutants uncovered a new chemotherapy resistance mechanism involving reduced feedback inhibition of de novo purine biosynthesis and competitive inhibition of thiopurine activation. Notably, the de novo purine synthesis inhibitor lometrexol can effectively abrogate PRPS1 mutant-driven drug resistance. Overall these results highlight the importance of constitutive activation of de novo purine pathway in thiopurine resistance, and offer therapeutic strategies for the treatment of relapsed and resistant ALL. PMID:25962120

  13. Use of arsenic trioxide in a hemodialysis-dependent patient with relapsed acute promyelocytic leukemia.

    PubMed

    Perreault, Sarah; Moeller, Julie; Patel, Kejal; Eyler, Rachel; Pham, Trinh; Russell, Kerry; Podoltsev, Nikolai

    2016-08-01

    Arsenic trioxide has been established for use in both relapsed and front-line treatment of acute promyelocytic leukemia. Dose adjustments are recommended to be considered in severe renal impairment although dosage reduction guidelines are not provided. In addition, toxicities of arsenic are significant. The use of arsenic trioxide has not been well studied in dialysis patients and there is a paucity of data in the literature to support the use in such a situation. We describe an 81-year-old relapsed acute promyelocytic leukemia hemodialysis-dependent patient with a pre-existing cardiac condition who was treated with 10 mg arsenic trioxide three times weekly after dialysis. These findings provide support along with the marginal amount of currently published data for an arsenic trioxide dosing regimen in hemodialysis patients. PMID:25972392

  14. Hematopoietic Stem-Cell Transplantation for Acute Leukemia in Relapse or Primary Induction Failure

    PubMed Central

    Duval, Michel; Klein, John P.; He, Wensheng; Cahn, Jean-Yves; Cairo, Mitchell; Camitta, Bruce M.; Kamble, Rammurti; Copelan, Edward; de Lima, Marcos; Gupta, Vikas; Keating, Armand; Lazarus, Hillard M.; Litzow, Mark R.; Marks, David I.; Maziarz, Richard T.; Rizzieri, David A.; Schiller, Gary; Schultz, Kirk R.; Tallman, Martin S.; Weisdorf, Daniel

    2010-01-01

    Purpose Patients with acute leukemia refractory to induction or reinduction chemotherapy have poor prognoses if they do not undergo hematopoietic stem-cell transplantation (HSCT). However, HSCT when a patient is not in complete remission (CR) is of uncertain benefit. We hypothesized that pretransplantation variables may define subgroups that have a better prognosis. Patients and Methods Overall, 2,255 patients who underwent transplantation for acute leukemia in relapse or with primary induction failure after myeloablative conditioning regimen between 1995 and 2004 were reported to the Center for International Blood and Marrow Transplant Research. The median follow-up of survivors was 61 months. We performed multivariate analysis of pretransplantation variables and developed a predictive scoring system for survival. Results The 3-year overall survival (OS) rates were 19% for acute myeloid leukemia (AML) and 16% for acute lymphoblastic leukemia (ALL). For AML, five adverse pretransplantation variables significantly influenced survival: first CR duration less than 6 months, circulating blasts, donor other than HLA-identical sibling, Karnofsky or Lansky score less than 90, and poor-risk cytogenetics. For ALL, survival was worse with the following: first refractory or second or greater relapse, ≥ 25% marrow blasts, cytomegalovirus-seropositive donor, and age of 10 years or older. Patients with AML who had a predictive score of 0 had 42% OS at 3 years, whereas OS was 6% for a score ≥ 3. Patients with ALL who had a score of 0 or 1 had 46% 3-year OS but only 10% OS rate for a score ≥ 3. Conclusion Pretransplantation variables delineate subgroups with different outcomes. HSCT during relapse can achieve long-term survival in selected patients with acute leukemia. PMID:20625136

  15. Mechanisms of clonal evolution in childhood acute lymphoblastic leukemia

    PubMed Central

    Park, Eugene; Papaemmanuil, Elli; Ford, Anthony; Kweon, Soo-Mi; Trageser, Daniel; Hasselfeld, Brian; Henke, Nadine; Mooster, Jana; Geng, Huimin; Schwarz, Klaus; Kogan, Scott C.; Casellas, Rafael; Schatz, David G.; Lieber, Michael R; Greaves, Mel F.; Müschen, Markus

    2015-01-01

    Childhood acute lymphoblastic leukemia can often be retraced to a pre-leukemic clone carrying a prenatal genetic lesion. Postnatally acquired mutations then drive clonal evolution towards overt leukemia. RAG1-RAG2 and AID enzymes, the diversifiers of immunoglobulin genes, are strictly segregated to early and late stages of B-lymphopoiesis, respectively. Here, we identified small pre-BII cells as a natural subset of increased genetic vulnerability owing to concurrent activation of these enzymes. Consistent with epidemiological findings on childhood ALL etiology, susceptibility to genetic lesions during B-lymphopoiesis at the large to small pre-BII transition is exacerbated by abnormal cytokine signaling and repetitive inflammatory stimuli. We demonstrate that AID and RAG1-RAG2 drive leukemic clonal evolution with repeated exposure to inflammatory stimuli, paralleling chronic infections in childhood. PMID:25985233

  16. Chronic myeloid leukemia relapsing ten years after allogenic bone marrow transplantation.

    PubMed

    Hino, Yutaro; Doki, Noriko; Yamamoto, Keita; Senoo, Yasushi; Sasajima, Satoshi; Sakaguchi, Masahiro; Hattori, Keiichiro; Kaito, Satoshi; Kurosawa, Shuhei; Harada, Kaito; Ikegawa, Shuntaro; Watanabe, Daisuke; Hagino, Takeshi; Yoshioka, Kosuke; Watakabe, Kyoko; Igarashi, Aiko; Najima, Yuho; Kobayashi, Takeshi; Kakihana, Kazuhiko; Sakamaki, Hisashi; Ohashi, Kazuteru

    2016-05-01

    A 58-year-old female was diagnosed with Philadelphia chromosome positive chronic myeloid leukemia (CML) in blast crisis (BC) in 2004. The patient received imatinib, which quickly induced molecular remission, and subsequently underwent bone marrow transplantation (BMT) from an unrelated human leukocyte antigen (HLA)-identical donor. The post-transplant clinical course was essentially uneventful. In 2014, ten years after the BMT, the patient was admitted to our hospital complaining of lymphadenopathy, and blasts were observed in peripheral blood. The patient was diagnosed as having a CML relapse in myeloid BC, with leukemic infiltration in lymph nodes, and was treated with dasatinib. Subsequently, pleural effusion developed and nilotinib was administered, which induced normal blood counts without blasts and partial cytogenetic remission, one month after administration. Six months after the relapse, this patient underwent a second BMT from an HLA-matched unrelated donor. Recent studies have demonstrated the cumulative incidence of CML relapse more than five years after allogeneic hematopoietic stem cell transplantation (allo-HSCT) to be higher than in acute myeloid leukemia. Although rare, the possibility of late relapse should be considered in patients diagnosed with CML after allo-HSCT. PMID:27263786

  17. Allogeneic hemopoietic stem cell transplants for patients with relapsed acute leukemia: long-term outcome.

    PubMed

    Bacigalupo, A; Lamparelli, T; Gualandi, F; Occhini, D; Bregante, S; Raiola, A M; Ibatici, A; di Grazia, C; Dominietto, A; Piaggio, G; Podesta, M; Bruno, B; Lombardi, A; Frassoni, F; Viscoli, C; Sacchi, N; Van Lint, M T

    2007-03-01

    We assessed the long-term outcome of patients with relapsed acute myeloid (n=86) or acute lymphoid leukemia (n=66), undergoing an allogeneic hemopoietic stem cell transplantation in our unit. The median blast count in the marrow was 30%. Conditioning regimen included total body irradiation (TBI) (10-12 Gy) in 115 patients. The donor was a matched donor (n=132) or a family mismatched donor (n=20). Twenty-two patients (15%) survive disease free, with a median follow-up of 14 years: 18 are off medications. The cumulative incidence of transplant related mortality is 40% and the cumulative incidence of relapse related death (RRD) is 45%. In multivariate analysis of survival, favorable predictors were chronic graft-versus-host disease (GvHD) (P=0.0003), donor other than family mismatched (P=0.02), donor age less than 34 years (P=0.02) and blast count less than 30% (P=0.07). Patients with all four favorable predictors had a 54% survival. In multivariate analysis of relapse, protective variables were the use of TBI (P=0.005) and cGvHD (P=0.01). This study confirms that a fraction of relapsed leukemias is cured with an allogeneic transplant: selection of patients with a blast count <30%, identification of young, human leukocyte antigen-matched donors and the use of total body radiation may significantly improve the outcome. PMID:17277788

  18. Childhood leukemia: electric and magnetic fields as possible risk factors.

    PubMed Central

    Brain, Joseph D; Kavet, Robert; McCormick, David L; Poole, Charles; Silverman, Lewis B; Smith, Thomas J; Valberg, Peter A; Van Etten, R A; Weaver, James C

    2003-01-01

    Numerous epidemiologic studies have reported associations between measures of power-line electric or magnetic fields (EMFs) and childhood leukemia. The basis for such associations remains unexplained. In children, acute lymphoblastic leukemia represents approximately three-quarters of all U.S. leukemia types. Some risk factors for childhood leukemia have been established, and others are suspected. Pathogenesis, as investigated in animal models, is consistent with the multistep model of acute leukemia development. Studies of carcinogenicity in animals, however, are overwhelmingly negative and do not support the hypothesis that EMF exposure is a significant risk factor for hematopoietic neoplasia. We may fail to observe effects from EMFs because, from a mechanistic perspective, the effects of EMFs on biology are very weak. Cells and organs function despite many sources of chemical "noise" (e.g., stochastic, temperature, concentration, mechanical, and electrical noise), which exceed the induced EMF "signal" by a large factor. However, the inability to detect EMF effects in bioassay systems may be caused by the choice made for "EMF exposure." "Contact currents" or "contact voltages" have been proposed as a novel exposure metric, because their magnitude is related to measured power-line magnetic fields. A contact current occurs when a person touches two conductive surfaces at different voltages. Modeled analyses support contact currents as a plausible metric because of correlations with residential magnetic fields and opportunity for exposure. The possible role of contact currents as an explanatory variable in the reported associations between EMFs and childhood leukemia will need to be clarified by further measurements, biophysical analyses, bioassay studies, and epidemiology. PMID:12782499

  19. Childhood leukemia and fallout from the Nevada nuclear tests

    SciTech Connect

    Land, C.E.; McKay, F.W.; Machado, S.G.

    1984-01-13

    Cancer mortality data from the National Center for Health Statistics, covering the period 1950 through 1978, were used to test a reported association between childhood leukemia and exposure to radioactive fallout from nuclear weapons tests in Nevada between 1951 and 1958. No pattern of temporal and geographic variation in risk supportive of the reported association was found. Comparison of these results with those presented in support of an association of risk with fallout suggests that the purported association merely reflects an anomalously low leukemia rate in southern Utah during the period 1944 to 1949. 14 references, 4 figures, 7 tables.

  20. Vorinostat, Cytarabine, and Etoposide in Treating Patients With Relapsed and/or Refractory Acute Leukemia or Myelodysplastic Syndromes or Myeloproliferative Disorders

    ClinicalTrials.gov

    2013-05-01

    Accelerated Phase Chronic Myelogenous Leukemia; 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(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); Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative; Blastic Phase Chronic Myelogenous Leukemia; Chronic Eosinophilic Leukemia; Chronic Myelomonocytic Leukemia; Chronic Neutrophilic Leukemia; de Novo Myelodysplastic Syndromes; Essential Thrombocythemia; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Polycythemia Vera; Previously Treated Myelodysplastic Syndromes; Primary Myelofibrosis; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes

  1. [Ocular findings in leukemia in childhood].

    PubMed

    Rochels, R; Heiland, I

    1987-11-01

    Primary and therapy-induced ocular manifestations of leukemia in 25 of 103 children suffering from the disease (60 patients with ALL, eight with AML, two with CML, 33 with NHL) were kept under observation for an average period of five years. The lens was involved in 10%, the retina in 9%, the optic nerve in 7%, and the orbit in 4% of these cases. The present authors' findings concurred with those published in the literature to date, in that they could not find a pathognomonic combination or a specific frequency of ocular symptoms related to one of the four types of leukemia. PMID:3481001

  2. 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.

  3. ABL kinase mutation and relapse in 4 pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia cases.

    PubMed

    Aoe, Michinori; Shimada, Akira; Muraoka, Michiko; Washio, Kana; Nakamura, Yoshimi; Takahashi, Takahide; Imada, Masahide; Watanabe, Toshiyuki; Okada, Ken; Nishiuchi, Ritsuo; Miyamura, Takako; Chayama, Kosuke; Shibakura, Misako; Oda, Megumi; Morishima, Tsuneo

    2014-01-01

    The tyrosine kinase inhibitor (TKI) imatinib mesylate (IM) revolutionized the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-ALL), which had showed poor prognosis before the dawn of IM treatment. However, if Ph-ALL patients showed IM resistance due to ABL kinase mutation, second-generation TKI, dasatinib or nilotinib, was recommended. We treated 4 pediatric Ph-ALL patients with both IM and bone marrow transplantation (BMT); however, 3 relapsed. We retrospectively examined the existence of ABL kinase mutation using PCR and direct sequencing methods, but there was no such mutation in all 4 diagnostic samples. Interestingly, two relapsed samples from patients who were not treated with IM before relapse did not show ABL kinase mutation and IM was still effective even after relapse. On the other hand, one patient who showed resistance to 3 TKI acquired dual ABL kinase mutations, F359C at the IM-resistant phase and F317I at the dasatinib-resistant phase, simultaneously. In summary, Ph-ALL patients relapsed with or without ABL kinase mutation. Furthermore, ABL kinase mutation was only found after IM treatment, so an IM-resistant clone might have been selected during the IM treatment and intensive chemotherapy. The appropriate combination of TKI and BMT must be discussed to cure Ph-ALL patients. PMID:24652384

  4. Profiling of somatic mutations in acute myeloid leukemia with FLT3-ITD at diagnosis and relapse.

    PubMed

    Garg, Manoj; Nagata, Yasunobu; Kanojia, Deepika; Mayakonda, Anand; Yoshida, Kenichi; Haridas Keloth, Sreya; Zang, Zhi Jiang; Okuno, Yusuke; Shiraishi, Yuichi; Chiba, Kenichi; Tanaka, Hiroko; Miyano, Satoru; Ding, Ling-Wen; Alpermann, Tamara; Sun, Qiao-Yang; Lin, De-Chen; Chien, Wenwen; Madan, Vikas; Liu, Li-Zhen; Tan, Kar-Tong; Sampath, Abhishek; Venkatesan, Subhashree; Inokuchi, Koiti; Wakita, Satoshi; Yamaguchi, Hiroki; Chng, Wee Joo; Kham, Shirley-Kow Yin; Yeoh, Allen Eng-Juh; Sanada, Masashi; Schiller, Joanna; Kreuzer, Karl-Anton; Kornblau, Steven M; Kantarjian, Hagop M; Haferlach, Torsten; Lill, Michael; Kuo, Ming-Chung; Shih, Lee-Yung; Blau, Igor-Wolfgang; Blau, Olga; Yang, Henry; Ogawa, Seishi; Koeffler, H Phillip

    2015-11-26

    Acute myeloid leukemia (AML) with an FLT3 internal tandem duplication (FLT3-ITD) mutation is an aggressive hematologic malignancy with a grave prognosis. To identify the mutational spectrum associated with relapse, whole-exome sequencing was performed on 13 matched diagnosis, relapse, and remission trios followed by targeted sequencing of 299 genes in 67 FLT3-ITD patients. The FLT3-ITD genome has an average of 13 mutations per sample, similar to other AML subtypes, which is a low mutation rate compared with that in solid tumors. Recurrent mutations occur in genes related to DNA methylation, chromatin, histone methylation, myeloid transcription factors, signaling, adhesion, cohesin complex, and the spliceosome. Their pattern of mutual exclusivity and cooperation among mutated genes suggests that these genes have a strong biological relationship. In addition, we identified mutations in previously unappreciated genes such as MLL3, NSD1, FAT1, FAT4, and IDH3B. Mutations in 9 genes were observed in the relapse-specific phase. DNMT3A mutations are the most stable mutations, and this DNMT3A-transformed clone can be present even in morphologic complete remissions. Of note, all AML matched trio samples shared at least 1 genomic alteration at diagnosis and relapse, suggesting common ancestral clones. Two types of clonal evolution occur at relapse: either the founder clone recurs or a subclone of the founder clone escapes from induction chemotherapy and expands at relapse by acquiring new mutations. Relapse-specific mutations displayed an increase in transversions. Functional assays demonstrated that both MLL3 and FAT1 exert tumor-suppressor activity in the FLT3-ITD subtype. An inhibitor of XPO1 synergized with standard AML induction chemotherapy to inhibit FLT3-ITD growth. This study clearly shows that FLT3-ITD AML requires additional driver genetic alterations in addition to FLT3-ITD alone. PMID:26438511

  5. Neuropsychological Functioning in Survivors of Childhood Leukemia.

    ERIC Educational Resources Information Center

    Reeb, Roger N.; Regan, Judith M.

    1998-01-01

    Examined neuropsychological functioning of survivors of acute lymphoblastic leukemia who underwent central-nervous-system prophylactic treatment. Findings replicated past research in showing survivors perform poorly on visual-motor integration tasks and develop a Nonverbal Learning Disability. Findings offer recommendations for future research and…

  6. No involvement of bovine leukemia virus in childhood acute lymphoblastic leukemia and non-Hodgkin's lymphoma

    SciTech Connect

    Bender, A.P.; Robison, L.L.; Kashmiri, S.V.; McClain, K.L.; Woods, W.G.; Smithson, W.A.; Heyn, R.; Finlay, J.; Schuman, L.M.; Renier, C.

    1988-05-15

    Bovine leukemia virus (BLV) is the causative agent of enzootic bovine lymphosarcoma. Much speculation continues to be directed at the role of BLV in human leukemia. To test this hypothesis rigorously, a case-control study of childhood acute lymphoblastic leukemia and non-Hodgkin's lymphoma was conducted between December 1983 and February 1986. Cases (less than or equal to 16 years at diagnosis) derived from patients diagnosed at the primary institutions and affiliated hospitals were matched (age, sex, and race) with regional population controls. DNA samples from bone marrow or peripheral blood from 157 cases (131 acute lymphoblastic leukemia, 26 non-Hodgkin's lymphoma) and peripheral blood from 136 controls were analyzed by Southern blot technique, under highly stringent conditions, using cloned BLV DNA as a probe. None of the 157 case or 136 control DNA samples hybridized with the probe. The high statistical power and specificity of this study provide the best evidence to date that genomic integration of BLV is not a factor in childhood acute lymphoblastic leukemia/non-Hodgkin's lymphoma.

  7. 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

  8. Whole-exome sequencing in relapsing chronic lymphocytic leukemia: clinical impact of recurrent RPS15 mutations

    PubMed Central

    Ljungström, Viktor; Cortese, Diego; Young, Emma; Pandzic, Tatjana; Mansouri, Larry; Plevova, Karla; Ntoufa, Stavroula; Baliakas, Panagiotis; Clifford, Ruth; Sutton, Lesley-Ann; Blakemore, Stuart J.; Stavroyianni, Niki; Agathangelidis, Andreas; Rossi, Davide; Höglund, Martin; Kotaskova, Jana; Juliusson, Gunnar; Belessi, Chrysoula; Chiorazzi, Nicholas; Panagiotidis, Panagiotis; Langerak, Anton W.; Smedby, Karin E.; Oscier, David; Gaidano, Gianluca; Schuh, Anna; Davi, Frederic; Pott, Christiane; Strefford, Jonathan C.; Trentin, Livio; Pospisilova, Sarka; Ghia, Paolo; Stamatopoulos, Kostas; Sjöblom, Tobias

    2016-01-01

    Fludarabine, cyclophosphamide, and rituximab (FCR) is first-line treatment of medically fit chronic lymphocytic leukemia (CLL) patients; however, despite good response rates, many patients eventually relapse. Although recent high-throughput studies have identified novel recurrent genetic lesions in adverse prognostic CLL, the mechanisms leading to relapse after FCR therapy are not completely understood. To gain insight into this issue, we performed whole-exome sequencing of sequential samples from 41 CLL patients who were uniformly treated with FCR but relapsed after a median of 2 years. In addition to mutations with known adverse-prognostic impact (TP53, NOTCH1, ATM, SF3B1, NFKBIE, and BIRC3), a large proportion of cases (19.5%) harbored mutations in RPS15, a gene encoding a component of the 40S ribosomal subunit. Extended screening, totaling 1119 patients, supported a role for RPS15 mutations in aggressive CLL, with one-third of RPS15-mutant cases also carrying TP53 aberrations. In most cases, selection of dominant, relapse-specific subclones was observed over time. However, RPS15 mutations were clonal before treatment and remained stable at relapse. Notably, all RPS15 mutations represented somatic missense variants and resided within a 7 amino-acid, evolutionarily conserved region. We confirmed the recently postulated direct interaction between RPS15 and MDM2/MDMX and transient expression of mutant RPS15 revealed defective regulation of endogenous p53 compared with wild-type RPS15. In summary, we provide novel insights into the heterogeneous genetic landscape of CLL relapsing after FCR treatment and highlight a novel mechanism underlying clinical aggressiveness involving a mutated ribosomal protein, potentially representing an early genetic lesion in CLL pathobiology. PMID:26675346

  9. Whole-exome sequencing in relapsing chronic lymphocytic leukemia: clinical impact of recurrent RPS15 mutations.

    PubMed

    Ljungström, Viktor; Cortese, Diego; Young, Emma; Pandzic, Tatjana; Mansouri, Larry; Plevova, Karla; Ntoufa, Stavroula; Baliakas, Panagiotis; Clifford, Ruth; Sutton, Lesley-Ann; Blakemore, Stuart J; Stavroyianni, Niki; Agathangelidis, Andreas; Rossi, Davide; Höglund, Martin; Kotaskova, Jana; Juliusson, Gunnar; Belessi, Chrysoula; Chiorazzi, Nicholas; Panagiotidis, Panagiotis; Langerak, Anton W; Smedby, Karin E; Oscier, David; Gaidano, Gianluca; Schuh, Anna; Davi, Frederic; Pott, Christiane; Strefford, Jonathan C; Trentin, Livio; Pospisilova, Sarka; Ghia, Paolo; Stamatopoulos, Kostas; Sjöblom, Tobias; Rosenquist, Richard

    2016-02-25

    Fludarabine, cyclophosphamide, and rituximab (FCR) is first-line treatment of medically fit chronic lymphocytic leukemia (CLL) patients; however, despite good response rates, many patients eventually relapse. Although recent high-throughput studies have identified novel recurrent genetic lesions in adverse prognostic CLL, the mechanisms leading to relapse after FCR therapy are not completely understood. To gain insight into this issue, we performed whole-exome sequencing of sequential samples from 41 CLL patients who were uniformly treated with FCR but relapsed after a median of 2 years. In addition to mutations with known adverse-prognostic impact (TP53, NOTCH1, ATM, SF3B1, NFKBIE, and BIRC3), a large proportion of cases (19.5%) harbored mutations in RPS15, a gene encoding a component of the 40S ribosomal subunit. Extended screening, totaling 1119 patients, supported a role for RPS15 mutations in aggressive CLL, with one-third of RPS15-mutant cases also carrying TP53 aberrations. In most cases, selection of dominant, relapse-specific subclones was observed over time. However, RPS15 mutations were clonal before treatment and remained stable at relapse. Notably, all RPS15 mutations represented somatic missense variants and resided within a 7 amino-acid, evolutionarily conserved region. We confirmed the recently postulated direct interaction between RPS15 and MDM2/MDMX and transient expression of mutant RPS15 revealed defective regulation of endogenous p53 compared with wild-type RPS15. In summary, we provide novel insights into the heterogeneous genetic landscape of CLL relapsing after FCR treatment and highlight a novel mechanism underlying clinical aggressiveness involving a mutated ribosomal protein, potentially representing an early genetic lesion in CLL pathobiology. PMID:26675346

  10. Targeting Mutant BRAF with Vemurafenib in Relapsed or Refractory Hairy Cell Leukemia

    PubMed Central

    Tiacci, Enrico; Park, Jae H.; De Carolis, Luca; Chung, Stephen S.; Broccoli, Alessandro; Scott, Sasinya; Zaja, Francesco; Devlin, Sean; Pulsoni, Alessandro; Chung, Young Rock; Cimminiello, Michele; Kim, Eunhee; Rossi, Davide; Stone, Richard M.; Motta, Giovanna; Saven, Alan; Varettoni, Marzia; Altman, Jessica K.; Anastasia, Antonella; Grever, Michael R.; Ambrosetti, Achille; Rai, Kanti R.; Fraticelli, Vincenzo; Lacouture, Mario E.; Carella, Angelo Michele; Levine, Ross L.; Leoni, Pietro; Rambaldi, Alessandro; Falzetti, Franca; Ascani, Stefano; Capponi, Monia; Martelli, Maria Paola; Park, Christopher Y.; Pileri, Stefano Aldo; Rosen, Neal; Foà, Robin; Berger, Michael F.; Zinzani, Pier Luigi; Abdel-Wahab, Omar; Falini, Brunangelo; Tallman, Martin S.

    2016-01-01

    BACKGROUND BRAF-V600E is the genetic lesion underlying hairy cell leukemia. We assessed the safety and activity of the oral BRAF inhibitor vemurafenib in patients with hairy cell leukemia who relapsed after or were refractory to purine analogues. METHODS We conducted in Italy and USA two phase-2 single-arm multicenter studies of vemurafenib (960 mg twice daily) given for a median of 16 and 18 weeks, respectively. Primary endpoints were complete remission rate and overall response rate. Patient enrollment was completed (n=28) in the Italian trial in April 2013 and is still open (n=26/36) in the American trial. RESULTS Drug-related adverse events were usually of grade 1-2, and those most frequently requiring dose reductions were rash and arthralgia/arthritis; secondary cutaneous tumors (treated with simple excision) developed in 6/50 patients. Overall response rates were 96% (25/26 evaluable Italian patients) and 100% (24/24 evaluable American patients), obtained after a median of 8 weeks and 12 weeks, respectively. Complete response rates were 34.6% (9/26) and 41.7% (10/24), respectively. In the Italian trial, after a median follow-up of 23 months, the median relapse-free and treatment-free survivals were respectively 19 and 25 months in complete responders, and 6 and 18 months in partial responders. In the American trial, 1-year progression-free and overall survival were 73% and 91%, respectively. Frequent persistence of phospho-ERK+ bone marrow leukemic cells at the end of treatment suggests bypass MEK-ERK reactivation as a resistance mechanism. CONCLUSIONS A short oral course of vemurafenib proved safe and highly effective in relapsed/refractory hairy cell leukemia patients (Funded by AIRC, ERC, Roche/Genentech and others; EudractCT number: 2011-005487-13, ClinicalTrials.gov number NCT01711632). PMID:26352686

  11. Temporal bone metastasis as a sign of relapsing chronic lymphocytic leukemia

    PubMed Central

    Aljafar, Hadeel M.; Alsuhibani, Sari S.; Alahmari, Mohammad S.; Alzahrani, Musaed A.

    2015-01-01

    Otologic manifestations in chronic lymphocytic leukemia (CLL) are common presentations. However, temporal bone metastasis is rarely described as a sign of relapsing CLL. A 65-year-old male diabetic patient known to have CLL on remission presented to the outpatient otolaryngology clinic with a one month history of progressive bilateral otalgia and right otorrhea, despite multiple courses of antibiotics. He was admitted with suspicion of malignant otitis externa. Left ear showed large hemorrhagic bullae on the posterior segment of tympanic membrane. Left sided facial paralysis developed on the third day of admission. Full recovery of facial paralysis is achieved by 10 days course of corticotherapy. Histological examination of middle ear tissue biopsy showed infiltration by monotonous small lymphoid cells, showing round nuclei, condensed chromatin suggestive of CLL. Although rare, unusual otologic manifestations should raise the suspicion of a temporal bone metastasis as a sign of relapsing CLL. PMID:26446337

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

    ClinicalTrials.gov

    2016-03-30

    Acute Leukemia of Ambiguous Lineage; 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); RUNX1-RUNX1T1; Adult Acute Myeloid Leukemia With t(9;11)(p22;q23); MLLT3-MLL; Adult Acute Promyelocytic Leukemia With t(15;17)(q22;q12); PML-RARA; Alkylating Agent-Related Acute Myeloid Leukemia; Childhood Acute Myeloid Leukemia in Remission; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

  13. Road Traffic and Childhood Leukemia: The ESCALE Study (SFCE)

    PubMed Central

    Amigou, Alicia; Sermage-Faure, Claire; Orsi, Laurent; Leverger, Guy; Baruchel, André; Bertrand, Yves; Nelken, Brigitte; Robert, Alain; Michel, Gérard; Margueritte, Geneviève; Perel, Yves; Mechinaud, Françoise; Bordigoni, Pierre; Hémon, Denis; Clavel, Jacqueline

    2011-01-01

    Background Traffic is a source of environmental exposures, including benzene, which may be related to childhood leukemia. Objectives A national registry–based case–control study [ESCALE (Etude Sur les Cancers et les Leucémies de l’Enfant, Study on Environmental and Genetic Risk Factors of Childhood Cancers and Leukemia)] carried out in France was used to assess the effect of exposure to road traffic exhaust fumes on the risk of childhood leukemia. Methods Over the study period, 2003–2004, 763 cases and 1,681 controls < 15 years old were included, and the controls were frequency matched with the cases on age and sex. The ESCALE data were collected by a standardized telephone interview of the mothers. Various indicators of exposure to traffic and pollution were determined using the geocoded addresses at the time of diagnosis for the cases and of interview for the controls. Indicators of the distance from, and density of, main roads and traffic nitrogen dioxide (NO2) concentrations derived from traffic emission data were used. Odds ratios (ORs) were estimated using unconditional regression models adjusted for potential confounders. Results Acute leukemia (AL) was significantly associated with estimates of traffic NO2 concentration at the place of residence > 27.7 μg/m3 compared with NO2 concentration < 21.9 μg/m3 [OR = 1.2; confidence interval (CI), 1.0–1.5] and with the presence of a heavy-traffic road within 500 m compared with the absence of a heavy-traffic road in the same area (OR = 2.0; 95% CI, 1.0–3.6). There was a significant association between AL and a high density of heavy-traffic roads within 500 m compared with the reference category with no heavy-traffic road within 500 m (OR = 2.2; 95% CI, 1.1–4.2), with a significant positive linear trend of the association of AL with the total length of heavy-traffic road within 500m. Conclusion This study supports the hypothesis that living close to heavy-traffic roads may increase the risk of

  14. A case of central nervous system relapse in acute promyelocytic leukemia.

    PubMed

    Hasuike, Yuhei; Yamaguchi, Hiroshi; Mitsui, Hideki; Nishikawa, Yoshiro; Sugai, Fuminobu

    2016-04-28

    A 70-year-old woman who have achieved complete remission (CR) of acute promyelocytic leukemia (APL) with all-trans retinoic acid and chemotherapy presented with abnormal sensation in the right lateral thigh and the bilateral legs. In addition, neurological examination revealed weakness of the left shoulder abduction, the right hand, and the bilateral lower limbs. Atypical promyelocytes were detected in the cerebrospinal fluid, in spite of normal finding in the peripheral blood smear. Magnetic resonance imaging showed gadolinium-enhanced multiple intradural/extramedullary lesions in the whole spine. Nerve conduction studies of the right limbs revealed sensorimotor conduction abnormalities, conspicuously in the posterior tibial and sural nerves. As a result, she was diagnosed as having intrathecal relapse of APL, associated with multiple mononeuropathy. The neurological symptoms were completely disappeared by intrathecal chemotherapy and whole-spine radiotherapy, suggesting that the neuropathy was possibly caused by meningeal infiltration affecting multiple spinal nerve roots. Since extramedullary or intrathecal relapse is extremely rare in APL compared with other types of leukemia, precise neurological evaluations and suitable treatment should be performed immediately, when APL patients with CR manifest some neurological symptoms. PMID:27025992

  15. Blinatumomab: Bridging the Gap in Adult Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia.

    PubMed

    Folan, Stephanie A; Rexwinkle, Amber; Autry, Jane; Bryan, Jeffrey C

    2016-08-01

    Adult patients with acute lymphoblastic leukemia who relapse after frontline therapy have extremely poor outcomes despite advances in chemotherapy and hematopoietic stem cell transplantation. Blinatumomab is a first-in-class bispecific T-cell engager that links T cells to tumor cells leading to T-cell activation and tumor cell lysis. In December 2014, the Food and Drug Administration approved blinatumomab for treatment of relapsed or refractory Philadelphia chromosome-negative precursor B-cell acute lymphoblastic leukemia. In a phase II trial, blinatumomab produced response rates of 43%, and 40% of patients achieving a complete remission proceeded to hematopoietic stem cell transplantation. Early use of blinatumomab was complicated with adverse effects, including cytokine release syndrome and neurotoxicity. Management strategies, including dexamethasone premedication and 2-step dose escalation during the first cycle of blinatumomab, have decreased the incidence and severity of these adverse effects. Blinatumomab currently is being studied for other B-cell malignancies and has the potential to benefit many patients with CD19+ malignancies in the future. PMID:27521320

  16. Diffuse leukoencephalopathy and brain edema: unusual presentations of CNS relapse of acute myeloid leukemia.

    PubMed

    Schumann, Michael; Kiewe, Philipp; Hartlieb, Sissel; Neumann, Martin; Schilling, Andreas; Koch, Hans-Christian; Thiel, Eckhard; Korfel, Agnieszka

    2010-04-01

    An isolated CNS relapse is rarely seen in acute myeloid leukemia. However, it has a potentially fatal clinical outcome. We herein present the case of a 39-year-old man, who presented to our emergency room with horizontal diplopic images, vertigo, bilateral deafness, and progressing somnolence. Cerebral imaging revealed cerebral and cerebellar edema and a diffuse leukoencephalopathy. With the one-year-old history of an initially successfully treated FAB-M0 acute myeloid leukemia (AML) in mind, a lumbar puncture was carried out that showed a vast number of myeloid blasts in the morphologic analysis of the cerebrospinal fluid. In conjunction with normal findings in the peripheral blood-count with differential and the bone marrow examination a diagnosis of an isolated CNS relapse of the AML was made. Cytarabine chemotherapy was initiated and the symptoms resolved rapidly. To our surprise, cerebral imaging in the course of the treatment not only showed a resolution of the brain edema but also of the leukoencephalopathy, pointing to a direct infiltration of brain parenchyma by leukemic blasts. The case highlights the relevance of the CNS as a pharmacologic "sanctuary" for tumor cells in patients that on prior treatments have not received intrathecal chemotherapy or chemotherapeutics that cross the blood-brain barrier. PMID:18826442

  17. Laryngotracheal stenosis requiring emergency tracheostomy as the first manifestation of childhood-relapsing polychondritis.

    PubMed

    Buscatti, Izabel M; Giacomin, Maria Fernanda A; Silva, Marco Felipe C; Campos, Lúcia M A; Sallum, Adriana M E; Silva, Clovis A

    2013-01-01

    Relapsing polychondritis is a rare childhood disorder of unknown etiology, characterized by inflammatory, recurrent and destructive cartilage lesions. The chondritis could be widespread and involves generally laryngeal and auricular hyaline cartilages. We described a 9 years and 4 months old girl, who presented recurrent acute laryngotracheitis and laryngotracheal stenosis, which were the first manifestations of relapsing polychondritis, and was submitted to emergency tracheostomy. She also had ear condritis and arthritis, being treated with prednisolone and methotrexate. In conclusion, we reported a rare case of relapsing polychondritis that presented a life-threatening laryngo-tracheo-bronchial disorder requiring tracheostomy. We suggest that the diagnosis of relapsing polychondritis should be considered for patients who present recurrent acute laryngotracheitis with other types of condritis, as well as musculoskeletal manifestations. PMID:24149019

  18. Evolution of a FLT3-TKD mutated subclone at meningeal relapse in acute promyelocytic leukemia.

    PubMed

    Bochtler, Tilmann; Fröhling, Stefan; Weichert, Wilko; Endris, Volker; Thiede, Christian; Hutter, Barbara; Hundemer, Michael; Ho, Anthony D; Krämer, Alwin

    2016-09-01

    Here, we report the case of an acute promyelocytic leukemia (APL) patient who-although negative for FLT3 mutations at diagnosis-developed isolated FLT3 tyrosine kinase II domain (FLT3-TKD)-positive meningeal relapse, which, in retrospect, could be traced back to a minute bone marrow subclone present at first diagnosis. Initially, the 48-yr-old female diagnosed with high-risk APL had achieved complete molecular remission after standard treatment with all-trans retinoic acid (ATRA) and chemotherapy according to the AIDA (ATRA plus idarubicin) protocol. Thirteen months after the start of ATRA maintenance, the patient suffered clinically overt meningeal relapse along with minute molecular traces of PML/RARA (promyelocytic leukemia/retinoic acid receptor alpha) in the bone marrow. Following treatment with arsenic trioxide and ATRA in combination with intrathecal cytarabine and methotrexate, the patient achieved a complete molecular remission in both cerebrospinal fluid (CSF) and bone marrow, which currently lasts for 2 yr after completion of therapy. Whole-exome sequencing and subsequent ultradeep targeted resequencing revealed a heterozygous FLT3-TKD mutation in CSF leukemic cells (p.D835Y, c.2503G>T, 1000/1961 reads [51%]), which was undetectable in the concurrent bone marrow sample. Interestingly, the FLT3-TKD mutated meningeal clone originated from a small bone marrow subclone present in a variant allele frequency of 0.4% (6/1553 reads) at initial diagnosis. This case highlights the concept of clonal evolution with a subclone harboring an additional mutation being selected as the "fittest" and leading to meningeal relapse. It also further supports earlier suggestions that FLT3 mutations may play a role for migration and clonal expansion in the CSF sanctuary site. PMID:27626069

  19. Evolution of a FLT3-TKD mutated subclone at meningeal relapse in acute promyelocytic leukemia

    PubMed Central

    Bochtler, Tilmann; Fröhling, Stefan; Weichert, Wilko; Endris, Volker; Thiede, Christian; Hutter, Barbara; Hundemer, Michael; Ho, Anthony D.; Krämer, Alwin

    2016-01-01

    Here, we report the case of an acute promyelocytic leukemia (APL) patient who—although negative for FLT3 mutations at diagnosis—developed isolated FLT3 tyrosine kinase II domain (FLT3-TKD)-positive meningeal relapse, which, in retrospect, could be traced back to a minute bone marrow subclone present at first diagnosis. Initially, the 48-yr-old female diagnosed with high-risk APL had achieved complete molecular remission after standard treatment with all-trans retinoic acid (ATRA) and chemotherapy according to the AIDA (ATRA plus idarubicin) protocol. Thirteen months after the start of ATRA maintenance, the patient suffered clinically overt meningeal relapse along with minute molecular traces of PML/RARA (promyelocytic leukemia/retinoic acid receptor alpha) in the bone marrow. Following treatment with arsenic trioxide and ATRA in combination with intrathecal cytarabine and methotrexate, the patient achieved a complete molecular remission in both cerebrospinal fluid (CSF) and bone marrow, which currently lasts for 2 yr after completion of therapy. Whole-exome sequencing and subsequent ultradeep targeted resequencing revealed a heterozygous FLT3-TKD mutation in CSF leukemic cells (p.D835Y, c.2503G>T, 1000/1961 reads [51%]), which was undetectable in the concurrent bone marrow sample. Interestingly, the FLT3-TKD mutated meningeal clone originated from a small bone marrow subclone present in a variant allele frequency of 0.4% (6/1553 reads) at initial diagnosis. This case highlights the concept of clonal evolution with a subclone harboring an additional mutation being selected as the “fittest” and leading to meningeal relapse. It also further supports earlier suggestions that FLT3 mutations may play a role for migration and clonal expansion in the CSF sanctuary site. PMID:27626069

  20. Naive Donor NK Cell Repertoires Associated with Less Leukemia Relapse after Allogeneic Hematopoietic Stem Cell Transplantation.

    PubMed

    Björklund, Andreas T; Clancy, Trevor; Goodridge, Jodie P; Béziat, Vivien; Schaffer, Marie; Hovig, Eivind; Ljunggren, Hans-Gustaf; Ljungman, Per T; Malmberg, Karl-Johan

    2016-02-01

    Acute and latent human CMV cause profound changes in the NK cell repertoire, with expansion and differentiation of educated NK cells expressing self-specific inhibitory killer cell Ig-like receptors. In this study, we addressed whether such CMV-induced imprints on the donor NK cell repertoire influenced the outcome of allogeneic stem cell transplantation. Hierarchical clustering of high-resolution immunophenotyping data covering key NK cell parameters, including frequencies of CD56(bright), NKG2A(+), NKG2C(+), and CD57(+) NK cell subsets, as well as the size of the educated NK cell subset, was linked to clinical outcomes. Clusters defining naive (NKG2A(+)CD57(-)NKG2C(-)) NK cell repertoires in the donor were associated with decreased risk for relapse in recipients with acute myeloid leukemia and myelodysplastic syndrome (hazard ratio [HR], 0.09; 95% confidence interval [CI]: 0.03-0.27; p < 0.001). Furthermore, recipients with naive repertoires at 9-12 mo after hematopoietic stem cell transplantation had increased disease-free survival (HR, 7.2; 95% CI: 1.6-33; p = 0.01) and increased overall survival (HR, 9.3; 95% CI: 1.1-77, p = 0.04). Conversely, patients with a relative increase in differentiated NK cells at 9-12 mo displayed a higher rate of late relapses (HR, 8.41; 95% CI: 6.7-11; p = 0.02), reduced disease-free survival (HR, 0.12; 95% CI: 0.12-0.74; p = 0.02), and reduced overall survival (HR, 0.07; 95% CI: 0.01-0.69; p = 0.02). Thus, our data suggest that naive donor NK cell repertoires are associated with protection against leukemia relapse after allogeneic HSCT. PMID:26746188

  1. [IDA-FLAG regimen in treatment of patients with refractory or relapsed acute leukemia].

    PubMed

    Qian, Si-Xuan; Li, Jian-Yong; Wu, Han-Xin; Zhang, Run; Hong, Ming; Xu, Wei; Qiu, Hong-Xia

    2009-04-01

    The objective of this study was to evaluate the efficacy and toxicity of the fludarabine combination with high-dose cytarabine (Ara C), idarubicin and granulocyte colony-stimulating factor (G-CSF) (IDA-FLAG regimen) in treatment of refractory/relapsed acute leukemia (AL) patients. 4 patients were male aged from 32 to 44 years, consisted of 3 cases of acute myeloid leukaemia (AML) and 1 cases of acute lymphocytic leukaemia (ALL). All the patients were treated with idarubicin (10 - 12 mg/m(2)/d, days 1 to 3), fludarabine (50 mg/d, days 1 to 5), cytarabine (2 g/m(2)/d, days 1 to 5) and granulocyte colony-stimulating factor (G-CSF, 300 microg/d, days 0 to 5). The results showed that after one course of induction therapy, 4 patients all achieved complete remission (CR), in which 2 patients were in continuous CR after a follow-up of 3 and 4 months; 1 patient relapsed after 10 months and another one patient died of thrombotic thrombocytopenic purpura at 4 months after allogeneic peripheral blood stem cell transplantation. Myelosuppression and infections due to neutropenia were the most frequent adverse effects, severe nonhematologic toxicity and the early death were not observed in these patients. In conclusion, the IDA-FLAG regimen is effective in treatment of patients with refractory and relapsed AL, the adverse effects from this regimen were well tolerated by patients, which gains time for further treatment. PMID:19379589

  2. Advances in the treatment of relapsed/refractory acute lymphoblastic leukemia: a case study compendium.

    PubMed

    Roboz, Gail J; Jabbour, Elias J; Faderl, Stefan; Douer, Dan

    2014-12-01

    Acute lymphoblastic leukemia (ALL) is a heterogeneous hematologic malignancy characterized by proliferation of immature lymphoid cells throughout the bone marrow and peripheral blood. Most cases are diagnosed before the age of 20 years. Adults have a worse prognosis than children. Approximately half of adult ALL patients relapse after their initial treatment. There is no standard treatment for ALL; strategies vary according to the patient’s age, comorbidities, and Philadelphia chromosome status. Regimens used in pediatric patients are being adapted for use in adults. Frontline management can include hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with cycles of high-dose methotrexate and cytarabine (hyper-CVAD) and the Berlin-Frankfurt-Münster regimen. Relapsed/refractory patients have several options, including a regimen consisting of fludarabine, high-dose cytarabine, and granulocyte colony–stimulating factor (FLAG); tyrosine kinase inhibitors; and chemotherapy. The US Food and Drug Administration recently approved 3 therapies for these patients: clofarabine, nelarabine, and vincristine sulfate liposome injection, a modified formulation of vincristine that allows the drug to be administered at a higher dosage. Several novel strategies are currently under investigation, including the monoclonal antibody blinatumomab, a bispecific T-cell engager that targets the B-cell–specific antigen CD19 and activates T cells to exert cytotoxic activity against the target B cell. This clinical roundtable monograph features case studies that illustrate important points in the management of adult patients with relapsed/refractory ALL. PMID:25768269

  3. Maternal and perinatal risk factors for childhood leukemia

    SciTech Connect

    Zack, M.; Adami, H.O.; Ericson, A. )

    1991-07-15

    This report describes an exploratory population-based study of maternal and perinatal risk factors for childhood leukemia in Sweden. The Swedish National Cancer Registry ascertained 411 cases in successive birth cohorts from 1973 through 1984 recorded in the Swedish Medical Birth Registry. Using the latter, we matched five controls without cancer to each case by sex and month and year of birth. Mothers of children with leukemia were more likely to have been exposed to nitrous oxide anesthesia during delivery than mothers of controls (odds ratio (OR) = 1.3; 95% confidence interval (CI) = 1.0, 1.6). Children with leukemia were more likely than controls to have Down's syndrome (OR = 32.5; 95% CI = 7.3, 144.0) or cleft lip or cleft palate (OR = 5.0; 95% CI = 1.0, 24.8); to have had a diagnosis associated with difficult labor but unspecified complications (OR = 4.5; 95% CI = 1.1, 18.2) or with other conditions of the fetus or newborn (OR = 1.5; 95% CI = 1.1, 2.1), specifically, uncomplicated physiological jaundice (OR = 1.9; 95% CI = 1.2, 2.9); or to have received supplemental oxygen (OR = 2.6; 95% CI = 1.3, 1.3, 4.9). Because multiple potential risk factors were analyzed in this study, future studies need to check these findings. The authors did not confirm the previously reported higher risks for childhood leukemia associated with being male, having a high birth weight, or being born to a woman of advanced maternal age.

  4. Beyond CD19: Opportunities for Future Development of Targeted Immunotherapy in Pediatric Relapsed-Refractory Acute Leukemia

    PubMed Central

    Shalabi, Haneen; Angiolillo, Anne; Fry, Terry J.

    2015-01-01

    Chimeric antigen receptor (CAR) T cell therapy has been used as a targeted approach in cancer therapy. Relapsed and refractory acute leukemia in pediatrics has been difficult to treat with conventional therapy due to dose-limiting toxicities. With the recent success of CD 19 CAR in pediatric patients with B cell acute lymphoblastic leukemia (ALL), this mode of therapy has become a very attractive option for these patients with high-risk disease. In this review, we will discuss current treatment paradigms of pediatric acute leukemia and potential therapeutic targets for additional high-risk populations, including T cell ALL, AML, and infant ALL. PMID:26484338

  5. Clinical activity of azacitidine in patients who relapse after allogeneic stem cell transplantation for acute myeloid leukemia

    PubMed Central

    Craddock, Charles; Labopin, Myriam; Robin, Marie; Finke, Juergen; Chevallier, Patrice; Yakoub-Agha, Ibrahim; Bourhis, Jean Henri; Sengelov, Henrik; Blaise, Didier; Luft, Thomas; Hallek, Michael; Kröger, Nicolaus; Nagler, Arnon; Mohty, Mohamad

    2016-01-01

    Disease relapse is the most common cause of treatment failure after allogeneic stem cell transplantation for acute myeloid leukemia and myelodysplastic syndromes, yet treatment options for such patients remain extremely limited. Azacitidine is an important new therapy in high-risk myelodysplastic syndromes and acute myeloid leukemia but its role in patients who relapse post allograft has not been defined. We studied the tolerability and activity of azacitidine in 181 patients who relapsed after an allograft for acute myeloid leukemia (n=116) or myelodysplastic syndromes (n=65). Sixty-nine patients received additional donor lymphocyte infusions. Forty-six of 157 (25%) assessable patients responded to azacitidine therapy: 24 (15%) achieved a complete remission and 22 a partial remission. Response rates were higher in patients transplanted in complete remission (P=0.04) and those transplanted for myelodysplastic syndromes (P=0.023). In patients who achieved a complete remission, the 2-year overall survival was 48% versus 12% for the whole population. Overall survival was determined by time to relapse post transplant more than six months (P=0.001) and percentage of blasts in the bone marrow at time of relapse (P=0.01). The concurrent administration of donor lymphocyte infusion did not improve either response rates or overall survival in patients treated with azacitidine. An azacitidine relapse prognostic score was developed which predicted 2-year overall survival ranging from 3%–37% (P=0.00001). We conclude that azacitidine represents an important new therapy in selected patients with acute myeloid leukemia/myelodysplastic syndromes who relapse after allogeneic stem cell transplantation. Prospective studies to confirm optimal treatment options in this challenging patient population are required. PMID:27081178

  6. PD-1hiTIM-3+ T cells associate with and predict leukemia relapse in AML patients post allogeneic stem cell transplantation

    PubMed Central

    Kong, Y; Zhang, J; Claxton, D F; Ehmann, W C; Rybka, W B; Zhu, L; Zeng, H; Schell, T D; Zheng, H

    2015-01-01

    Prognosis of leukemia relapse post allogeneic stem cell transplantation (alloSCT) is poor and effective new treatments are urgently needed. T cells are pivotal in eradicating leukemia through a graft versus leukemia (GVL) effect and leukemia relapse is considered a failure of GVL. T-cell exhaustion is a state of T-cell dysfunction mediated by inhibitory molecules including programmed cell death protein 1 (PD-1) and T-cell immunoglobulin domain and mucin domain 3 (TIM-3). To evaluate whether T-cell exhaustion and inhibitory pathways are involved in leukemia relapse post alloSCT, we performed phenotypic and functional studies on T cells from peripheral blood of acute myeloid leukemia patients receiving alloSCT. Here we report that PD-1hiTIM-3+ cells are strongly associated with leukemia relapse post transplantation. Consistent with exhaustion, PD-1hiTIM-3+ T cells are functionally deficient manifested by reduced production of interleukin 2 (IL-2), tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ). In addition, these cells demonstrate a phenotype consistent with exhausted antigen-experienced T cells by losing TN and TEMRA subsets. Importantly, increase of PD-1hiTIM-3+ cells occurs before clinical diagnosis of leukemia relapse, suggesting their predictive value. Results of our study provide an early diagnostic approach and a therapeutic target for leukemia relapse post transplantation. PMID:26230954

  7. PD-1(hi)TIM-3(+) T cells associate with and predict leukemia relapse in AML patients post allogeneic stem cell transplantation.

    PubMed

    Kong, Y; Zhang, J; Claxton, D F; Ehmann, W C; Rybka, W B; Zhu, L; Zeng, H; Schell, T D; Zheng, H

    2015-01-01

    Prognosis of leukemia relapse post allogeneic stem cell transplantation (alloSCT) is poor and effective new treatments are urgently needed. T cells are pivotal in eradicating leukemia through a graft versus leukemia (GVL) effect and leukemia relapse is considered a failure of GVL. T-cell exhaustion is a state of T-cell dysfunction mediated by inhibitory molecules including programmed cell death protein 1 (PD-1) and T-cell immunoglobulin domain and mucin domain 3 (TIM-3). To evaluate whether T-cell exhaustion and inhibitory pathways are involved in leukemia relapse post alloSCT, we performed phenotypic and functional studies on T cells from peripheral blood of acute myeloid leukemia patients receiving alloSCT. Here we report that PD-1(hi)TIM-3(+) cells are strongly associated with leukemia relapse post transplantation. Consistent with exhaustion, PD-1(hi)TIM-3(+) T cells are functionally deficient manifested by reduced production of interleukin 2 (IL-2), tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ). In addition, these cells demonstrate a phenotype consistent with exhausted antigen-experienced T cells by losing TN and TEMRA subsets. Importantly, increase of PD-1(hi)TIM-3(+) cells occurs before clinical diagnosis of leukemia relapse, suggesting their predictive value. Results of our study provide an early diagnostic approach and a therapeutic target for leukemia relapse post transplantation. PMID:26230954

  8. The role of blinatumomab in patients with relapsed/refractory acute lymphoblastic leukemia

    PubMed Central

    Benjamin, Jonathan E.; Stein, Anthony S.

    2016-01-01

    Adults with relapsed/refractory B-acute lymphoblastic leukemia (ALL) have a complete remission (CR) rate of 20–45% and median overall survival of 3–9 months, depending on the duration of the first remission and number of lines of salvage therapy. Allogeneic hematopoietic stem cell transplantation (alloHSCT) is the only curative option for adult patients with relapsed/refractory ALL, and achievement of CR is a crucial step before alloHSCT. Blinatumomab is a bispecific T-cell engager (BiTE®) antibody construct with dual specificity for CD19 and CD3, simultaneously binding CD3-positive cytotoxic T cells and CD19-positive B cells, resulting in T-cell-mediated serial lysis of normal and malignant B cells. It recently gained accelerated approval by the US Food and Drug Administration (FDA) for the treatment of relapsed/refractory Philadelphia chromosome-negative ALL, based on a large phase II trial of 189 adults with relapsed/refractory B-ALL, which showed a CR/CRh (CR with partial hematologic recovery) of 43% after two cycles of treatment. Toxicities include cytokine-release syndrome (CRS) and neurologic events (encephalopathy, aphasia, and seizure). CRS can be alleviated by step-up dosing and dexamethasone, without affecting the cytotoxic effect of blinatumomab. The cause of neurologic toxicity is unclear but is also observed with other T-cell therapies and may relate to variable expression of CD19 within the brain. This review encompasses the preclinical rationale of using the BITE® class of compounds (blinatumomab being the only one that is FDA approved), with clinical data using blinatumomab in the relapsed/refractory setting (pediatrics and adults), the minimal residual disease setting (adults), as well as Philadelphia chromosome-positive ALL. The review also examines the main adverse events: their prevention, recognition, and management; possible mechanisms of resistance; causes of relapse. It also summarizes future trials evaluating the drug earlier in the

  9. The role of blinatumomab in patients with relapsed/refractory acute lymphoblastic leukemia.

    PubMed

    Benjamin, Jonathan E; Stein, Anthony S

    2016-06-01

    Adults with relapsed/refractory B-acute lymphoblastic leukemia (ALL) have a complete remission (CR) rate of 20-45% and median overall survival of 3-9 months, depending on the duration of the first remission and number of lines of salvage therapy. Allogeneic hematopoietic stem cell transplantation (alloHSCT) is the only curative option for adult patients with relapsed/refractory ALL, and achievement of CR is a crucial step before alloHSCT. Blinatumomab is a bispecific T-cell engager (BiTE®) antibody construct with dual specificity for CD19 and CD3, simultaneously binding CD3-positive cytotoxic T cells and CD19-positive B cells, resulting in T-cell-mediated serial lysis of normal and malignant B cells. It recently gained accelerated approval by the US Food and Drug Administration (FDA) for the treatment of relapsed/refractory Philadelphia chromosome-negative ALL, based on a large phase II trial of 189 adults with relapsed/refractory B-ALL, which showed a CR/CRh (CR with partial hematologic recovery) of 43% after two cycles of treatment. Toxicities include cytokine-release syndrome (CRS) and neurologic events (encephalopathy, aphasia, and seizure). CRS can be alleviated by step-up dosing and dexamethasone, without affecting the cytotoxic effect of blinatumomab. The cause of neurologic toxicity is unclear but is also observed with other T-cell therapies and may relate to variable expression of CD19 within the brain. This review encompasses the preclinical rationale of using the BITE® class of compounds (blinatumomab being the only one that is FDA approved), with clinical data using blinatumomab in the relapsed/refractory setting (pediatrics and adults), the minimal residual disease setting (adults), as well as Philadelphia chromosome-positive ALL. The review also examines the main adverse events: their prevention, recognition, and management; possible mechanisms of resistance; causes of relapse. It also summarizes future trials evaluating the drug earlier in the

  10. The prognostic significance of early treatment response in pediatric relapsed acute myeloid leukemia: results of the international study Relapsed AML 2001/01

    PubMed Central

    Creutzig, Ursula; Zimmermann, Martin; Dworzak, Michael N.; Gibson, Brenda; Tamminga, Rienk; Abrahamsson, Jonas; Ha, Shau-Yin; Hasle, Henrik; Maschan, Alexey; Bertrand, Yves; Leverger, Guy; von Neuhoff, Christine; Razzouk, Bassem; Rizzari, Carmelo; Smisek, Petr; Smith, Owen P.; Stark, Batia; Reinhardt, Dirk; Kaspers, Gertjan L.

    2014-01-01

    The prognostic significance of early response to treatment has not been reported in relapsed pediatric acute myeloid leukemia. In order to identify an early and easily applicable prognostic factor allowing subsequent treatment modifications, we assessed leukemic blast counts in the bone marrow by morphology on days 15 and 28 after first reinduction in 338 patients of the international Relapsed-AML2001/01 trial. Both day 15 and day 28 status was classified as good (≤20% leukemic blasts) in 77% of patients. The correlation between day 15 and 28 blast percentages was significant, but not strong (Spearman correlation coefficient = 0.49, P<0.001). Survival probability decreased in a stepwise fashion along with rising blast counts at day 28. Patients with bone marrow blast counts at this time-point of ≤5%, 6–10%, 11–20% and >20% had 4-year probabilities of survival of 52%±3% versus 36%±10% versus 21%±9% versus 14%±4%, respectively, P<0.0001; this trend was not seen for day 15 results. Multivariate analysis showed that early treatment response at day 28 had the strongest prognostic significance, superseding even time to relapse (< or ≥12 months). In conclusion, an early response to treatment, measured on day 28, is a strong and independent prognostic factor potentially useful for treatment stratification in pediatric relapsed acute myeloid leukemia. This study was registered with ISRCTN code: 94206677. PMID:24763401

  11. Current Strategies for the Detection of Minimal Residual Disease in Childhood Acute Lymphoblastic Leukemia

    PubMed Central

    Rocha, Juliana Maria Camargos; Xavier, Sandra Guerra; de Lima Souza, Marcelo Eduardo; Assumpção, Juliana Godoy; Murao, Mitiko; de Oliveira, Benigna Maria

    2016-01-01

    Acute lymphoblastic leukemia (ALL) is the most common cancer in children. Current treatment strategies for childhood ALL result in long-term remission for approximately 90% of patients. However, the therapeutic response is worse among those who relapse. Several risk stratification approaches based on clinical and biological aspects have been proposed to intensify treatment in patients with high risk of relapse and reduce toxicity on those with a greater probability of cure. The detection of residual leukemic cells (minimal residual disease, MRD) is the most important prognostic factor to identify high-risk patients, allowing redefinition of chemotherapy. In the last decades, several standardized research protocols evaluated MRD using immunophenotyping by flow cytometry and/or real-time quantitative polymerase chain reaction at different time points during treatment. Both methods are highly sensitive (10−3 a 10−5), but expensive, complex, and, because of that, require qualified staff and frequently are restricted to reference centers. The aim of this article was to review technical aspects of immunophenotyping by flow cytometry and real-time quantitative polymerase chain reaction to evaluate MRD in ALL. PMID:27158437

  12. Current Strategies for the Detection of Minimal Residual Disease in Childhood Acute Lymphoblastic Leukemia.

    PubMed

    Rocha, Juliana Maria Camargos; Xavier, Sandra Guerra; de Lima Souza, Marcelo Eduardo; Assumpção, Juliana Godoy; Murao, Mitiko; de Oliveira, Benigna Maria

    2016-01-01

    Acute lymphoblastic leukemia (ALL) is the most common cancer in children. Current treatment strategies for childhood ALL result in long-term remission for approximately 90% of patients. However, the therapeutic response is worse among those who relapse. Several risk stratification approaches based on clinical and biological aspects have been proposed to intensify treatment in patients with high risk of relapse and reduce toxicity on those with a greater probability of cure. The detection of residual leukemic cells (minimal residual disease, MRD) is the most important prognostic factor to identify high-risk patients, allowing redefinition of chemotherapy. In the last decades, several standardized research protocols evaluated MRD using immunophenotyping by flow cytometry and/or real-time quantitative polymerase chain reaction at different time points during treatment. Both methods are highly sensitive (10(-3) a 10(-5)), but expensive, complex, and, because of that, require qualified staff and frequently are restricted to reference centers. The aim of this article was to review technical aspects of immunophenotyping by flow cytometry and real-time quantitative polymerase chain reaction to evaluate MRD in ALL. PMID:27158437

  13. Parental Tobacco Smoking and Acute Myeloid Leukemia: The Childhood Leukemia International Consortium.

    PubMed

    Metayer, Catherine; Petridou, Eleni; Aranguré, Juan Manuel Mejía; Roman, Eve; Schüz, Joachim; Magnani, Corrado; Mora, Ana Maria; Mueller, Beth A; de Oliveira, Maria S Pombo; Dockerty, John D; McCauley, Kathryn; Lightfoot, Tracy; Hatzipantelis, Emmanouel; Rudant, Jérémie; Flores-Lujano, Janet; Kaatsch, Peter; Miligi, Lucia; Wesseling, Catharina; Doody, David R; Moschovi, Maria; Orsi, Laurent; Mattioli, Stefano; Selvin, Steve; Kang, Alice Y; Clavel, Jacqueline

    2016-08-15

    The association between tobacco smoke and acute myeloid leukemia (AML) is well established in adults but not in children. Individual-level data on parental cigarette smoking were obtained from 12 case-control studies from the Childhood Leukemia International Consortium (CLIC, 1974-2012), including 1,330 AML cases diagnosed at age <15 years and 13,169 controls. We conducted pooled analyses of CLIC studies, as well as meta-analyses of CLIC and non-CLIC studies. Overall, maternal smoking before, during, or after pregnancy was not associated with childhood AML; there was a suggestion, however, that smoking during pregnancy was associated with an increased risk in Hispanics (odds ratio = 2.08, 95% confidence interval (CI): 1.20, 3.61) but not in other ethnic groups. By contrast, the odds ratios for paternal lifetime smoking were 1.34 (95% CI: 1.11, 1.62) and 1.18 (95% CI: 0.92, 1.51) in pooled and meta-analyses, respectively. Overall, increased risks from 1.2- to 1.3-fold were observed for pre- and postnatal smoking (P < 0.05), with higher risks reported for heavy smokers. Associations with paternal smoking varied by histological type. Our analyses suggest an association between paternal smoking and childhood AML. The association with maternal smoking appears limited to Hispanic children, raising questions about ethnic differences in tobacco-related exposures and biological mechanisms, as well as study-specific biases. PMID:27492895

  14. Sorafenib in Treating Patients With Refractory or Relapsed Acute Leukemia, Myelodysplastic Syndromes, or Blastic Phase Chronic Myelogenous Leukemia

    ClinicalTrials.gov

    2015-04-27

    Adult Acute Basophilic Leukemia; Adult Acute Eosinophilic Leukemia; 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); RUNX1-RUNX1T1; Adult Acute Myeloid Leukemia With t(9;11)(p22;q23); MLLT3-MLL; Adult Acute Myeloid Leukemia Without Maturation; Adult Acute Myelomonocytic Leukemia; Adult Acute Promyelocytic Leukemia With t(15;17)(q22;q12); PML-RARA; Adult Erythroleukemia; Adult Pure Erythroid Leukemia; Alkylating Agent-Related Acute Myeloid Leukemia; Blastic Phase; de Novo Myelodysplastic Syndrome; Previously Treated Myelodysplastic Syndrome; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndrome

  15. Disseminated intravascular coagulation observed following treatment with gemtuzumab ozogamicin for relapsed/refractory acute promyelocytic leukemia

    PubMed Central

    AZUMA, YOSHIKO; NAKAYA, AYA; HOTTA, MASAAKI; FUJITA, SHINYA; TSUBOKURA, YUKIE; YOSHIMURA, HIDEAKI; SATAKE, ATSUSHI; ISHII, KAZUYOSHI; ITO, TOMOKI; NOMURA, SHOSAKU

    2016-01-01

    Gemtuzumab ozogamicin (GO) is a recombinant humanized immunoglobulin G4 anti-cluster of differentiation (CD)33 monoclonal antibody conjugated to N-acetyl-γ calicheamicin dimethylhydrazide, a naturally potent antibiotic. It has been introduced for the treatment of acute promyelocytic leukemia (APL), since large quantities of CD33 are commonly expressed on the surface of APL cells. The present study reported two cases with prominent disseminated intravascular coagulation (DIC), which was transiently observed following treatment with GO with relapsed/refractory APL. Very limited information exists regarding DIC occurring following GO, and its mechanism remains to be elucidated. In the present study, recombinant human soluble thrombomodulin was used for DIC treatment, and the patients recovered promptly. Since DIC is the most serious adverse event associated with GO treatment, elucidation of its mechanism and establishment of a treatment strategy are warranted. PMID:27330760

  16. 5-Azacytidine treatment for relapsed or refractory acute myeloid leukemia after intensive chemotherapy.

    PubMed

    Ivanoff, Sarah; Gruson, Berengere; Chantepie, Sylvain P; Lemasle, Emilie; Merlusca, Lavinia; Harrivel, Veronique; Charbonnier, Amandine; Votte, Patrick; Royer, Bruno; Marolleau, Jean-Pierre

    2013-07-01

    Despite progress in the understanding of leukemia pathophysiology, the treatment of acute myeloid leukemia (AML) remains challenging. In patients with refractory or relapsed (R/R) AML, the prognosis is still poor and this group is targeted for new drug development. We reviewed the outcome of 47 patients, with R/R AML after at least one course of intensive chemotherapy, treated with 5-azacytidine in three different French institutions. The overall response rate was 38% including complete remission in 21%, partial remission in 11%, and hematological improvement in 6% of cases. Median time to relapse was 6 (range, 1-39) months. Median overall survival was 9 months (not reached by responders vs. 4.5 months for nonresponders patients, P = 0.0001). Univariate analysis identified the absence of peripheral blood blasts and <20% bone marrow blasts as prognostic factors for both overall response and survival, but not age, ECOG/PS, type of AML, cytogenetic, status of the disease, number of previous lines of therapy, previous hematological stem cell transplantation, or white blood cells count. Bone marrow blasts percentage <20% was the only independent prognostic factor identified by multivariate analysis for overall response (P = 0.0013) and survival (P = 0.0324). Six patients in remission could proceed to an allogenic hematological stem cell transplantation. The drug-related grade 3/4 adverse events were hematopoietic toxicities (38%) and infection (32%). In conclusion, this study suggests that a salvage therapy with 5-azacytidine is an interesting option for patients with R/R AML after intensive chemotherapy. Prospective randomized studies are needed to demonstrate a superiority of this approach over others strategies. PMID:23619977

  17. S1312, Inotuzumab Ozogamicin and Combination Chemotherapy in Treating Patients With Relapsed or Refractory Acute Leukemia

    ClinicalTrials.gov

    2016-04-14

    Acute Leukemias of Ambiguous Lineage; B-cell Adult Acute Lymphoblastic Leukemia; Philadelphia Chromosome Positive Adult Precursor Acute Lymphoblastic Leukemia; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Burkitt Lymphoma

  18. Eltrombopag Olamine in Treating Patients With Relapsed/Refractory Acute Myeloid Leukemia

    ClinicalTrials.gov

    2016-04-04

    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 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

  19. Selinexor and Chemotherapy in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

    ClinicalTrials.gov

    2015-12-15

    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 Myeloid Leukemia; Secondary Acute Myeloid Leukemia

  20. Clofarabine, Cytarabine, and G-CSF in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

    ClinicalTrials.gov

    2015-05-05

    Acute Myeloid Leukemia; 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 Promyelocytic Leukemia (M3); Recurrent Adult Acute Myeloid Leukemia

  1. Polymorphisms of the vincristine pathway and response to treatment in children with childhood acute lymphoblastic leukemia

    PubMed Central

    Ceppi, Francesco; Langlois-Pelletier, Chloé; Gagné, Vincent; Rousseau, Julie; Ciolino, Claire; Lorenzo, Samanta De; Kevin, Kojok M; Cijov, Diana; Sallan, Stephen E; Silverman, Lewis B; Neuberg, Donna; Kutok, Jeffery L; Sinnett, Daniel; Laverdière, Caroline; Krajinovic, Maja

    2015-01-01

    Background Vincristine (VCR) is a standard component in the treatment of childhood acute lymphoblastic leukemia (ALL). VCR cytotoxicity is primarily due to its ability to disrupt the formation of microtubules of the mitotic spindle. Patients & methods A total of 17 polymorphisms in regulatory and coding regions of genes controlling VCR targets (TUBB1, MAP4, ACTG1 and CAPG) or potentially influencing VCR levels (ABCB1 and CYP3A5) were investigated for an association with peripheral neuropathy and outcome in childhood ALL patients. Results High-grade neurotoxicity was more frequent in carriers of the A allele of synonymous (Ala310) G to A (rs1135989) variation in the ACTG1 gene. Substitution (rs4728709) in the promoter of the ABCB1 gene had a protective effect against lower grade neurotoxicity and C to A variation (rs3770102) located 17 nucleotides upstream from the transcription start site had a protective effect against high-grade neurotoxicity. Patients with the ABCB1 3435TT genotype had lower event-free survival; the association with event-free survival was not supported by the analysis in the replication patient set. Conclusion The polymorphisms in the ACTG1, CAPG and ABCB1 genes may modulate VCR-related neurotoxicity, whereas the risk of relapse seems not to be affected by the genes of the VCR pathway. PMID:25084203

  2. Intracellular Signaling Pathways Involved in Childhood Acute Lymphoblastic Leukemia; Molecular Targets.

    PubMed

    Layton Tovar, Cristian Fabián; Mendieta Zerón, Hugo

    2016-06-01

    Acute lymphoblastic leukemia (ALL) is a malignant disease characterized by an uncontrolled proliferation of immature lymphoid cells. ALL is the most common hematologic malignancy in early childhood, and it reaches peak incidence between the ages of 2 and 3 years. The prognosis of ALL is associated with aberrant gene expression, in addition to the presence of numerical or structural chromosomal alterations, age, race, and immunophenotype. The Relapse rate with regard to pharmacological treatment rises in childhood; thus, the expression of biomarkers associated with the activation of cell signaling pathways is crucial to establish the disease prognosis. Intracellular pathways involved in ALL are diverse, including Janus kinase/Signal transducers and transcription activators (JAK-STAT), Phosphoinositide-3-kinase-protein kinase B (PI3K-AKT), Ras mitogen-activated protein kinase (Ras-MAPK), Glycogen synthase kinase-3β (GSK-3β), Nuclear factor-kappa beta (NF-κB), and Hypoxia-inducible transcription factor 1α (HIF-1α), among others. In this review, we present several therapeutic targets, intracellular pathways, and molecular markers that are being studied extensively at present. PMID:27065575

  3. The role of idelalisib in the treatment of relapsed and refractory chronic lymphocytic leukemia

    PubMed Central

    Nair, Kruti Sheth; Cheson, Bruce

    2016-01-01

    Idelalisib is a first in class, delta isoform specific, PI3-kinase inhibitor. Based on its high level of efficacy and acceptable safety profile, this oral drug has been approved by the US Food and Drug Administration as a single agent for the treatment of relapsed or refractory small lymphocytic lymphoma, and follicular non-Hodgkin lymphoma, and in combination with rituximab for patients with chronic lymphocytic leukemia. Adverse effects of particular concern include diarrhea, pneumonitis, and transient elevations of hepatic transaminase levels. Efforts to improve on the activity of this drug have included combinations with standard chemotherapy agents, such as bendamustine, and other targeted therapies, including checkpoint inhibitors. However, other combinations have been associated with life-threatening and fatal toxicities. Thus, the development of such regimens should be conducted carefully in the context of a clinical research study. Idelalisib has a vital role as second-line therapy for chronic lymphocytic leukemia, especially for patients with high-risk disease and multiple comorbidities, and studies are exploring the use of this agent as front-line therapy to improve the outcome of patients with indolent B-cell malignancies. PMID:27054023

  4. The role of idelalisib in the treatment of relapsed and refractory chronic lymphocytic leukemia.

    PubMed

    Nair, Kruti Sheth; Cheson, Bruce

    2016-04-01

    Idelalisib is a first in class, delta isoform specific, PI3-kinase inhibitor. Based on its high level of efficacy and acceptable safety profile, this oral drug has been approved by the US Food and Drug Administration as a single agent for the treatment of relapsed or refractory small lymphocytic lymphoma, and follicular non-Hodgkin lymphoma, and in combination with rituximab for patients with chronic lymphocytic leukemia. Adverse effects of particular concern include diarrhea, pneumonitis, and transient elevations of hepatic transaminase levels. Efforts to improve on the activity of this drug have included combinations with standard chemotherapy agents, such as bendamustine, and other targeted therapies, including checkpoint inhibitors. However, other combinations have been associated with life-threatening and fatal toxicities. Thus, the development of such regimens should be conducted carefully in the context of a clinical research study. Idelalisib has a vital role as second-line therapy for chronic lymphocytic leukemia, especially for patients with high-risk disease and multiple comorbidities, and studies are exploring the use of this agent as front-line therapy to improve the outcome of patients with indolent B-cell malignancies. PMID:27054023

  5. Combined Molecular and Clinical Prognostic Index for Relapse and Survival in Cytogenetically Normal Acute Myeloid Leukemia

    PubMed Central

    Pastore, Friederike; Dufour, Annika; Benthaus, Tobias; Metzeler, Klaus H.; Maharry, Kati S.; Schneider, Stephanie; Ksienzyk, Bianka; Mellert, Gudrun; Zellmeier, Evelyn; Kakadia, Purvi M.; Unterhalt, Michael; Feuring-Buske, Michaela; Buske, Christian; Braess, Jan; Sauerland, Maria Cristina; Heinecke, Achim; Krug, Utz; Berdel, Wolfgang E.; Buechner, Thomas; Woermann, Bernhard; Hiddemann, Wolfgang; Bohlander, Stefan K.; Marcucci, Guido; Spiekermann, Karsten; Bloomfield, Clara D.; Hoster, Eva

    2014-01-01

    Purpose Cytogenetically normal (CN) acute myeloid leukemia (AML) is the largest and most heterogeneous cytogenetic AML subgroup. For the practicing clinician, it is difficult to summarize the prognostic information of the growing number of clinical and molecular markers. Our purpose was to develop a widely applicable prognostic model by combining well-established pretreatment patient and disease characteristics. Patients and Methods Two prognostic indices for CN-AML (PINA), one regarding overall survival (OS; PINAOS) and the other regarding relapse-free survival (RFS; PINARFS), were derived from data of 572 patients with CN-AML treated within the AML Cooperative Group 99 study (www.aml-score.org). Results On the basis of age (median, 60 years; range, 17 to 85 years), performance status, WBC count, and mutation status of NPM1, CEBPA, and FLT3-internal tandem duplication, patients were classified into the following three risk groups according to PINAOS and PINARFS: 29% of all patients and 32% of 381 responding patients had low-risk disease (5-year OS, 74%; 5-year RFS, 55%); 56% of all patients and 39% of responding patients had intermediate-risk disease (5-year OS, 28%; 5-year RFS, 27%), and 15% of all patients and 29% of responding patients had high-risk disease (5-year OS, 3%; 5-year RFS, 5%), respectively. PINAOS and PINARFS stratified outcome within European LeukemiaNet genetic groups. Both indices were confirmed on independent data from Cancer and Leukemia Group B/Alliance trials. Conclusion We have developed and validated, to our knowledge, the first prognostic indices specifically designed for adult patients of all ages with CN-AML that combine well-established molecular and clinical variables and that are easily applicable in routine clinical care. The integration of both clinical and molecular markers could provide a basis for individualized patient care through risk-adapted therapy of CN-AML. PMID:24711548

  6. Development and perspective of current Brazilian studies on the epidemiology of childhood leukemia.

    PubMed

    Pombo de Oliveira, Maria S; Koifman, Sergio; Vasconcelos, Gisele M; Emerenciano, Mariana; de Oliveira Novaes, Cristiane

    2009-01-01

    In this concise report, we describe the history and evolution of childhood acute leukemia studies in Brazil, and the application if key biomarkers for clinical trials and epidemiological studies over the past 8 years. Highlights of each ongoing study are summarized. A Brazilian network integrating hospitals and scientific institutions from all country regions has been established. This organization is made possible through informatics and computer networking, and the standardization of pathological reviews including immunophenotyping and molecular characterization of childhood leukemias. The unique characteristics of the Brazilian population combined with a large clinical and epidemiologic framework for patient ascertainment has enabled large-scale epidemiological studies on childhood leukemia in Brazil. PMID:19064327

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

    PubMed Central

    Bailey, Helen D; Fritschi, Lin; Metayer, Catherine; Infante-Rivard, Claire; Magnani, Corrado; Petridou, Eleni; Roman, Eve; Spector, Logan G; Kaatsch, Peter; Clavel, Jacqueline; Milne, Elizabeth; Dockerty, John D; Glass, Deborah C; Lightfoot, Tracy; Miligi, Lucia; Rudant, Jérémie; Baka, Margarita; Rondelli, Roberto; Amigou, Alicia; Simpson, Jill; Kang, Alice; Moschovi, Maria; Schüz, Joachim

    2014-01-01

    Purpose It has been suggested that parental occupational paint exposure around the time of conception or pregnancy increases the risk of childhood leukemia in the offspring. Methods We obtained individual level data from 13 case-control studies participating in the Childhood Leukemia International Consortium (CLIC). Occupational data were harmonized to a compatible format. Meta-analyses of study-specific odds ratios (ORs) were undertaken, as well as pooled analyses of individual data using unconditional logistic regression. Results Using individual data from fathers of 8,185 cases and 14,210 controls, the pooled OR for paternal exposure around conception and risk of acute lymphoblastic leukaemia (ALL) was 0.93 (95% confidence interval (CI) 0.76, 1.14). Analysis of data from 8,156 ALL case mothers and 14,568 control mothers produced a pooled OR of 0.81 (95% CI 0.39, 1.68) for exposure during pregnancy. For acute myeloid leukaemia (AML), the pooled ORs for paternal and maternal exposure were 0.96 (95% CI 0.65, 1.41) and 1.31 (95% CI 0.38, 4.47) respectively, based on data from 1,231 case and 11,392 control fathers and 1,329 case and 12,141 control mothers. Heterogeneity among the individual studies ranged from low to modest. Conclusions Null findings for paternal exposure for both ALL and AML are consistent with previous reports. Despite the large sample size, results for maternal exposure to paints in pregnancy were based on small numbers of exposed. Overall, we found no evidence that parental occupational exposure to paints increases the risk of leukemia in the offspring, but further data on home exposure are needed. PMID:25088805

  8. Phase I Combination of Midostaurin, Bortezomib, and Chemo in Relapsed/Refractory Acute Myeloid Leukemia

    ClinicalTrials.gov

    2016-04-05

    Acute Myeloid 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); Recurrent Adult Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia

  9. A 50-Year Journey to Cure Childhood Acute Lymphoblastic Leukemia

    PubMed Central

    Pui, Ching-Hon; Evans, William E.

    2013-01-01

    The 50th anniversary of Seminars in Hematology coincides with the 50th of St. Jude Children’s Research Hospital, and both milestones are inexorably linked to studies contributing to the cure of childhood acute lymphoblastic leukemia (ALL). We thought it fitting, therefore, to mark these events by traveling back in time to point out some of the achievements, institutions, study groups and individuals that have made cure of childhood ALL a reality. In many instances, progress was driven by new ideas, while in others it was driven by new experimental tools that allowed more precise assessment of the biology of leukemic blasts and their utility in selecting therapy. We also discuss a number of contemporary advances that point the way to exciting future directions. Whatever pathways are taken, a clear challenge will be to use emerging genome-based or immunologic-based treatment options in ways that will enhance, rather than duplicate or compromise, recent gains in outcome with classic cytotoxic chemotherapy. The theme of this journey serves as a reminder of the chief ingredient of any research directed to a catastrophic disease such as ALL. It is the audacity of a small group of investigators who confronted a childhood cancer with the goal of cure, not palliation, as their mindset. PMID:23953334

  10. Association between body mass index at diagnosis and pediatric leukemia mortality and relapse: a systematic review and meta-analysis.

    PubMed

    Amankwah, Ernest K; Saenz, Ashleigh M; Hale, Gregory A; Brown, Patrick A

    2016-05-01

    Obesity is a risk factor for mortality and relapse of certain cancers. However, existing evidence for pediatric leukemia is inconsistent. The aim of this systematic review and meta-analysis was to evaluate the association between obesity at diagnosis and pediatric acute leukemia mortality and relapse. This study systematically searched MEDLINE and EMBASE from inception to February 5, 2015. Random-effect models were used to generate pooled estimates of study-specific hazard ratios (HR) and 95% confidence intervals (CI). Eleven studies were included. An increased risk of mortality with a high BMI at diagnosis was observed (overall survival: HR = 1.30, 95% CI = 1.16-1.46 and event-free survival: HR = 1.46, 95% CI = 1.29-1.64). Only two studies reported HR for relapse; one reported a reduced risk, while the other reported an increased risk. A high BMI at diagnosis is associated with poor overall and event-free survival among pediatric acute leukemia patients. Targeted therapeutic approaches for obese pediatric leukemia patients may potentially improve survival outcomes. PMID:26453440

  11. Flavopiridol, Cytarabine, and Mitoxantrone in Treating Patients With Relapsed or Refractory Acute Leukemia

    ClinicalTrials.gov

    2013-09-27

    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); Malignant Neoplasm; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia

  12. Ixazomib in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

    ClinicalTrials.gov

    2016-06-24

    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

  13. CPX-351 in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome

    ClinicalTrials.gov

    2016-04-25

    Adult Acute Erythroid Leukemia (M6); Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia and Acute Monocytic Leukemia (M5); 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); de Novo Myelodysplastic Syndromes; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes

  14. AKT Inhibitor MK-2206 in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

    ClinicalTrials.gov

    2014-12-23

    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

  15. Arsenic Trioxide in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

    ClinicalTrials.gov

    2013-09-13

    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 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

  16. Cytarabine With or Without SCH 900776 in Treating Adult Patients With Relapsed Acute Myeloid Leukemia

    ClinicalTrials.gov

    2016-07-20

    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); RUNX1-RUNX1T1; Adult Acute Myeloid Leukemia With t(9;11)(p22;q23); MLLT3-MLL; Adult Acute Myeloid Leukemia Without Maturation; Adult Acute Myelomonocytic Leukemia; Adult Erythroleukemia; Adult Pure Erythroid Leukemia; Alkylating Agent-Related Acute Myeloid Leukemia; Recurrent Adult Acute Myeloid Leukemia

  17. Commentary on "Childhood Leukemia Survivors and Their Return to School: A Literature Review, Case Study, and Recommendations"

    ERIC Educational Resources Information Center

    Schmitt, Ara

    2011-01-01

    This commentary pertains to the article, "Childhood Leukemia Survivors and Their Return to School: A Literature Review, Case Study, and Recommendations" by D. Scott Hermann, Jill R. Thurber, Kenneth Miles, and Gloria Gilbert in this issue (2011) regarding pediatric leukemia. The authors present a literature review regarding leukemia in childhood,…

  18. 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

  19. CPI-613, Cytarabine, and Mitoxantrone Hydrochloride in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

    ClinicalTrials.gov

    2015-06-23

    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

  20. Lenalidomide and Cytarabine in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

    ClinicalTrials.gov

    2016-04-01

    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

  1. Mammalian Target of Rapamycin (mTOR) Activity Dependent Phospho-Protein Expression in Childhood Acute Lymphoblastic Leukemia (ALL)

    PubMed Central

    Márk, Ágnes; Hajdu, Melinda; Kenessey, István; Sticz, Tamás; Nagy, Eszter; Barna, Gábor; Váradi, Zsófia; Kovács, Gábor; Kopper, László; Csóka, Monika

    2013-01-01

    Modern treatment strategies have improved the prognosis of childhood ALL; however, treatment still fails in 25–30% of patients. Further improvement of treatment may depend on the development of targeted therapies. mTOR kinase, a central mediator of several signaling pathways, has recently attracted remarkable attention as a potential target in pediatric ALL. However, limited data exists about the activity of mTOR. In the present study, the amount of mTOR activity dependent phospho-proteins was characterized by ELISA in human leukemia cell lines and in lymphoblasts from childhood ALL patients (n = 49). Expression was measured before and during chemotherapy and at relapses. Leukemia cell lines exhibited increased mTOR activity, indicated by phospho-S6 ribosomal protein (p-S6) and phosphorylated eukaryotic initiation factor 4E binding protein (p-4EBP1). Elevated p-4EBP1 protein levels were detected in ALL samples at diagnosis; efficacy of chemotherapy was followed by the decrease of mTOR activity dependent protein phosphorylation. Optical density (OD) for p-4EBP1 (ELISA) was significantly higher in patients with poor prognosis at diagnosis, and in the samples of relapsed patients. Our results suggest that measuring mTOR activity related phospho-proteins such as p-4EBP1 by ELISA may help to identify patients with poor prognosis before treatment, and to detect early relapses. Determining mTOR activity in leukemic cells may also be a useful tool for selecting patients who may benefit from future mTOR inhibitor treatments. PMID:23573198

  2. Lithium Carbonate and Tretinoin in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

    ClinicalTrials.gov

    2015-10-19

    Adult Acute Megakaryoblastic Leukemia (M7); 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

  3. General Information about Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies

    MedlinePlus

    ... Other Myeloid Malignancies Treatment (PDQ®)–Patient Version General Information About Childhood Acute Myeloid Leukemia and Other Myeloid ... the PDQ Pediatric Treatment Editorial Board . Clinical Trial Information A clinical trial is a study to answer ...

  4. Maternal Exposure to Occupational Solvents and Childhood Leukemia

    PubMed Central

    Infante-Rivard, Claire; Siemiatycki, Jack; Lakhani, Ramzan; Nadon, Louise

    2005-01-01

    Many organic solvents are considered probable carcinogens. We carried out a population-based case–control study including 790 incident cases of childhood acute lymphoblastic leukemia and as many healthy controls, matched on age and sex. Maternal occupational exposure to solvents before and during pregnancy was estimated using the expert method, which involves chemists coding each individual’s job for specific contaminants. Home exposure to solvents was also evaluated. The frequency of exposure to specific agents or mixtures was generally low. Results were generally similar for the period ranging from 2 years before pregnancy up to birth and for the pregnancy period alone. For the former period, the odds ratio (OR), adjusted for maternal age and sex, for any exposure to all solvents together was 1.11 [95% confidence interval (CI), 0.88–1.40]. Increased risks were observed for specific exposures, such as to 1,1,1-trichloroethane (OR = 7.55; 95% CI, 0.92–61.97), toluene (OR = 1.88; 95% CI, 1.01–3.47), and mineral spirits (OR = 1.82; 95% CI, 1.05–3.14). There were stronger indications of moderately increased risks associated with exposure to alkanes (C5–C17; OR = 1.78; 95% CI, 1.11–2.86) and mononuclear aromatic hydrocarbons (OR = 1.64; 95% CI, 1.12–2.41). Risk did not increase with increasing exposure, except for alkanes, where a significant trend (p = 0.04) was observed. Home exposure was not associated with increased risk. Using an elaborate exposure coding method, this study shows that maternal exposure to solvents in the workplace does not seem to play a major role in childhood leukemia. PMID:15929905

  5. Decitabine, Vorinostat, and Cytarabine in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

    ClinicalTrials.gov

    2014-12-19

    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); RUNX1-RUNX1T1; Adult Acute Myeloid Leukemia With t(9;11)(p22;q23); MLLT3-MLL; Adult Acute Promyelocytic Leukemia With t(15;17)(q22;q12); PML-RARA; Alkylating Agent-Related Acute Myeloid Leukemia; Recurrent Adult Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia

  6. [Cytomegalovirus reactivation after allogeneic stem cell transplantation reduces the risk of relapse in patients with acute myeloid leukemia].

    PubMed

    Takenaka, Katsuto

    2015-07-01

    Cytomegalovirus (CMV) infection is still a major infectious complication after allogeneic hematopoietic cell transplantation (HCT). Recently, CMV reactivation was reported to be associated with a decreased risk of relapse in patients with acute myeloid leukemia (AML). We herein retrospectively evaluated the impact of early CMV reactivation on the incidence of disease relapse after allo-HCT using the database of the Transplant Registry Unified Management Program (TRUMP) at the JSHCT. Patients who underwent their first allo-HCT from HLA-matched related or unrelated donors between 2000 and 2009, and who survived without disease relapse until day 100 after transplantation, were analyzed. CMV reactivation was associated with a decreased cumulative incidence of relapse among patients with AML, but not in patients with other hematological malignancies in our study. However, this benefit was nullified by the increased rate of non-relapse mortality. The underlying mechanism is unclear, but the immunological reaction against CMV reactivation plays an essential role in this association. Thus, immune augmentation treatment options including vaccination and adoptive T-cell transfer might be useful for taking advantage of the efficacy of CMV reactivation while minimizing the increase in non-relapse mortality. PMID:26251145

  7. Preferentially Expressed Antigen of Melanoma (PRAME) and Wilms’ Tumor 1 (WT 1) Genes Expression in Childhood Acute Lymphoblastic Leukemia, Prognostic Role and Correlation with Survival

    PubMed Central

    Khateeb, Engy El; Morgan, Dalia

    2014-01-01

    BACKGROUND: Acute lymphocytic leukemia (ALL) is the most common hematologic malignancy in children. In young children it is also largely curable, with more than 90% of afflicted children achieving long-term remission. PRAME (Preferentially expressed antigen of melanoma) gene belongs to Group 3 class I HLA-restricted widely expressed antigens in which genes encoding widely expressed tumor antigens have been detected in many normal tissues as well as in histologically different types of tumors with no preferential expression on a certain type of cancer. It has been found to be expressed in a variety of cancer cells as leukemia & lymphoma. PRAME monitoring can be useful for detection of minimal residual disease and subsequent relapses particularly those leukemias in which specific tumor markers are unavailable. Wilms’ tumor1 (WT1) gene was identified as a gene that plays an important role in normal kidney development and inactivation of its function was shown to result in the development of Wilms’ tumors in paediatric patients. Disruption of WT1 function has been implicated in the formation of many different tumor types. AIM: to study how PRAME & WT 1 genes expression patterns influence cancer susceptibility & prognosis. PATIENTS & METHODS: 50 patients with denovo childhood acute lymphoblastic leukemia, as well as 50 age and sex matched apparently healthy volunteers were genotyped for PRAME and WT1 genes expression by reverse transcription polymerase chain reaction (RT-PCR). RESULTS: PRAME gene was expressed in 34 of the patients (68%) and WT1 gene was expressed in 26 of the patients (52%). Expression of both genes was significantly higher compared to controls (P < 0.0001). Analysis of relapse free survival among our patients revealed that patients expressing PRAME gene or WT1 gene had better relapse free survival (p value=0.02 and 0.01 respectively). Relapse free survival increased significantly among patients coexpressing PRAME and WT 1(p value =0

  8. Phase I study of azacitidine and bortezomib in adults with relapsed or refractory acute myeloid leukemia

    PubMed Central

    Walker, Alison R.; Klisovic, Rebecca B.; Garzon, Ramiro; Schaaf, Larry J.; Humphries, Kristina; Devine, Steven M.; Byrd, John C.; Grever, Michael R.; Marcucci, Guido; Blum, William

    2013-01-01

    We previously reported that bortezomib indirectly modulates transcription of DNA methyltransferase 1 (DNMT). We designed a phase I study of azacitidine (a direct DNMT inhibitor) plus bortezomib in acute myeloid leukemia (AML) to determine safety and tolerability. Twenty-three adults with relapsed/refractory AML received azacitidine 75mg/m2 daily on days 1-7. Bortezomib was dose escalated from 0.7mg/m2 on days 2 and 5 to 1.3mg/m2 on days 2, 5, 9, and 12. The target dose was reached without dose limiting toxicities. Infection and/or febrile neutropenia were frequent. Patients received a median of 2 cycles of therapy (range, 1-12+). Five of 23 patients achieved remission including two with morphologic and cytogenetic complete response (CR) and three with CR and incomplete count recovery (CRi). Of CR/CRi responders with cytogenetic abnormalities at baseline, three of four achieved cytogenetic CR. The combination of azacitidine and bortezomib was tolerable and active in this cohort of poor-risk previously-treated AML patients. PMID:23952243

  9. Midostaurin, bortezomib and MEC in relapsed/refractory acute myeloid leukemia.

    PubMed

    Walker, Alison R; Wang, Hongyan; Walsh, Katherine; Bhatnagar, Bhavana; Vasu, Sumithira; Garzon, Ramiro; Canning, Renee; Geyer, Susan; Wu, Yue-Zhong; Devine, Steven M; Klisovic, Rebecca; Blum, William; Marcucci, Guido

    2016-09-01

    Targeting aberrant tyrosine kinase activity may impact clinical outcome in acute myeloid leukemia (AML). We conducted a phase I study of the tyrosine kinase inhibitor midostaurin with bortezomib alone and in combination with chemotherapy in patients with AML. Patients on dose levels 1 and 2 (DL1 & 2) received midostaurin 50 mg bid and escalating doses of bortezomib (1 to 1.3 mg/m2). Patients on DL3 or higher received midostaurin and bortezomib following chemotherapy with mitoxantrone, etoposide, cytarabine (MEC). None of the patients enrolled to DL1 & 2 had dose-limiting toxicities (DLTs) or a clinical response. Among patients enrolled to DL3 or higher, DLTs were peripheral neuropathy, decrease in ejection fraction and diarrhea. A 56.5% CR rate and 82.5% overall response rate (CR + CR with incomplete neutrophil or platelet count recovery) were observed. The midostaurin/bortezomib/MEC combination is active in refractory/relapsed AML, but is associated with expected drug-related toxicities (NCT01174888). PMID:26784138

  10. ABCG2, Cytogenetics, and Age Predict Relapse after Allogeneic Stem Cell Transplantation for Acute Myeloid Leukemia in Complete Remission.

    PubMed

    Damiani, Daniela; Tiribelli, Mario; Geromin, Antonella; Cerno, Michela; Zanini, Francesca; Michelutti, Angela; Fanin, Renato

    2016-09-01

    Recent studies have shown that ABGG2 protein overexpression in acute myeloid leukemia (AML) may be associated with poor response to therapy and increased relapse risk. Few data are available in patients with AML undergoing allogeneic stem cell transplantation (SCT), particularly when in complete remission (CR). We analyzed 105 patients with AML who underwent allogeneic SCT in CR evaluating the role of ABCG2 and other pretransplantation features on subsequent transplantation outcomes. Factors negatively associated with leukemia-free survival (LFS) were unfavorable cytogenetics (3-year LFS 48% versus 80%, P = .0035) and ABCG2 positivity (65% versus 80%, P = .045). Three-year cumulative incidence of relapse (CIR) in the whole population was 20%; a higher incidence of relapse was associated with adverse cytogenetics (41% versus 16%, P = .018), ABCG2 overexpression (29% versus 15%, P = .04), and, marginally, age > 50 years (30% versus 14%, P = .06). We grouped patients according to the combination of these 3 risk factors: no patient relapsed within 3 years from SCT in the group without risk factors, whereas the 3-year CIR was 12% (95% confidence interval [CI], 2% to 25%) in the group with 1 risk factor and 47% (95% CI, 31% to 70%) in patients with 2 or 3 risk factors (P = .00005). In conclusion, allogeneic SCT does not seem to abrogate the negative prognosis associated with ABCG2 overexpression at diagnosis, specifically in terms of a higher relapse risk. ABCG2, age, and cytogenetics can predict AML relapse after SCT in patients who undergo transplantation while in CR. PMID:27178373

  11. Childhood Leukemia Survivors and Their Return to School: A Literature Review, Case Study, and Recommendations

    ERIC Educational Resources Information Center

    Herrmann, D. Scott; Thurber, Jill R.; Miles, Kenneth; Gilbert, Gloria

    2011-01-01

    Leukemias (blood cell cancers) and central nervous system tumors are the most frequently occurring types of cancer in children. Mortality rates from all childhood cancers have decreased over the past 2 decades. As a result, many childhood cancer survivors are now returning to their schools after having been successfully treated. Although most of…

  12. Rationale for an international consortium to study inherited genetic susceptibility to childhood acute lymphoblastic leukemia

    PubMed Central

    Sherborne, Amy L.; Hemminki, Kari; Kumar, Rajiv; Bartram, Claus R.; Stanulla, Martin; Schrappe, Martin; Petridou, Eleni; Semsei, Ágnes F.; Szalai, Csaba; Sinnett, Daniel; Krajinovic, Maja; Healy, Jasmine; Lanciotti, Marina; Dufour, Carlo; Indaco, Stefania; El-Ghouroury, Eman A; Sawangpanich, Ruchchadol; Hongeng, Suradej; Pakakasama, Samart; Gonzalez-Neira, Anna; Ugarte, Evelia L.; Leal, Valeria P.; Espinoza, Juan P.M.; Kamel, Azza M.; Ebid, Gamal T.A.; Radwan, Eman R.; Yalin, Serap; Yalin, Erdinc; Berkoz, Mehmet; Simpson, Jill; Roman, Eve; Lightfoot, Tracy; Hosking, Fay J.; Vijayakrishnan, Jayaram; Greaves, Mel; Houlston, Richard S.

    2011-01-01

    Acute lymphoblastic leukemia is the major pediatric cancer in developed countries. To date most association studies of acute lymphoblastic leukemia have been based on the candidate gene approach and have evaluated a restricted number of polymorphisms. Such studies have served to highlight difficulties in conducting statistically and methodologically rigorous investigations into acute lymphoblastic leukemia risk. Recent genome-wide association studies of childhood acute lymphoblastic leukemia have provided robust evidence that common variation at four genetic loci confers a modest increase in risk. The accumulated experience to date and relative lack of success of initial efforts to identify novel acute lymphoblastic leukemia predisposition loci emphasize the need for alternative study designs and methods. The International Childhood Acute Lymphoblastic Leukaemia Genetics Consortium includes 12 research groups in Europe, Asia, the Middle East and the Americas engaged in studying the genetics of acute lymphoblastic leukemia. The initial goal of this consortium is to identify and characterize low-penetrance susceptibility variants for acute lymphoblastic leukemia through association-based analyses. Efforts to develop genome-wide association studies of acute lymphoblastic leukemia, in terms of both sample size and single nucleotide polymorphism coverage, and to increase the number of single nucleotide polymorphisms taken forward to large-scale replication should lead to the identification of additional novel risk variants for acute lymphoblastic leukemia. Ethnic differences in the risk of acute lymphoblastic leukemia are well recognized and thus in assessing the interplay between inherited and non-genetic risk factors, analyses using different population cohorts with different incidence rates are likely to be highly informative. Given that the frequency of many acute lymphoblastic leukemia subgroups is small, identifying differential effects will realistically only be

  13. Stromal cell-mediated mitochondrial redox adaptation regulates drug resistance in childhood acute lymphoblastic leukemia

    PubMed Central

    Liu, Jizhong; Masurekar, Ashish; Johnson, Suzanne; Chakraborty, Sohini; Griffiths, John; Smith, Duncan; Alexander, Seema; Dempsey, Clare; Parker, Catriona; Harrison, Stephanie; Li, Yaoyong; Miller, Crispin; Di, Yujun; Ghosh, Zhumur; Krishnan, Shekhar; Saha, Vaskar

    2015-01-01

    Despite the high cure rates in childhood acute lymphoblastic leukemia (ALL), relapsed ALL remains a significant clinical problem. Genetic heterogeneity does not adequately explain variations in response to therapy. The chemoprotective tumor microenvironment may additionally contribute to disease recurrence. This study identifies metabolic reprogramming of leukemic cells by bone marrow stromal cells (BMSC) as a putative mechanism of drug resistance. In a BMSC-extracellular matrix culture model, BMSC produced chemoprotective soluble factors and facilitated the emergence of a reversible multidrug resistant phenotype in ALL cells. BMSC environment induced a mitochondrial calcium influx leading to increased reactive oxygen species (ROS) levels in ALL cells. In response to this oxidative stress, drug resistant cells underwent a redox adaptation process, characterized by a decrease in ROS levels and mitochondrial membrane potential with an upregulation of antioxidant production and MCL-1 expression. Similar expanded subpopulations of low ROS expressing and drug resistant cells were identified in pre-treatment bone marrow samples from ALL patients with slower response to therapy. This suggests that the bone marrow microenvironment induces a redox adaptation in ALL subclones that protects against cytotoxic stress and potentially gives rise to minimal residual disease. Targeting metabolic remodeling by inhibiting antioxidant production and antiapoptosis was able to overcome drug resistance. Thus metabolic plasticity in leukemic cell response to environmental factors contributes to chemoresistance and disease recurrence. Adjunctive strategies targeting such processes have the potential to overcome therapeutic failure in ALL. PMID:26474278

  14. Stromal cell-mediated mitochondrial redox adaptation regulates drug resistance in childhood acute lymphoblastic leukemia.

    PubMed

    Liu, Jizhong; Masurekar, Ashish; Johnson, Suzanne; Chakraborty, Sohini; Griffiths, John; Smith, Duncan; Alexander, Seema; Dempsey, Clare; Parker, Catriona; Harrison, Stephanie; Li, Yaoyong; Miller, Crispin; Di, Yujun; Ghosh, Zhumur; Krishnan, Shekhar; Saha, Vaskar

    2015-12-15

    Despite the high cure rates in childhood acute lymphoblastic leukemia (ALL), relapsed ALL remains a significant clinical problem. Genetic heterogeneity does not adequately explain variations in response to therapy. The chemoprotective tumor microenvironment may additionally contribute to disease recurrence. This study identifies metabolic reprogramming of leukemic cells by bone marrow stromal cells (BMSC) as a putative mechanism of drug resistance. In a BMSC-extracellular matrix culture model, BMSC produced chemoprotective soluble factors and facilitated the emergence of a reversible multidrug resistant phenotype in ALL cells. BMSC environment induced a mitochondrial calcium influx leading to increased reactive oxygen species (ROS) levels in ALL cells. In response to this oxidative stress, drug resistant cells underwent a redox adaptation process, characterized by a decrease in ROS levels and mitochondrial membrane potential with an upregulation of antioxidant production and MCL-1 expression. Similar expanded subpopulations of low ROS expressing and drug resistant cells were identified in pre-treatment bone marrow samples from ALL patients with slower response to therapy. This suggests that the bone marrow microenvironment induces a redox adaptation in ALL subclones that protects against cytotoxic stress and potentially gives rise to minimal residual disease. Targeting metabolic remodeling by inhibiting antioxidant production and antiapoptosis was able to overcome drug resistance. Thus metabolic plasticity in leukemic cell response to environmental factors contributes to chemoresistance and disease recurrence. Adjunctive strategies targeting such processes have the potential to overcome therapeutic failure in ALL. PMID:26474278

  15. The Progression of Bone Mineral Density Abnormalities After Chemotherapy for Childhood Acute Lymphoblastic Leukemia.

    PubMed

    Vitanza, Nicholas A; Hogan, Laura E; Zhang, Guangxiang; Parker, Robert I

    2015-07-01

    Although reduced bone mineral density in survivors of childhood acute lymphoblastic leukemia (ALL) is well documented, the degree of demineralization and relation to age are not well described. This is a retrospective chart analysis of 58 patients consecutively treated for ALL without relapse, cranial irradiation, or transplantation. Bone mineral densities were measured by dual-energy x-ray absorptiometry and patients were divided by sex and age (≤5, 6 to 10, and >10 y) at diagnosis. Serial scans for 6 years after therapy were analyzed as Z-scores. Over 6 years after therapy, 93.1% of patients exhibited a decreased Z-score in at least 1 anatomic site. The difference in Z-score among the age cohorts was significant at both the lumbar spine and femoral neck. Patients older than 10 years at diagnosis had the lowest Z-scores: -2.78 and -2.87 for boys and -2.39 and -2.91 for girls at the lumbar spine and femoral neck, respectively. Children after ALL therapy exhibit a significant bone mineral deficit shortly after completion of therapy that persists for at least 6 years. The degree of bone demineralization can be followed up by a dual-energy x-ray absorptiometry scan and is most severe in patients older than 10 years at the initiation of therapy. PMID:25222061

  16. Relapse After Methylprednisolone Oral Minipulse Therapy in Childhood Vitiligo: A 12-Month Follow-Up Study

    PubMed Central

    Majid, Imran; Imran, Saher

    2013-01-01

    Background: Oral minipulse (OMP) therapy with methylprednisolone is presently one of the most common oral treatments used for progressive vitiligo in children. The treatment is usually given for a period of 6 months during which majority of patients are reported to go into remission. However, there are no follow-up studies to comment upon what happens to the disease after OMP therapy is withdrawn. Aim of the study: To document the incidence of relapse over a period of 1 year after OMP therapy is stopped in children with vitiligo. Materials and Methods: The study was conducted in 180 patients of childhood vitiligo (<15 years of age) who had been on OMP therapy with oral methylprednisolone for at least 6 months and who had achieved a complete remission of their disease during the treatment period. The enrolled patients were followed up for a period of 1 year and examined clinically for any sign of reactivation of their disease over either the old lesions or at any new area of the body. Results: Forty-two patients were lost and could not complete the follow-up period of 1 year. Out of the 138 patients available at the end of 1 year, relapse was observed in 48 patients (34.8%). Rest of 90 patients remained in remission over the follow-up period of 1 year. Relapse was more common in patients below 10 years of age (47.4%) as compared with older children (25.9%). Conclusion: Relapse after using methylprednisolone OMP therapy in children with vitiligo is quite common especially in younger age groups. Studies are needed to see whether these relapses could be avoided by giving the treatment for a period longer than 6 months. PMID:23716799

  17. RNA sequencing unravels the genetics of refractory/relapsed T-cell acute lymphoblastic leukemia. Prognostic and therapeutic implications

    PubMed Central

    Gianfelici, Valentina; Chiaretti, Sabina; Demeyer, Sofie; Di Giacomo, Filomena; Messina, Monica; La Starza, Roberta; Peragine, Nadia; Paoloni, Francesca; Geerdens, Ellen; Pierini, Valentina; Elia, Loredana; Mancini, Marco; De Propris, Maria Stefania; Apicella, Valerio; Gaidano, Gianluca; Testi, Anna Maria; Vitale, Antonella; Vignetti, Marco; Mecucci, Cristina; Guarini, Anna; Cools, Jan; Foà, Robin

    2016-01-01

    Despite therapeutic improvements, a sizable number of patients with T-cell acute lymphoblastic leukemia still have a poor outcome. To unravel the genomic background associated with refractoriness, we evaluated the transcriptome of 19 cases of refractory/early relapsed T-cell acute lymphoblastic leukemia (discovery cohort) by performing RNA-sequencing on diagnostic material. The incidence and prognostic impact of the most frequently mutated pathways were validated by Sanger sequencing on genomic DNA from diagnostic samples of an independent cohort of 49 cases (validation cohort), including refractory, relapsed and responsive cases. Combined gene expression and fusion transcript analyses in the discovery cohort revealed the presence of known oncogenes and identified novel rearrangements inducing overexpression, as well as inactivation of tumor suppressor genes. Mutation analysis identified JAK/STAT and RAS/PTEN as the most commonly disrupted pathways in patients with chemorefractory disease or early relapse, frequently in association with NOTCH1/FBXW7 mutations. The analysis on the validation cohort documented a significantly higher risk of relapse, inferior overall survival, disease-free survival and event-free survival in patients with JAK/STAT or RAS/PTEN alterations. Conversely, a significantly better survival was observed in patients harboring only NOTCH1/FBXW7 mutations: this favorable prognostic effect was abrogated by the presence of concomitant mutations. Preliminary in vitro assays on primary cells demonstrated sensitivity to specific inhibitors. These data document the negative prognostic impact of JAK/STAT and RAS/PTEN mutations in T-cell acute lymphoblastic leukemia and suggest the potential clinical application of JAK and PI3K/mTOR inhibitors in patients harboring mutations in these pathways. PMID:27151993

  18. RNA sequencing unravels the genetics of refractory/relapsed T-cell acute lymphoblastic leukemia. Prognostic and therapeutic implications.

    PubMed

    Gianfelici, Valentina; Chiaretti, Sabina; Demeyer, Sofie; Di Giacomo, Filomena; Messina, Monica; La Starza, Roberta; Peragine, Nadia; Paoloni, Francesca; Geerdens, Ellen; Pierini, Valentina; Elia, Loredana; Mancini, Marco; De Propris, Maria Stefania; Apicella, Valerio; Gaidano, Gianluca; Testi, Anna Maria; Vitale, Antonella; Vignetti, Marco; Mecucci, Cristina; Guarini, Anna; Cools, Jan; Foà, Robin

    2016-08-01

    Despite therapeutic improvements, a sizable number of patients with T-cell acute lymphoblastic leukemia still have a poor outcome. To unravel the genomic background associated with refractoriness, we evaluated the transcriptome of 19 cases of refractory/early relapsed T-cell acute lymphoblastic leukemia (discovery cohort) by performing RNA-sequencing on diagnostic material. The incidence and prognostic impact of the most frequently mutated pathways were validated by Sanger sequencing on genomic DNA from diagnostic samples of an independent cohort of 49 cases (validation cohort), including refractory, relapsed and responsive cases. Combined gene expression and fusion transcript analyses in the discovery cohort revealed the presence of known oncogenes and identified novel rearrangements inducing overexpression, as well as inactivation of tumor suppressor genes. Mutation analysis identified JAK/STAT and RAS/PTEN as the most commonly disrupted pathways in patients with chemorefractory disease or early relapse, frequently in association with NOTCH1/FBXW7 mutations. The analysis on the validation cohort documented a significantly higher risk of relapse, inferior overall survival, disease-free survival and event-free survival in patients with JAK/STAT or RAS/PTEN alterations. Conversely, a significantly better survival was observed in patients harboring only NOTCH1/FBXW7 mutations: this favorable prognostic effect was abrogated by the presence of concomitant mutations. Preliminary in vitro assays on primary cells demonstrated sensitivity to specific inhibitors. These data document the negative prognostic impact of JAK/STAT and RAS/PTEN mutations in T-cell acute lymphoblastic leukemia and suggest the potential clinical application of JAK and PI3K/mTOR inhibitors in patients harboring mutations in these pathways. PMID:27151993

  19. High-Dose Vincristine Sulfate Liposome Injection for Advanced, Relapsed, and Refractory Adult Philadelphia Chromosome–Negative Acute Lymphoblastic Leukemia

    PubMed Central

    O'Brien, Susan; Schiller, Gary; Lister, John; Damon, Lloyd; Goldberg, Stuart; Aulitzky, Walter; Ben-Yehuda, Dina; Stock, Wendy; Coutre, Steven; Douer, Dan; Heffner, Leonard T.; Larson, Melissa; Seiter, Karen; Smith, Scott; Assouline, Sarit; Kuriakose, Philip; Maness, Lori; Nagler, Arnon; Rowe, Jacob; Schaich, Markus; Shpilberg, Ofer; Yee, Karen; Schmieder, Guenter; Silverman, Jeffrey A.; Thomas, Deborah; Deitcher, Steven R.; Kantarjian, Hagop

    2013-01-01

    Purpose Relapsed adult acute lymphoblastic leukemia (ALL) is associated with high reinduction mortality, chemotherapy resistance, and rapid progression leading to death. Vincristine sulfate liposome injection (VSLI), sphingomyelin and cholesterol nanoparticle vincristine (VCR), facilitates VCR dose-intensification and densification plus enhances target tissue delivery. We evaluated high-dose VSLI monotherapy in adults with Philadelphia chromosome (Ph) –negative ALL that was multiply relapsed, relapsed and refractory to reinduction, and/or relapsed after hematopoietic cell transplantation (HCT). Patients and Methods Sixty-five adults with Ph-negative ALL in second or greater relapse or whose disease had progressed following two or more leukemia therapies were treated in this pivotal phase II, multinational trial. Intravenous VSLI 2.25 mg/m2, without dose capping, was administered once per week until response, progression, toxicity, or pursuit of HCT. The primary end point was achievement of complete response (CR) or CR with incomplete hematologic recovery (CRi). Results The CR/CRi rate was 20% and overall response rate was 35%. VSLI monotherapy was effective as third-, fourth-, and fifth-line therapy and in patients refractory to other single- and multiagent reinduction therapies. Median CR/CRi duration was 23 weeks (range, 5 to 66 weeks); 12 patients bridged to a post-VSLI HCT, and five patients were long-term survivors. VSLI was generally well tolerated and associated with a low 30-day mortality rate (12%). Conclusion High-dose VSLI monotherapy resulted in meaningful clinical outcomes including durable responses and bridging to HCT in advanced ALL settings. The toxicity profile of VSLI was predictable, manageable, and comparable to standard VCR despite the delivery of large, normally unachievable, individual and cumulative doses of VCR. PMID:23169518

  20. Biomarkers in Bone Marrow Samples From Pediatric Patients With High-Risk Acute Myeloid Leukemia

    ClinicalTrials.gov

    2016-05-17

    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 Childhood Acute Myeloid Leukemia; Untreated Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies

  1. Meningosis prophylaxis with intrathecal /sup 198/Au-colloid and methotrexate in childhood acute lymphocytic leukemia

    SciTech Connect

    Metz, O.; Stoll, W.; Plenert, W.

    1982-01-15

    Since 1972, telecobalt irradiation plus intrathecal methotrexate (ITMTX) has been successfully replaced in Jena by intrathecal colloidal radioactive gold (/sup 198/Au) plus ITMTX for meningosis prophylaxis in leukemia. Seventy-three children with acute lymphocytic leukemia (ALL) were given 1.24-4.89 mCi (45.8-181 MBq) of colloidal 198Au IT after successful initiation of remission. During cytostatic therapy, the following relapses occurred: meningosis leucaemica, five patients (6.8%); bone-marrow relapse and the meningosis leucaemica, one patient; and bone-marrow relapse, 20 patients (27.4%). In 18 children, combination chemotherapy was terminated after two and a half or three years of treatment. After that time, one meningeal relapse and six bone-marrow relapses occurred. Within the first 24 hours after application of radioactive gold, headaches, vomiting, and fever occurred in less than 10% of the children. An apathy syndrome, leukecephalopathy, or severe infections, were not observed in a single case. Radioactive gold spreads in the subarachnoid space and is phagocytized by the arachnoidea. The tumoricide effect extends selectively over the space of distribution of the latent meningosis leucaemia. The cerebral parenchyma remains unaffected by radiation. Thus, radioactive gold may be preferable to telecobalt irradiation in preventing central nervous system leukemia.

  2. T-cell receptor excision circle levels after allogeneic stem cell transplantation are predictive of relapse in patients with acute myeloid leukemia and myelodysplastic syndrome.

    PubMed

    Uzunel, Mehmet; Sairafi, Darius; Remberger, Mats; Mattsson, Jonas; Uhlin, Michael

    2014-07-15

    In this retrospective study, 209 patients with malignant disease were analyzed for levels of T-cell receptor excision circles (TRECs) for the first 24 months after allogeneic stem cell transplantation. CD3(+) cells were separated by direct antibody-coupled magnetic beads, followed by DNA extraction according to a standard protocol. The δRec-ψJα signal joint TREC was measured with real-time quantitative PCR. Patients were grouped based on malignant disease: chronic myeloid leukemia, chronic lymphatic leukemia, acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), and myelodysplastic syndrome (MDS). Patients were further subdivided based on TREC levels below (low-TREC) or above (high-TREC) median at each time point. TREC levels were then correlated to relapse incidence and relapse-free survival (RFS). For patients with AML, low TREC levels 2 months post-transplantation were correlated to high relapse incidence at 5 years (P<0.05). In patients with chronic leukemia, high TREC levels were correlated with improved RFS (P<0.05). For patients with MDS, high TREC levels at 9 months post-transplantation were associated with higher RFS at 5 years (P<0.02) and lower relapse incidence (P<0.02). This study shows the potential use of TREC measurement in blood to predict relapse in patients with AML and MDS after allogeneic hematopoietic stem cell transplantation. PMID:24617310

  3. Entinostat and Clofarabine in Treating Patients With Newly Diagnosed, Relapsed, or Refractory Poor-Risk Acute Lymphoblastic Leukemia or Bilineage/Biphenotypic Leukemia

    ClinicalTrials.gov

    2014-07-16

    Acute Leukemias of Ambiguous Lineage; Philadelphia Chromosome Negative Adult Precursor Acute Lymphoblastic Leukemia; Recurrent Adult Acute Lymphoblastic Leukemia; Untreated Adult Acute Lymphoblastic Leukemia

  4. Absolute quantification of the pretreatment PML-RARA transcript defines the relapse risk in acute promyelocytic leukemia.

    PubMed

    Albano, Francesco; Zagaria, Antonella; Anelli, Luisa; Coccaro, Nicoletta; Tota, Giuseppina; Brunetti, Claudia; Minervini, Crescenzio Francesco; Impera, Luciana; Minervini, Angela; Cellamare, Angelo; Orsini, Paola; Cumbo, Cosimo; Casieri, Paola; Specchia, Giorgina

    2015-05-30

    In this study we performed absolute quantification of the PML-RARA transcript by droplet digital polymerase chain reaction (ddPCR) in 76 newly diagnosed acute promyelocytic leukemia (APL) cases to verify the prognostic impact of the PML-RARA initial molecular burden. ddPCR analysis revealed that the amount of PML-RARA transcript at diagnosis in the group of patients who relapsed was higher than in that with continuous complete remission (CCR) (272 vs 89.2 PML-RARA copies/ng, p = 0.0004, respectively). Receiver operating characteristic analysis detected the optimal PML-RARA concentration threshold as 209.6 PML-RARA/ng (AUC 0.78; p < 0.0001) for discriminating between outcomes (CCR versus relapse). Among the 67 APL cases who achieved complete remission after the induction treatment, those with >209.6 PML-RARA/ng had a worse relapse-free survival (p = 0.0006). At 5-year follow-up, patients with >209.6 PML-RARA/ng had a cumulative incidence of relapse of 50.3% whereas 7.5% of the patients with suffered a relapse (p < 0.0001). Multivariate analysis identified the amount of PML-RARA before induction treatment as the sole independent prognostic factor for APL relapse.Our results show that the pretreatment PML-RARA molecular burden could therefore be used to improve risk stratification in order to develop more individualized treatment regimens for high-risk APL cases. PMID:25944686

  5. Development of secondary skull sarcoma after treatment for childhood acute myeloid leukemia.

    PubMed

    Ohno, Makoto; Narita, Yoshitaka; Miyakita, Yasuji; Okita, Yoshiko; Kayama, Takamasa; Shibui, Soichiro

    2012-12-01

    Secondary cancer is a serious late complication in childhood leukemia survivors. Here, we report a case of secondary skull sarcoma developing after treatment for childhood acute myeloid leukemia, including bone marrow transplantation (BMT). This patient had breast cancer 1 year before treatment for the skull sarcoma. The patient underwent macroscopic total removal of the skull tumor with bone margin with postoperative radiation therapy and did not develop tumor recurrence for 25 months. Our patient's experience suggests that survivors of childhood leukemia are at risk of developing skull sarcoma and that multi-agent chemotherapy, including anthracycline, TBI used as conditioning for BMT, and development of GVHD, are possible risk factors. Considering the possibility of multiple secondary malignancies in such patients, careful long-term follow up is mandatory. PMID:22897987

  6. Adoptive T-cell therapies for refractory/relapsed leukemia and lymphoma: current strategies and recent advances

    PubMed Central

    McLaughlin, Lauren; Cruz, C. Russell; Bollard, Catherine M.

    2015-01-01

    Despite significant advancements in the treatment and outcome of hematologic malignancies, prognosis remains poor for patients who have relapsed or refractory disease. Adoptive T-cell immunotherapy offers novel therapeutics that attempt to utilize the noted graft versus leukemia effect. While CD19 chimeric antigen receptor (CAR)-modified T cells have thus far been the most clinically successful application of adoptive T immunotherapy, further work with antigen specific T cells and CARs that recognize other targets have helped diversify the field to treat a broad spectrum of hematologic malignancies. This article will focus primarily on therapies currently in the clinical trial phase as well as current downfalls or limitations. PMID:26622998

  7. Adoptive T-cell therapies for refractory/relapsed leukemia and lymphoma: current strategies and recent advances.

    PubMed

    McLaughlin, Lauren; Cruz, C Russell; Bollard, Catherine M

    2015-12-01

    Despite significant advancements in the treatment and outcome of hematologic malignancies, prognosis remains poor for patients who have relapsed or refractory disease. Adoptive T-cell immunotherapy offers novel therapeutics that attempt to utilize the noted graft versus leukemia effect. While CD19 chimeric antigen receptor (CAR)-modified T cells have thus far been the most clinically successful application of adoptive T immunotherapy, further work with antigen specific T cells and CARs that recognize other targets have helped diversify the field to treat a broad spectrum of hematologic malignancies. This article will focus primarily on therapies currently in the clinical trial phase as well as current downfalls or limitations. PMID:26622998

  8. Residential Pesticides and Childhood Leukemia: A Systematic Review and Meta-Analysis

    PubMed Central

    Turner, Michelle C.; Wigle, Donald T.; Krewski, Daniel

    2010-01-01

    Objective We conducted a systematic review and meta-analysis of previous observational epidemiologic studies examining the relationship between residential pesticide exposures during critical exposure time windows (preconception, pregnancy, and childhood) and childhood leukemia. Data sources Searches of MEDLINE and other electronic databases were performed (1950–2009). Reports were included if they were original epidemiologic studies of childhood leukemia, followed a case–control or cohort design, and assessed at least one index of residential/household pesticide exposure/use. No language criteria were applied. Data extraction Study selection, data abstraction, and quality assessment were performed by two independent reviewers. Random effects models were used to obtain summary odds ratios (ORs) and 95% confidence intervals (CIs). Data synthesis Of the 17 identified studies, 15 were included in the meta-analysis. Exposures during pregnancy to unspecified residential pesticides (summary OR = 1.54; 95% CI, 1.13–2.11; I2 = 66%), insecticides (OR = 2.05; 95% CI, 1.80–2.32; I2 = 0%), and herbicides (OR = 1.61; 95% CI, 1.20–2.16; I2 = 0%) were positively associated with childhood leukemia. Exposures during childhood to unspecified residential pesticides (OR = 1.38; 95% CI, 1.12–1.70; I2 = 4%) and insecticides (OR = 1.61; 95% CI, 1.33–1.95; I2 = 0%) were also positively associated with childhood leukemia, but there was no association with herbicides. Conclusions Positive associations were observed between childhood leukemia and residential pesticide exposures. Further work is needed to confirm previous findings based on self-report, to examine potential exposure–response relationships, and to assess specific pesticides and toxicologically related subgroups of pesticides in more detail. PMID:20056585

  9. Extramedullary relapse in lumbar spine of patient with acute promyelocytic leukemia after remission for 16 years: a case report and literature review

    PubMed Central

    He, Zhengmei; Tao, Shandong; Deng, Yuan; Chen, Yue; Song, Lixiao; Ding, Banghe; Chen, Kankan; Yu, Liang; Wang, Chunling

    2015-01-01

    Acute promyelocytic leukemia (APL) is a common myeloid leukemia. At the newly diagnosed stage, it can be fatal because of the serious complication-disseminated intravascular coagulation. With the advent and early application of all-trans retinoic acid, most APL patients can achieve a long-term survival, and only a minority of patients will develop extramedullary relapse after remission. The most common site of extramedullary relapse is central nervous system, while other sites are relatively rare. Here, we report a particularly rare APL patient who experienced extramedullary relapse with lumbar spine as the isolated site after a rather long time of remission for 16 years. At the time of relapse, the main clinical manifestations of the patient are obvious low back pain, weakness in lower limbs and limitation of activity. After treatment of local radiotherapy combined with ATRA and arsenic trioxide, the patient achieved and maintained a second complete remission by now. PMID:26885224

  10. Apolizumab in Treating Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

    ClinicalTrials.gov

    2013-07-15

    Noncontiguous Stage II Small Lymphocytic Lymphoma; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Stage III Small Lymphocytic Lymphoma; Stage IV Small Lymphocytic Lymphoma

  11. Methylenetetrahydrofolate reductase (MTHFR) polymorphisms and risk of molecularly defined subtypes of childhood acute leukemia.

    PubMed

    Wiemels, J L; Smith, R N; Taylor, G M; Eden, O B; Alexander, F E; Greaves, M F

    2001-03-27

    Low folate intake as well as alterations in folate metabolism as a result of polymorphisms in the enzyme methylenetetrahydrofolate reductase (MTHFR) have been associated with an increased incidence of neural tube defects, vascular disease, and some cancers. Polymorphic variants of MTHFR lead to enhanced thymidine pools and better quality DNA synthesis that could afford some protection from the development of leukemias, particularly those with translocations. We now report associations of MTHFR polymorphisms in three subgroups of pediatric leukemias: infant lymphoblastic or myeloblastic leukemias with MLL rearrangements and childhood lymphoblastic leukemias with either TEL-AML1 fusions or hyperdiploid karyotypes. Pediatric leukemia patients (n = 253 total) and healthy newborn controls (n = 200) were genotyped for MTHFR polymorphisms at nucleotides 677 (C-->T) and 1,298 (A-->C). A significant association for carriers of C677T was demonstrated for leukemias with MLL translocations (MLL+, n = 37) when compared with controls [adjusted odd ratios (OR) = 0.36 with a 95% confidence interval (CI) of 0.15-0.85; P = 0.017]. This protective effect was not evident for A1298C alleles (OR = 1.14). In contrast, associations for A1298C homozygotes (CC; OR = 0.26 with a 95% CI of 0.07--0.81) and C677T homozygotes (TT; OR = 0.49 with a 95% CI of 0.20--1.17) were observed for hyperdiploid leukemias (n = 138). No significant associations were evident for either polymorphism with TEL-AML1+ leukemias (n = 78). These differences in allelic associations may point to discrete attributes of the two alleles in their ability to alter folate and one-carbon metabolite pools and impact after DNA synthesis and methylation pathways, but should be viewed cautiously pending larger follow-up studies. The data provide evidence that molecularly defined subgroups of pediatric leukemias have different etiologies and also suggest a role of folate in the development of childhood leukemia. PMID:11274424

  12. Control of relapsed or refractory acute myeloid leukemia by clofarabine in preparation for allogeneic stem cell transplant.

    PubMed

    Loeffler, Claudia; Kapp, Markus; Grigoleit, Goetz-Ulrich; Mielke, Stephan; Loeffler, Jürgen; Heuschmann, Peter U; Malzahn, Uwe; Hupp, Elke; Einsele, Hermann; Stuhler, Gernot

    2015-01-01

    Allogeneic stem cell transplant is indicated for patients with refractory or relapsed acute myeloid leukemia (AML). Since elimination of the leukemic load is thought to be a prerequisite for treatment success, we here investigate toxicity and anti-leukemic activity of a clofarabine-AraC salvage protocol preceding transplant. In this retrospective analysis, we observed induction of objective remissions in 86% of patients receiving clofarabine-AraC as compared to 83% with sequential high dose AraC/mitoxantrone (S-HAM) and 50% after mitoxantrone/topotecane/AraC (MTC) salvage strategies. In addition, clofarabine conferred anti-leukemic activity to some patients who failed initial MTC or S-HAM therapy. For overall and leukemia-free survival, we identified cytogenetically defined adverse risk markers but not response to therapy to be a strong predictor. In summary, the clofarabine-AraC salvage strategy combines pronounced anti-leukemic activity with an acceptable toxicity profile and allows the majority of patients with relapsed or refractory AML to proceed to allo-SCT, even in cytogenetically defined high risk situations. PMID:26014275

  13. Endocrinological and Cardiological Late Effects Among Survivors of Childhood Acute Lymphoblastic Leukemia

    PubMed Central

    Karakaya, Pakize; Yılmaz, Şebnem; Tüfekçi, Özlem; Kır, Mustafa; Böber, Ece; İrken, Gülersu; Ören, Hale

    2013-01-01

    Objective: Survival rates for childhood acute lymphoblastic leukemia (ALL) have significantly improved and late effects of therapy have been important in the follow-up of survivors. The objective of this study is to identify the endocrinological and cardiological late effects of ALL patients treated in our pediatric hematology unit. Materials and Methods: Patients treated for ALL with BFM protocols after at least 5 years of diagnosis and not relapsed were included in the study. Endocrinological late effects (growth failure, obesity, insulin resistance, dyslipidemia, thyroid gland disorders, osteopenia/osteoporosis, and pubertal disorders) and cardiological late effects were evaluated. The study group was evaluated with anthropometric measurements, body mass index, and laboratory testing of fasting glucose, insulin, serum lipids, thyroid functions, and bone mineral densities. Echocardiography and pulsed wave Doppler imaging were performed for analysis of cardiac functions. Results: Of the 38 ALL survivors, at least 1 adverse event occurred in 23 (60%), with 8 of them (21%) having multiple problems. Six (16%) of the survivors were obese and 8 (21%) of them were overweight. Subjects who were overweight or obese at the time of diagnosis were more likely to be overweight or obese at last follow-up. Obesity was more frequently determined in patients who were younger than 6 years of age at the time of diagnosis. Insulin resistance was observed in 8 (21%) subjects. Insulin resistance was more frequently seen in subjects who had family history of type 2 diabetes mellitus. Hyperlipidemia was detected in 8 (21%) patients. Hypothyroidism or premature thelarche were detected in 2 children. Two survivors had osteopenia. Cardiovascular abnormalities occurred in one of the subjects with hypertension and cardiac diastolic dysfunction. Conclusion: We point out the necessity of follow-up of these patients for endocrinological and cardiological late effects, since at least one adverse

  14. The combination effects of bendamustine with antimetabolites against childhood acute lymphoblastic leukemia cells.

    PubMed

    Goto, Shoko; Goto, Hiroaki; Yokosuka, Tomoko

    2016-05-01

    Bendamustine combined with other drugs is clinically efficacious for some adult lymphoid malignancies, but to date there are no reports of the use of such combinatorial approaches in pediatric patients. We investigated the in vitro activity of bendamustine combined with other antimetabolite drugs on B cell precursor acute lymphoblastic leukemia (BCP-ALL) cell lines established from pediatric patients with refractory or relapsed ALL. We also developed a mathematically drown improved isobologram method to assess the data objectively. Three BCP-ALL cell lines; YCUB-2, YCUB-5, and YCUB-6, were simultaneously exposed to various concentrations of bendamustine and cladribine, cytarabine, fludarabine, or clofarabine. Cell growth inhibition was determined using the WST-8 assay. Combinatorial effects were estimated using our improved isobologram method with IC80 (drug concentration corresponding to 80 % of maximum inhibition). Bendamustine alone inhibited ALL cell growth with mean IC80 values of 11.30-18.90 μg/ml. Combinations of bendamustine with other drugs produced the following effects: (1) cladribine; synergistic-to-additive on all cell lines; (2) cytarabine; synergistic-to-additive on YCUB-5 and YCUB-6, and synergistic-to-antagonistic on YCUB-2; (3) fludarabine; additive-to-antagonistic on YCUB-5, and synergistic-to-antagonistic on YCUB-2 and YCUB-6; (4) clofarabine; additive-to-antagonistic on all cell lines. Flow cytometric analysis also showed the combination effects of bendamustine and cladribine. Bendamustine/cladribine or bendamustine/cytarabine may thus represent a promising combination for salvage treatment in childhood ALL. PMID:26886449

  15. Arsenic Trioxide in Treating Patients With Relapsed or Refractory Lymphoma or Leukemia

    ClinicalTrials.gov

    2013-01-31

    Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Nodal Marginal Zone B-cell Lymphoma; Prolymphocytic Leukemia; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Splenic Marginal Zone Lymphoma; Waldenström Macroglobulinemia

  16. Allogeneic hematopoietic cell transplantation for chronic myelomonocytic leukemia: relapse-free survival is determined by karyotype and comorbidities.

    PubMed

    Eissa, Hesham; Gooley, Ted A; Sorror, Mohamed L; Nguyen, Franchesca; Scott, Bart L; Doney, Kristine; Loeb, Keith R; Martin, Paul J; Pagel, John M; Radich, Jerry P; Sandmaier, Brenda M; Warren, E Houston; Storb, Rainer; Appelbaum, Frederick R; Deeg, H Joachim

    2011-06-01

    Hematopoietic cell transplantation (HCT) offers potentially curative therapy for chronic myelomonocytic leukemia (CMML). We evaluated HCT outcomes in 85 patients with CMML, 1.0-69.1 (median 51.7) years of age, with follow-up extending to 19 years. CMML was considered de novo in 71 and secondary in 14 patients. Conditioning regimens were of various intensities. Thirty-eight patients had related (34 HLA identical), and 47 (39 HLA matched) unrelated donors. The source of stem cells was marrow in 32 and peripheral blood progenitor cells in 53 patients. Acute graft-versus-host disease (aGVHD) grades II-IV occurred in 72% and chronic GVHD (cGVHD) in 26% of patients. Relapse incidence was 27% at 10 years. Relapse correlated with increasing scores by the MD Anderson prognostic score (P = .01). The major causes of death were relapse and infections ±GVHD. Progression-free survival (PFS) was 38% at 10 years. Mortality was negatively correlated with pre-HCT hematocrit (P = .007), and increased with high-risk cytogenetics (P = .02), higher HCT Comorbidity Index (P = .0008), and increased age (P = .02). WHO classification did not statistically significantly affect outcome. Thus, a proportion of patients with CMML have lasting remissions following allogeneic HCT and appear to be cured of their disease. PMID:20932924

  17. Allogeneic Hematopoietic Cell Transplantation for Chronic Myelomonocytic Leukemia: Relapse-Free Survival is Determined by Karyotype and Comorbidities

    PubMed Central

    Eissa, Hesham; Gooley, Ted A.; Sorror, Mohamed L.; Nguyen, Franchesca; Scott, Bart L.; Doney, Kristine; Loeb, Keith R.; Martin, Paul J.; Pagel, John M.; Radich, Jerry P.; Sandmaier, Brenda M.; Warren, E. Houston; Storb, Rainer; Appelbaum, Frederick R.; Deeg, H. Joachim

    2011-01-01

    Hematopoietic cell transplantation (HCT) offers potentially curative therapy for Chronic Myelomonocytic Leukemia (CMML). We evaluated HCT outcomes in 85 patients with CMML, 1.0–69.1 (median 51.7) years of age, with follow-up extending to 19 years. CMML was considered de novo in 71 and secondary in 14 patients. Conditioning regimens were of various intensities. Thirty-eight patients had related (34 HLA identical), and 47 (39 HLA matched) unrelated donors. The source of stem cells was marrow in 32 and peripheral blood progenitor cells in 53 patients. Acute GVHD grades II–IV occurred in 72% and chronic GVHD in 26% of patients. Relapse incidence was 27% at 10 years. Relapse correlated with increasing scores by the MD Anderson prognostic score (p=0.01). The major causes of death were relapse and infections ±GVHD. Progression-free survival was 38% at 10 years. Mortality was negatively correlated with pre-HCT hematocrit (p=0.007), and increased with high-risk cytogenetics (p=0.02), higher HCT Comorbidity Index (p=0.0008), and increased age (p=.02). WHO classification did not statistically significantly affect outcome. Thus, a proportion of patients with CMML have lasting remissions following allogeneic HCT and appear to be cured of their disease. PMID:20932924

  18. Impact of cytomegalovirus reactivation on relapse and survival in patients with acute leukemia who received allogeneic hematopoietic stem cell transplantation in first remission.

    PubMed

    Yoon, Jae-Ho; Lee, Seok; Kim, Hee-Je; Jeon, Young-Woo; Lee, Sung-Eun; Cho, Byung-Sik; Lee, Dong-Gun; Eom, Ki-Seong; Kim, Yoo-Jin; Min, Chang-Ki; Cho, Seok-Goo; Min, Woo-Sung; Lee, Jong Wook

    2016-03-29

    Cytomegalovirus (CMV)-reactivation is associated with graft-vs-leukemia (GVL) effect by stimulating natural-killer or T-cells, which showed leukemia relapse prevention after hematopoietic stem cell transplantation (HSCT). We enrolled patients with acute myeloid leukemia (n = 197) and acute lymphoid leukemia (n = 192) who underwent allogeneic-HSCT in first remission. We measured RQ-PCR weekly to detect CMV-reactivation and preemptively used ganciclovir (GCV) when the titer increased twice consecutively, but GCV was sometimes delayed in patients without significant graft-vs-host disease (GVHD) by reducing immunosuppressive agents. In the entire group, CMV-reactivation showed poor overall survival (OS). To evaluate subsequent effects of CMV-reactivation, we excluded early relapse and deaths within 100 days, during which most of the CMV-reactivation occurred. Untreated CMV-reactivated group (n = 173) showed superior OS (83.8% vs. 61.7% vs. 74.0%, p < 0.001) with lower relapse rate (10.1% vs 22.1% vs. 25.5%, p = 0.004) compared to GCV-treated CMV-reactivated group (n = 122) and CMV-undetected group (n = 42). After excluding chronic GVHD, untreated CMV-reactivated group still showed lower relapse rate (9.4% vs. 24.1% vs. 30.2%, p = 0.006). Multivariate analysis showed adverse-risk karyotype and patients in other than untreated CMV-reactivated group were independent factors for relapse prediction. Our data showed possible GVL effect of CMV-reactivation and minimizing antiviral therapy may benefit for relapse prevention in acute leukemia. PMID:26883100

  19. Impact of cytomegalovirus reactivation on relapse and survival in patients with acute leukemia who received allogeneic hematopoietic stem cell transplantation in first remission

    PubMed Central

    Yoon, Jae-Ho; Lee, Seok; Kim, Hee-Je; Jeon, Young-Woo; Lee, Sung-Eun; Cho, Byung-Sik; Lee, Dong-Gun; Eom, Ki-Seong; Kim, Yoo-Jin; Min, Chang-Ki; Cho, Seok-Goo; Min, Woo-Sung; Lee, Jong Wook

    2016-01-01

    Cytomegalovirus (CMV)-reactivation is associated with graft-vs-leukemia (GVL) effect by stimulating natural-killer or T-cells, which showed leukemia relapse prevention after hematopoietic stem cell transplantation (HSCT). We enrolled patients with acute myeloid leukemia (n = 197) and acute lymphoid leukemia (n = 192) who underwent allogeneic-HSCT in first remission. We measured RQ-PCR weekly to detect CMV-reactivation and preemptively used ganciclovir (GCV) when the titer increased twice consecutively, but GCV was sometimes delayed in patients without significant graft-vs-host disease (GVHD) by reducing immunosuppressive agents. In the entire group, CMV-reactivation showed poor overall survival (OS). To evaluate subsequent effects of CMV-reactivation, we excluded early relapse and deaths within 100 days, during which most of the CMV-reactivation occurred. Untreated CMV-reactivated group (n = 173) showed superior OS (83.8% vs. 61.7% vs. 74.0%, p < 0.001) with lower relapse rate (10.1% vs 22.1% vs. 25.5%, p = 0.004) compared to GCV-treated CMV-reactivated group (n = 122) and CMV-undetected group (n = 42). After excluding chronic GVHD, untreated CMV-reactivated group still showed lower relapse rate (9.4% vs. 24.1% vs. 30.2%, p = 0.006). Multivariate analysis showed adverse-risk karyotype and patients in other than untreated CMV-reactivated group were independent factors for relapse prediction. Our data showed possible GVL effect of CMV-reactivation and minimizing antiviral therapy may benefit for relapse prevention in acute leukemia. PMID:26883100

  20. High hyperdiploid childhood acute lymphoblastic leukemia: Chromosomal gains as the main driver event.

    PubMed

    Paulsson, Kajsa

    2016-01-01

    High hyperdiploid childhood acute lymphoblastic leukemia is characterized by multiple chromosomal gains. Recent results show that this subtype harbors relatively few genetic abnormalities besides the extra chromosomes, which appear to arise early and are likely the main driver event. Secondary hits primarily target genes in the rat sarcoma (RAS) signaling pathway and histone modifiers. PMID:27308574

  1. High hyperdiploid childhood acute lymphoblastic leukemia: Chromosomal gains as the main driver event

    PubMed Central

    Paulsson, Kajsa

    2016-01-01

    ABSTRACT High hyperdiploid childhood acute lymphoblastic leukemia is characterized by multiple chromosomal gains. Recent results show that this subtype harbors relatively few genetic abnormalities besides the extra chromosomes, which appear to arise early and are likely the main driver event. Secondary hits primarily target genes in the rat sarcoma (RAS) signaling pathway and histone modifiers. PMID:27308574

  2. High-Dose Busulfan and High-Dose Cyclophosphamide Followed By Donor Bone Marrow Transplant in Treating Patients With Leukemia, Myelodysplastic Syndrome, Multiple Myeloma, or Recurrent Hodgkin or Non-Hodgkin Lymphoma

    ClinicalTrials.gov

    2010-08-05

    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 Non-Hodgkin Lymphoma; Recurrent Adult T-cell Leukemia/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 Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Multiple Myeloma; Relapsing Chronic Myelogenous Leukemia; Secondary Myelodysplastic Syndromes; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Testicular Lymphoma; Waldenstrom Macroglobulinemia

  3. Vorinostat and Decitabine in Treating Patients With Advanced Solid Tumors or Relapsed or Refractory Non-Hodgkin's Lymphoma, Acute Myeloid Leukemia, Acute Lymphocytic Leukemia, or Chronic Myelogenous Leukemia

    ClinicalTrials.gov

    2014-08-26

    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); Blastic Phase Chronic Myelogenous Leukemia; 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 Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult 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; Secondary Acute Myeloid Leukemia; Splenic Marginal Zone 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 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 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 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

  4. Genomic, immunophenotypic, and NPM1/FLT3 mutational studies on 17 patients with normal karyotype acute myeloid leukemia (AML) followed by aberrant karyotype AML at relapse.

    PubMed

    Wang, Eunice S; Sait, Sheila N J; Gold, David; Mashtare, Terry; Starostik, Petr; Ford, Laurie Ann; Wetzler, Meir; Nowak, Norma J; Deeb, George

    2010-10-15

    Normal karyotype (NK) is the most common cytogenetic group in acute myeloid leukemia (AML) diagnosis; however, up to 50% of these patients at relapse will have aberrant karyotype (AK) AML. To determine the etiology of relapsed AK AML cells, we evaluated cytogenetic, immunophenotypic, and molecular results of 17 patients with diagnostic NK AML and relapsed AK AML at our institute. AK AML karyotype was diverse, involving no favorable and largely (8 of 17) complex cytogenetics. Despite clear cytogenetic differences, immunophenotype and NPM1/FLT3 gene mutation status did not change between presentation and relapse in 83% (10 of 12) and 94% (15 of 16) cases, respectively. High-resolution array-based comparative genomic hybridization (aCGH) performed via paired aCGH on NK AML and AK AML samples from the same patient confirmed cytogenetic aberrations only in the relapse sample. Analysis of 16 additional diagnostic NK AML samples revealed no evidence of submicroscopic aberrations undetected by conventional cytogenetics in any case. These results favor evolution of NK AML leukemia cells with acquisition of novel genetic changes as the most common etiology of AK AML relapse as opposed to secondary leukemogenesis. Additional studies are needed to confirm whether AK AML cells represent selection of rare preexisting clones below aCGH detection and to further characterize the molecular lesions found at time of AK AML relapse. PMID:20875872

  5. Leukemia

    MedlinePlus

    ... version of this page please turn Javascript on. Leukemia What Is Leukemia? Leukemia is a cancer of the blood cells. ... diagnosed with leukemia are over 50 years old. Leukemia Starts in Bone Marrow Click for more information ...

  6. Background radiation and childhood leukemia: A nationwide register-based case-control study.

    PubMed

    Nikkilä, Atte; Erme, Sini; Arvela, Hannu; Holmgren, Olli; Raitanen, Jani; Lohi, Olli; Auvinen, Anssi

    2016-11-01

    High doses of ionizing radiation are an established cause of childhood leukemia. However, substantial uncertainty remains about the effect of low doses of radiation, including background radiation and potential differences between genetic subgroups of leukemia have rarely been explored. We investigated the effect of the background gamma radiation on childhood leukemia using a nationwide register-based case-control study. For each of the 1,093 cases, three age- and gender matched controls were selected (N = 3,279). Conditional logistic regression analyses were adjusted for confounding by Down syndrome, birth weight (large for gestational age), and maternal smoking. Complete residential histories and previously collected survey data of the background gamma radiation in Finland were used to assess the exposure of the study subjects to indoor and outdoor gamma radiation. Overall, background gamma radiation showed a non-significant association with the OR of childhood leukemia (OR 1.01, 95% CI 0.97, 1.05 for 10 nSv/h increase in average equivalent dose rate to red bone marrow). In subgroup analyses, age group 2-<7 years displayed a larger effect (OR 1.27, 95% CI 1.01, 1.60 for 1 mSv increase in equivalent cumulative dose to red bone marrow). Suggestive difference in OR by genetic subtype was found. Our results provide further support to the notion that low doses of ionizing radiation increase the risk for childhood leukemia, particularly at age 2-<7 years. Our findings suggest a larger effect of radiation on leukemia with high hyperpdiploidy than other subgroups, but this result requires further confirmation. PMID:27405274

  7. DIGE-based proteomic analysis identifies nucleophosmin/B23 and nucleolin C23 as over-expressed proteins in relapsed/refractory acute leukemia.

    PubMed

    Hu, Jianda; Lin, Minhui; Liu, Tingbo; Li, Jing; Chen, Buyuan; Chen, Yingyu

    2011-08-01

    Drug resistance is a challenge in treatment of acute leukemia. To investigate novel protein changes involved in resistance, protein expression profiles between leukemia cell line HL-60 and adriamycin-resistant HL-60 (HL-60/ADR) were compared based on a proteomic approach-2D-DIGE followed by MALDI-TOF/MS. 13 protein spots were identified as up-regulated and 3 down-regulated in HL-60/ADR. Nucleophosmin/B23 (NPM B23) and nucleolin C23 (C23) were selected and verified by western blot, which showed an obvious up-regulation in leukemia cells, especially in 3 resistant leukemia cell lines and in relapsed/refractory patients. To a conclusion, B23 and C23 may be involved in drug resistance and be useful in assessing the prognosis of leukemia. PMID:21310483

  8. Role of hematopoietic stem cell transplantation for relapsed acute promyelocytic leukemia: a retrospective analysis of JALSG-APL97.

    PubMed

    Fujita, Hiroyuki; Asou, Norio; Iwanaga, Masako; Hyo, Rie; Nomura, Shosaku; Kiyoi, Hitoshi; Okada, Masaya; Inaguma, Youko; Matsuda, Mitsuhiro; Yamauchi, Takahiro; Ohtake, Shigeki; Izumi, Tohru; Nakaseko, Chiaki; Ishigatsubo, Yoshiaki; Shinagawa, Katsuji; Takeshita, Akihiro; Miyazaki, Yasushi; Ohnishi, Kazunori; Miyawaki, Shuichi; Naoe, Tomoki

    2013-10-01

    For patients with relapsed acute promyelocytic leukemia (APL), all-trans retinoic acid-based salvage regimens can achieve second complete remission (CR2), but the optimal post-remission strategy for APL patients after CR2 remains unclear. Hematopoietic stem cell transplantation (HSCT) during CR2 might be effective, but data on the role of HSCT for APL patients after CR2 are limited in Japan. We retrospectively analyzed outcomes for 57 relapsed APL patients who achieved CR2 in the JALSG APL97 study. Of those, six received autologous (auto)-HSCT, 21 received allogeneic (allo)-HSCT, and 30 received various regimens other than HSCT. The 5-year event-free survival (EFS) rate, overall survival (OS) rate and cumulative incidence of relapse (CIR) were 50.7%, 77.4% and 51.0% in the non-HSCT group, 41.7%, 83.3% and 58.3% in the auto-HSCT group and 71.1%, 76.2% and 9.8% in the allo-HSCT group, respectively. Both the EFS rate and CIR were significantly better in the allo-HSCT group than in other groups. Allo-HSCT appears effective in APL patients in CR2, with a low relapse rate beyond a relatively early transplantation-related mortality (19%). Among older patients (age ≥40 years), the 5-year OS was significantly better in the non-HSCT group than in the HSCT group (78.0% vs 40.5%; P = 0.04). Further prospective studies with larger patient numbers are required to confirm the impact of HSCT alone and in combination with arsenic trioxide on outcomes for patients with APL in CR2. PMID:23837667

  9. miR expression profiling at diagnosis predicts relapse in pediatric precursor B-cell acute lymphoblastic leukemia.

    PubMed

    Avigad, Smadar; Verly, Iedan R N; Lebel, Asaf; Kordi, Oshrit; Shichrur, Keren; Ohali, Anat; Hameiri-Grossman, Michal; Kaspers, Gertjan J L; Cloos, Jacqueline; Fronkova, Eva; Trka, Jan; Luria, Drorit; Kodman, Yona; Mirsky, Hadar; Gaash, Dafna; Jeison, Marta; Avrahami, Galia; Elitzur, Sarah; Gilad, Gil; Stark, Batia; Yaniv, Isaac

    2016-04-01

    Our aim was to identify miRNAs that can predict risk of relapse in pediatric patients with acute lymphoblastic leukemia (ALL). Following high-throughput miRNA expression analysis (48 samples), five miRs were selected for further confirmation performed by real time quantitative PCR on a cohort of precursor B-cell ALL patients (n = 138). The results were correlated with clinical parameters and outcome. Low expression of miR-151-5p, and miR-451, and high expression of miR-1290 or a combination of all three predicted inferior relapse free survival (P = 0.007, 0.042, 0.025, and <0.0001, respectively). Cox regression analysis identified aberrant expression of the three miRs as an independent prognostic marker with a 10.5-fold increased risk of relapse (P = 0.041) in PCR-MRD non-high risk patients. Furthermore, following exclusion of patients harboring IKZF1 deletion, the aberrant expression of all three miRs could identify patients with a 24.5-fold increased risk to relapse (P < 0.0001). The prognostic relevance of the three miRNAs was evaluated in a non-BFM treated precursor B-cell ALL cohort (n = 33). A significant correlation between an aberrant expression of at least one of the three miRs and poor outcome was maintained (P < 0.0001). Our results identify an expression profile of miR-151-5p, miR-451, and miR-1290 as a novel biomarker for outcome in pediatric precursor B-cell ALL patients, regardless of treatment protocol. The use of these markers may lead to improved risk stratification at diagnosis and allow early therapeutic interventions in an attempt to improve survival of high risk patients. PMID:26684414

  10. Adoptive transfer of T cells transduced with a chimeric antigen receptor to treat relapsed or refractory acute leukemia: efficacy and feasibility of immunotherapy approaches.

    PubMed

    Ding, Guoliang; Chen, Hu

    2016-07-01

    Treatment outcomes of acute leukemia (AL) have not improved over the past several decades and relapse rates remain high despite the availability of aggressive therapies. Conventional relapsed leukemia treatment includes second allogeneic hematopoietic stem cell transplantation (allo-HSCT) and donor lymphocyte infusion (DLI), which in most cases mediate, at best, a modest graft-versus-leukemia effect, although their clinical efficacy is still limited. Although allo-HSCT following myeloablative conditioning is a curative treatment option for younger patients with acute myeloid leukemia (AML) in a first complete remission (CR), allo-HSCT as a clinical treatment is usually limited because of treatment-related toxicity. The overall DLI remission rate is only 15%-42% and 2-year overall survival (OS) is approximately 15%-20%, with a high (40%-60%) incidence of DLI-related graft-versus-host disease (GVHD). Therefore, development of new, targeted treatment strategies for relapsed and refractory AL patients is ongoing. Adoptive transfer of T cells with genetically engineered chimeric antigen receptors (CARs) is an encouraging approach for treating hematological malignancies. These T cells are capable of selectively recognizing tumor-associated antigens and may overcome many limitations of conventional therapies, inducing remission in patients with chemotherapy-refractory or relapsed AL. In this review, we aimed to highlight the current understanding of this promising treatment modality, discussing its adverse effects and efficacy. PMID:27142351

  11. Clinical characteristics and outcome of isolated extramedullary relapse in acute leukemia after allogeneic stem cell transplantation: a single-center analysis.

    PubMed

    Shi, Ji-Min; Meng, Xiao-Jian; Luo, Yi; Tan, Ya-Min; Zhu, Xiao-Li; Zheng, Gao-Feng; He, Jing-Song; Zheng, Wei-Yan; Xie, Wan-Zhuo; Li, Li; Ye, Xiu-Jin; Zhang, Jie; Cai, Zhen; Lin, Mao-Fang; Huang, He

    2013-04-01

    Isolated extramedullary relapse (EMR) of acute leukemia (AL) is a rare occurrence. However, it appears to be more common after allogeneic stem cell transplantation (allo-SCT). To characterize what has been observed in isolated EMR, we investigated 287 consecutive AL patients (144 acute myeloid leukemia; 138 acute lymphocytic leukemia; 5 acute mixed-lineage leukemia) who underwent allo-SCT. Twelve cases experienced relapse at extramedullary sites without concomitant involvement of the bone marrow (BM). The onset to relapse after allo-SCT was longer in extramedullary sites than in the BM (median, 10 months versus 5.5 months). EMR sites varied widely and included the central nervous system, skin, bone, pelvis and breasts. Univariate analysis demonstrated that cytogenetic abnormalities were correlated significantly with the onset of isolated EMR (P=0.001). The prognosis for patients who develop EMR remained poor but was relatively better than that after BM relapse (overall survival, 10 versus 18 months). Compared with local or single therapy, patients treated with systemic treatment in combination with local treatment could yield a favorable prognosis. In conclusion, we observed a significant number of isolated cases of EMR in AL patients after allo-SCT, cytogenetic abnormalities were correlated significantly with the onset of isolated EMR. We found that intensive approaches combining local and systemic therapy could produce favorable responses which may cure a proportion of these patients. PMID:23347901

  12. Monitoring mixed lineage leukemia expression may help identify patients with mixed lineage leukemia--rearranged acute leukemia who are at high risk of relapse after allogeneic hematopoietic stem cell transplantation.

    PubMed

    Liu, Jing; Wang, Yu; Xu, Lan-Ping; Liu, Dai-Hong; Qin, Ya-Zhen; Chang, Ying-Jun; Liu, Kai-Yan; Huang, Xiao-Jun

    2014-07-01

    To evaluate the prognostic value of the expression of the mixed lineage leukemia (MLL) gene for predicting the relapse of patients with MLL-rearranged acute leukemia (AL) after allogeneic hematopoietic stem cell transplantation (allo-HSCT), the levels of MLL transcripts in bone marrow (BM) specimens were monitored serially by real-time quantitative polymerase chain reaction (RQ-PCR) at predetermined time points in 40 patients with MLL-rearranged AL who were treated with allo-HSCT. These patients were followed for a median of 24.5 months (range, 8 to 60 months). A total of 236 BM samples were collected and analyzed. Of these, 230 were monitored concurrently for minimal residual disease (MRD) by flow cytometry (FCM) for leukemia-associated aberrant immune phenotypes and by RQ-PCR for the expression of the Wilms tumor (WT1) gene. The 3-year cumulative incidence of relapse in patients who experienced MLL-positive patients (MLL > .0000%) (n = 9) after HSCT was 93.5% (95% confidence interval [CI], 87% to 100%) compared with 12.5% (95% CI, 5.6% to 19.4%) for MLL-negative patients (n = 31) (P < .001). For these 2 patient groups, the 3-year overall survival (OS) was 12.5% (95% CI, .8% to 24.2%) and 77.8% (95% CI, 68.4% to 87.2%) (P < .001), respectively, and the 3-year leukemia-free survival (LFS) was 0% and 72.2% (95% CI, 61.1% to 83.3%), respectively (P < .001). MLL positivity was associated with a higher rate of relapse (hazard ratio [HR], 18.643; 95% CI, 3.449 to 57.025; P = .001), lower LFS (HR, 7.267; 95% CI, 2.038 to 25.916; P = .002), and lower OS (HR, 8.259; 95% CI, 2.109 to 32.336; P = .002), as determined by Cox multivariate analysis. The expression of the MLL gene had a higher specificity and sensitivity than WT1 or MRD monitored by FCM for predicting the relapse of the patients with MLL + AL. Our results suggest that monitoring the expression of the MLL gene may help to identify patients with MLL + AL who are at high risk of relapse after allo-HSCT and may

  13. Immunotherapy for Pediatric Leukemia

    PubMed Central

    Shah, Nirali N.; Dave, Hema; Wayne, Alan S.

    2013-01-01

    Substantial progress has been made in the treatment of leukemia in childhood. Despite this, leukemia remains a leading cause of pediatric cancer-related mortality and the prognosis is guarded for individuals with relapsed or refractory disease. Standard therapies are associated with a wide array of acute and long-term toxicities and further treatment intensification may not be tolerable or beneficial. The curative potential of allogeneic stem cell transplantation is due in part to the graft-versus-leukemia effect, which provides evidence for the therapeutic capacity of immune-based therapies. In recent years there have been significant advances in the development and application of immunotherapy in the treatment of leukemias, including the demonstration of activity in chemotherapy-resistant cases. This review summarizes immunotherapeutic approaches in the treatment of pediatric leukemia including current results and future directions. PMID:23847759

  14. Studying Biomarkers in Samples From Younger Patients With Acute Myeloid Leukemia

    ClinicalTrials.gov

    2016-05-17

    Childhood Acute Monoblastic Leukemia (M5a); Childhood Acute Monocytic Leukemia (M5b); Childhood Acute Myeloblastic Leukemia Without Maturation (M1); Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies; Childhood Acute Myelomonocytic Leukemia (M4)

  15. Ipilimumab in Treating Patients With Relapsed or Refractory High-Risk Myelodysplastic Syndrome or Acute Myeloid Leukemia

    ClinicalTrials.gov

    2016-06-27

    Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome; Chronic Myelomonocytic Leukemia; Previously Treated Myelodysplastic Syndrome; Recurrent Adult Acute Myeloid Leukemia; Secondary Myelodysplastic Syndrome

  16. A Systematic Review and Meta-analysis of Childhood Leukemia and Parental Occupational Pesticide Exposure

    PubMed Central

    Wigle, Donald T.; Turner, Michelle C.; Krewski, Daniel

    2009-01-01

    Objectives We conducted a systematic review and meta-analysis of childhood leukemia and parental occupational pesticide exposure. Data sources Searches of MEDLINE (1950–2009) and other electronic databases yielded 31 included studies. Data extraction Two authors independently abstracted data and assessed the quality of each study. Data synthesis Random effects models were used to obtain summary odds ratios (ORs) and 95% confidence intervals (CIs). There was no overall association between childhood leukemia and any paternal occupational pesticide exposure (OR = 1.09; 95% CI, 0.88–1.34); there were slightly elevated risks in subgroups of studies with low total-quality scores (OR = 1.39; 95% CI, 0.99–1.95), ill-defined exposure time windows (OR = 1.36; 95% CI, 1.00–1.85), and exposure information collected after offspring leukemia diagnosis (OR = 1.34; 95% CI, 1.05–1.70). Childhood leukemia was associated with prenatal maternal occupational pesticide exposure (OR = 2.09; 95% CI, 1.51–2.88); this association was slightly stronger for studies with high exposure-measurement-quality scores (OR = 2.45; 95% CI, 1.68–3.58), higher confounder control scores (OR = 2.38; 95% CI, 1.56–3.62), and farm-related exposures (OR = 2.44; 95% CI, 1.53–3.89). Childhood leukemia risk was also elevated for prenatal maternal occupational exposure to insecticides (OR = 2.72; 95% CI, 1.47–5.04) and herbicides (OR = 3.62; 95% CI, 1.28–10.3). Conclusions Childhood leukemia was associated with prenatal maternal occupational pesticide exposure in analyses of all studies combined and in several subgroups. Associations with paternal occupational pesticide exposure were weaker and less consistent. Research needs include improved pesticide exposure indices, continued follow-up of existing cohorts, genetic susceptibility assessment, and basic research on childhood leukemia initiation and progression. PMID:20019898

  17. A review and meta-analysis of outdoor air pollution and risk of childhood leukemia.

    PubMed

    Filippini, Tommaso; Heck, Julia E; Malagoli, Carlotta; Del Giovane, Cinzia; Vinceti, Marco

    2015-01-01

    Leukemia is the most frequent malignant disease affecting children. To date, the etiology of childhood leukemia remains largely unknown. Few risk factors (genetic susceptibility, infections, ionizing radiation, etc.) have been clearly identified, but they appear to explain only a small proportion of cases. Considerably more uncertain is the role of other environmental risk factors, such as indoor and outdoor air pollution. We sought to summarize and quantify the association between traffic-related air pollution and risk of childhood leukemia, and further examined results according to method of exposure assessment, study quality, leukemia subtype, time period, and continent where studies took place. After a literature search yielded 6 ecologic and 20 case-control studies, we scored the studies based on the Newcastle-Ottawa Scale. The studies assessed residential exposure to pollutants from motorized traffic by computing traffic density in the neighboring roads or vicinity to petrol stations, or by using measured or modeled nitrogen dioxide and benzene outdoor air levels. Because heterogeneity across studies was observed, random-effects summary odds ratios (OR) and 95% confidence intervals (CI) were reported. Whenever possible we additionally conducted stratified analyses comparing acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Limiting the analysis to high-quality studies (Newcastle-Ottawa Scale ≥ 7), those using traffic density as the exposure assessment metric showed an increase in childhood leukemia risk in the highest exposure category (OR = 1.07, 95% CI 0.93-1.24). However, we observed evidence of publication bias. Results for NO2 exposure and benzene showed an OR of 1.21 (95% CI 0.97-1.52) and 1.64 (95% CI 0.91-2.95) respectively. When stratifying by leukemia type, the results based upon NO2 were 1.21 (95% CI 1.04-1.41) for ALL and 1.06 (95% CI 0.51-2.21) for AML; based upon benzene were 1.09 (95% CI 0.67-1.77) for ALL and 2.28 (95% CI

  18. A Review and Meta-Analysis of Outdoor Air Pollution and Risk of Childhood Leukemia

    PubMed Central

    Filippini, Tommaso; E. Heck, Julia; Malagoli, Carlotta; Del Giovane, Cinzia; Vinceti, Marco

    2015-01-01

    Leukemia is the most frequent malignant disease affecting children. To date, the etiology of childhood leukemia remains largely unknown. Few risk factors (genetic susceptibility, infections, ionizing radiation, etc.) have been clearly identified, but they appear to explain only a small proportion of cases. Considerably more uncertain is the role of other environmental risk factors, such as indoor and outdoor air pollution. We sought to summarize and quantify the association between traffic-related air pollution and risk of childhood leukemia, and further examined results according to method of exposure assessment, study quality, leukemia subtype, time period and continent where studies took place. After a literature search yielded 6 ecologic and 20 case-control studies, we scored the studies based upon the Newcastle-Ottawa Scale. The studies assessed residential exposure to pollutants from motorized traffic by computing traffic density in the neighboring roads or vicinity to petrol stations, or by using measured or modeled nitrogen dioxide and benzene outdoor air levels. Because heterogeneity across studies was observed, random-effects summary odds ratios (OR) and 95% confidence intervals (CI) were reported. Whenever possible we additionally conducted stratified analyses comparing acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Limiting the analysis to high-quality studies (Newcastle-Ottawa Scale ≥ 7), those using traffic density as the exposure assessment metric showed an increase in childhood leukemia risk in the highest exposure category (OR=1.07, 95% CI 0.93 – 1.24). However, we observed evidence of publication bias. Results for NO2 exposure and benzene showed an OR of 1.21 (95% CI 0.97 – 1.52) and 1.64 (95% CI 0.91 – 2.95) respectively. When stratifying by leukemia type, the results based upon NO2 were 1.21 (95% CI 1.04 – 1.41) for ALL and 1.06 (95% CI 0.51 – 2.21) for AML; based upon benzene were 1.09 (95% CI 0.67 – 1

  19. RUNX1 amplification in lineage conversion of childhood B-cell acute lymphoblastic leukemia to acute myelogenous leukemia.

    PubMed

    Podgornik, Helena; Debeljak, Marusa; Zontar, Darja; Cernelc, Peter; Prestor, Veronika Velensek; Jazbec, Janez

    2007-10-01

    Amplification of RUNX1 (alias AML1) is a recurrent karyotypic abnormality in childhood acute lymphoblastic leukemia (ALL) that is generally associated with a poor outcome. It does not occur with other primary chromosomal abnormalities in acute ALL. AML1 amplification in acute myelogenous leukemia (AML) is a rare secondary event described mainly in therapy-related cases. AML1 amplification was found in a 13-year-old patient with AML M4/M5 leukemia that occurred 5 years after she had been diagnosed with common B-cell ALL. Conventional cytogenetic, fluorescent in situ hybridization (FISH), and polymerase chain reaction methods revealed no other chromosomal change expected to occur in a disease that we assumed to be a secondary leukemia. Due to the lack of cytogenetic data from the diagnostic sample, we developed a new approach to analyze the archived bone marrow smear, which had been stained previously with May-Grünwald-Geimsa by the FISH method. This analysis confirmed that in addition to t(12;21), AML1 amplification and overexpression existed already at the time the diagnosis was made. The chromosomal changes, however, were found in different clones of bone marrow cells. While the first course of chemotherapy successfully eradicated the cell line with the t(12;21), the second cell line with AML1 amplification remained latent during the time of complete remission and reappeared with a different immunophenotype. PMID:17889714

  20. Phase I Dose-Escalation Trial of Clofarabine Followed by Escalating Doses of Fractionated Cyclophosphamide in Children With Relapsed or Refractory Acute Leukemias

    ClinicalTrials.gov

    2010-09-21

    Myelodysplastic Syndrome; Acute Myeloid Leukemia; Myeloproliferative Disorders; Acute Lymphocytic Leukemia; Acute Promyelocytic Leukemia; Acute Leukemia; Chronic Myelogenous Leukemia; Myelofibrosis; Chronic Myelomonocytic Leukemia; Juvenile Myelomonocytic Leukemia

  1. Outcome after relapse of acute lymphoblastic leukemia in adult patients included in four consecutive risk-adapted trials by the PETHEMA Study Group

    PubMed Central

    Oriol, Albert; Vives, Susana; Hernández-Rivas, Jesús-María; Tormo, Mar; Heras, Inmaculada; Rivas, Concepción; Bethencourt, Concepción; Moscardó, Federico; Bueno, Javier; Grande, Carlos; del Potro, Eloy; Guardia, Ramon; Brunet, Salut; Bergua, Juan; Bernal, Teresa; Moreno, Maria-José; Calvo, Carlota; Bastida, Pilar; Feliu, Evarist; Ribera, Josep-Maria

    2010-01-01

    Background About one half of adults with acute lymphoblastic leukemia are not cured of the disease and ultimately die. The objective of this study was to explore the factors influencing the outcome of adult patients with relapsed acute lymphoblastic leukemia. Design and Methods We analyzed the characteristics, the outcome and the prognostic factors for survival after first relapse in a series of 263 adult patients with acute lymphoblastic leukemia (excluding those with mature B-cell acute lymphoblastic leukemia) prospectively enrolled in four consecutive risk-adapted PETHEMA trials. Results The median overall survival after relapse was 4.5 months (95% CI, 4–5 months) with a 5-year overall survival of 10% (95% CI, 8%–12%); 45% of patients receiving intensive second-line treatment achieved a second complete remission and 22% (95% CI, 14%–30%) of them remained disease free at 5 years. Factors predicting a good outcome after rescue therapy were age less than 30 years (2-year overall survival of 21% versus 10% for those over 30 years old; P<0.022) and a first remission lasting more than 2 years (2-year overall survival of 36% versus 17% among those with a shorter first remission; P<0.001). Patients under 30 years old whose first complete remission lasted longer than 2 years had a 5-year overall survival of 38% (95% CI, 23%–53%) and a 5-year disease-free survival of 53% (95% CI, 34%–72%). Conclusions The prognosis of adult patients with acute lymphoblastic leukemia who relapse is poor. Those aged less than 30 years with a first complete remission lasting longer than 2 years have reasonable possibilities of becoming long-term survivors while patients over this age or those who relapse early cannot be successfully rescued using the therapies currently available. PMID:20145276

  2. Hypertension and Life-Threatening Bleeding in Children with Relapsed Acute Myeloblastic Leukemia Treated with FLT3 Inhibitors.

    PubMed

    Yılmaz Karapınar, Deniz; Karadaş, Nihal; Önder Siviş, Zühal; Balkan, Can; Kavaklı, Kaan; Aydınok, Yeşim

    2015-09-01

    Experiences with new multikinase inhibitors are limited, especially in children. In this report we summarize our experience with 2 patients with relapsed acute myeloblastic leukemia (AML), one with FMS-like tyrosine kinase-3-internal tandem duplication mutation and the other with a single base mutation (D835Y). Both patients received sorafenib, one for 19 days and the other for 42 days, with clofarabine-including chemotherapy. One additionally received sunitinib for a total of 20 days. Both patients developed severe pancytopenia, hypertension, life-threatening bleedings from the gastrointestinal system, and, finally, intrapulmonary hemorrhage. Although both reached severe aplasia of the bone marrow without blastic infiltration, death occurred with neutropenic sepsis. PMID:25912283

  3. Central nervous system involvement at first relapse in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline monochemotherapy without intrathecal prophylaxis

    PubMed Central

    Montesinos, Pau; Díaz-Mediavilla, Joaquín; Debén, Guillermo; Prates, Virginia; Tormo, Mar; Rubio, Vicente; Pérez, Inmaculada; Fernández, Isolda; Viguria, Maricruz; Rayón, Chelo; González, José; de la Serna, Javier; Esteve, Jordi; Bergua, Juan M.; Rivas, Concha; González, Marcos; González, Jose D.; Negri, Silvia; Brunet, Salut; Lowenberg, Bob; Sanz, Miguel A.

    2009-01-01

    Background The prevalence of and risk factors for central nervous system recurrence in patients with acute promyelocytic leukemia are not well established and remain a controversial matter. Design and Methods Between 1996 and 2005, 739 patients with newly diagnosed acute promyelocytic leukemia enrolled in two consecutive trials (PETHEMA LPA96 and LPA99) received induction therapy with all-trans retinoic acid and idarubicin. Consolidation therapy comprised three courses of anthracycline monochemotherapy (LPA96), with all-trans retinoic acid and reinforced doses of idarubicin in patients with an intermediate or high risk of relapse (LPA99). Central nervous system prophylaxis was not given. Results Central nervous system relapse was documented in 11 patients. The 5-year cumulative incidence of central nervous system relapse was 1.7% (LPA96 3.2% and LPA99 1.2%; p=0.09). The cumulative incidence was 0%, 0.8%, and 5.5% in low-, intermediate-, and high-risk patients, respectively. Relapse risk score (p=0.0001) and the occurrence of central nervous system hemorrhage during induction (5-year cumulative incidence 18.7%, p=0.006) were independent risk factors for central nervous system relapse. Conclusions This study shows a low incidence of central nervous system relapse in patients with acute promyelocytic leukemia following therapy with all-trans retinoic acid and anthracycline without specific central nervous system prophylaxis. Central nervous system relapse was significantly associated with high white blood cell counts and prior central nervous system hemorrhage, which emerged as independent prognostic factors. PMID:19608685

  4. Decitabine, Donor Natural Killer Cells, and Aldesleukin in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

    ClinicalTrials.gov

    2016-01-07

    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; Secondary Acute Myeloid Leukemia

  5. Phase II Study of Lenalidomide and Rituximab As Salvage Therapy for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia

    PubMed Central

    Badoux, Xavier C.; Keating, Michael J.; Wen, Sijin; Wierda, William G.; O'Brien, Susan M.; Faderl, Stefan; Sargent, Rachel; Burger, Jan A.; Ferrajoli, Alessandra

    2013-01-01

    Purpose Lenalidomide is an immunomodulatory drug active as salvage therapy for chronic lymphocytic leukemia (CLL). We combined lenalidomide with rituximab to improve response rates in patients with relapsed or refractory CLL. Patients and Methods Fifty-nine adult patients (age 42 to 82 years) with relapsed or refractory CLL were enrolled onto a phase II study of lenalidomide and rituximab. Patients had received prior fludarabine-based therapy or chemoimmunotherapy. Rituximab (375 mg/m2 intravenously) was administered weekly during cycle one and on day 1 of cycles three to 12. Lenalidomide was started on day 9 of cycle one at 10 mg orally and administered daily continuously. Each cycle was 28 days. Rituximab was administered for 12 cycles; lenalidomide could continue indefinitely if patients benefitted clinically. Results The overall response rate was 66%, including 12% complete responses and 12% nodular partial remissions. Time to treatment failure was 17.4 months. Median overall survival has not been reached; estimated survival at 36 months is 71%. The most common grade 3 or 4 toxicity was neutropenia (73% of patients). Fourteen patients (24%) experienced a grade 3 to 4 infection or febrile episode. There was one episode of grade 3 tumor lysis; one patient experienced renal failure during the first cycle of therapy, and one venous thromboembolic event occurred during the study. Conclusion The combination of lenalidomide and rituximab is active in patients with recurrent CLL and warrants further investigation. PMID:23270003

  6. Phase 1 study of clofarabine in pediatric patients with relapsed/refractory acute lymphoblastic leukemia in Japan.

    PubMed

    Koh, Katsuyoshi; Ogawa, Chitose; Okamoto, Yasuhiro; Kudo, Kazuko; Inagaki, Jiro; Morimoto, Tsuyoshi; Mizukami, Hideya; Ecstein-Fraisse, Evelyne; Kikuta, Atsushi

    2016-08-01

    A phase 1 study was conducted to evaluate the safety, pharmacokinetics (PK), efficacy and pharmacogenetic characteristics of clofarabine in seven Japanese pediatric patients with relapsed/refractory acute lymphoblastic leukemia (ALL). Patients in Cohort 1 received clofarabine 30 mg/m(2)/day for 5 days, followed by 52 mg/m(2)/day for 5 days in subsequent cycles. Cohort 2 patients were consistently treated with 52 mg/m(2)/day for 5 days. No more than six cycles were performed. Every patient had at least one ≥Grade 3 adverse event (AE). AEs (≥Grade 3) related to clofarabine were anaemia, neutropenia, febrile neutropenia, thrombocytopenia, alanine aminotransferase increased, aspartate aminotransferase increased, haemoglobin decreased, and platelet (PLT) count decreased. C max and AUC of clofarabine increased in a dose-dependent fashion, but its elimination half-life (T 1/2) did not appear to be dependent on dose or duration of treatment. Clofarabine at 52 mg/m(2)/day shows similarly tolerable safety and PK profiles compared to those in previous studies. No complete remission (CR), CR without PLT recovery, or partial remission was observed. Since clofarabine is already used as a key drug for relapsed/refractory ALL patients in many countries, the efficacy of clofarabine in Japanese pediatric patients should be evaluated in larger study including more patients, such as by post-marketing surveillance. PMID:27086352

  7. Low efficacy and high mortality associated with clofarabine treatment of relapsed/refractory acute myeloid leukemia and myelodysplastic syndromes.

    PubMed

    Roberts, Daniel A; Wadleigh, Martha; McDonnell, Anne M; DeAngelo, Daniel J; Stone, Richard M; Steensma, David P

    2015-02-01

    Clofarabine, a second-generation nucleoside analog, has clinical activity in relapsed or refractory acute myelogenous leukemia (AML) and higher-risk myelodysplastic syndromes (MDS). However, there are few data evaluating performance of clofarabine in populations of patients not enrolled in clinical trials. We reviewed outcomes for 84 patients treated with clofarabine for relapsed or refractory AML or MDS, either with clofarabine as monotherapy (n=19) or in combination with cytarabine (n=65). Using International Working Group (IWG) response criteria, the overall response rate (ORR) of all treated patients was 21%, with a complete response rate with either complete or incomplete hematopoietic recovery (CRR=CR+CRi) of 14%. For combination therapy, ORR was 22% with CRR of 18%, and monotherapy patients had an ORR of 21% with CRR of 11%. Although limited by small numbers, subgroup analysis did not reveal variation in response rates when comparing different risk factors. The 30-day mortality was 21% and median survival was 3 months; a subset of 12 patients who were able to go to transplant had an 18-month median survival. Clofarabine's efficacy in a "real-world" setting appears to be less than has been reported in clinical trials, and treatment is associated with a high early mortality rate. PMID:25554239

  8. Outcome of older patients with acute myeloid leukemia in first relapse.

    PubMed

    Sarkozy, Clémentine; Gardin, Claude; Gachard, Nathalie; Merabet, Fathia; Turlure, Pascal; Malfuson, Jean-Valère; Pautas, Cécile; Micol, Jean-Baptiste; Thomas, Xavier; Quesnel, Bruno; Celli-Lebras, Karine; Preudhomme, Claude; Terré, Christine; Fenaux, Pierre; Chevret, Sylvie; Castaigne, Sylvie; Dombret, Hervé

    2013-09-01

    To provide data for future drug evaluation, we analyzed the outcome of 393 patients aged 50 years or older (median, 64 years) with AML in first relapse after treatment in recent ALFA trials. Salvage options were retrospectively classified as follows: best supportive care (BSC), low-dose cytarabine (LDAC), gemtuzumab ozogamicin (GO), intensive chemotherapy (ICT), or ICT combined with GO. Second complete remission (CR2) rate was 31% and median post-relapse survival was 6.8 months (0, 17, 42.5, 53, and 80% and 3.2, 5.6, 8.9, 9, and 19.8 months in BSC, LDAC, GO, ICT, and ICT + GO subsets, respectively). Age, performance status, WBC, CR1 duration, and favorable AML karyotype, but not other cytogenetic or molecular features, influenced post-relapse outcome. Multivariate adjustment and propensity score matching showed that intensive salvage (ICT/ICT+GO/GO versus LDAC/BSC) was associated with longer post-relapse survival, at least in patients with CR1 duration ≥12 months (P = 0.001 and 0.0005, respectively). Of interest, GO appeared to be as effective as standard ICT, and ICT + GO combination more effective than standard ICT. In conclusion, older patients with CR1 duration ≥12 months appeared to benefit from intensive salvage and results observed with GO-containing salvage suggest that GO combination studies should be actively pursued in this setting. PMID:23749683

  9. Randomized controlled trials in relapsed/refractory chronic lymphocytic leukemia: a systematic review and meta-analysis.

    PubMed

    Police, Rachel L; Trask, Peter C; Wang, Jianmin; Olivares, Robert; Khan, Shahnaz; Abbe, Adeline; Colosia, Ann; Njue, Annete; Sherrill, Beth; Ruiz-Soto, Rodrigo; Kaye, James A; Hamadani, Mehdi

    2015-04-01

    This systematic literature review with meta-analysis was conducted on the clinical efficacy and safety of interventions used in the treatment of chronic lymphocytic leukemia (CLL). We systematically searched databases (PubMed, Cochrane Library, and Embase; 1997 to August 2, 2012), conference abstracts, bibliographic reference lists, recent reviews, and Clinicaltrials.gov. Primary efficacy outcomes were objective response rate, progression-free survival, and overall survival. Safety end points were Grade 3/4 toxicities, serious adverse events, withdrawals because of toxicity, and deaths due to toxicity. Studies were selected if they were randomized controlled trials (RCTs) reporting on the efficacy or safety of relapsed or refractory CLL and if outcomes for CLL were reported separately from trials that included other lymphoid neoplasms. We used the Bucher method for conducting adjusted indirect comparisons within a meta-analysis. We identified 6 RCTs of pharmacologic treatment for relapsed/refractory CLL. The most common drugs investigated (alone or in combination) were fludarabine and cyclophosphamide. When reported, median overall survival ranged from 27.3 to 52.9 months, and overall response rate from 58% to 82%. Although meta-analysis of efficacy results was considered, details are not presented because only 3 studies qualified and the common comparator treatment was not clinically relevant. The relatively small number of RCTs, few overlapping treatment arms, and variability in end points studied make it difficult to formally compare therapies for relapsed/refractory CLL. Significant variability in RCT features presents a further challenge to meaningful comparisons. Additional well-designed RCTs are needed to fully understand the relative efficacy and safety of older and more recently developed therapies. PMID:25445467

  10. Five years of experience with rituximab plus high-dose dexamethasone for relapsed/refractory chronic lymphocytic leukemia

    PubMed Central

    Šimkovič, Martin; Motyčková, Monika; Belada, David; Vodárek, Pavel; Kapoor, Rahul; Jaffar, Hamna; Vrbacký, Filip; Žák, Pavel

    2015-01-01

    Introduction High-dose methylprednisolone (HDMP) in combination with rituximab is active in the treatment of relapsed/refractory chronic lymphocytic leukemia (CLL), but serious infections are frequent. Recently published data suggested that high-dose dexamethasone might be equally effective as HDMP despite a lower cumulative dose. Material and methods We performed retrospective analysis of 60 patients with relapsed/refractory CLL (median age: 66 years; range: 37–86) treated with rituximab plus dexamethasone (R-dex) at a single tertiary center between September 2008 and October 2012. The schedule of R-dex consisted of rituximab 500 mg/m2 i.v. day 1 (375 mg/m2 in cycle 1) and dexamethasone 40 mg orally on days 1-4 and 10-13 repeated every 3 weeks for a maximum of 8 cycles. Unfavorable prognostic features were frequent (Rai stages III/IV in 67%, unmutated IgVH 82%, del 11q 43%, TP53 mutation/deletion 23%, bulky lymphadenopathy 58% of patients). Results Overall response (OR)/complete remission (CR) was achieved in 75/3%. At the median follow-up of 21 months, median progression-free survival (PFS) was 8 months, median time to next treatment 12.9 months and median overall survival 25.5 months. Refractoriness to fludarabine (p = 0.04) and age ≥ 65 years (p = 0.03) were significant predictors of shorter PFS. R-dex was successfully used for debulking before allogenic stem cell transplantation in 7 patients (12%). Serious (CTCAE grade III/IV) infections occurred in 27% of patients; 20% of patients developed steroid diabetes requiring temporary short-acting insulin. Conclusions Our results show that R-dex is an active and well-tolerated regimen for patients with relapsed/refractory CLL; however, major infections remain frequent despite combined antimicrobial prophylaxis.

  11. AR-42 in Treating Patients With Advanced or Relapsed Multiple Myeloma, Chronic Lymphocytic Leukemia, or Lymphoma

    ClinicalTrials.gov

    2016-03-16

    Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic 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; Peripheral T-cell Lymphoma; Post-transplant Lymphoproliferative Disorder; Prolymphocytic 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 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 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

  12. Progress and Prospects in Pediatric Leukemia.

    PubMed

    Madhusoodhan, P Pallavi; Carroll, William L; Bhatla, Teena

    2016-07-01

    Pediatric leukemia is the single most common malignancy affecting children, representing up to 30% of all pediatric cancers. Dramatic improvements in survival for acute lymphoblastic leukemia (ALL) have taken place over the past 4 decades with outcomes approaching 90% in the latest studies. However, progress has been slower for myeloid leukemia and certain subgroups like infant ALL, adolescent/young adult ALL, and relapsed ALL. Recent advances include recognition of molecularly defined subgroups, which has ushered in precision medicine approaches. We discuss the current understanding of the biology of the various childhood leukemias, recent advances in research, and future challenges in this field. PMID:27283082

  13. Imatinib Mesylate in Treating Patients With Relapsed or Refractory Solid Tumors of Childhood

    ClinicalTrials.gov

    2015-04-14

    Childhood Desmoplastic Small Round Cell Tumor; Childhood Synovial Sarcoma; Gastrointestinal Stromal Tumor; Lung Metastases; Recurrent Childhood Soft Tissue Sarcoma; Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Recurrent Neuroblastoma; Recurrent Osteosarcoma

  14. A 25-Year-Old Man with Exudative Retinal Detachments and Infiltrates without Hematological or Neurological Findings Found to Have Relapsed Precursor T-Cell Acute Lymphoblastic Leukemia

    PubMed Central

    Johnson, Jordan S.; Lopez, James S.; Kavanaugh, Arthur Scott; Liang, Chanping; Mata, Douglas A.

    2015-01-01

    Background Precursor T-cell acute lymphoblastic leukemia (pre-T-ALL) may cause ocular pathologies such as cotton-wool spots, retinal hemorrhage, and less commonly, retinal detachment or leukemic infiltration of the retina itself. However, these findings are typically accompanied by the pathognomonic hematological signs of acute leukemia. Case Presentation In this case report and review of the literature, we describe a particularly unusual case of a 25-year-old man who presented to our hospital with bilateral exudative retinal detachments associated with posterior pole thickening without any hematological or neurological findings. The patient, who had a history of previously treated pre-T-ALL in complete remission, was found to have leukemia cell infiltration on retinal biopsy. Conclusion Our case underscores the fact that the ophthalmologist may be the first provider to detect the relapse of previously treated leukemia, and that ophthalmic evaluation is critical for detecting malignant ocular infiltrates. PMID:26483676

  15. Risk assessment of relapse by lineage-specific monitoring of chimerism in children undergoing allogeneic stem cell transplantation for acute lymphoblastic leukemia

    PubMed Central

    Preuner, Sandra; Peters, Christina; Pötschger, Ulrike; Daxberger, Helga; Fritsch, Gerhard; Geyeregger, Rene; Schrauder, André; von Stackelberg, Arend; Schrappe, Martin; Bader, Peter; Ebell, Wolfram; Eckert, Cornelia; Lang, Peter; Sykora, Karl-Walter; Schrum, Johanna; Kremens, Bernhard; Ehlert, Karoline; Albert, Michael H.; Meisel, Roland; Lawitschka, Anita; Mann, Georg; Panzer-Grümayer, Renate; Güngör, Tayfun; Holter, Wolfgang; Strahm, Brigitte; Gruhn, Bernd; Schulz, Ansgar; Woessmann, Wilhelm; Lion, Thomas

    2016-01-01

    Allogeneic hematopoietic stem cell transplantation is required as rescue therapy in about 20% of pediatric patients with acute lymphoblastic leukemia. However, the relapse rates are considerable, and relapse confers a poor outcome. Early assessment of the risk of relapse is therefore of paramount importance for the development of appropriate measures. We used the EuroChimerism approach to investigate the potential impact of lineage-specific chimerism testing for relapse-risk analysis in 162 pediatric patients with acute lymphoblastic leukemia after allogeneic stem cell transplantation in a multicenter study based on standardized transplantation protocols. Within a median observation time of 4.5 years, relapses have occurred in 41/162 patients at a median of 0.6 years after transplantation (range, 0.13–5.7 years). Prospective screening at defined consecutive time points revealed that reappearance of recipient-derived cells within the CD34+ and CD8+ cell subsets display the most significant association with the occurrence of relapses with hazard ratios of 5.2 (P=0.003) and 2.8 (P=0.008), respectively. The appearance of recipient cells after a period of pure donor chimerism in the CD34+ and CD8+ leukocyte subsets revealed dynamics indicative of a significantly elevated risk of relapse or imminent disease recurrence. Assessment of chimerism within these lineages can therefore provide complementary information for further diagnostic and, potentially, therapeutic purposes aiming at the prevention of overt relapse. This study was registered at clinical.trials.gov with the number NC01423747. PMID:26869631

  16. Temsirolimus and Imatinib Mesylate in Treating Patients With Chronic Myelogenous Leukemia

    ClinicalTrials.gov

    2013-01-11

    Accelerated Phase Chronic Myelogenous Leukemia; Blastic Phase Chronic Myelogenous Leukemia; Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Chronic Phase Chronic Myelogenous Leukemia; Relapsing Chronic Myelogenous Leukemia

  17. Decitabine and Valproic Acid in Treating Patients With Refractory or Relapsed Acute Myeloid Leukemia or Previously Treated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

    ClinicalTrials.gov

    2013-09-27

    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 Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Untreated Adult Acute Myeloid Leukemia

  18. MEK Inhibitor MEK162, Idarubicin, and Cytarabine in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

    ClinicalTrials.gov

    2016-04-25

    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(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 Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Recurrent Adult Acute Myeloid Leukemia

  19. Cyclosporine, Pravastatin Sodium, Etoposide, and Mitoxantrone Hydrochloride in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

    ClinicalTrials.gov

    2012-06-18

    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

  20. Minimal Residual Disease Evaluation in Childhood Acute Lymphoblastic Leukemia: An Economic Analysis

    PubMed Central

    2016-01-01

    Background Minimal residual disease (MRD) testing by higher performance techniques such as flow cytometry and polymerase chain reaction (PCR) can be used to detect the proportion of remaining leukemic cells in bone marrow or peripheral blood during and after the first phases of chemotherapy in children with acute lymphoblastic leukemia (ALL). The results of MRD testing are used to reclassify these patients and guide changes in treatment according to their future risk of relapse. We conducted a systematic review of the economic literature, cost-effectiveness analysis, and budget-impact analysis to ascertain the cost-effectiveness and economic impact of MRD testing by flow cytometry for management of childhood precursor B-cell ALL in Ontario. Methods A systematic literature search (1998–2014) identified studies that examined the incremental cost-effectiveness of MRD testing by either flow cytometry or PCR. We developed a lifetime state-transition (Markov) microsimulation model to quantify the cost-effectiveness of MRD testing followed by risk-directed therapy to no MRD testing and to estimate its marginal effect on health outcomes and on costs. Model input parameters were based on the literature, expert opinion, and data from the Pediatric Oncology Group of Ontario Networked Information System. Using predictions from our Markov model, we estimated the 1-year cost burden of MRD testing versus no testing and forecasted its economic impact over 3 and 5 years. Results In a base-case cost-effectiveness analysis, compared with no testing, MRD testing by flow cytometry at the end of induction and consolidation was associated with an increased discounted survival of 0.0958 quality-adjusted life-years (QALYs) and increased discounted costs of $4,180, yielding an incremental cost-effectiveness ratio (ICER) of $43,613/QALY gained. After accounting for parameter uncertainty, incremental cost-effectiveness of MRD testing was associated with an ICER of $50,249/QALY gained. In

  1. Critical windows of exposure to household pesticides and risk of childhood leukemia.

    PubMed Central

    Ma, Xiaomei; Buffler, Patricia A; Gunier, Robert B; Dahl, Gary; Smith, Martyn T; Reinier, Kyndaron; Reynolds, Peggy

    2002-01-01

    The potential etiologic role of household pesticide exposures was examined in the Northern California Childhood Leukemia Study. A total of 162 patients (0-14 years old) with newly diagnosed leukemia were rapidly ascertained during 1995-1999, and 162 matched control subjects were randomly selected from the birth registry. The use of professional pest control services at any time from 1 year before birth to 3 years after was associated with a significantly increased risk of childhood leukemia [odds ratio (OR) = 2.8; 95% confidence interval (CI), 1.4-5.7], and the exposure during year 2 was associated with the highest risk (OR = 3.6; 95% CI, 1.6-8.3). The ORs for exposure to insecticides during the 3 months before pregnancy, pregnancy, and years 1, 2, and 3 were 1.8 (95% CI, 1.1-3.1), 2.1 (95% CI, 1.3-3.5), 1.7 (95% CI, 1.0-2.9), 1.6 (95% CI, 1.0-2.7), and 1.2 (95% CI, 0.7-2.1), respectively. Insecticide exposures early in life appear to be more significant than later exposures, and the highest risk was observed for exposure during pregnancy. Additionally, more frequent exposure to insecticides was associated with a higher risk. In contrast to insecticides, the association between herbicides and leukemia was weak and nonsignificant. Pesticides were also grouped based on where they were applied. Exposure to indoor pesticides was associated with an increased risk, whereas no significant association was observed for exposure to outdoor pesticides. The findings suggest that exposure to household pesticides is associated with an elevated risk of childhood leukemia and further indicate the importance of the timing and location of exposure. PMID:12204832

  2. Mutated Nucleophosmin-1 (NPM1) in patients with Acute Myeloid Leukemia (AML) in remission and relapse

    PubMed Central

    Jain, Preetesh; Kantarjian, Hagop; Patel, Keyur; Faderl, Stefan; Garcia-Manero, Guillermo; Benjamini, Ohad; Borthakur, Gautam; Pemmaraju, Naveen; Kadia, Tapan; Daver, Naval; Nazha, Aziz; Luthra, Raja; Pierce, Sherry; Cortes, Jorge; Ravandi, Farhad

    2014-01-01

    Patients with newly diagnosed AML (n=360) including 137 (38%) with normal karyotype (NK) were evaluated. Overall, 60 (16.6%) patients including 46 of the 137 (33.5%) NK patients had NPM1 mutation at baseline. Thirty nine patients (30 NK) had available NPM1 status at the time of CR and all (100%) were negative for mutated NPM1. Among the patients with mutated NPM1 at baseline, 10/39 overall (25%) and 7/30 NK (23%) patients relapsed. NPM1 status was available for 8 patients (6 with NK) at the time of relapse. Among them, 7/8 overall (87%) and 5/6 NK (83%) patients had mutated NPM1, while 1/8 overall (12%) and 1/6 NK (16%) patients remained NPM1 wild type. Among the 300 patients (including 91 with NK) with wild type NPM1 at diagnosis, none acquired a mutated NPM1 clone, either at CR or at relapse. We conclude that mutated NPM1 is a stable and reliable prognostic marker in AML and can be used to assess MRD. PMID:24004182

  3. MS-275 and GM-CSF in Treating Patients With Myelodysplastic Syndrome and/or Relapsed or Refractory Acute Myeloid Leukemia or Acute Lymphocytic Leukemia

    ClinicalTrials.gov

    2013-01-08

    Adult Acute Lymphoblastic Leukemia in Remission; 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); Chronic Myelomonocytic Leukemia; de Novo Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Refractory Anemia; Refractory Anemia With Excess Blasts; Refractory Anemia With Ringed Sideroblasts; Refractory Cytopenia With Multilineage Dysplasia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Adult Acute Myeloid Leukemia

  4. Efficacy of lenalidomide in relapsed/refractory chronic lymphocytic leukemia patient: a systematic review and meta-analysis.

    PubMed

    Liang, Liang; Zhao, Ming; Zhu, Yuan-Chao; Hu, Xin; Yang, Li-Ping; Liu, Hui

    2016-09-01

    Therapeutic results of relapsed/refractory chronic lymphocytic leukemia (CLL) are very disappointing at present. Lenalidomide has been proved to be effective for relapsed/refractory CLL as a single agent or in combination with various chemo-immunotherapeutic regimens. However, current clinical experience in its usage is still limited. Because of existing considerable variability in different studies, a systematic review and meta-analysis was conducted to describe overall response rate (ORR) of lenalidomide in patients with relapsed/refractory CLL. Pooled estimate of cumulative prevalence of total ORR was 42.23 % (95 % confidence interval [CI], 32.49-52.61 %), while pooled ORR in regimen with lenalidomide plus anti-CD20 monoclonal antibody (mAbs) and lenalidomide mono-therapy were 60.01 % (95 % CI, 53.86-65.86 %) and 24.38 % (95 % CI, 16.15-35.06 %), respectively. There was no significant difference between L + R (lenalidomide plus rituximab) group and L + O (lenalidomide plus ofatumumab) group, with pooled ORR of 66.38 % (95 % CI, 57.96-73.87 %) and 57.40 % (95 % CI, 46.46-67.65 %), respectively. When co-administrated with anti-CD20 mAbs, dosage of lenalidomide was not the key factor of ORR in combination therapy. Pooled ORR of patient with high-risk cytogenetic in L + anti-CD20 mAbs group was 56.74 % (95 % CI, 45.53-67.30 %). In comparison with patients without high-risk cytogenetic receiving the same treatment regimen, no significant difference was observed, with relative risk (RR) of 0.87 (95 % CI 0.68-1.11). Our finding demonstrated that lenalidomide plus anti-CD20 mAbs could be an efficient therapy regimen for relapsed/refractory CLL patients, especially for those with high-risk cytogenetic factor. PMID:27329288

  5. The Association Between Atopy and Childhood/Adolescent Leukemia: A Meta-Analysis

    PubMed Central

    Linabery, Amy M.; Jurek, Anne M.; Duval, Sue; Ross, Julie A.

    2010-01-01

    Atopic disease is hypothesized to be protective against several malignancies, including childhood/adolescent leukemia. To summarize the available epidemiologic evidence, the authors performed a meta-analysis of associations between atopy/allergies, asthma, eczema, hay fever, and hives and childhood/adolescent leukemia, acute lymphoblastic leukemia (ALL), and acute myeloid leukemia (AML). They searched MEDLINE literature (1952–March 2009) and queried international experts to identify eligible studies. Ten case-control studies were included. Summary odds ratios and 95% confidence intervals were computed via random-effects models. Odds ratios for atopy/allergies were 1.42 (95% confidence interval (CI): 0.60, 3.35) for 3 studies of leukemia overall, 0.69 (95% CI: 0.54, 0.89) for 6 studies of ALL, and 0.87 (95% CI: 0.62, 1.22) for 2 studies of AML, with high levels of heterogeneity detected for leukemia overall and ALL. Inverse associations were observed for ALL and asthma (odds ratio (OR) = 0.79, 95% CI: 0.61, 1.02), eczema (OR = 0.74, 95% CI: 0.58, 0.96), and hay fever (OR = 0.55, 95% CI: 0.46, 0.66) examined separately. Odds ratios for ALL differed by study design, exposure data source, and latency period, indicating that these factors affect study results. These results should be interpreted cautiously given the modest number of studies, substantial heterogeneity, and potential exposure misclassification but are useful in designing future research. PMID:20228139

  6. Childhood leukemia and parental occupation: a register-based case-control study

    SciTech Connect

    Van Steensel-Moll, H.A.; Valkenburg, H.A.; Van Zanen, G.E.

    1985-02-01

    To explore possible etiologic factors of childhood leukemia, a case-control study was performed in the Netherlands. Cases were selected from a complete nationwide register of cases of childhood leukemia which were diagnosed between 1973 and 1980. Controls were matched with cases for year of birth, sex, and place of residence at the time of diagnosis. Information about possible exposure was collected by a postal questionnaire addressed to the parents. This report concerns the results of the analysis of parental occupations and occupational exposures for 519 children with acute lymphocytic leukemia and 507 controls. During pregnancy, more mothers of patients were working in ''hydrocarbon-related'' occupations; relative risk (RR) = 2.5 (95% confidence interval (CI) = 0.7 - 9.4). Likewise, greater occupational exposure to chemicals (paint, petroleum products, and unspecified chemicals) during pregnancy was found for mothers of patients (RR = 2.4, 95% CI = 1.2 - 4.6). The kind of work being performed by the mothers one year before diagnosis did not differ between cases and controls. For the fathers, no relationship was found between a hydrocarbon-related occupation or occupational exposure to chemicals and leukemia in the offspring. Adjustment for birth order, social class, and degree of urbanization did not materially change the relative risks. 16 references, 5 tables.

  7. Reversal of FLT3 mutational status and sustained expression of NPM1 mutation in paired presentation, and relapse samples in a patient with acute myeloid leukemia.

    PubMed

    Radojkovic, Milica; Tosic, Natasa; Colovic, Natasa; Ristic, Slobodan; Pavlovic, Sonja; Colovic, Milica

    2012-01-01

    We report a case of de novo acute myeloid leukemia (AML) with unstable FLT3 gene mutations and stable NPM1 mutation. FLT3/D835 and NPM1 (Type A) mutations were detected upon diagnosis. During the relapse, the FLT3/D835 mutation changed to an FLT3/ITD mutation while the NPM1 (Type A) mutation was retained. Cytogenetic analyses showed the normal karyotype at diagnosis and relapse. Our findings raise interesting questions about the significance of these mutations in the leukemogenic process, about their stability during the evolution of the disease, and regarding the selection of appropriate molecular markers for the monitoring of minimal residual disease. PMID:22585616

  8. Residential Proximity to Agricultural Pesticide Applications and Childhood Acute Lymphoblastic Leukemia

    PubMed Central

    Rull, Rudolph P.; Gunier, Robert; Von Behren, Julie; Hertz, Andrew; Crouse, Vonda; Buffler, Patricia A.; Reynolds, Peggy

    2009-01-01

    Ambient exposure from residential proximity to applications of agricultural pesticides may contribute to the risk of childhood acute lymphoblastic leukemia (ALL). Using residential histories collected from the families of 213 ALL cases and 268 matched controls enrolled in the Northern California Childhood Leukemia Study, the authors assessed residential proximity within a half-mile (804.5 meters) of pesticide applications by linking address histories with reports of agricultural pesticide use. Proximity was ascertained during different time windows of exposure, including the first year of life and the child’s lifetime through the date of diagnosis for cases or reference for controls. Agricultural pesticides were categorized a priori into groups based on similarities in toxicological effects, physicochemical properties, and target pests or uses. The effects of moderate and high exposure for each group of pesticides were estimated using conditional logistic regression. Elevated ALL risk was associated with lifetime moderate exposure, but not high exposure, to certain physicochemical categories of pesticides, including organophosphates, cholorinated phenols, and triazines, and with pesticides classified as insecticides or fumigants. A similar pattern was also observed for several toxicological groups of pesticides. These findings suggest future directions for the identification of specific pesticides that may play a role in the etiology of childhood leukemia. PMID:19700145

  9. Decitabine Followed by Idarubicin and Cytarabine in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndromes

    ClinicalTrials.gov

    2013-10-09

    Adult Acute Megakaryoblastic Leukemia (M7); 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); Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Myeloid Leukemia; Refractory Anemia With Excess Blasts

  10. Outcome of refractory and relapsed acute myeloid leukemia in children treated during 2005–2011 – experience of the Polish Pediatric Leukemia/Lymphoma Study Group (PPLLSG)

    PubMed Central

    Wachowiak, Jacek; Skalska-Sadowska, Jolanta; Wachowiak, Jacek; Zając-Spychała, Olga; Niewiadomska-Wojnałowicz, Izabela; Januszkiewicz-Lewandowska, Danuta; Balwierz, Walentyna; Pawińska-Wąsikowska, Katarzyna; Goździk, Jolanta; Chybicka, Alicja; Potocka, Kinga; Krawczuk-Rybak, Maryna; Muszyńska-Rosłan, Katarzyna; Adamkiewicz-Drożyńska, Elżbieta; Maciejka-Kapuścińska, Lucyna; Karolczyk, Grażyna; Kowalczyk, Jerzy; Wójcik, Beata; Badowska, Wanda; Urasiński, Tomasz; Ociepa, Tomasz; Matysiak, Michał; Sikorska-Fic, Barbara; Szczepański, Tomasz; Tomaszewska, Renata; Sobol, Grażyna; Wieczorek, Maria; Karpińska-Derda, Irena

    2014-01-01

    Aim of the study Recent studies showed relatively better outcome for children with refractory (refAML) and relapsed acute myeloid leukemia (relAML). Treatment of these patients has not been unified within Polish Pediatric Leukemia/Lymphoma Study Group (PPLLSG) so far. The goal of this study is to analyze the results of this therapy performed between 2005–2011. Material and methods The outcome data of 16 patients with refAML and 62 with relAML were analyzed retrospectively. Reinduction was usually based on idarubicine, fludarabine and cytarabine with allogenic hematopoietic stem cell transplant (alloHSCT) in 5 refAML and 30 relAML children. Results Seventy seven percent relAML patients entered second complete remission (CR2). Five-year OS and disease-free survival (DFS) were estimated at 16% and 30%. The outcome for patients after alloHSCT in CR2 (63%) was better than that of those not transplanted (36%) with 5-year OS of 34% vs. 2-year of 7% and 5-year DFS of 40% vs. 12.5%. Second complete remission achievement and alloHSCT were the most significant predictors of better prognosis (p = 0.000 and p = 0.024). The outcome of refAML children was significantly worse than relAML with first remission (CR1) rate of 33%, OS and DFS of 25% at 3 years and 53% at 2 years, respectively. All survivors of refAML were treated with alloHSCT after CR1. Conclusions The uniform reinduction regimen of the documented efficacy and subsequent alloHSCT in remission is needed to improve the outcome for ref/relAML children treated within PPLLSG. The focus should be on the future risk-directed both front and second line AML therapy. PMID:24876821

  11. Temporal changes in water quality at a childhood leukemia cluster

    USGS Publications Warehouse

    Seiler, R.L.

    2004-01-01

    Since 1997, 15 cases of acute lymphocytic leukemia and one case of acute myelocytic leukemia have been diagnosed in children and teenagers who live, or have lived, in an area centered on the town of Fallon, Nevada. The expected rate for the population is about one case every five years. In 2001, 99 domestic and municipal wells and one industrial well were sampled in the Fallon area. Twenty-nine of these wells had been sampled previously in 1989. Statistical comparison of concentrations of major ions and trace elements in those 29 wells between 1989 and 2001 using the nonparametric Wilcoxon signed-rank test indicate water quality did not substantially change over that period; however, short-term changes may have occurred that were not detected. Volatile organic compounds were seldom detected in ground water samples and those that are regulated were consistently found at concentrations less than the maximum contaminant level (MCL). The MCL for gross-alpha radioactivity and arsenic, radon, and uranium concentrations were commonly exceeded, and sometimes were greatly exceeded. Statistical comparisons using the nonparametric Wilcoxon rank-sum test indicate gross-alpha and -beta radioactivity, arsenic, uranium, and radon concentrations in wells used by families having a child with leukemia did not statistically differ from the remainder of the domestic wells sampled during this investigation. Isotopic measurements indicate the uranium was natural and not the result of a 1963 underground nuclear bomb test near Fallon. In arid and semiarid areas where trace-element concentrations can greatly exceed the MCL, household reverse-osmosis units may not reduce their concentrations to safe levels. In parts of the world where radon concentrations are high, water consumed first thing in the morning may be appreciably more radioactive than water consumed a few minutes later after the pressure tank has been emptied because secular equilibrium between radon and its immediate daughter

  12. Temporal changes in water quality at a childhood leukemia cluster.

    PubMed

    Seiler, Ralph L

    2004-01-01

    Since 1997, 15 cases of acute lymphocytic leukemia and one case of acute myelocytic leukemia have been diagnosed in children and teenagers who live, or have lived, in an area centered on the town of Fallon, Nevada. The expected rate for the population is about one case every five years. In 2001, 99 domestic and municipal wells and one industrial well were sampled in the Fallon area. Twenty-nine of these wells had been sampled previously in 1989. Statistical comparison of concentrations of major ions and trace elements in those 29 wells between 1989 and 2001 using the nonparametric Wilcoxon signed-rank test indicate water quality did not substantially change over that period; however, short-term changes may have occurred that were not detected. Volatile organic compounds were seldom detected in ground water samples and those that are regulated were consistently found at concentrations less than the maximum contaminant level (MCL). The MCL for gross-alpha radioactivity and arsenic, radon, and uranium concentrations were commonly exceeded, and sometimes were greatly exceeded. Statistical comparisons using the nonparametric Wilcoxon rank-sum test indicate gross-alpha and -beta radioactivity, arsenic, uranium, and radon concentrations in wells used by families having a child with leukemia did not statistically differ from the remainder of the domestic wells sampled during this investigation. Isotopic measurements indicate the uranium was natural and not the result of a 1963 underground nuclear bomb test near Fallon. In arid and semiarid areas where trace-element concentrations can greatly exceed the MCL, household reverse-osmosis units may not reduce their concentrations to safe levels. In parts of the world where radon concentrations are high, water consumed first thing in the morning may be appreciably more radioactive than water consumed a few minutes later after the pressure tank has been emptied because secular equilibrium between radon and its immediate daughter

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

    ClinicalTrials.gov

    2016-04-07

    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

  14. Genetic markers in a multi-ethnic sample for childhood acute lymphoblastic leukemia risk.

    PubMed

    Kennedy, Amy E; Kamdar, Kala Y; Lupo, Philip J; Okcu, M Fatih; Scheurer, Michael E; Dorak, M Tevfik

    2015-01-01

    Genome-wide association studies have identified multiple risk loci for childhood acute lymphoblastic leukemia (ALL), but mostly in European/White populations, despite Hispanics having a greater risk. We re-examined single nucleotide polymorphisms (SNPs) of known associations with childhood ALL and known human leukocyte antigen (HLA) region lymphoma risk markers in a multi-ethnic population. Significant associations were found in two ARID5B variants (rs7089424 and rs10821936). We replicated a strong risk association in non-Hispanic White males with rs2395185, a protective marker for lymphoma. Another HLA region marker, rs2647012, showed a risk association among Hispanics only, while a strong protective association was found with rs1048456, a follicular lymphoma risk marker. Our study validated this new case-control sample by confirming genetic markers associated with childhood ALL, and yielded new associations with lymphoma markers. Despite positive results, our study did not provide any clues as to why Hispanics have a higher susceptibility to childhood leukemia, suggesting that environmental factors may have a strong contribution. PMID:24707947

  15. Cediranib Maleate in Treating Patients With Relapsed, Refractory, or Untreated Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome

    ClinicalTrials.gov

    2014-09-18

    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); de Novo Myelodysplastic Syndromes; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Untreated Adult Acute Myeloid Leukemia

  16. Childhood Leukemia in the Vicinity of the Geesthacht Nuclear Establishments near Hamburg, Germany

    PubMed Central

    Hoffmann, Wolfgang; Terschueren, Claudia; Richardson, David B.

    2007-01-01

    Background During 1990–1991 a childhood leukemia cluster was observed in the sparsely populated region surrounding two nuclear establishments southeast of Hamburg, Germany. Since then, several new cases have been reported. Recently a possible accidental release of radionuclides in 1986 was hypothesized. Objective The objective of this study was to analyze the childhood leukemia incidence in this area since 1990. Methods All incident cases (< 15 years of age) were ascertained during 1990–2005 within a 5-km radius of the Krümmel nuclear power plant. We derived standardized incidence ratios (SIRs) using county and national leukemia incidence rates as referents. We stratified analyses by calendar period and attained age, and by subdividing the study region into areas north versus south of the Elbe river. Results Fourteen cases were ascertained in the study area, whereas 4.0 were expected based on national referent rates [1990–2005: SIR = 3.5; 95% confidence interval (CI), 1.9–5.9]. The excess was not confined to the early 1990s; for the more recent time period 1999–2005, the SIR is still elevated (SIR = 2.7; 95% CI, 0.9–6.2). SIRs of greatest magnitude were observed for children 0–4 years of age (SIR = 4.9; 95% CI, 2.4–9.0) and for residents south of the Elbe (SIR = 7.5; 95% CI, 2.8–16.4). Conclusions The incidence in this region is significantly higher than the childhood leukemia incidence for Germany as a whole. To date, no unique hazards have been identified in this population. The fact that the elevated rates have persisted in this community for > 15 years warrants further investigation. PMID:17589605

  17. Residential Exposure to Polychlorinated Biphenyls and Organochlorine Pesticides and Risk of Childhood Leukemia

    PubMed Central

    Ward, Mary H.; Colt, Joanne S.; Metayer, Catherine; Gunier, Robert B.; Lubin, Jay; Crouse, Vonda; Nishioka, Marcia G.; Reynolds, Peggy; Buffler, Patricia A.

    2009-01-01

    Background Incidence of childhood leukemia in industrialized countries rose significantly during 1975–2004, and the reasons for the increase are not understood. Objectives We used carpet dust as an exposure indicator to examine the risk of childhood leukemia in relation to residential exposure to persistent organochlorine chemicals: six polychlorinated biphenyl (PCB) congeners and the pesticides α- and γ-chlordane, p,p′-DDT (dichlorodiphenyltrichloroethane), p,p′-DDE (dichlorodiphenyldichloroethylene), methoxychlor, and pentachlorophenol. Methods We conducted a population-based case–control study in 35 counties in northern and central California in 2001–2006. The study included 184 acute lymphocytic leukemia (ALL) cases 0–7 years of age and 212 birth certificate controls matched to cases by birth date, sex, race, and Hispanic ethnicity. We collected carpet dust samples from the room where the child spent the most time before diagnosis (similar date for controls) using a specialized vacuum. Results Detection of any PCB congener in the dust conferred a 2-fold increased risk of ALL [odds ratio (OR) = 1.97; 95% confidence interval (CI), 1.22–3.17]. Compared with those in the lowest quartile of total PCBs, the highest quartile was associated with about a 3-fold risk (OR = 2.78; 95% CI, 1.41–5.48), and the positive trend was significant (p = 0.017). Significant positive trends in ALL risk were apparent with increasing concentrations of PCB congeners 118, 138, and 153. We observed no significant positive associations for chlordane, DDT, DDE, methoxychlor, or pentachlorophenol. The associations with PCBs were stronger among non-Hispanic whites than among Hispanics despite similar distributions of PCB levels among controls in each racial/ethnic group. Conclusions Our findings suggest that PCBs, which are considered probable human carcinogens and cause perturbations of the immune system, may represent a previously unrecognized risk factor for childhood

  18. Protective effect of cytomegalovirus reactivation on relapse after allogeneic hematopoietic cell transplantation in acute myeloid leukemia patients is influenced by conditioning regimen.

    PubMed

    Manjappa, Shivaprasad; Bhamidipati, Pavan Kumar; Stokerl-Goldstein, Keith E; DiPersio, John F; Uy, Geoffrey L; Westervelt, Peter; Liu, Jingxia; Schroeder, Mark A; Vij, Ravi; Abboud, Camille N; Fehniger, Todd A; Cashen, Amanda F; Pusic, Iskra; Jacoby, Meagan; Meera, Srinidhi J; Romee, Rizwan

    2014-01-01

    Cytomegalovirus (CMV) reactivation after allogeneic hematopoietic cell transplant (allo-HCT) has been associated with a reduced risk of relapse in patients with acute myeloid leukemia (AML). However, the influence of the conditioning regimen on this protective effect of CMV reactivation after allo-HCT is relatively unexplored. To address this, we evaluated the risk of relapse in 264 AML patients who received T cell-replete, 6/6 HLA matched sibling or 10/10 HLA matched unrelated donor transplantation at a single institution between 2006 and 2011. Of these 264 patients, 206 received myeloablative (MA) and 58 received reduced-intensity conditioning (RIC) regimens. CMV reactivation was observed in 88 patients with MA conditioning and 37 patients with RIC. At a median follow-up of 299 days, CMV reactivation was associated with significantly lower risk of relapse in patients who received MA conditioning both in univariate (P = .01) and multivariate analyses (hazard ratio, .5246; P = .006); however, CMV reactivation did not significantly affect the risk of relapse in our RIC cohort. These results confirm the protective effect of CMV reactivation on relapse in AML patients after allo-HCT reported by previous studies but suggest this protective effect of CMV reactivation on relapse is influenced by the conditioning regimen used with the transplant. PMID:24120526

  19. Population-based case-control study of childhood leukemia in Shanghai

    SciTech Connect

    Shu, X.O.; Gao, Y.T.; Brinton, L.A.; Linet, M.S.; Tu, J.T.; Zheng, W.; Fraumeni, J.F. Jr.

    1988-08-01

    A population-based case-control interview study of 309 childhood leukemia cases and 618 healthy population control children was conducted in urban Shanghai, China. Like some studies in other countries, excess risks for both acute lymphocytic leukemia (ALL) and acute nonlymphocytic leukemia (ANLL) were associated with intrauterine and paternal preconception diagnostic x-ray exposure, and with maternal employment in the chemical and agricultural industries during pregnancy. ANLL was linked to maternal occupational exposure to benzene during pregnancy, whereas both ALL and ANLL were significantly associated with maternal exposure to gasoline and the patient's prior use of chloramphenicol. New findings, previously unsuspected, included an association of ANLL with younger maternal age at menarche (odds ratio (OR) = 4.3; 95% confidence interval (CI) = 1.3-13.9); a protective effect for long-term (greater than 1 year) use of cod liver oil containing vitamins A and D for both ALL (OR = 0.4; 95% CI = 0.2-0.9) and ANLL (OR = 0.3; 95% CI = 0.1-1.0); and excess risks of ANLL among children whose mothers were employed in metal refining and processing (OR = 4.6; 95% CI = 1.3-17.2) and of ALL associated with maternal occupational exposure to pesticides (OR = 3.5; 95% CI = 1.1-11.2). No relationships were found with late maternal age, certain congenital disorders, or familial occurrence, which have been related to childhood leukemia in other studies. In contrast with other reports, an excess of leukemia, primarily ANLL, occurred among second or later-born rather than firstborn children.

  20. High concordance of subtypes of childhood acute lymphoblastic leukemia within families: lessons from sibships with multiple cases of leukemia.

    PubMed

    Schmiegelow, K; Lausten Thomsen, U; Baruchel, A; Pacheco, C E; Pieters, Rob; Pombo-de-Oliveira, M S; Andersen, E W; Rostgaard, K; Hjalgrim, H; Pui, C-H

    2012-04-01

    Polymorphic genes have been linked to the risk of acute lymphoblastic leukemia (ALL). Surrogate markers for a low burden of early childhood infections are also related to increased risk for developing childhood ALL. It remains uncertain, whether siblings of children with ALL have an increased risk of developing ALL. This international collaboration identified 54 sibships with two (N = 51) or more (N = 3) cases of childhood ALL (ages <18 years). The 5-year event-free survival for 61 patients diagnosed after 1 January 1990 was 0.83 ± 0.05. Ages at diagnosis (Spearman correlation coefficient, r(S) = 0.41, P = 0.002) were significantly correlated, but not WBCs (r(S) = 0.23, P = 0.11). In 18 sibships with successful karyotyping in both cases, six were concordant for high-hyperdiploidy (N = 3), t(12;21) [ETV6/RUNX1] (N = 1), MLL rearrangement (N = 1) or t(1;19)(q23/p13) (N = 1). Eleven sibships were ALL-subtype concordant, being T-cell ALL (T-ALL) (N = 5, of a total of six sibships, where the first-born had T-ALL) or B-lineage ALL belonging to the same cytogenetic subset (N = 6), a finding that differs significantly from the expected chance distribution (κ: 0.58; P < 0.0001). These data indicate strong genetic and/or environmental risk factors for childhood ALL that are restricted to specific ALL subtypes, which must be taken into account, when performing epidemiological studies to reveal etiological factors. PMID:22005784

  1. [The efficacy of sorafenib to prevent relapse in patients with FLT3-ITD mutation positive acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation].

    PubMed

    Zu, Y L; Zhang, Y L; Zhou, J; Han, L J; Zhao, H F; Gui, R R; Hou, Y J; Song, Y P

    2016-08-01

    To study the efficacy of sorafenib to prevent relapse in patients with FLT3-ITD mutation positive acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). A total of 7 cases with FLT3-ITD positive AML have received allo-HSCT in our department from May 2013 to January 2015. Six cases were administrated with sorafenib after hematopoietic reconstruction. Another patient relapsed on day 192 past allo-HSCT, then she started to use sorafenib after remission of re-induction regimens. Five patients survived. The median progression free survival was 280(126-366)day. This study suggests that sorafenib might prevent relapse past allo-HSCT and improve survival in patients with FLT3-ITD positive AML. PMID:27480560

  2. Prolonged Response in Patient With Multiply Relapsed B-cell Acute Lymphoblastic Leukemia and Monosomy-7 to Bortezomib, Lenalidomide, and Dexamethasone.

    PubMed

    Vundamati, Divya; Bostrom, Bruce

    2016-08-01

    Isolated monosomy-7, a rare cytogenetic abnormality in patients with pediatric acute lymphoblastic leukemia (ALL), portends a worse prognosis. Despite improvements in treatment, outcomes for patients with relapsed ALL remain poor. Novel treatments adopted from the B-cell malignancy multiple myeloma may have a role in treatment of ALL. Bortezomib is one such agent currently in phase III trials for B and T ALL. This study presents a patient with B-cell ALL and monosomy-7 who relapsed off therapy. The combination of bortezomib, lenalidomide, and dexamethasone was used to attain remission before bone marrow transplant after conventional relapse therapy failed. A recurrence after bone marrow transplant was controlled for a prolonged period with the same therapy. The case supports the hypothesis that bortezomib, lenalidomide, and dexamethasone should be further explored in the treatment of B-cell ALL with monosomy-7. PMID:27299598

  3. Efficacy and safety of intrathecal liposomal cytarabine for the treatment of meningeal relapse in acute lymphoblastic leukemia: experience of two pediatric institutions.

    PubMed

    Parasole, Rosanna; Menna, Giuseppe; Marra, Nicoletta; Petruzziello, Fara; Locatelli, Franco; Mangione, Argia; Misuraca, Aldo; Buffardi, Salvatore; Di Cesare-Merlone, Alessandra; Poggi, Vincenzo

    2008-08-01

    The treatment of meningeal relapse in acute lymphoblastic leukemia (ALL) remains a challenging clinical problem. Liposomal cytarabine (DepoCyte) permits to decrease frequency of lumbar punctures, without loss of efficacy, because intrathecal levels of the drug remain cytotoxic for up to 14 days. We investigated the efficacy and safety of intrathecal DepoCyte in six children with meningeal relapse, treated in two pediatric institutions. DepoCyte was well tolerated in all patients, who achieved complete clearance of blasts from the cerebrospinal fluid after the first three intrathecal drug administrations. Five of the six patients were concurrently treated with high-dose administration of systemic cytarabine, without additional neurological side effects. Our results suggest that DepoCyte is a valid option for children with ALL experiencing meningeal relapse; it deserves further investigation in intensive treatment regimens, taking into due consideration potential neurotoxicity. PMID:18766969

  4. Associations between genetic variants in folate and drug metabolizing pathways and relapse risk in pediatric acute lymphoid leukemia on CCG-1952

    PubMed Central

    Vujkovic, Marijana; Kershenbaum, Aaron; Wray, Lisa; McWilliams, Thomas; Cannon, Shannon; Devidas, Meenakshi; Stork, Linda; Aplenc, Richard

    2015-01-01

    Genetic variation in drug detoxification pathways may influence outcomes in pediatric acute lymphoblastic leukemia (ALL). We evaluated relapse risk and 24 variants in 17 genes in 714 patients in CCG-1961. Three TPMT and 1 MTR variant were associated with increased risks of relapse (rs4712327, OR 3.3, 95%CI 1.2–8.6; rs2842947, OR 2.7, 95%CI 1.1–6.8; rs2842935, OR 2.5, 95%CI 1.1–5.0; rs10925235, OR 4.9, 95%CI 1.1–25.1). One variant in SLC19A1 showed a protective effect (rs4819128, OR 0.5, 95%CI 0.3–0.9). Our study provides data that relapse risk in pediatric ALL is associated with germline variations in TPMT, MTR and SLC19A1. PMID:26605150

  5. Quantification of subclonal distributions of recurrent genomic aberrations in paired pre-treatment and relapse samples from patients with B-cell chronic lymphocytic leukemia

    PubMed Central

    Knight, S J L; Yau, C; Clifford, R; Timbs, A T; Sadighi Akha, E; Dréau, H M; Burns, A; Ciria, C; Oscier, D G; Pettitt, A R; Dutton, S; Holmes, C C; Taylor, J; Cazier, J-B; Schuh, A

    2012-01-01

    Genome-wide array approaches and sequencing analyses are powerful tools for identifying genetic aberrations in cancers, including leukemias and lymphomas. However, the clinical and biological significance of such aberrations and their subclonal distribution are poorly understood. Here, we present the first genome-wide array based study of pre-treatment and relapse samples from patients with B-cell chronic lymphocytic leukemia (B-CLL) that uses the computational statistical tool OncoSNP. We show that quantification of the proportion of copy number alterations (CNAs) and copy neutral loss of heterozygosity regions (cnLOHs) in each sample is feasible. Furthermore, we (i) reveal complex changes in the subclonal architecture of paired samples at relapse compared with pre-treatment, (ii) provide evidence supporting an association between increased genomic complexity and poor clinical outcome (iii) report previously undefined, recurrent CNA/cnLOH regions that expand or newly occur at relapse and therefore might harbor candidate driver genes of relapse and/or chemotherapy resistance. Our findings are likely to impact on future therapeutic strategies aimed towards selecting effective and individually tailored targeted therapies. PMID:22258401

  6. Cranial radiation in childhood acute lymphocytic leukemia. Neuropsychologic sequelae

    SciTech Connect

    Whitt, J.K.; Wells, R.J.; Lauria, M.M.; Wilhelm, C.L.; McMillan, C.W.

    1984-08-01

    A battery of neuropsychologic tests was administered ''blindly'' to 18 children with acute lymphocytic leukemia (ALL) who had been randomly assigned to treatment regimens with or without cranial radiation. These children were all in complete continuous remission for more than 3 1/2 years and were no longer receiving therapy. The results indicated no substantial differences between groups as a function of radiation therapy. However, decreased neuropsychologic performance was found when the entire sample was compared with population norms. These data do not support the hypothesis that cranial radiation therapy is responsible for the neuropsychologic sequelae seen in these survivors of ALL. Post hoc multiple regression analysis indicated that parental education levels accounted for more of the neuropsychologic variability seen in these children than other factors such as age at diagnosis, type of therapy, or sex of child.

  7. Patient, physician, and general population preferences for treatment characteristics in relapsed or refractory chronic lymphocytic leukemia: A conjoint analysis.

    PubMed

    Landfeldt, Erik; Eriksson, Jennifer; Ireland, Steve; Musingarimi, Patience; Jackson, Claire; Tweats, Emma; Gaudig, Maren

    2016-01-01

    Due to the disease heterogeneity, treatments for chronic lymphocytic leukemia (CLL) have differed with respect to efficacy and toxicity. Limited options have also been available regarding modalities of administration. Our study objective was to estimate preferences for treatment characteristics (or "attributes") in relapsed/refractory (r/r) CLL. Patients, physicians (hematologists/oncologists), and members from the general population from Germany and Sweden completed a conjoint analysis comprising six CLL treatment attributes: (i) overall survival (OS), (ii) progression-free survival (PFS), (iii) fatigue, (iv) nausea, (v) risk of serious infections, and (vi) treatment administration (each described in three levels). We estimated the relative importance of each attribute by fitting a hierarchical Bayesian model. A total of 190 German and 121 Swedish individuals participated. In the pooled sample, OS was the most important attribute (36%), followed by risk of serious infection (21%), treatment administration (13%), fatigue (12%), PFS (11%), and nausea (7%). Treatment administration was more important to patients (all p<0.004), OS was more important to physicians (all p<0.001), and risk of serious infections was more important to the general population than to physicians (p<0.001). Our results could be helpful to align therapeutic decision-making in r/r CLL with patient preferences to improve care satisfaction and treatment compliance. PMID:26654707

  8. Final results of a multicenter phase 1 study of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia.

    PubMed

    Wendtner, Clemens-Martin; Hillmen, Peter; Mahadevan, Daruka; Bühler, Andreas; Uharek, Lutz; Coutré, Steven; Frankfurt, Olga; Bloor, Adrian; Bosch, Francesc; Furman, Richard R; Kimby, Eva; Gribben, John G; Gobbi, Marco; Dreisbach, Luke; Hurd, David D; Sekeres, Mikkael A; Ferrajoli, Alessandra; Shah, Sheetal; Zhang, Jennie; Moutouh-de Parseval, Laure; Hallek, Michael; Heerema, Nyla A; Stilgenbauer, Stephan; Chanan-Khan, Asher A

    2012-03-01

    Based on clinical activity in phase 2 studies, lenalidomide was evaluated in a phase 2/3 study in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). Following tumor lysis syndrome (TLS) complications, the protocol was amended to a phase 1 study to identify the maximum tolerated dose-escalation level (MTDEL). Fifty-two heavily pretreated patients, 69% with bulky disease and 48% with high-risk genomic abnormalities, initiated lenalidomide at 2.5 mg/day, with dose escalation until the MTDEL or the maximum assigned dose was attained. Lenalidomide was safely titrated to 20 mg/day; the MTDEL was not reached. Most common grade 3-4 adverse events were neutropenia and thrombocytopenia; TLS was mild and rare. The low starting dose and conservative dose escalation strategy resulted in six partial responders and 30 patients obtaining stable disease. In summary, lenalidomide 2.5 mg/day is a safe starting dose that can be titrated up to 20 mg/day in patients with CLL. PMID:21879809

  9. High incidence of obesity in young adults after treatment of acute lymphoblastic leukemia in childhood.

    PubMed

    Didi, M; Didcock, E; Davies, H A; Ogilvy-Stuart, A L; Wales, J K; Shalet, S M

    1995-07-01

    To determine whether obesity complicated the treatment of childhood acute lymphoblastic leukemia, we studied the body mass index (BMI) of 63 female when and 51 male patients from the time of diagnosis of acute lymphoblastic leukemia to the time when final height was attained. The BMI z score was calculated for each patient at diagnosis, at end of treatment, and at attainment of final height. Obesity at attainment of final height was defined as a BMI greater than the 85th percentile of the normal reference population. At final height 23 of 51 male (45%) and 30 of 63 female patients (47%) were obese. Girls became obese between diagnosis and the end of chemotherapy (p = 0.02), after which they had no further increase, indicating that chemotherapy may have played a role in their obesity. Boys had a progressive and gradual increase in BMI z score through to attainment of final height. Obesity did not appear to be associated with growth hormone insufficiency, disproportionate growth, or abnormal timing of puberty. We conclude that approximately half the survivors of leukemia in childhood become obese young adults. Many of those treated with the more recent regimens studied are still only in their mid or preteen years and should be advised regarding a more active lifestyle and a healthy diet in an attempt to reduce the incidence of obesity. PMID:7608813

  10. HLA-A11 is associated with poor prognosis in childhood acute lymphoblastic leukemia (ALL).

    PubMed

    Orgad, S; Cohen, I J; Neumann, Y; Vogel, R; Kende, G; Ramot, B; Zaizov, R; Gazit, E

    1988-12-01

    A possible association between HLA antigens, susceptibility or resistance to leukemia, and responsiveness to treatment has been studied in 144 patients with childhood acute lymphoblastic leukemia (ALL) and compared to other prognostic factors, i.e. white blood cell (WBC) counts, age at onset, sex, ethnic origin, and cell surface markers. All sequentially newly diagnosed children (97) comprised the group for the prospective study (PSG) and were followed for 6 years. The group included 37 patients classified as T-ALL, 41 as CALLA+, 27 as NULL, 12 as B and pre-B, and 27 unclassified patients, who were diagnosed before 1980. During the follow-up period, 45 patients of the PSG died. Forty-seven patients designated long-term survivors (LTS) have been followed 6-20 years after diagnosis, having completed a 3-5 year course of anti-leukemia therapy, and having remained disease free thereafter. High WBC counts at diagnosis and T-cell-surface markers were associated with poor prognosis, as were enthnic origin and specific HLA antigens. Thus, there was one (1) a significant increase in HLA-A30 and a decrease in HLA B-14 in the PSG Jewish patients; and (2) a complete absence of HLA-ALL in LTS while, in the PSG, 8 of 9 HLA-All-positive patients died during the follow-up period. This suggests that HLA-All is associated with poor prognosis in childhood ALL. PMID:3199882

  11. 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

  12. Exposure to residential electric and magnetic fields and risk of childhood leukemia

    SciTech Connect

    Peters, J.M.; Thomas, D.C.; Bowman, J.D.; Sobel, E.; London, S.J.; Cheng, T.C.

    1991-11-01

    This study was conducted on 232 cases of childhood leukemia occurring in children age 10 and under between 1980 and 1987 in Los Angeles County. Two hundred thirty-two controls were selected from the same geographic area and were matched on sex, age and race. The parents of the 464 subjects were interviewed by telephone to elicit information on medical histories of the parents and child, residential histories of the subjects, occupational histories of both parents, environmental chemical histories, personal histories including drug use and smoking habits, and time and space occupancy of subjects, including exposures to electrical appliances. An extensive assessment of exposure to electric and magnetic fields was made by determining wiring configurations of most subjects (90%), by measuring electric and magnetic fields in various areas of the inside and outside of the home, and by measuring magnetic fields for 24 to 72 hours in the child`s sleeping area (66%). We conclude that our data offer no support for a relationship between measured electric field exposure and leukemia risk, little support for the relationship between measured magnetic field exposure and leukemia risk, considerable support for a relationship between wiring configuration and leukemia risk, and considerable support for a relationship between children`s electrical appliance use and leukemia risk. The reason(s) why wiring configuration correlates with leukemia risk better than measured exposure are not clear. It is also not clear whether short-term, very high exposure of children to magnetic (or electric) fields from electric appliances are responsible for the observed risk or whether associated exposures or recall biases are responsible. These latter two issues deserve continued research. 41 refs., 31 tabs.

  13. Exposure to residential electric and magnetic fields and risk of childhood leukemia

    SciTech Connect

    Peters, J.M.; Thomas, D.C.; Bowman, J.D.; Sobel, E.; London, S.J.; Cheng, T.C. )

    1991-11-01

    This study was conducted on 232 cases of childhood leukemia occurring in children age 10 and under between 1980 and 1987 in Los Angeles County. Two hundred thirty-two controls were selected from the same geographic area and were matched on sex, age and race. The parents of the 464 subjects were interviewed by telephone to elicit information on medical histories of the parents and child, residential histories of the subjects, occupational histories of both parents, environmental chemical histories, personal histories including drug use and smoking habits, and time and space occupancy of subjects, including exposures to electrical appliances. An extensive assessment of exposure to electric and magnetic fields was made by determining wiring configurations of most subjects (90%), by measuring electric and magnetic fields in various areas of the inside and outside of the home, and by measuring magnetic fields for 24 to 72 hours in the child's sleeping area (66%). We conclude that our data offer no support for a relationship between measured electric field exposure and leukemia risk, little support for the relationship between measured magnetic field exposure and leukemia risk, considerable support for a relationship between wiring configuration and leukemia risk, and considerable support for a relationship between children's electrical appliance use and leukemia risk. The reason(s) why wiring configuration correlates with leukemia risk better than measured exposure are not clear. It is also not clear whether short-term, very high exposure of children to magnetic (or electric) fields from electric appliances are responsible for the observed risk or whether associated exposures or recall biases are responsible. These latter two issues deserve continued research. 41 refs., 31 tabs.

  14. Azacitidine in Combination With Mitoxantrone, Etoposide Phosphate, and Cytarabine in Treating Patients With Relapsed and Refractory Acute Myeloid Leukemia

    ClinicalTrials.gov

    2016-08-23

    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); RUNX1-RUNX1T1; Adult Acute Myeloid Leukemia With t(9;11)(p22;q23); MLLT3-MLL; Adult Acute Promyelocytic Leukemia With t(15;17)(q22;q12); PML-RARA; Alkylating Agent-Related Acute Myeloid Leukemia; Recurrent Adult Acute Myeloid Leukemia

  15. Socioeconomic status, area remoteness, and survival from childhood leukemia: results from the Nationwide Registry for Childhood Hematological Malignancies in Greece.

    PubMed

    Sergentanis, Theodoros; Dessypris, Nick; Kanavidis, Prodromos; Skalkidis, Ilias; Baka, Margarita; Polychronopoulou, Sophia; Athanassiadou, Fani; Stiakaki, Eftichia; Frangandrea, Ioanna; Moschovi, Maria; Petridou, Eleni T

    2013-09-01

    The aim of the present nationwide Greek study is to assess whether survival from acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) is modified by socioeconomic status (SES) and area remoteness. Detailed precoded information derived from a personal interview conducted by specially trained health personnel with the child guardians was available for 883 ALL and 111 AML incident childhood cases registered in the Nationwide Registry for Childhood Hematological Malignancies during the period 1996-2010. Parental socioprofessional category was recorded on the basis of ISCO68 and ISCO88 codes; the exact traveling distance between residence and the treating hospital was ad hoc calculated. Multivariate Cox's proportional hazards models were applied to examine the mutually adjusted associations between survival and potential predictors. Children from a lower parental socioprofessional category experienced 40% worse survival (P=0.02) independent of age, sex, and ALL subtype, whereas those whose parents were married had better outcomes (rate ratio: 0.47, P=0.01). Urbanization of residence at diagnosis or 'residence to treating hospital' distance was not nominally associated with survival from ALL. By contrast, no noteworthy associations implicating SES were found for AML survival, probably because of the burden of the disease and small numbers. Lower SES indicators and a single-parenthood family milieu seem to be independently associated with unfavorable outcomes from childhood ALL. Area remoteness might not be a significant outcome predictor during recent years, following considerable improvements in the motorway infrastructures and care delivery patterns. This study may provide a valuable snapshot capturing the impact of socioeconomic covariates before the burst of the Greek financial crisis. PMID:23238585

  16. Paternal Smoking and Risk of Childhood Acute Lymphoblastic Leukemia: Systematic Review and Meta-Analysis

    PubMed Central

    Liu, Ruiling; Zhang, Luoping; McHale, Cliona M.; Hammond, S. Katharine

    2011-01-01

    Objective. To investigate the association between paternal smoking and childhood acute lymphoblastic leukemia (ALL). Method. We identified 18 published epidemiologic studies that reported data on both paternal smoking and childhood ALL risk. We performed a meta-analysis and analyzed dose-response relationships on ALL risk for smoking during preconception, during pregnancy, after birth, and ever smoking. Results. The summary odds ratio (OR) of childhood ALL associated with paternal smoking was 1.11 (95% Confidence Interval (CI): 1.05–1.18, I2 = 18%) during any time period, 1.25 (95% CI: 1.08–1.46, I2 = 53%) preconception; 1.24 (95% CI: 1.07–1.43, I2 = 54%) during pregnancy, and 1.24 (95% CI: 0.96–1.60, I2 = 64%) after birth, with a dose-response relationship between childhood ALL and paternal smoking preconception or after birth. Conclusion. The evidence supports a positive association between childhood ALL and paternal ever smoking and at each exposure time period examined. Future epidemiologic studies should assess paternal smoking during well-defined exposure windows and should include biomarkers to assess smoking exposure and toxicological mechanisms. PMID:21765828

  17. Brain sarcoma of meningeal origin after cranial irradiation in childhood acute lymphocytic leukemia. Case report

    SciTech Connect

    Tiberin, P.; Maor, E.; Zaizov, R.; Cohen, I.J.; Hirsch, M.; Yosefovich, T.; Ronen, J.; Goldstein, J.

    1984-10-01

    The authors report their experience with an unusual case of intracerebral sarcoma of meningeal cell origin in an 8 1/2-year-old girl. This tumor occurred 6 1/2 years after cranial irradiation at relatively low dosage (2200 rads) had been delivered to the head in the course of a multimodality treatment for acute lymphocytic leukemia. The tumor recurred approximately 10 months after the first surgical intervention. Macroscopic total excision of the recurrent growth followed by whole-brain irradiation (4500 rads) failed to eradicate it completely and local recurrence prompted reoperation 18 months later. This complication of treatment in long-term childhood leukemia survivors is briefly discussed, as well as the pathology of meningeal sarcomas.

  18. Childhood leukemia and cancers near German nuclear reactors: significance, context, and ramifications of recent studies.

    PubMed

    Nussbaum, Rudi H

    2009-01-01

    A government-sponsored study of childhood cancer in the proximity of German nuclear power plants (German acronym KiKK) found that children < 5 years living < 5 km from plant exhaust stacks had twice the risk for contracting leukemia as those residing > 5 km. The researchers concluded that since "this result was not to be expected under current radiation-epidemiological knowledge" and confounders could not be identified, the observed association of leukemia incidence with residential proximity to nuclear plants "remains unexplained." This unjustified conclusion illustrates the dissonance between evidence and assumptions. There exist serious flaws and gaps in the knowledge on which accepted models for population exposure and radiation risk are based. Studies with results contradictory to those of KiKK lack statistical power to invalidate its findings. The KiKK study's ramifications add to the urgency for a public policy debate regarding the health impact of nuclear power generation. PMID:19650588

  19. Minimal residual disease quantification using consensus primers and high-throughput IGH sequencing predicts post-transplant relapse in chronic lymphocytic leukemia

    PubMed Central

    Logan, A C; Zhang, B; Narasimhan, B; Carlton, V; Zheng, J; Moorhead, M; Krampf, M R; Jones, C D; Waqar, A N; Faham, M; Zehnder, J L; Miklos, D B

    2013-01-01

    Quantification of minimal residual disease (MRD) following allogeneic hematopoietic cell transplantation (allo-HCT) predicts post-transplant relapse in patients with chronic lymphocytic leukemia (CLL). We utilized an MRD-quantification method that amplifies immunoglobulin heavy chain (IGH) loci using consensus V and J segment primers followed by high-throughput sequencing (HTS), enabling quantification with a detection limit of one CLL cell per million mononuclear cells. Using this IGH–HTS approach, we analyzed MRD patterns in over 400 samples from 40 CLL patients who underwent reduced-intensity allo-HCT. Nine patients relapsed within 12 months post-HCT. Of the 31 patients in remission at 12 months post-HCT, disease-free survival was 86% in patients with MRD <10−4 and 20% in those with MRD ⩾10−4 (relapse hazard ratio (HR) 9.0; 95% confidence interval (CI) 2.5–32; P<0.0001), with median follow-up of 36 months. Additionally, MRD predicted relapse at other time points, including 9, 18 and 24 months post-HCT. MRD doubling time <12 months with disease burden ⩾10−5 was associated with relapse within 12 months of MRD assessment in 50% of patients, and within 24 months in 90% of patients. This IGH–HTS method may facilitate routine MRD quantification in clinical trials. PMID:23419792

  20. CD56dimCD57+NKG2C+ NK cell expansion is associated with reduced leukemia relapse after reduced intensity HCT.

    PubMed

    Cichocki, F; Cooley, S; Davis, Z; DeFor, T E; Schlums, H; Zhang, B; Brunstein, C G; Blazar, B R; Wagner, J; Diamond, D J; Verneris, M R; Bryceson, Y T; Weisdorf, D J; Miller, J S

    2016-02-01

    We have recently described a specialized subset of human natural killer (NK) cells with a CD56(dim)CD57(+)NKG2C(+) phenotype that expand specifically in response to cytomegalovirus (CMV) reactivation in hematopoietic cell transplant (HCT) recipients and exhibit properties characteristic of adaptive immunity. We hypothesize that these cells mediate relapse protection and improve post-HCT outcomes. In 674 allogeneic HCT recipients, we found that those who reactivated CMV had lower leukemia relapse (26% (17-35%), P=0.05) and superior disease-free survival (DFS) (55% (45-65%) P=0.04) 1 year after reduced intensity conditioning (RIC) compared with CMV seronegative recipients who experienced higher relapse rates (35% (27-43%)) and lower DFS (46% (38-54%)). This protective effect was independent of age and graft-vs-host disease and was not observed in recipients who received myeloablative regimens. Analysis of the reconstituting NK cells demonstrated that CMV reactivation is associated with both higher frequencies and greater absolute numbers of CD56(dim)CD57(+)NKG2C(+) NK cells, particularly after RIC HCT. Furthermore, expansion of these cells at 6 months posttransplant independently trended toward a lower 2-year relapse risk. Together, our data suggest that the protective effect of CMV reactivation on posttransplant relapse is in part driven by adaptive NK cell responses. PMID:26416461

  1. Lineage switch with t(6;11)(q27;q23) from T-cell lymphoblastic lymphoma to acute monoblastic leukemia at relapse.

    PubMed

    Higuchi, Yusuke; Tokunaga, Kenji; Watanabe, Yuko; Kawakita, Toshiro; Harada, Naoko; Yamaguchi, Shunichiro; Nosaka, Kisato; Mitsuya, Hiroaki; Asou, Norio

    2016-06-01

    We present a patient with T-cell lymphoblastic lymphoma (T-LBL) harboring t(6;11)(q27;q23) that converted to acute monoblastic leukemia at relapse. A 27-year-old man developed T-LBL with a mediastinal mass. He exhibited several recurrences in the central nervous system and marrow. A fifth relapse occurred in the marrow, with 42.8% blasts with CD4, CD5, CD7, CD10, CD33, CD34, HLA-DR and cytoplasmic (cy) CD3. While achieving complete remission with nelarabine, sixth relapse occurred in the marrow with 6.8% blasts, which had characteristics of monoblastic features, 2 months later. Marrow blasts were positive for myeloperoxidase, CD4, CD33, CD56, CD64, and HLA-DR, but were negative for cyCD3, CD5, CD7, CD10, and CD34. Marrow cells at both the 5th lymphoid and 6th myeloid relapses had t(6;11)(q27;q23) and the same MLL-MLLT4 fusion transcript. In addition, the MLL-MLLT4 fusion sequences documented in the initial mediastinal cells were the same as seen in peripheral blood cells at the 6th relapse. The patient continues 7th remission after one course of gemtuzumab ozogamicin therapy followed by cord blood transplantation for more than 3 years. Sequential phenotypic and cytogenetic studies may yield valuable insights into the mechanism of leukemic recurrence and possible implications for treatment selection. PMID:27268298

  2. CD56dimCD57+NKG2C+ NK cell expansion is associated with reduced leukemia relapse after reduced intensity HCT

    PubMed Central

    Cichocki, Frank; Cooley, Sarah; Davis, Zachary; DeFor, Todd E.; Schlums, Heinrich; Zhang, Bin; Brunstein, Claudio G.; Blazar, Bruce R.; Wagner, John; Diamond, Don J.; Verneris, Michael R.; Bryceson, Yenan T.; Weisdorf, Daniel J.; Miller, Jeffrey S.

    2015-01-01

    We have recently described a specialized subset of human natural killer (NK) cells with a CD56dimCD57+NKG2C+ phenotype that expand specifically in response to cytomegalovirus (CMV) reactivation in hematopoietic cell transplant (HCT) recipients and exhibit properties characteristic of adaptive immunity. We hypothesize that these cells mediate relapse protection and improve post-HCT outcomes. In 674 allogeneic HCT recipients, we found that those who reactivated CMV had lower leukemia relapse (26% [17–35%], p=0.05) and superior disease-free survival (DFS) (55% [45–65%] p=0.04) 1 year after reduced intensity conditioning (RIC) compared to CMV seronegative recipients who experienced higher relapse rates (35% [27–43%]) and lower DFS (46% [38–54%]). This protective effect was independent of age and graft-versus-host disease (GvHD) and was not observed in recipients who received myeloablative (MA) regimens. Analysis of the reconstituting NK cells demonstrated that CMV reactivation is associated with both higher frequencies and greater absolute numbers of CD56dimCD57+NKG2C+ NK cells, particularly after RIC HCT. Furthermore, expansion of these cells at 6 months post-transplant independently trended toward a lower 2-year relapse risk. Together, our data suggest that the protective effect of CMV reactivation on post-transplant relapse is in part driven by adaptive NK cell responses. PMID:26416461

  3. High-dose cytarabine as salvage therapy for relapsed or refractory acute myeloid leukemia-is more better or more of the same?

    PubMed

    Wolach, Ofir; Itchaki, Gilad; Bar-Natan, Michal; Yeshurun, Moshe; Ram, Ron; Herscovici, Corina; Shpilberg, Ofer; Douer, Dan; Tallman, Martin S; Raanani, Pia

    2016-03-01

    Cytarabine is the backbone of most chemotherapeutic regimens for acute myeloid leukemia (AML), yet the optimal dose for salvage therapy of refractory or relapsed AML (RR-AML) has not been established. Very high dose single-agent cytarabine at 36 g/m(2) (ARA-36) was previously shown to be effective and tolerable in RR-AML. In this retrospective analysis, we aim to describe the toxicity and efficacy of ARA-36 as salvage therapy for patients with AML who are primary refractory to intensive daunorubicin-containing induction or those relapsing after allogeneic stem cell transplant (alloSCT). Fifteen patients, median age 53 years, were included in the analysis. Six patients were treated for induction failure, one had resistant APL, and eight relapsed after alloSCT. Complete remission was achieved in 60% of patients. Surviving patients were followed for a median of 8.5 months. One-year overall survival was 54% (95% CI 30%-86%), and relapse rate from remission (n = 9) was 56%. Grade III/IV pulmonary, infectious, ocular and gastrointestinal toxicities occurred in 26%, 20%, 20% and 20% of patients respectively. Salvage therapy with ARA-36 regimen for RR-AML has considerable efficacy with manageable toxicity in patients with induction failure or post-transplant relapse. Overall survival in these high-risk patients still remains poor. Copyright © 2015 John Wiley & Sons, Ltd. PMID:25689584

  4. High expression of the Ets-related gene (ERG) is an independent prognostic marker for relapse-free survival in patients with acute promyelocytic leukemia.

    PubMed

    Hecht, Anna; Nowak, Daniel; Nowak, Verena; Hanfstein, Benjamin; Faldum, Andreas; Büchner, Thomas; Spiekermann, Karsten; Sauerland, Cristina; Lengfelder, Eva; Hofmann, Wolf-Karsten; Nolte, Florian

    2013-04-01

    In acute promyelocytic leukemia (APL), relapse occurs in about 15 % of cases and is a major cause for death. Molecular markers identifying patients at high risk for relapse are not well established. High expression of the transcription factor Ets-related gene (ERG) is associated with inferior overall survival (OS) and disease-free survival in different types of hematologic malignancies. There are no data available about the impact of ERG expression in APL. ERG expression levels were analyzed in bone marrow samples of 86 APL patients at initial diagnosis. High ERG expression was significantly associated with an inferior OS in patients who had reached first complete remission. It was also significantly correlated with inferior relapse-free survival (RFS) and time to relapse (i.e., relapse-free interval, RFI). In multivariate analysis, high ERG expression had an independent negative impact on RFS and RFI. High ERG expression was significantly associated with inferior OS, RFS, and RFI. Moreover, in multivariate analysis, it maintained its value as an independent negative prognostic factor with regard to RFS and RFI. Therefore, ERG expression might serve as a molecular marker for risk stratification in APL and might identify patients who could benefit from intensified treatment regimens. PMID:23250622

  5. Terminal Deoxynucleotidyl Transferase in a Case of Childhood Acute Lymphoblastic Leukemia

    PubMed Central

    McCaffrey, Ronald; Smoler, Donna F.; Baltimore, David

    1973-01-01

    Cells from a patient with childhood acute lymphoblastic leukemia contain an apparent DNA polymerase activity that was not found in any other cells except thymus cells. The enzyme has the properties of terminal transferase, an enzyme known to be found in thymocytes. The cells also contain the three major DNA polymerases found in growing cells. The results suggest that these tumor cells arose from a block in the differentiation of thymocytes. Terminal transferase may be a marker for the origin of leukemic cells. PMID:4346893

  6. Childhood acute lymphoblastic leukemia presenting as ''cold'' lesions on bone scan: a report of two cases

    SciTech Connect

    Caudle, R.J.; Crawford, A.H.; Gelfand, M.J.; Gruppo, R.A.

    1987-01-01

    ''Cold'' lesions on bone scan have been reported in a variety of disease processes, including infection, avascular necrosis, and cysts. We present two cases of children who presented with large ''cold'' areas on technetium bone scans and were treated initially for septic processes. Acute childhood leukemia frequently presents with bone or joint pain, fever, and elevation of the erythrocyte sedimentation rate. Although the diagnosis may be difficult if the characteristic clinical signs and laboratory findings are absent, the presence of anemia should alert the physician to the possibility of malignancy. Bone scanning provides a sensitive method of localizing pathology, but diagnosis requires biopsy or marrow aspiration.

  7. Cardiac Failure 30 Years after Treatment Containing Anthracycline for Childhood Acute Lymphoblastic Leukemia

    PubMed Central

    Goldberg, John M.; Scully, Rebecca E.; Sallan, Stephen E.; Lipshultz, Steven E.

    2012-01-01

    In 1977, a 5-year-old girl diagnosed with acute lymphoblastic leukemia (ALL) was treated on DFCI Childhood ALL Protocol 77-01, receiving a cumulative doxorubicin dose of 465 mg/m2, cranial radiation, and other drugs. After being in continuous complete remission for 34 months, she developed heart failure (HF) and was treated with digoxin and furosemide. At 16, she was diagnosed and treated for dilated cardiomyopathy. Over the years she continued to have bouts of HF, which became less responsive to treatment. At 36, she received a heart transplant. Six months later, she stopped taking her medications and suffered a sudden cardiac death. PMID:22584777

  8. Laboratory Treated T Cells in Treating Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia, Non-Hodgkin Lymphoma, or Acute Lymphoblastic Leukemia

    ClinicalTrials.gov

    2016-08-16

    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 Chronic Lymphocytic Leukemia; Refractory Diffuse Large B-Cell Lymphoma; Refractory Mantle Cell Lymphoma; Refractory Non-Hodgkin Lymphoma; Refractory Small Lymphocytic Lymphoma

  9. Severe Hypertriglyceridemia During Therapy For Childhood Acute Lymphoblastic Leukemia

    PubMed Central

    Bhojwani, Deepa; Darbandi, Rashid; Pei, Deqing; Ramsey, Laura B.; Chemaitilly, Wassim; Sandlund, John T.; Cheng, Cheng; Pui, Ching-Hon; Relling, Mary V.; Jeha, Sima; Metzger, Monika L.

    2014-01-01

    Background Asparaginase and steroids can cause hypertriglyceridemia in children with acute lymphoblastic leukemia (ALL). There are no guidelines for screening or management of patients with severe hypertriglyceridemia (>1000 mg/dL) during ALL therapy. Patients and Methods Fasting lipid profiles were obtained prospectively at 4 time-points for 257 children consecutively enrolled on a frontline ALL study. Risk factors were evaluated by the exact chi-square test. Details of adverse events and management of hypertriglyceridemia were extracted retrospectively. Results Eighteen of 257 (7%) patients developed severe hypertriglyceridemia. Older age and treatment with higher doses of asparaginase and steroids on the standard/high-risk arm were significant risk factors. Severe hypertriglyceridemia was not associated with pancreatitis after adjustment for age and treatment arm or with osteonecrosis after adjustment for age. However, patients with severe hypertriglyceridemia had a 2.5 to 3 times higher risk of thrombosis compared to patients without, albeit the difference was not statistical significant. Of the 30 episodes of severe hypertriglyceridemia in 18 patients, 7 were managed conservatively while the others with pharmacotherapy. Seventeen of 18 patients continued to receive asparaginase and steroids. Triglyceride levels normalized after completion of ALL therapy in all 12 patients with available measurements. Conclusion Asparaginase- and steroid-induced transient hypertriglyceridemia can be adequately managed with dietary modifications and close monitoring without altering chemotherapy. Patients with severe hypertriglyceridemia were not at increased risk of adverse events, with a possible exception of thrombosis. The benefit of pharmacotherapy in decreasing symptoms and potential complications requires further investigation. PMID:25087182

  10. Epigenetic landscape correlates with genetic subtype but does not predict outcome in childhood acute lymphoblastic leukemia.

    PubMed

    Gabriel, Alem S; Lafta, Fadhel M; Schwalbe, Edward C; Nakjang, Sirintra; Cockell, Simon J; Iliasova, Alice; Enshaei, Amir; Schwab, Claire; Rand, Vikki; Clifford, Steven C; Kinsey, Sally E; Mitchell, Chris D; Vora, Ajay; Harrison, Christine J; Moorman, Anthony V; Strathdee, Gordon

    2015-01-01

    Although children with acute lymphoblastic leukemia (ALL) generally have a good outcome, some patients do relapse and survival following relapse is poor. Altered DNA methylation is highly prevalent in ALL and raises the possibility that DNA methylation-based biomarkers could predict patient outcome. In this study, genome-wide methylation analysis, using the Illumina Infinium HumanMethylation450 BeadChip platform, was carried out on 52 diagnostic patient samples from 4 genetic subtypes [ETV6-RUNX1, high hyperdiploidy (HeH), TCF3-PBX1 and dic(9;20)(p11-13;q11)] in a 1:1 case-control design with patients who went on to relapse (as cases) and patients achieving long-term remission (as controls). Pyrosequencing assays for selected loci were used to confirm the array-generated data. Non-negative matrix factorization consensus clustering readily clustered samples according to genetic subgroups and gene enrichment pathway analysis suggested that this is in part driven by epigenetic disruption of subtype specific signaling pathways. Multiple bioinformatics approaches (including bump hunting and individual locus analysis) were used to identify CpG sites or regions associated with outcome. However, no associations with relapse were identified. Our data revealed that ETV6-RUNX1 and dic(9;20) subtypes were mostly associated with hypermethylation; conversely, TCF3-PBX1 and HeH were associated with hypomethylation. We observed significant enrichment of the neuroactive ligand-receptor interaction pathway in TCF3-PBX1 as well as an enrichment of genes involved in immunity and infection pathways in ETV6-RUNX1 subtype. Taken together, our results suggest that altered DNA methylation may have differential impacts in distinct ALL genetic subtypes. PMID:26237075

  11. Outcomes in Patients With Relapsed or Refractory Acute Promyelocytic Leukemia Treated With or Without Autologous or Allogeneic Hematopoietic Stem Cell Transplantation

    PubMed Central

    Pemmaraju, Naveen; Tanaka, Maria Florencia; Ravandi, Farhad; Lin, Heather; Baladandayuthapani, Veerabhadran; Rondon, Gabriela; Giralt, Sergio A.; Chen, Julianne; Pierce, Sherry; Cortes, Jorge; Kantarjian, Hagop; Champlin, Richard E.; De Lima, Marcos; Qazilbash, Muzaffar H.

    2014-01-01

    Outcomes in patients with acute promyelocytic leukemia have improved; however, a subset of patients relapse despite receiving all-trans-retinoic acid and/or arsenic-based therapies. Among 40 patients with acute promyelocytic leukemia who were treated at our institution (1980–2010), 24 received hematopoietic stem cell transplantation (HCT) (autologous HCT, 7; allogeneic HCT, 14; both, 3); 16 received chemotherapy only. All 3 strategies (autologous HCT, allogeneic HCT, chemotherapy) were feasible in patients with relapsed acute promyelocytic leukemia and result in long-term disease control in selected patients. Background Outcomes in patients with acute promyelocytic leukemia (APL) have improved; however, a significant number of patients still relapse despite receiving all-trans-retinoic acid (ATRA) and arsenic-based therapies. Patients and Methods Outcomes of patients with relapsed APL who were treated at our institution (1980–2010) and who received HCT were compared with those who received chemotherapy (CT) only. Results Among 40 patients, 24 received HCT (autologous [auto] HCT, 7; allogeneic [allo] HCT, 14; both, 3); 16 received CT only. The median age at diagnosis was 36 years (range, 13–50 years), 31 years (range, 16–58 years), and 44 years (range, 24–79 years) for the auto-HCT, allo-HCT, and CT groups, respectively. Ten (100%) patients who received auto-HCT and 12 (71%) who received allo-HCT were in complete remission at the time of the HCT. The median follow-ups in the auto-HCT, allo-HCT, and CT groups were 74 months (range, 26–135 months), 118 months (range, 28–284 months), and 122 months (range, 32–216 months), respectively. Transplantation-related mortality (1 year) after auto-HCT and allo-HCT were 10% and 29%, respectively. The 7-year event-free survival after auto-HCT and allo-HCT was 68.6% and 40.6%, respectively (P = .45). The 7-year overall survival was 85.7%, 49.4%, and 40% in the auto-HCT, allo-HCT, and CT groups, respectively (P

  12. Peripheral blood minimal residual disease may replace bone marrow minimal residual disease as an immunophenotypic biomarker for impending relapse in acute myeloid leukemia.

    PubMed

    Zeijlemaker, W; Kelder, A; Oussoren-Brockhoff, Y J M; Scholten, W J; Snel, A N; Veldhuizen, D; Cloos, J; Ossenkoppele, G J; Schuurhuis, G J

    2016-03-01

    As relapses are common in acute myeloid leukemia (AML), early relapse prediction is of high importance. Although conventional minimal residual disease (MRD) measurement is carried out in bone marrow (BM), peripheral blood (PB) would be an advantageous alternative source. This study aims to investigate the specificity of leukemia-associated immunophenotypes used for MRD detection in blood samples. Consistency of PB MRD as compared with BM MRD was determined in flow cytometric data of 205 paired BM and PB samples of 114 AML patients. A significant correlation was found between PB and BM MRD (r=0.67, P<0.001), while median PB MRD percentage was factor 4-5 lower compared with BM MRD. Primitive blast (CD34+/CD117+/CD133+) frequency was significantly lower in PB (median factor 23.7), indicating that PB MRD detection is more specific than BM. Cumulative incidence of relapse 1 year after induction therapy was 29% for PB MRD-negative and 89% for PB MRD-positive patients (P<0.001). Three-year OS was 52% for MRD-negative and 15% for MRD-positive patients (P=0.034). Similar differences were found after consolidation therapy. As PB MRD appeared to be an independent predictor for response duration, the highly specific PB MRD assay may have a prominent role in future MRD assessment in AML. PMID:26373238

  13. The HELIOS trial protocol: a phase III study of ibrutinib in combination with bendamustine and rituximab in relapsed/refractory chronic lymphocytic leukemia.

    PubMed

    Hallek, Michael; Kay, Neil E; Osterborg, Anders; Chanan-Khan, Asher A; Mahler, Michelle; Salman, Mariya; Wan, Ying; Sun, Steven; Zhuang, Sen Hong; Howes, Angela

    2015-01-01

    Ibrutinib is an orally administered, covalent inhibitor of Bruton's tyrosine kinase with activity in B-cell malignancies based on Phase I/II studies. We describe the design and rationale for the Phase III HELIOS trial (trial registration: EudraCT No. 2012-000600-15; UTN No. U1111-1135-3745) investigating whether ibrutinib added to bendamustine and rituximab (BR) provides benefits over BR alone in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. Eligible patients must have relapsed/refractory disease measurable on CT scan and meet ≥ 1 International Workshop on Chronic Lymphocytic Leukemia criterion for requiring treatment; patients with del(17p) are excluded. All patients receive BR (maximum six cycles) as background therapy and are randomized 1:1 to placebo or ibrutinib 420 mg/day. Treatment with ibrutinib or placebo will start concomitantly with BR and continue until disease progression or unacceptable toxicity. The primary end point is progression-free survival. Secondary end points include safety, objective response rate, overall survival, rate of minimal residual disease-negative remissions, and patient-reported outcomes. Tumor response will be assessed using the International Workshop on Chronic Lymphocytic Leukemia guidelines. PMID:24901734

  14. Leukemia.

    PubMed

    Juliusson, Gunnar; Hough, Rachael

    2016-01-01

    Leukemias are a group of life threatening malignant disorders of the blood and bone marrow. In the adolescent and young adult (AYA) population, the acute leukemias are most prevalent, with chronic myeloid leukemia being infrequently seen. Factors associated with more aggressive disease biology tend to increase in frequency with increasing age, whilst tolerability of treatment strategies decreases. There are also challenges regarding the effective delivery of therapy specific to the AYA group, consequences on the unique psychosocial needs of this age group, including compliance. This chapter reviews the current status of epidemiology, pathophysiology, treatment strategies and outcomes of AYA leukemia, with a focus on acute lymphoblastic leukemia and acute myeloid leukemia. PMID:27595359

  15. Household pesticide exposure and the risk of childhood acute leukemia in Shanghai, China.

    PubMed

    Zhang, Yan; Gao, Yu; Shi, Rong; Chen, Didi; Wang, Xiaojin; Kamijima, Michihiro; Sakai, Kiyoshi; Nakajima, Tamie; Khalequzzaman, Md; Zhou, Yijun; Zheng, Ying; Bao, Pingping; Tian, Ying

    2015-08-01

    Childhood acute leukemia (AL) is the most common malignant tumor in children, but its etiology remains largely unknown. We investigated the relationship between household exposure to pesticides and childhood AL. Between 2009 and 2010 in Shanghai, a total of 248 newly diagnosed cases of AL and 111 gender-, age-, and hospital-matched controls were included. Five nonspecific dialkyl phosphate (DAP) metabolites of organophosphate pesticides (OPPs) [including dimethyl phosphate (DMP), diethyl phosphate (DEP), dimethyl thiophosphate (DMTP), diethyl thiophosphate (DETP), and diethyl dithiophosphate (DEDTP)] in the urine were analyzed by gas chromatography. The results showed that the median DMP, DEP, DMTP, DETP, and DEDEP levels adjusted for creatinine (Cr) in cases (13.2, 10.0, 31.3, 8.5, and 6.1 μg g(-1), respectively) were all significantly elevated compared with those in controls (3.6, 3.6, 13.3, 2.7, and 1.7 μg g(-1), respectively) (P < 0.05). The household use of mosquito repellent was significantly associated with an increased risk of childhood AL (odds ratio (OR) = 1.9; 95% confidence interval (CI) 1.2-3.1). Moreover, higher exposures were significantly associated with an elevated risk of childhood AL for DMs, DEs, and DAPs. Our findings support the notion that the household use of pesticides may play a role in the etiology of childhood AL and provide some evidence to warrant further investigation of the link between household pesticide exposures and childhood AL in Shanghai. PMID:25854207

  16. 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

    2014-01-23

    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

  17. Parental, In Utero, and Early-Life Exposure to Benzene and the Risk of Childhood Leukemia: A Meta-Analysis.

    PubMed

    Carlos-Wallace, Frolayne M; Zhang, Luoping; Smith, Martyn T; Rader, Gabriella; Steinmaus, Craig

    2016-01-01

    Benzene is an established cause of adult leukemia, but whether it is associated with childhood leukemia remains unclear. We conducted a meta-analysis in which we reviewed the epidemiologic literature on this topic and explored causal inference, bias, and heterogeneity. The exposure metrics that we evaluated included occupational and household use of benzenes and solvents, traffic density, and traffic-related air pollution. For studies of occupational and household product exposure published from 1987 to 2014, the summary relative risk for childhood leukemia was 1.96 (95% confidence interval (CI): 1.53, 2.52; n = 20). In these studies, the summary relative risk was higher for acute myeloid leukemia (summary relative risk (sRR) = 2.34, 95% CI: 1.72, 3.18; n = 6) than for acute lymphoblastic leukemia (sRR = 1.57; 95% CI: 1.21, 2.05; n = 14). The summary relative risk was higher for maternal versus paternal exposure, in studies that assessed benzene versus all solvents, and in studies of gestational exposure. In studies of traffic density or traffic-related air pollution published from 1999 to 2014, the summary relative risk was 1.48 (95% CI: 1.10, 1.99; n = 12); it was higher for acute myeloid leukemia (sRR = 2.07; 95% CI: 1.34, 3.20) than for acute lymphoblastic leukemia (sRR = 1.49; 95% CI: 1.07, 2.08) and in studies that involved detailed models of traffic pollution (sRR = 1.70; 95% CI: 1.16, 2.49). Overall, we identified evidence of associations between childhood leukemia and several different potential metrics of benzene exposure. PMID:26589707

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

    ClinicalTrials.gov

    2016-03-16

    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

  19. Cognitive functioning in long-term survivors of childhood leukemia: A prospective analysis

    SciTech Connect

    Rubenstein, C.L.; Varni, J.W.; Katz, E.R. )

    1990-12-01

    Treatment-related cognitive impairments have been reported for survivors of childhood leukemia following prophylactic central nervous system (CNS) treatment with 2400 cGy craniospinal irradiation and intrathecal chemotherapy. The present study was designed to prospectively evaluate cognitive functioning of 24 children prior to CNS prophylaxis of 1800 cGy of craniospinal irradiation and intrathecal drugs, and at intervals of 1 and 4-5 years. At diagnosis, prior to CNS treatment, all 24 subjects performed in the average range of intelligence, as measured by the Wechsler Intelligence Scales. Subjects continued to perform in the average range with no significant declines at the 1-year follow-up. Significant declines in cognitive functioning, however, were found at the 4- to 5-year follow-up period, with five subjects (21%) performing in the low average or borderline levels of intelligence. Of the 19 subjects performing in the average range, five showed significant discrepancies between Verbal and Performance IQ scores. Nine subjects exhibited poor performance on a subtest cluster assessing perceptual and attentional processes. With regard to school experiences, 50% of the subjects had received some type of special education services. The findings indicate the need for annual evaluations of cognitive functioning in long-term survivors of childhood leukemia who received 1800 cGy craniospinal irradiation, to identify potential cognitive late effects of treatment requiring appropriate special education services.

  20. Leukemia

    MedlinePlus

    Leukemia is cancer of the white blood cells. White blood cells help your body fight infection. Your blood cells form in your bone marrow. In leukemia, the bone marrow produces abnormal white blood cells. ...

  1. Comprehensive genomic analysis reveals FLT3 activation and a therapeutic strategy for a patient with relapsed adult B-lymphoblastic leukemia.

    PubMed

    Griffith, Malachi; Griffith, Obi L; Krysiak, Kilannin; Skidmore, Zachary L; Christopher, Matthew J; Klco, Jeffery M; Ramu, Avinash; Lamprecht, Tamara L; Wagner, Alex H; Campbell, Katie M; Lesurf, Robert; Hundal, Jasreet; Zhang, Jin; Spies, Nicholas C; Ainscough, Benjamin J; Larson, David E; Heath, Sharon E; Fronick, Catrina; O'Laughlin, Shelly; Fulton, Robert S; Magrini, Vincent; McGrath, Sean; Smith, Scott M; Miller, Christopher A; Maher, Christopher A; Payton, Jacqueline E; Walker, Jason R; Eldred, James M; Walter, Matthew J; Link, Daniel C; Graubert, Timothy A; Westervelt, Peter; Kulkarni, Shashikant; DiPersio, John F; Mardis, Elaine R; Wilson, Richard K; Ley, Timothy J

    2016-07-01

    The genomic events responsible for the pathogenesis of relapsed adult B-lymphoblastic leukemia (B-ALL) are not yet clear. We performed integrative analysis of whole-genome, whole-exome, custom capture, whole-transcriptome (RNA-seq), and locus-specific genomic assays across nine time points from a patient with primary de novo B-ALL. Comprehensive genome and transcriptome characterization revealed a dramatic tumor evolution during progression, yielding a tumor with complex clonal architecture at second relapse. We observed and validated point mutations in EP300 and NF1, a highly expressed EP300-ZNF384 gene fusion, a microdeletion in IKZF1, a focal deletion affecting SETD2, and large deletions affecting RB1, PAX5, NF1, and ETV6. Although the genome analysis revealed events of potential biological relevance, no clinically actionable treatment options were evident at the time of the second relapse. However, transcriptome analysis identified aberrant overexpression of the targetable protein kinase encoded by the FLT3 gene. Although the patient had refractory disease after salvage therapy for the second relapse, treatment with the FLT3 inhibitor sunitinib rapidly induced a near complete molecular response, permitting the patient to proceed to a matched-unrelated donor stem cell transplantation. The patient remains in complete remission more than 4 years later. Analysis of this patient's relapse genome revealed an unexpected, actionable therapeutic target that led to a specific therapy associated with a rapid clinical response. For some patients with relapsed or refractory cancers, this approach may indicate a novel therapeutic intervention that could alter outcome. PMID:27181063

  2. Treatment of relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma with everolimus (RAD001) and alemtuzumab: a Phase I/II study.

    PubMed

    Zent, Clive S; Bowen, Deborah A; Conte, Michael J; LaPlant, Betsy R; Call, Timothy G

    2016-07-01

    Patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL), and especially those with purine analogue refractory disease or TP53 deletion/mutation, had a poor prognosis prior to the introduction of therapy targeting B cell receptor signaling. The mammalian target of rapamycin (mTOR) inhibitor everolimus has biological activity in CLL and can mobilize CLL cells from the lymphoid tissues into the circulation. In this clinical trial we determined the maximum tolerated dose (MTD) of everolimus together with eight weeks of standard dose subcutaneous alemtuzumab (Phase I) and then evaluated the tolerability and efficacy of therapy of relapsed/refractory CLL with the combination of everolimus and alemtuzumab (Phase II). The maximum tolerated dose of oral everolimus was 2.5 mg three times/week. Therapy with everolimus and alemtuzumab was tolerable, but not sufficiently efficacious (33% partial responses, no complete responses) to recommend further development of the regimen. PMID:26699397

  3. Late thyroid complications in survivors of childhood acute leukemia. An L.E.A. study.

    PubMed

    Oudin, Claire; Auquier, Pascal; Bertrand, Yves; Chastagner, Philippe; Kanold, Justyna; Poirée, Maryline; Thouvenin, Sandrine; Ducassou, Stephane; Plantaz, Dominique; Tabone, Marie-Dominique; Dalle, Jean-Hugues; Gandemer, Virginie; Lutz, Patrick; Sirvent, Anne; Villes, Virginie; Barlogis, Vincent; Baruchel, André; Leverger, Guy; Berbis, Julie; Michel, Gérard

    2016-06-01

    Thyroid complications are known side effects of irradiation. However, the risk of such complications in childhood acute leukemia survivors who received either central nervous system irradiation or hematopoietic stem cell transplantation is less described. We prospectively evaluated the incidence and risk factors for thyroid dysfunction and tumors in survivors of childhood acute myeloid or lymphoid leukemia. A total of 588 patients were evaluated for thyroid function, and 502 individuals were assessed for thyroid tumors (median follow-up duration: 12.6 and 12.5 years, respectively). The cumulative incidence of hypothyroidism was 17.3% (95% CI: 14.1-21.1) and 24.6% (95% CI: 20.4-29.6) at 10 and 20 years from leukemia diagnosis, respectively. Patients who received total body irradiation (with or without prior central nervous system irradiation) were at higher risk of hypothyroidism (adjusted HR: 2.87; P=0.04 and 2.79, P=0.01, respectively) as compared with transplanted patients who never received any irradiation. Patients transplanted without total body irradiation who received central nervous system irradiation were also at higher risk (adjusted HR: 3.39; P=0.02). Patients irradiated or transplanted at older than 10 years of age had a lower risk (adjusted HR: 0.61; P=0.02). Thyroid malignancy was found in 26 patients (5.2%). Among them, two patients had never received any type of irradiation: alkylating agents could also promote thyroid cancer. The cumulative incidence of thyroid malignancy was 9.6% (95% CI: 6.0-15.0) at 20 years. Women were at higher risk than men (adjusted HR: 4.74; P=0.002). In conclusion, thyroid complications are frequent among patients who undergo transplantation after total body irradiation and those who received prior central nervous system irradiation. Close monitoring is thus warranted for these patients. Clinicaltrials.gov identifier: NCT 01756599. PMID:26969082

  4. Late thyroid complications in survivors of childhood acute leukemia. An L.E.A. study

    PubMed Central

    Oudin, Claire; Auquier, Pascal; Bertrand, Yves; Chastagner, Philippe; Kanold, Justyna; Poirée, Maryline; Thouvenin, Sandrine; Ducassou, Stephane; Plantaz, Dominique; Tabone, Marie-Dominique; Dalle, Jean-Hugues; Gandemer, Virginie; Lutz, Patrick; Sirvent, Anne; Villes, Virginie; Barlogis, Vincent; Baruchel, André; Leverger, Guy; Berbis, Julie; Michel, Gérard

    2016-01-01

    Thyroid complications are known side effects of irradiation. However, the risk of such complications in childhood acute leukemia survivors who received either central nervous system irradiation or hematopoietic stem cell transplantation is less described. We prospectively evaluated the incidence and risk factors for thyroid dysfunction and tumors in survivors of childhood acute myeloid or lymphoid leukemia. A total of 588 patients were evaluated for thyroid function, and 502 individuals were assessed for thyroid tumors (median follow-up duration: 12.6 and 12.5 years, respectively). The cumulative incidence of hypothyroidism was 17.3% (95% CI: 14.1–21.1) and 24.6% (95% CI: 20.4–29.6) at 10 and 20 years from leukemia diagnosis, respectively. Patients who received total body irradiation (with or without prior central nervous system irradiation) were at higher risk of hypothyroidism (adjusted HR: 2.87; P=0.04 and 2.79, P=0.01, respectively) as compared with transplanted patients who never received any irradiation. Patients transplanted without total body irradiation who received central nervous system irradiation were also at higher risk (adjusted HR: 3.39; P=0.02). Patients irradiated or transplanted at older than 10 years of age had a lower risk (adjusted HR: 0.61; P=0.02). Thyroid malignancy was found in 26 patients (5.2%). Among them, two patients had never received any type of irradiation: alkylating agents could also promote thyroid cancer. The cumulative incidence of thyroid malignancy was 9.6% (95% CI: 6.0–15.0) at 20 years. Women were at higher risk than men (adjusted HR: 4.74; P=0.002). In conclusion, thyroid complications are frequent among patients who undergo transplantation after total body irradiation and those who received prior central nervous system irradiation. Close monitoring is thus warranted for these patients. Clinicaltrials.gov identifier: NCT 01756599. PMID:26969082

  5. [Markers of metabolic syndrome and peptides regulating metabolism in survivors of childhood acute lymphoblastic leukemia].

    PubMed

    Skoczeń, Szymon; Tomasik, Przemysław; Balwierz, Walentyna; Surmiak, Marcin; Sztefko, Krystyna; Galicka-Latała, Danuta

    2011-01-01

    Along with the growing epidemic of overweight the risk of atherosclerosis, cardiovascular disease morbidity and mortality are increasing markedly. Metabolic syndrome (MS) is a condition clustering together several risk factors of those complications such as visceral obesity, glucose intolerance, arterial hypertension and dislipidemia. The risk of obesity in acute lymphoblastic leukemia (ALL) survivors is higher than in general population. We aimed to assess (1) the relationships between chosen adipokines and neuropeptides, chemotherapy, CRT, and body fatness and (2) evaluate adipokines and neuropeptides concentrations as a new markers of MS in children. We conducted cross-sectional evaluation of 82 ALL survivors (median age: 13.2 years; range: 4,8-26,2; median time from treatment: 3.2 years), including fasting laboratory testing: peptides (leptin, GLP-1, orexin, PYY, apelin), total cholesterol and its fractions, triglycerides; anthropometric measurements (weight, height), systolic and diastolic blood pressure. We estimated percentiles of body mass index and percentiles of blood pressure. Between 82 survivors overweight and diastolic hypertension was diagnosed in 31% of patients (35% in CRT group) and 15% respectively. At least one abnormality in lipids concentrations was found in 43%. Girls were more affected than boys. Statistically significant increased in leptin and apelin concentrations and decreased in soluble leptin receptor concentrations in the overweight group were observed compared to the non overweight subjects. Significant increase in orexin levels in females who had received CRT compared to those who had not received CRT was found. CRT is the main risk factor of elevated of body mass among survivors of childhood leukemia. Dyslipidemia and hypertension, along with increased adiposity indicate higher risk of MS development. Girls are more affected than boys. Leptin, orexin and apelin seem to be good markers of increased adiposity especially after CRT

  6. Nonadherence to Oral Mercaptopurine and Risk of Relapse in Hispanic and Non-Hispanic White Children With Acute Lymphoblastic Leukemia: A Report From the Children's Oncology Group

    PubMed Central

    Bhatia, Smita; Landier, Wendy; Shangguan, Muyun; Hageman, Lindsey; Schaible, Alexandra N.; Carter, Andrea R.; Hanby, Cara L.; Leisenring, Wendy; Yasui, Yutaka; Kornegay, Nancy M.; Mascarenhas, Leo; Ritchey, A. Kim; Casillas, Jacqueline N.; Dickens, David S.; Meza, Jane; Carroll, William L.; Relling, Mary V.; Wong, F. Lennie

    2012-01-01

    Purpose Systemic exposure to mercaptopurine (MP) is critical for durable remissions in children with acute lymphoblastic leukemia (ALL). Nonadherence to oral MP could increase relapse risk and also contribute to inferior outcome in Hispanics. This study identified determinants of adherence and described impact of adherence on relapse, both overall and by ethnicity. Patients and Methods A total of 327 children with ALL (169 Hispanic; 158 non-Hispanic white) participated. Medication event-monitoring system caps recorded date and time of MP bottle openings. Adherence rate, calculated monthly, was defined as ratio of days of MP bottle opening to days when MP was prescribed. Results After 53,394 person-days of monitoring, adherence declined from 94.7% (month 1) to 90.2% (month 6; P < .001). Mean adherence over 6 months was significantly lower among Hispanics (88.4% v 94.8%; P < .001), patients age ≥ 12 years (85.8% v 93.1%; P < .001), and patients from single-mother households (80.6% v 93.1%; P = .001). A progressive increase in relapse was observed with decreasing adherence (reference: adherence ≥ 95%; 94.9% to 90%: hazard ratio [HR], 4.1; 95% CI,1.2 to 13.5; P = .02; 89.9% to 85%: HR, 4.0; 95% CI, 1.0 to 15.5; P = .04; < 85%: HR. 5.7; 95% CI, 1.9 to 16.8; P = .002). Cumulative incidence of relapse (± standard deviation) was higher among Hispanics (16.5% ± 4.0% v 6.3% ± 2.2%; P = .02). Association between Hispanic ethnicity and relapse (HR, 2.6; 95% CI, 1.1 to 6.1; P = .02) became nonsignificant (HR, 1.8; 95% CI, 0.6 to 5.2; P = .26) after adjusting for adherence and socioeconomic status. At adherence rates ≥ 90%, Hispanics continued to demonstrate higher relapse, whereas at rates < 90%, relapse risk was comparable to that of non-Hispanic whites. Conclusion Lower adherence to oral MP increases relapse risk. Ethnic difference in relapse risk differs by level of adherence—an observation currently under investigation. PMID:22564992

  7. High rate of hematological responses to sorafenib in FLT3-ITD acute myeloid leukemia relapsed after allogeneic hematopoietic stem cell transplantation.

    PubMed

    De Freitas, Tiago; Marktel, Sarah; Piemontese, Simona; Carrabba, Matteo G; Tresoldi, Cristina; Messina, Carlo; Lupo Stanghellini, Maria Teresa; Assanelli, Andrea; Corti, Consuelo; Bernardi, Massimo; Peccatori, Jacopo; Vago, Luca; Ciceri, Fabio

    2016-06-01

    Relapse represents the most significant cause of failure of allogeneic hematopoietic stem cell transplantation (HSCT) for FLT3-ITD-positive acute myeloid leukemia (AML), and available therapies are largely unsatisfactory. In this study, we retrospectively collected data on the off-label use of the tyrosine kinase inhibitor sorafenib, either alone or in association with hypomethylating agents and adoptive immunotherapy, in 13 patients with post-transplantation FLT3-ITD-positive AML relapses. Hematological response was documented in 12 of 13 patients (92%), and five of 13 (38%) achieved complete bone marrow remission. Treatment was overall manageable in the outpatient setting, although all patients experienced significant adverse events, especially severe cytopenias (requiring a donor stem cell boost in five patients) and typical hand-foot syndrome. None of the patients developed graft-vs.-host disease following sorafenib alone, whereas this was frequently observed when this was given in association with donor T-cell infusions. Six patients are alive and in remission at the last follow-up, and four could be bridged to a second allogeneic HSCT, configuring a 65 ± 14% overall survival at 100 d from relapse. Taken together, our data suggest that sorafenib might represent a valid treatment option for patients with FLT3-ITD-positive post-transplantation relapses, manageable also in combination with other therapeutic strategies. PMID:26260140

  8. The prognostic impact of FLT3-ITD and NPM1 mutations in patients with relapsed acute myeloid leukemia and intermediate-risk cytogenetics

    PubMed Central

    How, J; Sykes, J; Minden, M D; Gupta, V; Yee, K W L; Schimmer, A D; Schuh, A C; Kamel-Reid, S; Brandwein, J M

    2013-01-01

    Internal tandem duplication of the fms-like tyrosine kinase-3 gene (FLT3-ITD) and nucleophosmin-1 (NPM1) mutations have prognostic importance in acute myeloid leukemia (AML) patients with intermediate-risk karyotype at diagnosis, but less is known about their utility to predict outcomes at relapse. We retrospectively analysed outcomes of 70 patients with relapsed, intermediate-risk karyotype AML who received a uniform reinduction regimen, with respect to FLT3-ITD and NPM1 mutation status and first complete remission (CR1) duration. CR1 duration, but not molecular status, was significantly correlated with CR2 rate. On univariate analysis, patients with mutated FLT3-ITD (FLT3+) had significantly worse overall survival (OS) compared with those with neither an NPM1 nor FLT3-ITD mutation (NPM1-/FLT3-). On multivariate analysis, shorter CR1 duration was significantly correlated with inferior OS at relapse (P<0.0001), while FLT3 and NPM1 mutation status and age were not significantly correlated with OS. Patients who subsequently underwent allogeneic stem cell transplant (alloSCT) had a superior OS regardless of CR1 duration, but outcomes were better in patients with CR1 duration>12 months. In intermediate-risk karyotype AML patients receiving reinduction, CR1 duration remains the most important predictor of OS at relapse; FLT3-ITD and NPM1 status are not independent predictors of survival. PMID:23708641

  9. The prognostic impact of FLT3-ITD and NPM1 mutations in patients with relapsed acute myeloid leukemia and intermediate-risk cytogenetics.

    PubMed

    How, J; Sykes, J; Minden, M D; Gupta, V; Yee, K W L; Schimmer, A D; Schuh, A C; Kamel-Reid, S; Brandwein, J M

    2013-01-01

    Internal tandem duplication of the fms-like tyrosine kinase-3 gene (FLT3-ITD) and nucleophosmin-1 (NPM1) mutations have prognostic importance in acute myeloid leukemia (AML) patients with intermediate-risk karyotype at diagnosis, but less is known about their utility to predict outcomes at relapse. We retrospectively analysed outcomes of 70 patients with relapsed, intermediate-risk karyotype AML who received a uniform reinduction regimen, with respect to FLT3-ITD and NPM1 mutation status and first complete remission (CR1) duration. CR1 duration, but not molecular status, was significantly correlated with CR2 rate. On univariate analysis, patients with mutated FLT3-ITD (FLT3+) had significantly worse overall survival (OS) compared with those with neither an NPM1 nor FLT3-ITD mutation (NPM1-/FLT3-). On multivariate analysis, shorter CR1 duration was significantly correlated with inferior OS at relapse (P<0.0001), while FLT3 and NPM1 mutation status and age were not significantly correlated with OS. Patients who subsequently underwent allogeneic stem cell transplant (alloSCT) had a superior OS regardless of CR1 duration, but outcomes were better in patients with CR1 duration>12 months. In intermediate-risk karyotype AML patients receiving reinduction, CR1 duration remains the most important predictor of OS at relapse; FLT3-ITD and NPM1 status are not independent predictors of survival. PMID:23708641

  10. Commentary on "Childhood Leukemia Survivors and Their Return to School: A Literature Review, Case Study, and Recommendations"

    ERIC Educational Resources Information Center

    Long, Lori A.

    2011-01-01

    This is a commentary on the article, "Childhood Leukemia Survivors and Their Return to School: A Literature Review, Case Study, and Recommendations" by D. Scott Hermann, Jill R. Thurber, Kenneth Miles, and Gloria Gilbert in this issue (2011). This article addresses issues related to the compatibility of the suggested practices with contemporary…

  11. Corrigendum: The Associations Between Maternal Factors During Pregnancy and the Risk of Childhood Acute Lymphoblastic Leukemia: A Meta-Analysis.

    PubMed

    Yan, Kangkang; Xu, Xuejing; Liu, Xiaodong; Wang, Xikui; Hua, Shucheng; Wang, Chunpeng; Liu, Xin

    2016-05-01

    Because of the erroneous application of multiple publications, the conclusions of our recent paper (Pediatr Blood Cancer 2015;62:1162-70) were not reliable. The corrected results show that coffee drinking during pregnancy was risk factor for childhood acute lymphoblastic leukemia (OR = 1.44, 95% confidence interval = 1.07-1.92). PMID:26999072

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

    ClinicalTrials.gov

    2014-05-13

    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

  13. Father's occupational exposure to radiation and the raised level of childhood leukemia near the Sellafield Nuclear Plant

    SciTech Connect

    Gardner, M.J. )

    1991-08-01

    The first indications that childhood leukemia rates may be raised near the Sellafield nuclear plant in West Cumbria, England, came from largely anecdotal evidence in a television program Windscale: The Nuclear Laundry shown during 1983. During subsequent years, various epidemiological studies have investigated the claim in more detail. Geographical analyses of childhood leukemia incidence in the northern region and mortality in England and Wales using routinely available data made the first contribution. As a result, it was confirmed that leukemia rates in the area, particularly the neighboring village of Seascale, were high compared to other districts, although not totally extreme. Cohort studies of children born in Seascale or attending schools in Seascale were carried out to resolve some of the difficulties of interpretation of geographical analysis. Cohort studies indicated that the excess of leukemia was concentrated among children born in Seascale and was not found among those moving in after birth and suggested that any causal factors may be acting before birth or very early in life. A case-control study of leukemia (and lymphoma) among young people in West Cumbria has examined potentially important individual factors in detail. The study demonstrated a relationship between the raised incidence of leukemia in children and father's recorded external radiation dose during work at Sellafield before his child's conception. The association can effectively explain statistically the observed geographical excess.

  14. Idarubicin and Cytarabine With or Without Bevacizumab in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia

    ClinicalTrials.gov

    2013-01-23

    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 Myelomonocytic Leukemia (M4); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Childhood Acute Basophilic Leukemia; Childhood Acute Eosinophilic Leukemia; 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); Secondary Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia; Untreated Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies

  15. Filgrastim, Cladribine, Cytarabine, and Mitoxantrone Hydrochloride in Treating Patients With Newly Diagnosed or Relapsed/Refractory Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndromes

    ClinicalTrials.gov

    2016-03-30

    Acute Biphenotypic Leukemia; de Novo Myelodysplastic Syndrome; Previously Treated Myelodysplastic Syndrome; Recurrent Adult Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndrome; Untreated Adult Acute Myeloid Leukemia

  16. Dust-metal Loadings and the Risk of Childhood Acute Lymphoblastic Leukemia

    PubMed Central

    Whitehead, Todd P.; Ward, Mary H.; Colt, Joanne S.; Dahl, Gary; Ducore, Jonathan; Reinier, Kyndaron; Gunier, Robert B.; Hammond, S. Katharine; Rappaport, Stephen M.; Metayer, Catherine

    2015-01-01

    We evaluated the relationship between the risk of childhood acute lymphoblastic leukemia (ALL) and levels of metals in carpet dust. A dust sample was collected from the homes of 142 ALL cases and 187 controls participating in the California Childhood Leukemia Study using a high volume small surface sampler (2001–2006). Samples were analyzed using microwave-assisted acid digestion in combination with inductively-coupled plasma mass spectrometry for arsenic, cadmium, chromium, copper, lead, nickel, tin, tungsten, and zinc. Eight metals were detected in at least 85% of the case and control homes; tungsten was detected in less than 15% of homes. Relationships between dust-metal loadings (μg metal per m2 carpet) and ALL risk were modeled using multivariable logistic regression, adjusting for the child’s age, sex, and race/ethnicity and confounders, including household annual income. A doubling of dust-metal loadings was not associated with significant changes in ALL risk [odds ratio (95% confidence interval): arsenic: 0.94 (0.83, 1.05), cadmium: 0.91 (0.80, 1.04), chromium: 0.99 (0.87, 1.12), copper: 0.96 (0.90, 1.03), lead: 1.01 (0.93, 1.10), nickel: 0.92 (0.80, 1.07), tin: 0.93 (0.82, 1.05), and zinc: 0.91 (0.81, 1.02)]. Our findings do not support the hypothesis that metals in carpet dust are risk factors for childhood ALL. PMID:25736162

  17. Fractionated gemtuzumab ozogamicin and standard dose cytarabine produced prolonged second remissions in patients over the age of 55 years with acute myeloid leukemia in late first relapse.

    PubMed

    Pilorge, Sylvain; Rigaudeau, Sophie; Rabian, Florence; Sarkozy, Clémentine; Taksin, Anne L; Farhat, Hassan; Merabet, Fathia; Ghez, Stéphanie; Raggueneau, Victoria; Terré, Christine; Garcia, Isabelle; Renneville, Aline; Preudhomme, Claude; Castaigne, Sylvie; Rousselot, Philippe

    2014-04-01

    Gemtuzumab ozogamicin (fGO), a humanized anti-CD33 monoclonal antibody linked to calicheamicin in combination with intensive chemotherapy gives high response rates in adult acute myeloid leukemia (AML) patients in relapse. However, reduced intensity chemotherapy in combination with fractionated GO has not been tested in aged relapsing patients. Patients from our institution with CD33+ AML aged 55 years or more in first late relapse (≥ 6 months) were proposed participation in a GO compassionate use program. Induction therapy consisted in fractionated GO (fGO; 3 mg/m², days 1, 4, 7) with standard-dose cytarabine (200 mg/m² /day, 7 days). Patients were consolidated with two courses of GO and intermediate dose cytarabine. Twenty-four patients (median age 68 years) received fGO with cytarabine. Median follow-up was 42 months. The response rate was 75%, including complete remission (CR) in 16 patients and CR with incomplete platelet recovery (CRp) in two patients. Two-year overall survival (OS) was 51% (95% CI: 28-69) and 2 years relapse-free survival (RFS) was 51% (95%CI: 25-72). Duration of second CR (CR2) was longer than first CR (CR1) in 9 out of 18 patients. Minimal residual disease (MRD) was negative in evaluable patients in CR2, particularly in NPM1 mutated cases. Toxicity was in line with that of the same fractionated single agent GO schedule. Fractionated GO with low intensity chemotherapy produced high response rates and prolonged CR2 in aged AML patients in first late relapse. PMID:24375467

  18. Phase II study of methotrexate, vincristine, pegylated-asparaginase, and dexamethasone (MOpAD) in patients with relapsed/refractory acute lymphoblastic leukemia

    PubMed Central

    Kadia, Tapan M.; Kantarjian, Hagop M.; Thomas, Deborah A.; O’Brien, Susan; Estrov, Zeev; Ravandi, Farhad; Jabbour, Elias; Pemmaraju, Naveen; Daver, Naval; Wang, Xuemei; Jain, Preetesh; Pierce, Sherry; Brandt, Mark; Garcia-Manero, Guillermo; Cortes, Jorge; Borthakur, Gautam

    2015-01-01

    Newer approaches are needed for the treatment of relapsed and refractory acute lymphoblastic leukemia (ALL). Asparaginase-based regimens are active in the treatment of pediatric ALL and may be important in salvage therapy for adult patients. We conducted a pilot trial combining methotrexate, vincristine, PEGylated-asparaginase, and dexamethasone (MOpAD) in adults with relapsed or refractory ALL. We added tyrosine kinase inhibitors in patients with Philadelphia chromosome positive (Ph+) ALL and rituximab in patients with CD20 positive B-cell ALL. Among 37 patients treated (median age 42 years; median 2 prior therapies), the complete remission (CR) rate was 28% and an overall response rate (ORR) was 39%. The median CR duration was 4.3 months. Patients with Ph+ ALL had CR and ORR of 50% and 67%, respectively and the CR and ORR in patients with T-cell leukemia were 45% and 56%, respectively. The median survival in patients with CR/CRp was 10.4 versus 3.4 months in nonresponders (P =0.02). The most common grade 3 or 4 nonhematologic toxicities were elevations in bilirubin and transaminases, nausea, peripheral neuropathy, and hyperglycemia, which were managed with supportive care, dose adjustments, and interruptions. PMID:25368968

  19. The anti-CD19 antibody-drug conjugate SAR3419 prevents hematolymphoid relapse post induction therapy in preclinical models of pediatric acute lymphoblastic leukemia

    PubMed Central

    Carol, Hernan; Szymanska, Barbara; Evans, Kathryn; Boehm, Ingrid; Houghton, Peter J; Smith, Malcolm A; Lock, Richard B

    2013-01-01

    Purpose Relapsed or refractory pediatric acute lymphoblastic leukemia (ALL) remains a major cause of death from cancer in children. In this study we evaluated the efficacy of SAR3419, an antibody-drug conjugate of the maytansinoid DM4 and a humanized anti-CD19 antibody, against B cell precursor (BCP)-ALL and infant mixed lineage leukemia (MLL) xenografts. Experimental Design ALL xenografts were established as systemic disease in immune-deficient (NOD/SCID) mice from direct patient explants. SAR3419 was administered as a single agent and in combination with an induction-type regimen of vincristine/dexamethasone/L-asparaginase (VXL). Leukemia progression and response to treatment were assessed in real-time, and responses were evaluated using strict criteria modeled after the clinical setting. Results SAR3419 significantly delayed the progression of four out of four CD19+ BCP-ALL and three out of three MLL-ALL xenografts, induced objective responses in all but one xenograft, but was ineffective against T-lineage ALL xenografts. Relative surface CD19 expression across the xenograft panel significantly correlated with leukemia progression delay and objective response measure scores. SAR3419 also exerted significant efficacy against chemoresistant BCP-ALL xenografts over a large (10-fold) dose range, and significantly enhanced VXL-induced leukemia progression delay in two highly chemoresistant xenografts by up to 82 days. When administered as protracted therapy following remission induction with VXL, SAR3419 prevented disease recurrence into hematolymphoid and other major organs with the notable exception of central nervous system involvement. Conclusion These results suggest that incorporation of SAR3419 into remission induction protocols may improve the outcome for high-risk pediatric and adult CD19+ ALL. PMID:23426279

  20. Genetic alterations in glucocorticoid signaling pathway components are associated with adverse prognosis in children with relapsed ETV6/RUNX1-positive acute lymphoblastic leukemia.

    PubMed

    Grausenburger, Reinhard; Bastelberger, Stephan; Eckert, Cornelia; Kauer, Maximilian; Stanulla, Martin; Frech, Christian; Bauer, Eva; Stoiber, Dagmar; von Stackelberg, Arend; Attarbaschi, Andishe; Haas, Oskar A; Panzer-Grümayer, Renate

    2016-05-01

    The ETV6/RUNX1 gene fusion defines the largest genetic subgroup of childhood ALL with overall rapid treatment response. However, up to 15% of cases relapse. Because an impaired glucocorticoid pathway is implicated in disease recurrence we studied the impact of genetic alterations by SNP array analysis in 31 relapsed cases. In 58% of samples, we found deletions in various glucocorticoid signaling pathway-associated genes, but only NR3C1 and ETV6 deletions prevailed in minimal residual disease poor responding and subsequently relapsing cases (p < 0.05). To prove the necessity of a functional glucocorticoid receptor, we reconstituted wild-type NR3C1 expression in mutant, glucocorticoid-resistant REH cells and studied the glucocorticoid response in vitro and in a xenograft mouse model. While these results prove that glucocorticoid receptor defects are crucial for glucocorticoid resistance in an experimental setting, they do not address the essential clinical situation where glucocorticoid resistance at relapse is rather part of a global drug resistance. PMID:26327566

  1. Residential Proximity to Heavy-Traffic Roads, Benzene Exposure, and Childhood Leukemia-The GEOCAP Study, 2002-2007.

    PubMed

    Houot, Jennifer; Marquant, Fabienne; Goujon, Stéphanie; Faure, Laure; Honoré, Cécile; Roth, Marie-Hélène; Hémon, Denis; Clavel, Jacqueline

    2015-10-15

    Childhood leukemia may be associated with traffic-related environmental exposure to benzene, and additional data are needed. The Géolocalisation des Cancers Pédiatriques (GEOCAP) Study, a nationwide French case-control study, was designed to avoid selection bias due to differential participation and misclassification. The study compared the 2,760 childhood leukemia cases diagnosed in France between 2002 and 2007 (including 2,275 cases of acute lymphoblastic leukemia (ALL) and 418 cases of acute myeloblastic leukemia (AML)) with 30,000 contemporaneous child population controls. The residence addresses were precisely geocoded, and 3 indicators of residential proximity to traffic were considered. Estimates of benzene concentrations were also available for the Île-de-France region (including Paris). A 300-m increase in major road length within 150 m of the geocoded address was significantly associated with AML (odds ratio = 1.2, 95% confidence interval: 1.0, 1.4) but not with ALL (odds ratio = 1.0, 95% confidence interval: 0.9, 1.1), and the association was reinforced in the Île-de-France region when this indicator was combined with benzene estimates. These results, which were free from any participation bias and based on objectively determined indices of exposure, showed an increased incidence of AML associated with heavy-traffic road density near a child's home. The results support a role for traffic-related benzene exposure in the etiology of childhood AML. PMID:26377958

  2. Molecular Analysis of Central Nervous System Disease Spectrum in Childhood Acute Lymphoblastic Leukemia

    PubMed Central

    Hicks, Chindo; Sitthi-Amorn, Jitsuda; Douglas, Jessica; Ramani, Ritika; Miele, Lucio; Vijayakumar, Vani; Karlson, Cynthia; Chipeta, James; Megason, Gail

    2016-01-01

    Treatment of the central nervous system (CNS) is an essential therapeutic component in childhood acute lymphoblastic leukemia (ALL). The goal of this study was to identify molecular signatures distinguishing patients with CNS disease from those without the disease in pediatric patients with ALL. We analyzed gene expression data from 207 pediatric patients with ALL. Patients without CNS were classified as CNS1, while those with mild and advanced CNS disease were classified as CNS2 and CNS3, respectively. We compared gene expression levels among the three disease classes. We identified gene signatures distinguishing the three disease classes. Pathway analysis revealed molecular networks and biological pathways dysregulated in response to CNS disease involvement. The identified pathways included the ILK, WNT, B-cell receptor, AMPK, ERK5, and JAK signaling pathways. The results demonstrate that transcription profiling could be used to stratify patients to guide therapeutic decision-making in pediatric ALL. PMID:26997880

  3. Health promotion for adolescent childhood leukemia survivors: building on prevention science and ehealth.

    PubMed

    Elliot, Diane L; Lindemulder, Susan J; Goldberg, Linn; Stadler, Diane D; Smith, Jennifer

    2013-06-01

    Teenage survivors of childhood acute lymphoblastic leukemia (ALL) have increased morbidity likely due to their prior multicomponent treatment. Habits established in adolescence can impact individuals' subsequent adult behaviors. Accordingly, healthy lifestyles, avoiding harmful actions, and appropriate disease surveillance are of heightened importance among teenage survivors. We review the findings from prevention science and their relevance to heath promotion. The capabilities and current uses of eHealth components including e-learning, serious video games, exergaming, behavior tracking, individual messaging, and social networking are briefly presented. The health promotion needs of adolescent survivors are aligned with those eHealth aspects to propose a new paradigm to enhance the wellbeing of adolescent ALL survivors. PMID:23109253

  4. Health Promotion for Adolescent Childhood Leukemia Survivors: Building on Prevention Science and eHealth

    PubMed Central

    Elliot, Diane L.; Lindemulder, Susan J.; Goldberg, Linn; Stadler, Diane D.; Smith, Jennifer

    2014-01-01

    Teenage survivors of childhood acute lymphoblastic leukemia (ALL) have increased morbidity likely due to their prior multicomponent treatment. Habits established in adolescence can impact individuals’ subsequent adult behaviors. Accordingly, healthy lifestyles, avoiding harmful actions, and appropriate disease surveillance are of heightened importance among teenage survivors. We review the findings from prevention science and their relevance to heath promotion. The capabilities and current uses of eHealth components including e-learning, serious video games, exergaming, behavior tracking, individual messaging, and social networking are briefly presented. The health promotion needs of adolescent survivors are aligned with those eHealth aspects to propose a new paradigm to enhance the wellbeing of adolescent ALL survivors. PMID:23109253

  5. Significance of CD66c expression in childhood acute lymphoblastic leukemia.

    PubMed

    Kiyokawa, Nobutaka; Iijima, Kazutoshi; Tomita, Osamu; Miharu, Masashi; Hasegawa, Daisuke; Kobayashi, Kenichiro; Okita, Hajime; Kajiwara, Michiko; Shimada, Hiroyuki; Inukai, Takeshi; Makimoto, Atsushi; Fukushima, Takashi; Nanmoku, Toru; Koh, Katsuyoshi; Manabe, Atsushi; Kikuchi, Akira; Sugita, Kanji; Fujimoto, Junichiro; Hayashi, Yasuhide; Ohara, Akira

    2014-01-01

    Upon analyzing 696 childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) cases, we identified the characteristics of CD66c expression. In addition to the confirmation of strong correlation with BCR-ABL positivity and hyperdiploid, we further observed that CD66c is frequently expressed in CRLF2-positive (11/15, p<0.01 against chimeric gene-negative) as well as hypodiploid cases (3/4), whereas it is never expressed in ETV6-RUNX1, MLL-AF4, MLL-AF9, MLL-ENL, and E2A-PBX1-positive cases. Although the expression of CD66c itself is not directly linked to the prognosis, the accompanying genetic abnormalities are important prognostic factors for BCP-ALL, indicating the importance of CD66c expression in the initial diagnosis of BCP-ALL. PMID:24231528

  6. T cells recognizing leukemic CD34+ progenitor cells mediate the antileukemic effect of donor lymphocyte infusions for relapsed chronic myeloid leukemia after allogeneic stem cell transplantation

    PubMed Central

    Smit, Willem M.; Rijnbeek, Marion; van Bergen, Cornelis A. M.; Fibbe, Willem E.; Willemze, Roel; Falkenburg, J. H. Frederik

    1998-01-01

    Adoptive immunotherapy with donor lymphocyte infusions (DLI) is an effective treatment for relapsed chronic myeloid leukemia (CML) after allogeneic stem cell transplantation. To identify the effector and target cell populations responsible for the elimination of the leukemic cells in vivo we developed an assay to measure the frequency of T lymphocyte precursor cells capable of suppressing leukemic progenitor cells. Target cells in this assay were CML cells that were cultured in the presence of stem cell factor, interleukin 3, granulocyte–macrophage colony-stimulating factor, granulocyte colony-stimulating factor, and erythropoietin. [3H]thymidine incorporation at day 7 represented the proliferation of the progeny of the CD34+ CML progenitor cells, and not of the more mature CD34− CML cells. Effector cells were mononuclear cells, which were used in a limiting dilution analysis to measure the frequencies of CML progenitor cell-inhibitory lymphocyte precursors (PCILp) in peripheral blood of seven patients before and after DLI for relapsed CML. In the six patients who entered complete remission, a 5- to 100-fold increase of PCILp was found during the clinical response. In the patient with resistant relapse the frequency of PCILp was <10 per ml before and after DLI. Leukemia-reactive helper T lymphocyte precursor frequencies remained unchanged after DLI. A significant increase in cytotoxic T lymphocyte precursor frequency against more mature leukemic cells was found in only two responding patients. These results indicate that T cells specifically directed against CD34+ CML progenitor cells mediate the antileukemic effect of DLI. PMID:9707616

  7. Tobacco Smoke Exposure and the Risk of Childhood Acute Lymphoblastic and Myeloid Leukemias by Cytogenetic Subtype

    PubMed Central

    Metayer, Catherine; Zhang, Luoping; Wiemels, Joseph L.; Bartley, Karen; Schiffman, Joshua; Ma, Xiaomei; Aldrich, Melinda C.; Chang, Jeffrey S.; Selvin, Steve; Fu, Cecilia H.; Ducore, Jonathan; Smith, Martyn T.; Buffler, Patricia A.

    2013-01-01

    Background Tobacco smoke contains carcinogens known to damage somatic and germ cells. We investigated the effect tobacco smoke on the risk of childhood acute lymphoblastic leukemia (ALL) and myeloid leukemia (AML), especially subtypes of pre-natal origin like ALL with translocation t(12;21) or high-hyperdiploidy (51–67 chromosomes). Methods We collected information on exposures to tobacco smoking before conception, during pregnancy, and after birth in 767 ALL cases, 135 AML cases, and 1,139 controls (1996–2008). Among cases, chromosome translocations, deletions, or aneuploidy were identified by conventional karyotype and fluorescence in-situ hybridization. Results Multivariable regression analyses for ALL and AML overall showed no definite evidence of associations with self-reported (yes/no) parental prenatal active smoking and child's passive smoking. However, children with history of paternal prenatal smoking combined with postnatal passive smoking had a 1.5-fold increased risk of ALL (95% CI: 1.01–2.23), compared to those without smoking history (ORs for pre- or postnatal smoking only were close to one). This joint effect was seen for B-cell precursor ALL with t(12;21) (OR=2.08; 95% CI: 1.04–4.16), but not high hyperdiploid B-cell ALL. Similarly, child's passive smoking was associated with an elevated risk of AML with chromosome structural changes (OR=2.76; 95% CI: 1.01–7.58), but not aneuploidy. Conclusions our data suggest that exposure to tobacco smoking before were associated with increased risks of childhood ALL and AML; and risks varied by timing of exposure (before and/or after birth) and cytogenetic subtype, based on imprecise estimates. Impact Parents should limit exposures to tobacco smoke before and after the child's birth. PMID:23853208

  8. A phase II Study of Decitabine and Gemtuzumab Ozogamicin in Newly Diagnosed and Relapsed Acute Myeloid Leukemia and High-risk Myelodysplastic Syndrome

    PubMed Central

    Daver, Naval; Kantarjian, Hagop; Ravandi, Farhad; Estey, Elihu; Wang, Xuemei; Garcia-Manero, Guillermo; Jabbour, Elias; Konopleva, Marina; O’Brien, Susan; Verstovsek, Srdan; Kadia, Tapan; Dinardo, Courtney; Pierce, Sherry; Huang, Xuelin; Pemmaraju, Naveen; Diaz-Pines-Mateo, Maria; Cortes, Jorge; Borthakur, Gautam

    2016-01-01

    Background Decitabine may open the chromatin structure of leukemia cells making them accessible to the calicheamicin epitope of gemtuzumab ozogamicin (GO). Methods 110 patients (median age 70 years; range 27–89 years) were treated with decitabine and GO in a trial designed on model based futility to accommodate subject heterogeneity: Group 1: relapsed/refractory AML with complete remission duration (CRD) < 1 year (N=28, 25%); Group 2: relapsed/refractory AML with CRD ≥1 year (N=5, 5%); Group 3: untreated AML unfit for intensive chemotherapy or untreated MDS or untreated MF (N=57, 52%); and Group 4: AML evolving from MDS or relapsed/refractory MDS or MF (N=20, 18%). Treatment consisted of decitabine 20mg/m2 daily for 5 days and GO 3 mg/m2 on day 5. Post-induction therapy included 5 cycles of decitabine+GO followed by decitabine alone. Results CR/CRi was achieved in 39 (35%) patients; Group 1= 5/28 (17%), Group 2 = 3/5 (60%), Group 3 = 24/57 (42%), and Group 4 = 7/20 (35%). The 8-week mortality in Groups 3 and 4 was 16% and 10%, respectively. Common drug-related adverse events included nausea, mucositis and hemorrhage. Conclusion Decitabine and GO improved the response rate but not OS compared to historical outcomes in untreated AML ≥60 years. PMID:26365212

  9. Intrathecal donor lymphocyte infusion for isolated leukemia relapse in the central nervous system following allogeneic stem cell transplantation: a case report and literature review.

    PubMed

    Yanagisawa, Ryu; Nakazawa, Yozo; Sakashita, Kazuo; Saito, Shoji; Tanaka, Miyuki; Shiohara, Masaaki; Shimodaira, Shigetaka; Koike, Kenichi

    2016-01-01

    An 8-year-old boy with a bone marrow relapse of T cell acute lymphoblastic leukemia underwent stem-cell transplantation from a human leukocyte antigen (HLA)-haploidentical mother. Five months later, he relapsed with central nervous system (CNS) involvement. Systemic chemotherapy and repeated intrathecal chemotherapy induced consciousness disturbances and frequent arrhythmia, prompting us to discontinue the chemotherapy. He had already received an 18-Gy prophylactic cranial irradiation, an 8-Gy total body irradiation, and a 15-Gy local irradiation for pituitary gland involvement. We therefore performed five intrathecal donor lymphocyte infusions (IDLIs) in escalating doses from 1 × 10(4) up to 1 × 10(6) cells/kg. All IDLIs were safe without infusion reactions or graft-versus-host disease. After the second and later IDLIs, donor mononuclear cells were continuously detected in cerebrospinal fluid; however, he did not achieve donor-dominant chimerism. Based on our case and four cases reported in the literature, the efficacy of IDLI therapy is limited for CNS relapse of hematological malignancies. However, we suggest that IDLI remains a feasible and safe option, as no GVHD or other adverse effects occurred, even in the HLA-haploidentical setting. We will make further efforts to increase the efficacy. PMID:26586462

  10. An open-label, pilot study of fludarabine, cyclophosphamide, and alemtuzumab in relapsed/refractory patients with B-cell chronic lymphocytic leukemia.

    PubMed

    Montillo, Marco; Tedeschi, Alessandra; Petrizzi, Valeria Belsito; Ricci, Francesca; Crugnola, Monica; Spriano, Mauro; Spedini, Pierangelo; Ilariucci, Fiorella; Uziel, Lilj; Attolico, Immacolata; Vismara, Eleonora; De Blasio, Angelo; Zaccaria, Alfonso; Morra, Enrica

    2011-10-13

    Although combination regimens have improved outcomes over monotherapy in chronic lymphocytic leukemia (CLL), patients eventually relapse. Combined fludarabine, cyclophosphamide, and monoclonal anti-CD52 antibody alemtuzumab (FCC) provided synergistic cytotoxicity with effective clearing of minimal residual disease. This phase 2 study determined FCC efficacy and safety in relapsed/refractory CD52(+) B-CLL after ≥ 1 line of treatment. From January 2005 through June 2008, up to 6 courses of oral fludarabine 40 mg/m² per day, oral cyclophosphamide 250 mg/m² per day, and subcutaneous alemtuzumab (Mab-Campath) 10 mg (increased to 20 mg after first 10-patient cohort) were administered days 1 to 3 every 28 days. The primary objective was overall response rate (ORR); secondary objectives included response duration, time to disease progression, and safety and tolerability. ORR was 67% in 43 patients; 30% achieved complete response. ORR significantly improved with 1 versus ≥ 2 prior therapies (P = .018), and without versus with previous monoclonal antibody treatment (P = .003). Median progression-free survival was 24.4 months, not reached in patients achieving complete response. Median overall survival was 33.6 months. Myelosuppression was the most common adverse event, with a low percentage of cytomegalovirus reactivations and manageable infections. However, close vigilance of opportunistic infections is warranted. FCC provides effective immunotherapy in relapsed/refractory CLL, including in patients with poor-risk prognostic factors. PMID:21772050

  11. Association of ITPA Genotype with Event-Free Survival and Relapse Rates in Children with Acute Lymphoblastic Leukemia Undergoing Maintenance Therapy

    PubMed Central

    Smid, Alenka; Karas-Kuzelicki, Natasa; Milek, Miha; Jazbec, Janez; Mlinaric-Rascan, Irena

    2014-01-01

    Although the treatment of acute lymphoblastic leukemia (ALL) has improved significantly over recent decades, failure due to treatment-related toxicities and relapse of the disease still occur in about 20% of patients. This retrospective study included 308 pediatric ALL patients undergoing maintenance therapy and investigated the effects of genetic variants of enzymes involved in the 6-mercaptopurine (6-MP) metabolism and folate pathway on survival and relapse rates. The presence of at least one of the non-functional ITPA alleles (94C>A and/or IVS2+21A>C variant) was associated with longer event-free survival compared to patients with the wild-type ITPA genotype (p = 0.033). Furthermore, patients carrying at least one non-functional ITPA allele were shown to be at a lower risk of suffering early (p = 0.003) and/or bone marrow relapse (p = 0.017). In conclusion, the ITPA genotype may serve as a genetic marker for the improvement of risk stratification and therapy individualization for patients with ALL. PMID:25303517

  12. Quantitative morphologic evaluation of magnetic resonance imaging during and after treatment of childhood leukemia

    PubMed Central

    Reddick, Wilburn E.; Laningham, Fred H.; Glass, John O.; Pui, Ching-Hon

    2008-01-01

    Introduction Medical advances over the last several decades, including CNS prophylaxis, have greatly increased survival in children with leukemia. As survival rates have increased, clinicians and scientists have been afforded the opportunity to further develop treatments to improve the quality of life of survivors by minimizing the long-term adverse effects. When evaluating the effect of antileukemia therapy on the developing brain, magnetic resonance (MR) imaging has been the preferred modality because it quantifies morphologic changes objectively and noninvasively. Method and results Computer-aided detection of changes on neuroimages enables us to objectively differentiate leukoencephalopathy from normal maturation of the developing brain. Quantitative tissue segmentation algorithms and relaxometry measures have been used to determine the prevalence, extent, and intensity of white matter changes that occur during therapy. More recently, diffusion tensor imaging has been used to quantify microstructural changes in the integrity of the white matter fiber tracts. MR perfusion imaging can be used to noninvasively monitor vascular changes during therapy. Changes in quantitative MR measures have been associated, to some degree, with changes in neurocognitive function during and after treatment Conclusion In this review, we present recent advances in quantitative evaluation of MR imaging and discuss how these methods hold the promise to further elucidate the pathophysiologic effects of treatment for childhood leukemia. PMID:17653705

  13. Elevated incidence of childhood leukemia in Woburn, Massachusetts: NIEHS Superfund Basic Research Program searches for causes.

    PubMed Central

    Durant, J L; Chen, J; Hemond, H F; Thilly, W G

    1995-01-01

    Between 1966 and 1986, the childhood leukemia rate in Woburn, Massachusetts, was 4-fold higher than the national average. A multidisciplinary research team from MIT, which is being supported by the NIEHS Superfund Basic Research Program, has explored the possible importance of a temporal correlation between the period of elevated leukemia and a previously unrecognized mobilization of toxic metals from a waste disposal site in north Woburn. Residents of Woburn may have been exposed to arsenic (70 micrograms/l) and chromium (240 micrograms/l) at levels in excess of federal drinking water standards (50 micrograms/l for each metal) by consuming municipal groundwater contaminated with these metals. Research is currently underway a) to elucidate the mechanisms and the pathways by which these metals were transported from the waste disposal site to the drinking water supply; b) to determine the identity of the principal human cell mutagens in samples of aquifer materials collected from the site of the municipal supply wells; and c) to measure the extent of exposure and genetic change in residents who consumed the contaminated well water. Images Figure 8. PMID:8549500

  14. Childhood Leukemia and 50 Hz Magnetic Fields: Findings from the Italian SETIL Case-Control Study

    PubMed Central

    Salvan, Alberto; Ranucci, Alessandra; Lagorio, Susanna; Magnani, Corrado

    2015-01-01

    We report on an Italian case-control study on childhood leukemia and exposure to extremely low frequency magnetic fields (ELF-MF). Eligible for inclusion were 745 leukemia cases, aged 0–10 years at diagnosis in 1998–2001, and 1475 sex- and age-matched population controls. Parents of 683 cases and 1044 controls (92% vs. 71%) were interviewed. ELF-MF measurements (24–48 h), in the child’s bedroom of the dwelling inhabited one year before diagnosis, were available for 412 cases and 587 controls included in the main conditional regression analyses. The magnetic field induction was 0.04 μT on average (geometric mean), with 0.6% of cases and 1.6% of controls exposed to >0.3 μT. The impact of changes in the statistical model, exposure metric, and data-set restriction criteria was explored via sensitivity analyses. No exposure-disease association was observed in analyses based on continuous exposure, while analyses based on categorical variables were characterized by incoherent exposure-outcome relationships. In conclusion, our results may be affected by several sources of bias and they are noninformative at exposure levels >0.3 μT. Nonetheless, the study may contribute to future meta- or pooled analyses. Furthermore, exposure levels among population controls are useful to estimate attributable risk. PMID:25689995

  15. Childhood leukemia and 50 Hz magnetic fields: findings from the Italian SETIL case-control study.

    PubMed

    Salvan, Alberto; Ranucci, Alessandra; Lagorio, Susanna; Magnani, Corrado

    2015-02-01

    We report on an Italian case-control study on childhood leukemia and exposure to extremely low frequency magnetic fields (ELF-MF). Eligible for inclusion were 745 leukemia cases, aged 0-10 years at diagnosis in 1998-2001, and 1475 sex- and age-matched population controls. Parents of 683 cases and 1044 controls (92% vs. 71%) were interviewed. ELF-MF measurements (24-48 h), in the child's bedroom of the dwelling inhabited one year before diagnosis, were available for 412 cases and 587 controls included in the main conditional regression analyses. The magnetic field induction was 0.04 μT on average (geometric mean), with 0.6% of cases and 1.6% of controls exposed to >0.3 μT. The impact of changes in the statistical model, exposure metric, and data-set restriction criteria was explored via sensitivity analyses. No exposure-disease association was observed in analyses based on continuous exposure, while analyses based on categorical variables were characterized by incoherent exposure-outcome relationships. In conclusion, our results may be affected by several sources of bias and they are noninformative at exposure levels >0.3 μT. Nonetheless, the study may contribute to future meta- or pooled analyses. Furthermore, exposure levels among population controls are useful to estimate attributable risk. PMID:25689995

  16. Heavy Metal Content in Airborne Dust of Childhood Leukemia Cluster Areas: Even Small Towns Have Air Pollutants

    NASA Astrophysics Data System (ADS)

    Sheppard, P. R.; Witten, M. L.

    2004-12-01

    Currently in the US, there are at least two ongoing clusters of childhood leukemia, where the incidence rate over the last several years has exceeded the national norm. In Fallon, Nevada, a town of 8,000 people, 16 children have been diagnosed with leukemia since 1995, three of whom have died. In Sierra Vista, Arizona, a town of 38,000 people, 12 children have been diagnosed since 1998, two of whom have died. A possible third cluster of childhood leukemia and other cancers is being monitored in Elk Grove, California, a suburb of Sacramento. For the purpose of characterizing the heavy metal content of airborne dust of these three communities, total suspended particulate samples were collected from each town as well as from nearby towns that could be considered as control comparisons. Sampling was done using portable high-volume blowers and glass- or quartz-fiber filter media. Filters were measured for elemental concentrations using inductively coupled plasma mass spectroscopy. To date, our most notable results are from the Nevada region. Compared to other control towns in the region, Fallon had significantly more tungsten in its airborne dust. Uranium was also higher in dust of Fallon than in other control towns. Uranium is a known health hazard, though it is not necessarily specifically related to childhood leukemia. The role of tungsten in childhood leukemia has not been widely studied. However, other research has identified tungsten exposure as an environmental concern in Fallon. A CDC study of human tissue samples from Fallon has shown high tungsten levels in people of Fallon, and a USGS study of drinking water in Fallon also has shown high tungsten there. Tree-ring research on selected trees has shown high tungsten values in recent rings compared to earlier rings. While these multiple indications of tungsten in the Fallon environment do not directly lead to the conclusion that tungsten causes leukemia, they do combine to suggest that biomedical research on the

  17. Genomic profiling of pediatric acute myeloid leukemia reveals a changing mutational landscape from disease diagnosis to relapse | Office of Cancer Genomics

    Cancer.gov

    The genomic and clinical information used to develop and implement therapeutic approaches for AML originated primarily from adult patients and has been generalized to patients with pediatric AML. However, age-specific molecular alterations are becoming more evident and may signify the need to age-stratify treatment regimens. The NCI/COG TARGET-AML initiative employed whole exome capture sequencing (WXS) to interrogate the genomic landscape of matched trios representing specimens collected upon diagnosis, remission, and relapse from 20 cases of de novo childhood AML.

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

    ClinicalTrials.gov

    2016-04-08

    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

  19. Residential Levels of Polybrominated Diphenyl Ethers and Risk of Childhood Acute Lymphoblastic Leukemia in California

    PubMed Central

    Colt, Joanne S.; Deziel, Nicole C.; Whitehead, Todd P.; Reynolds, Peggy; Gunier, Robert B.; Nishioka, Marcia; Dahl, Gary V.; Rappaport, Stephen M.; Buffler, Patricia A.; Metayer, Catherine

    2014-01-01

    Background: House dust is a major source of exposure to polybrominated diphenyl ethers (PBDEs), which are found at high levels in U.S. homes. Methods: We studied 167 acute lymphoblastic leukemia (ALL) cases 0–7 years of age and 214 birth certificate controls matched on date of birth, sex, and race/ethnicity from the Northern California Childhood Leukemia Study. In 2001–2007, we sampled carpets in the room where the child spent the most time while awake; we used a high-volume small-surface sampler or we took dust from the home vacuum. We measured concentrations of 14 PBDE congeners including penta (28, 47, 99, 100, 153, 154), octa (183, 196, 197, 203), and decaBDEs (206–209). Odds ratios (ORs) were calculated using logistic regression, adjusting for demographics, income, year of dust collection, and sampling method. Results: BDE-47, BDE-99, and BDE-209 were found at the highest concentrations (medians, 1,173, 1,579, and 938 ng/g, respectively). Comparing the highest to lowest quartile, we found no association with ALL for summed pentaBDEs (OR = 0.7; 95% CI: 0.4, 1.3), octaBDEs (OR = 1.3; 95% CI: 0.7, 2.3), or decaBDEs (OR = 1.0; 95% CI: 0.6, 1.8). Comparing homes in the highest concentration (nanograms per gram) tertile to those with no detections, we observed significantly increased ALL risk for BDE-196 (OR = 2.1; 95% CI: 1.1, 3.8), BDE-203 (OR = 2.0; 95% CI: 1.1, 3.6), BDE-206 (OR = 2.1; 95% CI: 1.1, 3.9), and BDE-207 (OR = 2.0; 95% CI: 1.03, 3.8). Conclusion: We found no association with ALL for common PBDEs, but we observed positive associations for specific octa and nonaBDEs. Additional studies with repeated sampling and biological measures would be informative. Citation: Ward MH, Colt JS, Deziel NC, Whitehead TP, Reynolds P, Gunier RB, Nishioka M, Dahl GV, Rappaport SM, Buffler PA, Metayer C. 2014. Residential levels of polybrominated diphenyl ethers and risk of childhood acute lymphoblastic leukemia in California. Environ Health Perspect 122:1110–1116

  20. [Phenomenon of the evolution of clonal chromosomal abnormalities in childhood acute myeloid leukemia].

    PubMed

    Andreeva, S V; Drozdova, V D; Kavardakova, N V

    2010-01-01

    Analysis of chromosomal abnormalities in bone marrow cells in 116 children with diagnosis of acute myeloid leukemia (AML) was performed. Frequency of evolution of clonal chromosome abnormalities in AML constituted 42,3%. The most abundant among them were numerical abnormalities of chromosomes 8, 9, and 21 as well as secondary structural abnormalities in region 12p12, 9p22, 9q22, 9q34, 11q14-23, and 16q22. Numerical abnormalities were registered in 26,7% cases. The basic mechanism of leukemic clone evolution was trisomy, deletion and monosomy. The frequency of evolution was 7 times higher in the age group up to 2 years and twice higher in the age group up to 5 years. The high frequency of evolution was established at t(15;17)(q22;q22) and the absence at inv(16)(p13q22). The patients with clonal evolution died earlier, before reaching remission, that can be connected with heavy initial state and high frequency of relapse. Conception of abnormality clone evolution was proposed at some stages: I--appearance of balanced rearrangement; II--trisomy; III--lose of chromosomal material. Appearance of unbalanced genome in evolution possess an advantage in proliferate activity and can be connected with the answer on chemotherapy. Identity of abnormal chromosome structure at diagnosis and relapse of disease can be an evidence of the influence of chemical agent on establishment of some types of evolution of chromosome abnormalities in leukemic cells in AML in children. PMID:20608159

  1. [Clinical efficacy of decitabine combined with modified CAG regimen for relapsed-refractory acute myeloid leukemia with AML1-ETO⁺].

    PubMed

    Jing, Yu; Zhu, Cheng-Ying; Zhang, Qi; Niu, Jian-Hua; Yang, Hua; Liu, Shi-Yan; Zhu, Hai-Yan; Yu, Li

    2014-10-01

    This study was aimed to investigate the clinical characteristics of relapsed-refractory acute myeloid leukemia (AML) with AML1-ETO⁺, and its therapeutic efficacy and side effects when decitabine combined with modified CAG regimen was used. Clinical data of 5 cases of AML with AML1-ETO⁺ from January 2013 to Agust 2013 were analyzed retrospectively. The analyzed data included age, sex, initial symptoms, peripheral blood and bone marrow characteristics. Meanwhile, the therapeutic effecacy and side effects of decitabine combined with modified CAG regimen were evaluated. The 5 patients were with median age of 35 (17-43) years. Among these 5 patients, 2 patients were relapsed and other 3 patients were relapsed-refractory patients, their median white blood cell count was 12.55 (7.8-66.55) × 10⁹/L, median platelets count was 44 (20-72) × 10⁹/L, median hemoglobin level was 110 (77-128) g/L, median lactate dehydrogenase level was 312.9 U/L (123.6-877.8) at the initial diagnosis. The results showed that after decitabine combined with modified CAG regimen was administered, 4 patients achieved complete remission, 1 patient did not achieve remission, the overall remission rate was 80% (4/5). The main side effects of this regimen was myelosuppression, these were no new lung infection and other serious complications, one case without complete remission treated with FLAG once again died of heart failure when being mobilized for transplantation. It is concluded that according to preliminary results of decitabine combined with modified CAG regimen for relapsed and refractory AML patients with AML1-ETO⁺ displays higher remission rate and lower side effects, which worthy to further explore for clinal application. PMID:25338566

  2. Human leukocyte antigen-DRB1 polymorphism in childhood acute lymphoblastic leukemia

    PubMed Central

    EL ANSARY, MERVAT M.; MOHAMMED, LAMIAA A.; HASSAN, TAMER H.; BARAKA, AHMED; AHMED, ALSHYMAA A.

    2015-01-01

    Similar to autoimmune diseases, there are clear associations between resistance or susceptibility to cancer and the classic human leukocyte antigen (HLA) profile of an individual. HLA-associated susceptibility to childhood acute lymphoblastic leukemia (ALL) may provide clues to leukemogenesis in general and to the role of other risk factors. The present study aimed to determine the association between the HLA-DRB1 genotype and susceptibility to ALL in children and to assess the prognostic value of HLA-DRB1 alleles in these patients. This study included 50 ALL patients who were consecutively admitted to the Pediatric Oncology Unit of Zagazig University Hospital and 50 gender-matched healthy volunteers as a control group. The patients were subjected to full clinical history, thorough clinical examination and routine laboratory investigations. Molecular HLA-DRB1 typing for patients and controls using the reverse sequence-specific oligonucleotide probe technique was performed. HLA-DRB1*04 allele frequency was significantly higher in female patients compared to that in female controls (P=0.03) and in patients aged <10 years compared to those aged ≥10 years at the time of diagnosis (P=0.01). HLA-DRB1*11 allele frequency was significantly higher in high-risk compared to standard-risk patients (P=0.01) and in refractory patients compared to those who achieved remission (P=0.02). In conclusion, the HLA-DRB1*04 allele appears to be a female-specific susceptibility factor for the acquisition of childhood ALL and it may affect the age of onset of ALL. In addition, the HLA-DRB1*11 allele may be of prognostic significance in childhood ALL. However, further larger studies are required to support the conclusions drawn from this study. PMID:25798280

  3. Next-generation-sequencing of recurrent childhood high hyperdiploid acute lymphoblastic leukemia reveals mutations typically associated with high risk patients.

    PubMed

    Chen, Cai; Bartenhagen, Christoph; Gombert, Michael; Okpanyi, Vera; Binder, Vera; Röttgers, Silja; Bradtke, Jutta; Teigler-Schlegel, Andrea; Harbott, Jochen; Ginzel, Sebastian; Thiele, Ralf; Husemann, Peter; Krell, Pina F I; Borkhardt, Arndt; Dugas, Martin; Hu, Jianda; Fischer, Ute

    2015-09-01

    20% of children suffering from high hyperdiploid acute lymphoblastic leukemia develop recurrent disease. The molecular mechanisms are largely unknown. Here, we analyzed the genetic landscape of five patients at relapse, who developed recurrent disease without prior high-risk indication using whole-exome- and whole-genome-sequencing. Oncogenic mutations of RAS pathway genes (NRAS, KRAS, FLT3, n=4) and deactivating mutations of major epigenetic regulators (CREBBP, EP300, each n=2 and ARID4B, EZH2, MACROD2, MLL2, each n=1) were prominent in these cases and virtually absent in non-recurrent cases (n=6) or other pediatric acute lymphoblastic leukemia cases (n=18). In relapse nucleotide variations were detected in cell fate determining transcription factors (GLIS1, AKNA). Structural genomic alterations affected genes regulating B-cell development (IKZF1, PBX1, RUNX1). Eleven novel translocations involved the genes ART4, C12orf60, MACROD2, TBL1XR1, LRRN4, KIAA1467, and ELMO1/MIR1200. Typically, patients harbored only single structural variations, except for one patient who displayed massive rearrangements in the context of a germline tumor suppressor TP53 mutation and a Li-Fraumeni syndrome-like family history. Another patient harbored a germline mutation in the DNA repair factor ATM. In summary, the relapse patients of our cohort were characterized by somatic mutations affecting the RAS pathway, epigenetic and developmental programs and germline mutations in DNA repair pathways. PMID:26189108

  4. Ibrutinib or Idelalisib in Treating Patients With Persistent or Relapsed Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, or Non-Hodgkin Lymphoma After Donor Stem Cell Transplant

    ClinicalTrials.gov

    2016-04-08

    Chronic Lymphocytic Leukemia; Non-Hodgkin Lymphoma; Prolymphocytic Leukemia; Recurrent Chronic Lymphocytic Leukemia; Recurrent Non-Hodgkin Lymphoma; Recurrent Small Lymphocytic Lymphoma; Small Lymphocytic Lymphoma

  5. Reentry of nondividing leukemic cells into a proliferative phase in acute childhood leukemia

    PubMed Central

    Saunders, E. F.; Mauer, A. M.

    1969-01-01

    Reentry of small leukemic blast cells into a proliferative phase was demonstrated in a 3 yr old girl with untreated acute lymphoblastic leukemia. Since the proliferating leukemic cell compartment in this disease is not self-maintaining, continual entry of cells into this compartment is necessary to prevent depletion of proliferating cells. In order to identify the source of replacement cells, the rate of change of tritiated thymidine-labeled cells in the proliferating compartment was observed by means of serial bone marrow samples under two conditions. In the first study period only 10% of small leukemic blast cells were labeled, and in the second study period 72% of this population had become lebeled. During the first period the proliferating blast cells were rapidly replaced by unlabeled cells, while during the second period the replacement cells were coming largely from a labeled cell source. The only identifiable source of cells for maintenance of the proliferating population which was virtually unlabeled during the first period and largely labeled during the second period was the population of small leukemic blast cells. The finding that the small blast cells are only temporarily nonproliferative could account for effectiveness of therapy directed primarily against a dividing cell population. Persistence of some cells with longer resting times into remission could provide a focus for subsequent relapse. PMID:5256065

  6. Experience with four consecutive BFM-based protocols for treatment of childhood with non-promyelocytic acute myeloblastic leukemia in Argentina.

    PubMed

    Felice, Maria S; Rossi, Jorge G; Alonso, Cristina N; Gallego, Marta S; Eberle, Silvia Eandi; Alfaro, Elizabeth M; Guitter, Myriam R; Bernasconi, Andrea R; Rubio, Patricia L; Coccé, Mariela C; Zubizarreta, Pedro A

    2016-09-01

    Childhood acute myeloid leukemia (AML) achieves event-free-survival (EFS) rates of ∼50%. Double induction phase has been introduced for improving these results. Four consecutive protocols for AML treatment were evaluated to assess the impact of the addition of a second induction course in our setting. From January 1990 to January 2014, 307 evaluable AML patients were accrued. They were classified into low-risk (LR) and high-risk (HR) according to cytogenetic/molecular findings and response on day 15. The first two studies administered one induction cycle while the latter two protocols administered double induction. Relapse was the most frequent event and early-deaths were reduced by 50% in the last protocol. Statistically significant differences were observed when comparing EFS in LR and HR groups. Patients from both risk-groups who received double induction achieved significantly better outcome. EFS improved in protocols with double induction and early-deaths rate was decreased. Cytogenetic/molecular features and early-response were confirmed as prognostic factors. PMID:26734812

  7. Alemtuzumab and Combination Chemotherapy in Treating Patients With Untreated Acute Lymphoblastic Leukemia

    ClinicalTrials.gov

    2014-03-20

    Acute Undifferentiated Leukemia; B-cell Adult Acute Lymphoblastic Leukemia; B-cell Childhood Acute Lymphoblastic Leukemia; L1 Adult Acute Lymphoblastic Leukemia; L1 Childhood Acute Lymphoblastic Leukemia; L2 Adult Acute Lymphoblastic Leukemia; L2 Childhood Acute Lymphoblastic Leukemia; Philadelphia Chromosome Negative Adult Precursor Acute Lymphoblastic Leukemia; Philadelphia Chromosome Positive Adult Precursor Acute Lymphoblastic Leukemia; Philadelphia Chromosome Positive Childhood Precursor Acute Lymphoblastic Leukemia; T-cell Adult Acute Lymphoblastic Leukemia; T-cell Childhood Acute Lymphoblastic Leukemia; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Childhood Acute Lymphoblastic Leukemia

  8. 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

    2016-04-05

    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); RUNX1-RUNX1T1; Adult Acute Myeloid Leukemia With t(9;11)(p22;q23); MLLT3-MLL; 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; 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

  9. Growth hormone deficiency predicts cardiovascular risk in young adults treated for acute lymphoblastic leukemia in childhood.

    PubMed

    Link, Katarina; Moëll, Christian; Garwicz, Stanislaw; Cavallin-Ståhl, Eva; Björk, Jonas; Thilén, Ulf; Ahrén, Bo; Erfurth, Eva Marie

    2004-10-01

    Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy, and until recently prophylactic cranial radiotherapy (CRT) was important for achieving long-term survival. Hypothalamic-pituitary hormone insufficiency is a well-recognized consequence of CRT for childhood cancer. Another problem is increased cardiovascular risk, which has been shown in long-term survivors of other childhood cancers. In the only previously reported study on cardiovascular risk after childhood ALL, obesity and dyslipidemia were recorded in a small subgroup treated with CRT, compared with patients treated with chemotherapy. The mechanisms behind the increase in cardiovascular risk in survivors of childhood cancer are not clarified. The aim of the present study was to elucidate mechanisms of increased cardiovascular risk in former childhood ALL patients. A group of 44 ALL survivors (23 males, median age 25 yr, range 19-32 yr at the time of study) treated with CRT (median 24 Gy, 18-30 Gy) at a median age of 5 yr (1-18 yr) and chemotherapy were investigated for prevalence of GH deficiency and cardiovascular risk factors. Comparison was made with controls randomly selected from the general population and individually matched for sex, age, smoking habits, and residence. All patients and controls underwent a GHRH-arginine test, and patients with a peak GH 3.9 microg/liter or greater were further investigated with an additional insulin tolerance test. Significantly higher plasma levels of insulin (P = 0.002), blood glucose (P = 0.01), and serum levels of low-density lipoprotein cholesterol, apolipoprotein (Apo) B, triglycerides, fibrinogen, and leptin (all P

  10. Same sibling marrow following cord allogeneic transplantation as therapy for second relapse acute promyelocytic leukemia in a pediatric patient.

    PubMed

    De Oliveira, Satiro N; Kao, Roy L; Pham, Andrew; Smith, LaMarr Taylor; Kempert, Pamela; Moore, Theodore B

    2016-03-01

    Optimal therapy for relapsed APL in pediatric patients is controversial. Allogeneic HSCT is an alternative, with event-free survival of 70-75%. We report a pediatric patient with APL who relapsed 28 months after CBT from her sibling and then was treated with BMT from the same donor. Bone marrow was selected for higher cell dose, donor availability, and partial donor chimerism. Persistent molecular remission was achieved, currently at 65 months after BMT. This case suggests the potential role of GVL activity in APL and illustrates the use of different cell sources from the same donor in allogeneic transplantation for pediatric patients. PMID:26849401

  11. Prelabor cesarean delivery and early-onset acute childhood leukemia risk.

    PubMed

    Thomopoulos, Thomas P; Skalkidou, Alkistis; Dessypris, Nick; Chrousos, George; Karalexi, Maria A; Karavasilis, Theodoros G; Baka, Margarita; Hatzipantelis, Emmanuel; Kourti, Maria; Polychronopoulou, Sophia; Sidi, Vasiliki; Stiakaki, Eftichia; Moschovi, Maria; Loutradis, Dimitrios; Petridou, Eleni Th

    2016-03-01

    The long-term impact of cesarean delivery (CD) on the health of the offspring is being explored methodically. We sought to investigate the effect of birth by (a) prelabor and (b) during-labor CD on the risk of early-onset (≤3 years) acute lymphoblastic leukemia (ALL), specifically of its prevailing precursor B (B-ALL) subtype. A total of 1099 incident cases of ALL (957 B-ALL), 131 of acute myeloid leukemia (AML), and their 1 : 1 age-matched and sex-matched controls, derived from the Nationwide Registry for Childhood Hematological Malignancies (1996-2013), were analyzed using multivariate regression models. A null association was found between prelabor and/or during labor CD and either ALL (B-ALL) or AML in the 0-14 age range. By contrast, birth by CD increased significantly the risk of early-onset ALL [odds ratioCD (ORCD)=1.57, 95% confidence interval (CI): 1.10-2.24] mainly on account of prelabor CD (ORprelaborCD=1.66, 95% CI: 1.13-2.43). The respective figures were even higher for the early-onset precursor B-ALL (ORCD=1.66, 95% CI: 1.15-2.40 and ORprelaborCD=1.79, 95% CI: 1.21-2.66), whereas no association emerged for early-onset AML. Prelabor CD, which deprives exposure of the fetus/infant to the presumably beneficial effect of stress hormones released in both vaginal labor and during labor CD, was associated exclusively with an increased risk of early-onset ALL, particularly the precursor B-ALL subtype. If confirmed, these adverse long-term outcomes of CD may point to re-evaluation of prelabor CD practices and prompt scientific discussion on the best ways to simulate the effects of vaginal delivery, such as a precesarean induction of labor. PMID:25793919

  12. Chemotherapy versus Hypomethylating Agents for the Treatment of Relapsed Acute Myeloid Leukemia and Myelodysplastic Syndrome after Allogeneic Stem Cell Transplant.

    PubMed

    Motabi, Ibraheem H; Ghobadi, Armin; Liu, Jingxia; Schroeder, Mark; Abboud, Camille N; Cashen, Amanda F; Stockler-Goldstein, Keith E; Uy, Geoffrey L; Vij, Ravi; Westervelt, Peter; DiPersio, John F

    2016-07-01

    Allogeneic stem cell transplantation (allo-SCT) is a potentially curative treatment for high-risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). For patients with relapsed disease after transplantation, intensive chemotherapy followed by donor lymphocyte infusion (DLI) or a second allo-SCT may result in a durable response in some patients. High-intensity chemotherapy and less aggressive therapy with hypomethylating agents (HAs) with and without DLI are often used for relapse after allo-SCT. Here we compared the treatment outcomes of intensive chemotherapy with that of HAs in relapsed AML and MDS after allo-SCT. Patients who had received a second SCT within 90 days of the relapse date were excluded. The primary endpoints were overall response rate (ORR) and overall survival (OS). Secondary endpoints were complete remission (CR) rate and progression-free survival (PFS). One hundred patients were included: 73 patients received chemotherapy and 27 patients received an HA. Fifty-six percent of patients in the chemotherapy group and 33% of patients in the HA group received at least 1 DLI after treatment. Treatment with chemotherapy resulted in a higher ORR (51% versus 19%, P = .004) and a higher CR rate (40% versus 7%, P = .002). The median OS (6 versus 3.9 months, P = .01) and PFS (4.9 versus 3.8 months, P = .02) were longer in the chemotherapy group. Similar benefit of chemotherapy over HAs was maintained in all treatment outcomes after controlling for the use of DLI. The use of chemotherapy followed by DLI offered the greatest benefit (ORR, 68%; CR, 59%, 1-year OS, 44%; and median OS, 9.8 months). In conclusion, in our hands, with limited numbers, the use of more conventional salvage chemotherapy, with DLI when possible, for the treatment of relapsed AML and MDS after allo-SCT is associated with better outcomes than nonchemotherapy (HA) options. PMID:27026249

  13. Phase I Trial of AZD1775 and Belinostat in Treating Patients With Relapsed or Refractory Myeloid Malignancies or Untreated Acute Myeloid Leukemia

    ClinicalTrials.gov

    2016-07-20

    Blast Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Previously Treated Myelodysplastic Syndrome; Recurrent Adult Acute Myeloid Leukemia; Refractory Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Secondary Acute Myeloid Leukemia; Therapy-Related Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

  14. Phase II Randomized Study of p53 Antisense Oligonucleotide (Cenersen) plus Idarubicin With or Without Cytarabine in Refractory and Relapsed Acute Myeloid Leukemia

    PubMed Central

    Cortes, J; Kantarjian, H; Ball, E D; DiPersio, J; Kolitz, J E; Fernandez, H F; Goodman, M; Borthakur, G; Baer, Maria R; Wetzler, Meir

    2016-01-01

    Background The p53 antisense oligonucleotide cenersen has been shown to sensitize acute myeloid leukemia (AML) stem cells to DNA damaging agents. Methods To determine if cenersen merits testing in larger efficacy studies, an exploratory study of cenersen in combination with idarubicin either alone or with one of two doses of cytarabine was performed in first salvage AML patients. Patients who either had failed to respond to a single induction course or had responded to induction but relapsed within 12 months were enrolled. Stopping rules based on an expected 14% complete response (CR) rate were applied to each treatment arm. Results Fifty-three patients were treated and none of the arms was terminated for lack of activity. Nearly all patients received a single course unless they responded. Ten of the 53 (19%) patients responded (8 CR and 2 CR with incomplete platelet recovery [CRp]). There was a positive trend for a better response rate with increasing intensity of chemotherapy in the patients refractory to frontline treatment compared to those who had previously relapsed. One-third (17/53) of the patients received cenersen inhibitors (acetaminophen and/or high dose antioxidants) during treatment and none of these responded to treatment. No unique toxicity was attributed to cenersen. Conclusion These results suggest that the combination of cenersen with chemotherapy may have clinical efficacy and additional studies are warranted to explore its full potential. PMID:21717444

  15. Lenalidomide treatment and prognostic markers in relapsed or refractory chronic lymphocytic leukemia: data from the prospective, multicenter phase-II CLL-009 trial

    PubMed Central

    Bühler, A; Wendtner, C-M; Kipps, T J; Rassenti, L; Fraser, G A M; Michallet, A-S; Hillmen, P; Dürig, J; Gregory, S A; Kalaycio, M; Aurran-Schleinitz, T; Trentin, L; Gribben, J G; Chanan-Khan, A; Purse, B; Zhang, J; De Bedout, S; Mei, J; Hallek, M; Stilgenbauer, S

    2016-01-01

    Efficacy of lenalidomide was investigated in 103 patients with relapsed/refractory chronic lymphocytic leukemia (CLL) treated on the prospective, multicenter randomized phase-II CLL-009 trial. Interphase cytogenetic and mutational analyses identified TP53 mutations, unmutated IGHV, or del(17p) in 36/96 (37.5%), 68/88 (77.3%) or 22/92 (23.9%) patients. The overall response rate (ORR) was 40.4% (42/104). ORRs were similar irrespective of TP53 mutation (36.1% (13/36) vs 43.3% (26/60) for patients with vs without mutation) or IGHV mutation status (45.0% (9/20) vs 39.1% (27/68)); however, patients with del(17p) had lower ORRs than those without del(17p) (21.7% (5/22) vs 47.1% (33/70); P=0.049). No significant differences in progression-free survival and overall survival (OS) were observed when comparing subgroups defined by the presence or absence of high-risk genetic characteristics. In multivariate analyses, only multiple prior therapies (⩾3 lines) significantly impacted outcomes (median OS: 21.2 months vs not reached; P=0.019). This analysis indicates that lenalidomide is active in patients with relapsed/refractory CLL with unfavorable genetic profiles, including TP53 inactivation or unmutated IGHV. (ClinicalTrials.gov identifier: NCT00963105). PMID:26967821

  16. Spontaneous remission of acute myeloid leukemia relapse after hematopoietic cell transplantation in a high-risk patient with 11q23/MLL abnormality.

    PubMed

    Hudecek, Michael; Bartsch, Kristina; Jäkel, Nadja; Heyn, Simone; Pfannes, Roald; Al-Ali, Haifa Kathrin; Cross, Michael; Pönisch, Wolfram; Gerecke, Ulrich; Edelmann, Jeanett; Ittel, Thomas; Niederwieser, Dietger

    2008-01-01

    A 35-year-old female patient was diagnosed with acute myeloid leukemia with multiple genetic aberrations [48 XX, del(3)(q21), +6, t(11;15)(q23;q15), +21] including an 11q23/MLL abnormality. The patient achieved a complete remission after one induction chemotherapy cycle. After three courses of consolidation, a matched unrelated hematopoietic cell transplantation (HCT) was performed. Following an upper respiratory tract infection 7 years after transplant, her blood counts declined to leukocytes of 1 x 10(9)/l, platelets of 51 x 10(9)/l and hemoglobin of 7.5 g/dl. A bone marrow aspirate revealed 55% leukemic blasts carrying the unfavorable genetic aberrations seen at initial diagnosis (11q23/MLL). In the absence of any disease-specific treatment, the leukemic blasts cleared from the bone marrow within 6 days after diagnosis of relapse and peripheral blood counts returned to normal. Molecular analysis of the 11q23/MLL rearrangement was used to evaluate minimal residual disease, which became undetectable in repetitive FISH analyses. This is the first report of spontaneous remission in a patient with initially a multiaberrant leukemic cell clone and a proven 11q23/MLL abnormality at relapse after HCT. PMID:18367831

  17. Relapse and Late Mortality in 5-Year Survivors of Myeloablative Allogeneic Hematopoietic Cell Transplantation for Chronic Myeloid Leukemia in First Chronic Phase

    PubMed Central

    Goldman, John M.; Majhail, Navneet S.; Klein, John P.; Wang, Zhiwei; Sobocinski, Kathleen A.; Arora, Mukta; Horowitz, Mary M.; Rizzo, J. Douglas

    2010-01-01

    Purpose Allogeneic hematopoietic cell transplantation (HCT) is curative therapy for chronic myeloid leukemia (CML), but its long-term outcomes are not well described. We studied the long-term outcomes of CML patients in first chronic phase who receive an allogeneic HCT. Patients and Methods Our study included 2,444 patients who received myeloablative HCT for CML in first chronic phase between 1978 and 1998 and survived in continuous complete remission for at least 5 years (median follow-up, 11 years; range, 5 to 25 years). Donor sources were human leukocyte antigen–matched siblings in 1,692 patients, unrelated donors in 639 patients, and other related donors in 113 patients. Results Overall survival rates at 15 years were 88% (95% CI, 86% to 90%) for sibling HCT and 87% (95% CI, 83% to 90%) for unrelated donor HCT. Corresponding cumulative incidences of relapse were 8% (95% CI, 7% to 10%) and 2% (95% CI, 1% to 4%), respectively. The latest relapse was reported 18 years post-HCT. In multivariable analyses, history of chronic graft-versus-host disease increased risks of late overall mortality and nonrelapse mortality but reduced risks of relapse. In comparison with age-, race-, and sex-adjusted normal populations, the mortality of HCT recipients was significantly higher until 14 years post-HCT; thereafter, mortality rates were similar to those of the general population (relative mortality ratio at 15 years, 2.3; 95% CI, 0 to 4.9). Conclusion Recipients of allogeneic HCT for CML in first chronic phase who remain in remission for at least 5 years have favorable subsequent long-term survival, and their mortality rates eventually approach those of the general population. PMID:20212247

  18. Quantification of Acute Lymphoblastic Leukemia Clonotypes in Leukapheresed Peripheral Blood Progenitor Cells Predicts Relapse Risk after Autologous Hematopoietic Stem Cell Transplantation.

    PubMed

    Mannis, Gabriel N; Martin, Thomas G; Damon, Lloyd E; Andreadis, Charalambos; Olin, Rebecca L; Kong, Katherine A; Faham, Malek; Hwang, Jimmy; Ai, Weiyun Z; Gaensler, Karin M L; Sayre, Peter H; Wolf, Jeffrey L; Logan, Aaron C

    2016-06-01

    Since the incorporation of tyrosine kinase inhibitors into the treatment of Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL), the notion that all patients with "high-risk" ALL uniformly require allogeneic (allo) hematopoietic cell transplantation (HCT) has received increasing scrutiny. Although multiple studies have shown superiority of alloHCT over autologous (auto) hematopoietic cell transplantation for high-risk patients, these findings may be explained, in part, by contamination of the peripheral blood progenitor cell (PBPC) leukapheresis product by residual leukemic cells in patients undergoing autoHCT. We retrospectively evaluated minimal residual disease (MRD) using next-generation sequencing (NGS) in the PBPC leukapheresis product of 32 ALL patients who underwent autoHCT. Twenty-eight patients (88%) had diagnostic samples with quantifiable immunoreceptor rearrangements to follow for MRD. Twelve (38%) patients had Ph+ B-ALL, 12 (38%) had Philadelphia chromosome-negative (Ph-) B-ALL, and 4 (14%) had T cell ALL. With a median follow-up of 41 months (range, 3 to 217), median relapse-free survival (RFS) and overall survival for the entire cohort were 3.2 and 4.2 years, respectively; at 5 years after transplantation, 42% of patients remain alive and relapse free. Using MRD detection at a threshold of ≥ 1 × 10(-6), median RFS for patients with detectable MRD was 6.5 months and was not reached for patients without detectable disease (P = .0005). In multivariate analysis, the only factor significantly associated with relapse was the presence of MRD ≥1 × 10(-6) (odds ratio, 23.8; confidence interval, 1.8 to 312.9; P = .0158). Our findings suggest that NGS for MRD detection can predict long-term RFS in patients undergoing autoHCT for high-risk ALL. PMID:26899561

  19. Voxel Based Analysis of T2 Hyperintensities in White Matter During Treatment for Childhood Leukemia

    PubMed Central

    Reddick, Wilburn E.; Glass, John O.; Johnson, David P.; Laningham, Fred H.; Pui, Ching-Hon

    2009-01-01

    Background and Purpose White matter (WM) hyperintensities on T2-weighted MRI are the most common imaging manifestation of neurotoxic effects of therapy for central nervous system prophylaxis in childhood acute lymphoblastic leukemia (ALL). This project uses voxel-based analyses of T2-weighted imaging of patients during treatment to identify which WM regions are preferentially damaged. Material and Methods Two sets of conventional T2-weighted axial images were acquired on a 1.5T MRI from 197 consecutive patients (85 female / 112 male; aged 1.0-18.9 years) enrolled on an institutional ALL treatment protocol. Images were acquired after completion of induction therapy and after the final of the four courses of intravenous high-dose methotrexate in consolidation therapy (3.9±0.8 months apart). Voxel-wise statistical testing of the incremental change between normalized longitudinal T2 images was performed with radiologist reading (normal or abnormal) and treatment risk-arm as covariates. Results Two highly significant bilateral clusters of T2 signal intensity change were identified in both one-group and two-group analyses. The regions were symmetrical in size, shape, and average signal intensity. Increased T2-weighted signal intensity from these regions both within and between examinations were nonlinear functions of age at examination and the difference between the examinations was greater for older subjects which received more intense therapy. Conclusion These analyses identified specific WM tracts involving predominantly the anterior, superior, and posterior corona radiata and superior longitudinal fasciculus, which were at increased risk of developing T2-weighted hyperintensities during therapy for childhood ALL. These vulnerable regions may be the etiology of subsequent cognitive difficulties consistently observed in survivors. PMID:19643920

  20. Mutational analysis of the candidate tumor suppressor genes TEL and KIP1 in childhood acute lymphoblastic leukemia.

    PubMed

    Stegmaier, K; Takeuchi, S; Golub, T R; Bohlander, S K; Bartram, C R; Koeffler, H P

    1996-03-15

    We have shown previously that loss of heterozygosity at chromosome band 12p13 is among the most frequent genetic abnormalities identified in acute lymphoblastic leukemia (ALL) of childhood. Two known genes map within the critically deleted region of 12p: TEL, the gene encoding a new member of the ETS family of transcription factors, which is rearranged in a variety of hematological malignancies; and KIP1, the gene encoding the cyclin-dependent kinase inhibitor p27. Both genes are, therefore, excellent candidate tumor suppressor genes. In this report, we determined the exon organization of the TEL gene and performed mutational analysis of TEL and KIP1 in 33 childhood ALL patients known to have loss of heterozygosity at this locus. No mutations in either TEL or KIP1 were found; this suggest that neither TEL nor KIP1 is the critical 12p tumor suppressor gene in childhood ALL. PMID:8640833

  1. A phase I trial of the aurora kinase inhibitor, ENMD-2076, in patients with relapsed or refractory acute myeloid leukemia or chronic myelomonocytic leukemia.

    PubMed

    Yee, Karen W L; Chen, Hsiao-Wei T; Hedley, David W; Chow, Sue; Brandwein, Joseph; Schuh, Andre C; Schimmer, Aaron D; Gupta, Vikas; Sanfelice, Deborah; Johnson, Tara; Le, Lisa W; Arnott, Jamie; Bray, Mark R; Sidor, Carolyn; Minden, Mark D

    2016-10-01

    ENMD-2076 is a novel, orally-active molecule that inhibits Aurora A kinase, as well as c-Kit, FLT3 and VEGFR2. A phase I study was conducted to determine the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D) and toxicities of ENMD-2076 in patients with acute myeloid leukemia (AML) and chronic myelomonocytic leukemia (CMML). Patients received escalating doses of ENMD-2076 administered orally daily [225 mg (n = 7), 375 mg (n = 6), 325 mg (n = 9), or 275 mg (n = 5)]. Twenty-seven patients were treated (26 AML; 1 CMML-2). The most common non-hematological toxicities of any grade, regardless of association with drug, were fatigue, diarrhea, dysphonia, dyspnea, hypertension, constipation, and abdominal pain. Dose-limiting toxicities (DLTs) consisted of grade 3 fatigue, grade 3 typhilitis, grade 3 syncope and grade 3 QTc prolongation). Of the 16 evaluable patients, one patient achieved a complete remission with incomplete count recovery (CRi), three experienced a morphologic leukemia-free state (MLFS) with a major hematologic improvement in platelets (HI-P), and 5 other patients had a reduction in marrow blast percentage (i.e. 11-65 %). The RP2D in this patient population is 225 mg orally once daily. PMID:27406088

  2. Decitabine and Total-Body Irradiation Followed By Donor Bone Marrow Transplant and Cyclophosphamide in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

    ClinicalTrials.gov

    2016-07-08

    Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome; 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 Myeloid Leukemia; Secondary Acute Myeloid Leukemia

  3. 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

    2013-10-29

    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

  4. Dissecting the clonal origins of childhood acute lymphoblastic leukemia by single-cell genomics

    PubMed Central

    Gawad, Charles; Koh, Winston; Quake, Stephen R.

    2014-01-01

    Many cancers have substantial genomic heterogeneity within a given tumor, and to fully understand that diversity requires the ability to perform single cell analysis. We performed targeted sequencing of a panel of single nucleotide variants (SNVs), deletions, and IgH sequences in 1,479 single tumor cells from six acute lymphoblastic leukemia (ALL) patients. By accurately segregating groups of cooccurring mutations into distinct clonal populations, we identified codominant clones in the majority of patients. Evaluation of intraclonal mutation patterns identified clone-specific punctuated cytosine mutagenesis events, showed that most structural variants are acquired before SNVs, determined that KRAS mutations occur late in disease development but are not sufficient for clonal dominance, and identified clones within the same patient that are arrested at varied stages in B-cell development. Taken together, these data order the sequence of genetic events that underlie childhood ALL and provide a framework for understanding the development of the disease at single-cell resolution. PMID:25425670

  5. Effects of different forms of central nervous system prophylaxis on neuropsychologic function in childhood leukemia

    SciTech Connect

    Rowland, J.H.; Glidewell, O.J.; Sibley, R.F.; Holland, J.C.; Tull, R.; Berman, A.; Brecher, M.L.; Harris, M.; Glicksman, A.S.; Forman, E.

    1984-12-01

    A comparison of the late effects on intellectual and neuropsychologic function of three different CNS prophylaxis regimens was conducted in 104 patients treated for childhood acute lymphocytic leukemia. Of the children studied, 33 were randomized to treatment with intrathecal (IT) methotrexate alone, 36 to IT methotrexate plus 2,400 rad cranial irradiation, and 35 to IT methotrexate plus intravenous intermediate dose methotrexate. All patients were in their first (complete) continuous remission, were a minimum of one year post-CNS prophylaxis and had no evidence of CNS disease at the time of evaluation. In contrast to the other two treatment groups, children whose CNS prophylaxis included cranial irradiation attained significantly lower mean Full Scale IQs, performed more poorly on the Wide Range Achievement Test, a measure of school abilities, and exhibited a greater number of difficulties on a variety of other neuropsychologic measures. The poorer performance of the irradiated group was independent of sex of the patient, time since treatment and age at diagnosis. These data suggest that the addition of 2,400 rad cranial irradiation to CNS prophylaxis in ALL puts these children at greater risk for mild global loss in intellectual and neuropsychologic ability.

  6. Endothelial Health in Childhood Acute Lymphoid Leukemia Survivors: Pilot Evaluation with Peripheral Artery Tonometry

    PubMed Central

    Ruble, Kathy; Davis, Catherine L; Han, Hae-Ra

    2014-01-01

    Background 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 is to evaluate vascular health using peripheral artery tonometry in ALL survivors and compare results to healthy siblings. Procedure Sixteen ALL survivor, healthy sibling pairs, ages 8-20, 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. Results 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). Conclusion 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. PMID:24577544

  7. 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

  8. A computer-aided method to expedite the evaluation of prognosis for childhood acute lymphoblastic leukemia.

    PubMed

    Wang, Xingwei; Li, Shibo; Liu, Hong; Mulvihill, John J; Chen, Wei; Zheng, Bin

    2006-08-01

    This study presented a fully-automated computer-aided method (scheme) to detect metaphase chromosomes depicted on microscopic digital images, count the total number of chromosomes in each metaphase cell, compute the DNA index, and correlate the results to the prognosis of childhood acute lymphoblastic leukemia (ALL). The computer scheme first uses image filtering, threshold, and labeling algorithms to segment and count the number of the suspicious "chromosome," and then computes a feature vector for each "detected chromosome." Based on these features, a knowledge-based classifier is used to eliminate those "non-chromosome" objects (i.e., inter-phase cells, stain debris, and other kinds of background noises). Due to the possible overlap of the chromosomes, a classification criterion was used to identify the overlapped chromosomes and adjust the initially counted number of the total chromosomes in each image. In this preliminary study with 60 testing images (depicting metaphase chromosome cells) acquired from three pediatric patients, the computer scheme generated results matched with the diagnostic results provided by the clinical cytogeneticists. The results demonstrated the feasibility or potential of using a computerized method to replace the tedious and the reader-dependent diagnostic methods commonly used in genetic laboratories to date. PMID:16866573

  9. FLT3 and NPM1 gene mutations in childhood acute myeloblastic leukemia.

    PubMed

    Mukda, Ekchol; Pintaraks, Katsarin; Sawangpanich, Rachchadol; Wiangnon, Surapon; Pakakasama, Samart

    2011-01-01

    Mutations of receptor tyrosine kinases are implicated in the constitutive activation and development of human hematologic malignancies. Mutations in fms-like tyrosine kinase 3 (FLT3) gene including internal tandem duplication (ITD) and point mutation in the tyrosine kinase domain (TKD) as well as in nucleoplasmin (NPM1) gene are associated with pathogenesis of acute myeloblastic leukemia (AML). Several reports have demonstrated high incidences of the FLT3 and NPM1 mutations in adult AML patients. Since the pathogenesis of pediatric AML is different from that of adult and the FLT3 and NPM1 mutations have not been well characterized in childhood AML. Therefore, the objective of this study was to determine the frequencies of FLT3 and NPM1 mutations in 64 newly diagnosed childhood AML patients. All blood and bone marrow samples were previously diagnosed with AML by using flow cytometry and/or cytochemistry. FLT3-ITD and FLT3-TKD were detected by PCR and PCR-RFLP methods, respectively. The NPM1 mutation was analyzed by PCR and direct DNA sequencing. The FLT3 mutations were detected in 7 of 64 (11.1%), including FLT3-ITD in 4 of 64 (6.3%) and FLT-TKD in 3 of 62 (4.8%). The NPM1 mutation was not detected in this cohort. By multivariate analysis, white blood cell counts, peripheral blood and bone marrow blast cell counts at diagnosis were significantly higher in children with FLT3-ITD (P<0.05). In addition, the median percentage of CD117 was significantly higher in leukemic blast cells with FLT3-ITD than those with wild type (P=0.01). We did not find any FLT3 mutations in children aged less than 5 years. The AML M3 cell type was most frequently associated with FLT3 gene mutations (50%). In conclusion, the FLT3 mutations was found in 11.1% but none of NPM1 mutation was detected in Thai children with AML. These data support the hypothesis of different biology and pathogenesis between adult and childhood AML. PMID:22126574

  10. Impact of prophylactic cranial irradiation for childhood leukemia on subsequent cognitive and problem-solving skills

    SciTech Connect

    Hays, R.C.

    1989-01-01

    Previous research has indicated that children with acute lymphocytic leukemia (ALL), treated with a CNS prophylaxis of 2,400 cGy radiation and intrathecal methotrexate (IT-MTX), demonstrate a decline in both global and specific aspects of their cognitive functioning. Recent changes in treatment protocols for ALL have resulted in a significant reduction in radiation to a dosage of 1,800 cGy, or the elimination of radiation altogether. Today, it is recognized that for low- and average-risk ALL patients the use of intrathecal methotrexate is equally effective for reducing the occurrence of CNS leukemic relapse. Current research has not yet fully determined the impact of this lowered dosage of radiation on later intellectual functioning in survivors of ALL. The present research compared the standardized-test performance of a group of children receiving 1,800 cGy radiation and IT-MTX (n = 15) to a group receiving IT-MTX only (n = 10) as a CNS prophylaxis. All subjects were treated with one leg of the Childrens Cancer Study Group protocols {number sign}161 or {number sign}162, and were evaluated at least 5 years post-diagnosis, while in remission from the disease process. Subjects ranged in age from seven to twelve at the time of participation. Tests administered included the Wechsler Intelligence Scale for Children (WISC-R), the Mental Processing subtests of the Kaufman Assessment Battery for Children (K-ABC), and a variety of tasks which have been indicated to measure different aspects of children's cognitive strategy usage (including Tower of Hanoi and Matching Familiar Figures tasks). Analysis revealed significant performance-differences between these groups as reflected on the WISC-R (Verbal IQ) and on the K-ABC (Sequential Processing score), with the Radiated group performing more poorly than the Non-radiated group.

  11. A comparison of spatial clustering and cluster detection techniques for childhood leukemia incidence in Ohio, 1996 – 2003

    PubMed Central

    Wheeler, David C

    2007-01-01

    Background Spatial cluster detection is an important tool in cancer surveillance to identify areas of elevated risk and to generate hypotheses about cancer etiology. There are many cluster detection methods used in spatial epidemiology to investigate suspicious groupings of cancer occurrences in regional count data and case-control data, where controls are sampled from the at-risk population. Numerous studies in the literature have focused on childhood leukemia because of its relatively large incidence among children compared with other malignant diseases and substantial public concern over elevated leukemia incidence. The main focus of this paper is an analysis of the spatial distribution of leukemia incidence among children from 0 to 14 years of age in Ohio from 1996–2003 using individual case data from the Ohio Cancer Incidence Surveillance System (OCISS). Specifically, we explore whether there is statistically significant global clustering and if there are statistically significant local clusters of individual leukemia cases in Ohio using numerous published methods of spatial cluster detection, including spatial point process summary methods, a nearest neighbor method, and a local rate scanning method. We use the K function, Cuzick and Edward's method, and the kernel intensity function to test for significant global clustering and the kernel intensity function and Kulldorff's spatial scan statistic in SaTScan to test for significant local clusters. Results We found some evidence, although inconclusive, of significant local clusters in childhood leukemia in Ohio, but no significant overall clustering. The findings from the local cluster detection analyses are not consistent for the different cluster detection techniques, where the spatial scan method in SaTScan does not find statistically significant local clusters, while the kernel intensity function method suggests statistically significant clusters in areas of central, southern, and eastern Ohio. The

  12. Persistent Multiyear Control of Relapsed T-Cell Acute Lymphoblastic Leukemia With Successive Donor Lymphocyte Infusions: A Case Report.

    PubMed

    Huo, Jeffrey S; Symons, Heather J; Robey, Nancy; Borowitz, Michael J; Schafer, Eric S; Chen, Allen R

    2016-07-01

    There are few therapeutic options for patients with T-cell acute lymphoblastic leukemia (T-ALL) who have recurrent disease after initial matched sibling hematopoietic stem cell transplantation. While a second hematopoietic stem cell transplant (HSCT) from a haploidentical donor offers the conceptual possibility of greater graft versus leukemia effect, there is minimal literature to describe the efficacy of this approach in recurrent pediatric T-ALL. We present the case of a now 9-year-old female in whom second haploidentical HSCT, followed by successive donor lymphocyte infusions in response to minimal residual disease reemergence, has led to 3+ years of ongoing disease control without graft versus host disease and excellent quality of life. PMID:26990138

  13. 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

  14. Viremia during pregnancy and risk of childhood leukemia and lymphomas in the offspring: Nested case-control study.

    PubMed

    Bzhalava, Davit; Hultin, Emilie; Arroyo Mühr, Laila Sara; Ekström, Johanna; Lehtinen, Matti; de Villiers, Ethel-Michele; Dillner, Joakim

    2016-05-01

    A possible role for infections of the pregnant mother in the development of childhood acute leukemias and lymphomas has been suggested. However, no specific infectious agent has been identified. Offspring of 74,000 mothers who had serum samples taken during pregnancy and stored in a large-scale biobank were followed up to the age of 15 years (750,000 person years) through over-generation linkages between the biobank files, the Swedish national population and cancer registers to identify incident leukemia/lymphoma cases in the offspring. First-trimester sera from mothers of 47 cases and 47 matched controls were retrieved and analyzed using next generation sequencing. Anelloviruses were the most common viruses detected, found in 37/47 cases and in 40/47 controls, respectively (OR: 0.6, 95% CI: 0.2-1.9). None of the detected viruses was associated with leukemia/lymphoma in the offspring. Viremia during pregnancy was common, but no association with leukemia/lymphoma risk in the offspring was found. PMID:26132655

  15. Maternal Benzene Exposure during Pregnancy and Risk of Childhood Acute Lymphoblastic Leukemia: A Meta-Analysis of Epidemiologic Studies

    PubMed Central

    Li, Zhen; Zhu, Jie; Bi, Yongyi; Bai, YuE; Wang, Hong

    2014-01-01

    Background The prevalence of childhood leukemia is increasing rapidly all over the world. However, studies on maternal benzene exposure during pregnancy and childhood acute lymphoblastic leukemia (ALL) have not been systematically assessed. Therefore, we performed a meta-analysis to investigate the association between maternal solvent, paint, petroleum exposure, and smoking during pregnancy and risk of childhood ALL. Methods Relevant studies up to September 1st, 2013 were identified by searching the PubMed, EMBASE, Cochrane library and the Web of Science databases. The effects were pooled using either fixed or random effect models based on the heterogeneity of the studies. Results Twenty-eight case-control studies and one cohort study were included for analysis, with a total of 16,695 cases and 1,472,786 controls involved. Pooled odds ratio (OR) with 95% confidence interval (CI) for ALL was 1.25 (1.09, 1.45) for solvent, 1.23 (1.02, 1.47) for paint, 1.42 (1.10, 1.84) for petroleum exposure, and 0.99 (0.93, 1.06) for maternal smoking during pregnancy. No publication bias was found in this meta-analysis and consistent results were observed for subgroup and sensitivity analyses. Conclusions Childhood ALL was associated with maternal solvent, paint, and petroleum exposure during pregnancy. No association was found between ALL and maternal smoking during pregnancy. Avoidance of maternal occupational and environmental benzene exposure during pregnancy could contribute to a decrease in the risk of childhood ALL. PMID:25333868

  16. Antibody Therapy for Pediatric Leukemia

    PubMed Central

    Vedi, Aditi; Ziegler, David S.

    2014-01-01

    Despite increasing cure rates for pediatric leukemia, relapsed disease still carries a poor prognosis with significant morbidity and mortality. Novel targeted therapies are currently being investigated in an attempt to reduce adverse events and improve survival outcomes. Antibody therapies represent a form of targeted therapy that offers a new treatment paradigm. Monoclonal antibodies are active in pediatric acute lymphoblastic leukemia (ALL) and are currently in Phase III trials. Antibody-drug conjugates (ADCs) are the next generation of antibodies where a highly potent cytotoxic agent is bound to an antibody by a linker, resulting in selective targeting of leukemia cells. ADCs are currently being tested in clinical trials for pediatric acute myeloid leukemia and ALL. Bispecific T cell engager (BiTE) antibodies are a construct whereby each antibody contains two binding sites, with one designed to engage the patient’s own immune system and the other to target malignant cells. BiTE antibodies show great promise as a novel and effective therapy for childhood leukemia. This review will outline recent developments in targeted agents for pediatric leukemia including monoclonal antibodies, ADCs, and BiTE antibodies. PMID:24795859

  17. Radium-226-contaminated drinking water: Hypothesis on an exposure pathway in a population with elevated childhood leukemia

    SciTech Connect

    Hoffmann, W.; Kranefeld, A.; Schmitz-Feuerhake, I.

    1993-10-01

    A recent epidemiological survey on childhood malignant disease in the region of Ellweiler, Rheinland-Pfalz, Germany, revealed a significantly increased incidence of childhood leukemia, but observed incidences of lymphoma and solid tumors were normal. Established risk factors such as individual exposure to chemicals as well as hereditary genetic disorders were ruled out in interviews with the patients or their families. The general population in the region, however, is subjected to considerable doses of ionizing radiation due to high levels of external {gamma} radiation and high activities of indoor radon. Radiation-specific chromosome aberrations were found in one of two healthy siblings and one father of leukemia patients as well as in any of three probands living in houses with high indoor radon activities. Radon and natural {gamma} radiation, however, cannot explain the geographical pattern of the cases. Four out of seven cases were observed in two particular villages near a uranium processing plant. The drinking water of these villages partly came from a small river that was contaminated with radium-226 washed out from the dumps of the uranium plant. Only sparse measurements of {sup 226}Ra are available, but derived red bone marrow doses for children in the two villages obtained from a simple radio-ecological model show the significance of the drinking water pathway. Prenatal {sup 226}Ra exposure of fetuses due to placental transfer and accumulation may have led to significant doses and may explain the excess cases of childhood leukemia in the region even in quantitative terms. 11 refs., 6 tabs.

  18. Clofarabine and Cytarabine in Treating Older Patients With Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndromes That Have Relapsed or Not Responded to Treatment

    ClinicalTrials.gov

    2013-08-06

    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); Myelodysplastic Syndrome With Isolated Del(5q); Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Myeloid Leukemia

  19. A Phase I Trial of Vorinostat and Alvocidib in Patients with Relapsed, Refractory or Poor Prognosis Acute Leukemia, or Refractory Anemia with Excess Blasts-2

    PubMed Central

    Holkova, Beata; Supko, Jeffrey G.; Ames, Matthew M.; Reid, Joel M.; Shapiro, Geoffrey I.; Tombes, Mary Beth; Honeycutt, Connie; McGovern, Renee M.; Kmieciak, Maciej; Shrader, Ellen; Wellons, Martha D.; Sankala, Heidi; Roberts, John D.; Grant, Steven

    2013-01-01

    Purpose This phase I study was conducted to identify the MTD of alvocidib when combined vorinostat in patients with relapsed, refractory, or poor prognosis acute leukemia, or refractory anemia with excess blasts-2 (RAEB-2). Secondary objectives included investigating the pharmacokinetic and pharmacodynamic effects of the combination. Experimental Design Patients received vorinostat (200 mg orally, 3 times a day [TID], for 14 days), on a 21-day cycle, combined with 2 different alvocidib administration schedules: a 1-h intravenous infusion, daily x 5; or a 30-min loading infusion followed by a 4-h maintenance infusion, weekly x 2. The alvocidib dose was escalated using a standard 3+3 design. Results Twenty-eight patients were enrolled and treated. The alvocidib MTD was 20 mg/m2 (30-min loading infusion) followed by 20 mg/m2 (4-h maintenance infusion) on days 1 and 8, in combination with vorinostat. The most frequently encountered toxicities were cytopenias, fatigue, hyperglycemia, hypokalemia, hypophosphatemia, and QT prolongation. Dose limiting toxicities (DLTs) were cardiac arrhythmia-atrial fibrillation and QT prolongation. No objective responses were achieved, although 13 of 26 evaluable patients exhibited stable disease. Alvocidib appeared to alter vorinostat pharmacokinetics, whereas alvocidib pharmacokinetics were unaffected by vorinostat. Ex vivo exposure of leukemia cells to plasma obtained from patients after alvocidib treatment blocked vorinostat-mediated p21CIP1 induction and down-regulated Mcl-1 and p-RNA Pol II for some specimens, although parallel in vivo bone marrow responses were infrequent. Conclusions Alvocidib combined with vorinostat is well tolerated. Although disease stabilization occurred in some heavily pretreated patients, objective responses were not obtained with these schedules. PMID:23515411

  20. Severe Hypercalcemia in a Child With Acute Lymphoblastic Leukemia Relapse: Successful Management With Combination of Calcitonin and Bisphosphonate.

    PubMed

    Tagiyev, Anar; Demirbilek, Huseyin; Tavil, Betul; Buyukyilmaz, Gonul; Gumruk, Fatma; Cetin, Mualla

    2016-04-01

    Hypercalcemia is a rare complication of hematological malignancy in children. An 8-year-old girl with CALLA (+) Pre-B-cell ALL developed hypercalcemia during bone marrow relapse. She had nausea, vomiting, leg pain, polyuria, polydipsia, and muscle weakness. At the time of relapse, the ionized calcium level was 1.99 mmol/L. Rehydration with 0.9% saline and furosemide and methylprednisolone (MP) treatment were used for the treatment of hypercalcemia. The serum ionized calcium level increased to 2.2 mmol/L despite hydration, furosemide, and MP treatment. Then, a single-dose pamidronate (1 mg/kg/dose) was administered. Despite pamidronate treatment, the calcium level continued to rise. Next, calcitonin at a dose of 8 IU/kg/dose, 4 doses per day, was added to the treatment. After commencement of calcitonin treatment, her ionized calcium level decreased to normal reference ranges. In conclusion, because of the postponed effect of bisphosphonate treatment, pamidronate and calcitonin combination is an effective treatment option in the early resolution of malignancy-related hypercalcemia. PMID:26907650

  1. Vaccine Therapy Plus Immune Adjuvant in Treating Patients With Chronic Myeloid Leukemia, Acute Myeloid Leukemia, or Myelodysplastic Syndrome

    ClinicalTrials.gov

    2013-01-04

    Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Myeloid Leukemia in Remission; Chronic Phase Chronic Myelogenous Leukemia; Previously Treated Myelodysplastic Syndromes; Refractory Anemia With Excess Blasts; Refractory Anemia With Excess Blasts in Transformation; Relapsing Chronic Myelogenous Leukemia

  2. Sedation and Analgesia With Fentanyl and Etomidate for Intrathecal Injection in Childhood Leukemia Patients

    PubMed Central

    Yang, Chun-Hui; Tian, Xin; Yin, Hai-Bin; Gao, Xiao-Hui; Li, Na

    2015-01-01

    Abstract In this study, we tried to find a safe as well as fast effective treatment for sedation and analgesia for intrathecal injection in childhood leukemia patients, relieving treatment difficulties and pain, increasing the success rate of single intrathecal injection. The patients were divided into the experimental group (fentanyl combined with etomidate) and the control group (lidocaine only) randomly. The experimental group was given fentanyl 1 to 2 μg/kg intravenously first, then etomidate 0.1 to 0.3 mg/kg intravenously after the pipe washed. The patients younger than 1.5 years or who did not achieve satisfied sedative and analgesic situation received an additional time of etomidate (0.1–0.3 mg/kg). The patients were given oxygen at the rate of 4–5 L/min during the whole operation, and the finger pulse oximeter was used simultaneously to detect the changes in heart rate (HR) and blood oxygen saturation (SpO2). The doctors who performed the procedures assessed the quality of sedation and analgesia. In the experimental group, the patients’ HR increased slightly after given fentanyl combined with etomidate. The patients’ SpO2 was stable. Most patients achieved a good sedative and analgesic state within 1 to 2 minutes, and no case of respiration depression or cardiac arrhythmias occurred during the whole operation. The wake-up time was 55.42 ± 20.62 min. In the control group, the patients were not very cooperative during the intrathecal injection, which made the procedures very difficult. During intrathecal injection, pain obviously reduced and the success rate of single lumbar puncture increased. It is safe and effective to apply fentanyl combined with etomidate for sedation and analgesia. PMID:25569654

  3. Tobacco Smoke and Risk of Childhood Acute Non-Lymphocytic Leukemia: Findings from the SETIL Study

    PubMed Central

    Mattioli, Stefano; Farioli, Andrea; Legittimo, Patrizia; Miligi, Lucia; Benvenuti, Alessandra; Ranucci, Alessandra; Salvan, Alberto; Rondelli, Roberto; Magnani, Corrado

    2014-01-01

    Background Parental smoking and exposure of the mother or the child to environmental tobacco smoke (ETS) as risk factors for Acute non-Lymphocytic Leukemia (AnLL) were investigated. Methods Incident cases of childhood AnLL were enrolled in 14 Italian Regions during 1998–2001. We estimated odds ratios (OR) and 95% confidence intervals (95%CI) conducting logistic regression models including 82 cases of AnLL and 1,044 controls. Inverse probability weighting was applied adjusting for: age; sex; provenience; birth order; birth weight; breastfeeding; parental educational level age, birth year, and occupational exposure to benzene. Results Paternal smoke in the conception period was associated with AnLL (OR for ≥11 cigarettes/day  = 1.79, 95% CI 1.01–3.15; P trend 0.05). An apparent effect modification by maternal age was identified: only children of mothers aged below 30 presented increased risks. We found weak statistical evidence of an association of AnLL with maternal exposure to ETS (OR for exposure>3 hours/day  = 1.85, 95%CI 0.97–3.52; P trend 0.07). No association was observed between AnLL and either maternal smoking during pregnancy or child exposure to ETS. Conclusions This study is consistent with the hypothesis that paternal smoke is associated with AnLL. We observed statistical evidence of an association between maternal exposure to ETS and AnLL, but believe bias might have inflated our estimates. PMID:25401754

  4. Different molecular mechanisms causing 9p21 deletions in acute lymphoblastic leukemia of childhood.

    PubMed

    Novara, Francesca; Beri, Silvana; Bernardo, Maria Ester; Bellazzi, Riccardo; Malovini, Alberto; Ciccone, Roberto; Cometa, Angela Maria; Locatelli, Franco; Giorda, Roberto; Zuffardi, Orsetta

    2009-10-01

    Deletion of chromosome 9p21 is a crucial event for the development of several cancers including acute lymphoblastic leukemia (ALL). Double strand breaks (DSBs) triggering 9p21 deletions in ALL have been reported to occur at a few defined sites by illegitimate action of the V(D)J recombination activating protein complex. We have cloned 23 breakpoint junctions for a total of 46 breakpoints in 17 childhood ALL (9 B- and 8 T-lineages) showing different size deletions at one or both homologous chromosomes 9 to investigate which particular sequences make the region susceptible to interstitial deletion. We found that half of 9p21 deletion breakpoints were mediated by ectopic V(D)J recombination mechanisms whereas the remaining half were associated to repeated sequences, including some with potential for non-B DNA structure formation. Other mechanisms, such as microhomology-mediated repair, that are common in other cancers, play only a very minor role in ALL. Nucleotide insertions at breakpoint junctions and microinversions flanking the breakpoints have been detected at 20/23 and 2/23 breakpoint junctions, respectively, both in the presence of recombination signal sequence (RSS)-like sequences and of other unspecific sequences. The majority of breakpoints were unique except for two cases, both T-ALL, showing identical deletions. Four of the 46 breakpoints coincide with those reported in other cases, thus confirming the presence of recurrent deletion hotspots. Among the six cases with heterozygous 9p deletions, we found that the remaining CDKN2A and CDKN2B alleles were hypermethylated at CpG islands. PMID:19484265

  5. Energy balance and fitness in adult survivors of childhood acute lymphoblastic leukemia

    PubMed Central

    DeLany, James P.; Kaste, Sue C.; Mulrooney, Daniel A.; Pui, Ching-Hon; Chemaitilly, Wassim; Karlage, Robyn E.; Lanctot, Jennifer Q.; Howell, Carrie R.; Lu, Lu; Srivastava, Deo Kumar; Robison, Leslie L.; Hudson, Melissa M.

    2015-01-01

    There is limited information on body composition, energy balance, and fitness among survivors of childhood acute lymphoblastic leukemia (ALL), especially those treated without cranial radiation therapy (CRT). This analysis compares these metrics among 365 ALL survivors with a mean age of 28.6 ± 5.9 years (149 treated with and 216 without CRT) and 365 age-, sex-, and race-matched peers. We also report risk factors for outcomes among survivors treated without CRT. Male survivors not exposed to CRT had abnormal body composition when compared with peers (% body fat, 26.2 ± 8.2 vs 22.7 ± 7.1). Survivors without CRT had similar energy balance but had significantly impaired quadriceps strength (−21.9 ± 6.0 Newton-meters [Nm]/kg, 60°/s) and endurance (−11.4 ± 4.6 Nm/kg, 300°/s), exercise capacity (−2.0 ± 2.1 ml/kg per minute), low-back and hamstring flexibility (−4.7 ± 1.6 cm), and dorsiflexion range of motion (−3.1 ± 0.9°) and higher modified total neuropathy scores (+1.6 ± 1.1) than peers. Cumulative asparaginase dose ≥120 000 IU/m2 was associated with impaired flexibility, vincristine dose ≥39 mg/m2 with peripheral neuropathy, glucocorticoid (prednisone equivalent) dose ≥8000 mg/m2 with hand weakness, and intrathecal methotrexate dose ≥225 mg with dorsiflexion weakness. Physical inactivity was associated with hand weakness and decreased exercise capacity. Smoking was associated with peripheral neuropathy. Elimination of CRT from ALL therapy has improved, but not eliminated, body-composition outcomes. Survivors remain at risk for impaired fitness. PMID:25814529

  6. Phase 1 and pharmacologic study of MS-275, a histone deacetylase inhibitor, in adults with refractory and relapsed acute leukemias

    PubMed Central

    Jiemjit, Anchalee; Trepel, Jane B.; Sparreboom, Alex; Figg, William D.; Rollins, Sandra; Tidwell, Michael L.; Greer, Jacqueline; Chung, Eun Joo; Lee, Min-Jung; Gore, Steven D.; Sausville, Edward A.; Zwiebel, James; Karp, Judith E.

    2007-01-01

    MS-275 is a benzamide derivative with potent histone deacetylase (HDAC) inhibitory and antitumor activity in preclinical models. We conducted a phase 1 trial of orally administered MS-275 in 38 adults with advanced acute leukemias. Cohorts of patients were treated with MS-275 initially once weekly × 2, repeated every 4 weeks from 4 to 8 mg/m2, and after 13 patients were treated, once weekly × 4, repeated every 6 weeks from 8 to 10 mg/m2. The maximum-tolerated dose was 8 mg/m2 weekly for 4 weeks every 6 weeks. Dose-limiting toxicities (DLTs) included infections and neurologic toxicity manifesting as unsteady gait and somnolence. Other frequent non-DLTs were fatigue, anorexia, nausea, vomiting, hypoalbuminemia, and hypocalcemia. Treatment with MS-275 induced increase in protein and histone H3/H4 acetylation, p21 expression, and caspase-3 activation in bone marrow mononuclear cells. No responses by classical criteria were seen. Our results show that MS-275 effectively inhibits HDAC in vivo in patients with advanced myeloid leukemias and should be further tested, preferably in patients with less-advanced disease. PMID:17179232

  7. Efficacy and Pharmacologic Data of Second-Generation Tyrosine Kinase Inhibitor Nilotinib in BCR-ABL-Positive Leukemia Patients with Central Nervous System Relapse after Allogeneic Stem Cell Transplantation

    PubMed Central

    Reinwald, Mark; Schleyer, Eberhard; Kiewe, Philipp; Blau, Igor Wolfgang; Burmeister, Thomas; Pursche, Stefan; Neumann, Martin; Notter, Michael; Thiel, Eckhard; Hofmann, Wolf-Karsten; Kolb, Hans-Jochem; Burdach, Stefan; Bender, Hans-Ulrich

    2014-01-01

    Central nervous system (CNS) involvement is a severe complication of BCR-ABL-positive leukemia after allogenic stem cell transplantation (alloSCT) associated with fatal outcome. Although second-generation tyrosine-kinase inhibitors (TKI) such as nilotinib have shown activity in systemic BCR-ABL+ disease, little data exists on their penetration and efficacy within the CNS. Four patients (3 male, 1 female; age 15–49) with meningeal relapse after alloSCT and subsequent treatment with nilotinib were identified. A total of 17 cerebrospinal fluid (csf) and serum samples were assessed for nilotinib concentration and patient outcome was recorded. Nilotinib concentrations showed a low median csf/plasma ratio of 0.53% (range 0.23–1.5%), yet pronounced clinical efficacy was observed with long-lasting responses (>1 year) in three patients. Comparison with historical data showed a trend towards superior efficacy of nilotinib versus imatinib. Despite poor csf penetration, nilotinib showed significant clinical activity in CNS relapse of BCR-ABL+ leukemias. As nilotinib has a high protein-binding affinity, the low-protein concentration in csf could translate into a relatively higher amount of free and therefore active nilotinib in csf as compared to blood, possibly explaining the observed efficacy. Thus, treatment with a 2nd generation TKI warrants further investigation and should be considered in cases of CNS relapse of BCR-ABL-positive leukemia after alloSCT. PMID:25025064

  8. The hypomethylating agent decitabine prior to chemotherapy improves the therapy efficacy in refractory/relapsed acute myeloid leukemia patients

    PubMed Central

    Jiang, Xuejie; Wang, Zhixiang; Ding, Bingjie; Yin, Changxin; Zhong, Qingxiu; Carter, Bing Z.; Yu, Guopan; Jiang, Ling; Ye, Jieyu; Dai, Min; Zhang, Yu; Liang, Shuang; Zhao, Qingxia; Liu, Qifa; Meng, Fanyi

    2015-01-01

    In this study, we investigated the effect of pre-treatment with demethylating agent decitabine on susceptibility to chemotherapeutic drugs in HL60/ADR, Kasumi-1 and primary AML cells. Cytotoxic effect was increased by decitabine through activation of p53 and inhibition of c-Myc, Survivin and Bcl-2. We demonstrated in clinic that combination of decitabine and HAA consisting of harringtonine, aclarubicin and cytarabine was effective and safe to treat patients with refractory, relapsed or high-risk AML. Decitabine prior to HAA regimen improved the first induction complete response rate, and significantly prolonged overall survival and disease-free survival in these patients compared with HAA alone. These findings support clinic protocols based on decitabine prior to chemotherapy to overcome resistance and improve therapeutic efficacy in AML patients. PMID:26384351

  9. Controlled trial of disodium cromoglycate in prevention of relapse of steroid-responsive nephrotic syndrome of childhood.

    PubMed Central

    Trompeter, R S; Thomson, P D; Barratt, T M; Soothill, J F

    1978-01-01

    A controlled trial of disodium cromoglycate treatment of steroid-responsive nephrotic syndrome failed to show a therapeutic effect on the tendency to relapse after withdrawal of corticosteroids. PMID:96741

  10. Association of SHMT1 gene polymorphisms with the risk of childhood acute lymphoblastic leukemia in a sample of Iranian population.

    PubMed

    Bahari, G; Hashemi, M; Naderi, M; Sadeghi-Bojd, S; Taheri, M

    2016-01-01

    The enzymes serine hydroxymethyltransferase 1 (SHMT1) regulate key reaction in folate-mediated one-carbon metabolism. In the current study we aimed to examine the possible association between SHMT1 gene polymorphisms and childhood acute lymphoblastic leukemia (ALL) in a sample of Iranian population. The rs9901160, rs2273027, rs9909104, rs1979277, and rs11868708 gene polymorphisms of SHMT1 were genotyped in 120 children diagnosed with ALL and 120 healthy children by the polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). The results showed that rs9901160, rs2273027 as well as rs1979277 polymorphism significantly increased the risk of childhood ALL (P<0.05). While, rs9909104 polymorphism significantly decreased the ALL risk (P<0.05). The rs11868708 variant was not associated with risk/protection of childhood ALL (P>0.05). In conclusion, our results suggest that the polymorphisms of SHMT1 gene are associated with childhood ALL risk in a sample of Iranian population. Further studies with larger sample sizes and different ethnicities are necessary to verify our findings. PMID:26950450

  11. Clinical impact of circulating microRNAs as blood-based marker in childhood acute lymphoblastic leukemia.

    PubMed

    Swellam, Menha; El-Khazragy, Nashwa

    2016-08-01

    Aberrant microRNA (miRNA) expression participates in childhood acute lymphoblastic leukemia (ALL). This study aimed to investigate the expression of miRNA-100, miRNA-196a, and miRNA-146a among childhood ALL and study their correlation with other hematological parameters and different phenotypes. Peripheral blood mononuclear cells (PMNCs) were obtained from 85 childhood ALL and 25 healthy children for the detection of miRNA expression using quantitative real-time PCR. Significant higher median levels were reported for ALL compared to control children. The diagnostic efficacy for miRNA-146a was superior as both sensitivity and specificity were absolute. A significant correlation was observed between higher expression of miRNA-100 and lower platelet and lymphocyte counts; high expression of miRNA-146a showed significant correlation with low total leukocyte count (TLC) and lymphocyte counts. Significant relation was reported between studied miRNAs and different phenotyping. miRNA-100, miRNA-196a, and miRNA-146a have significant role in childhood ALL leukemogenesis, and they may be useful as biological diagnostic molecular markers. PMID:26857279

  12. Induction of autophagy-dependent necroptosis is required for childhood acute lymphoblastic leukemia cells to overcome glucocorticoid resistance

    PubMed Central

    Bonapace, Laura; Bornhauser, Beat C.; Schmitz, Maike; Cario, Gunnar; Ziegler, Urs; Niggli, Felix K.; Schäfer, Beat W.; Schrappe, Martin; Stanulla, Martin; Bourquin, Jean-Pierre

    2010-01-01

    In vivo resistance to first-line chemotherapy, including to glucocorticoids, is a strong predictor of poor outcome in children with acute lymphoblastic leukemia (ALL). Modulation of cell death regulators represents an attractive strategy for subverting such drug resistance. Here we report complete resensitization of multidrug-resistant childhood ALL cells to glucocorticoids and other cytotoxic agents with subcytotoxic concentrations of obatoclax, a putative antagonist of BCL-2 family members. The reversal of glucocorticoid resistance occurred through rapid activation of autophagy-dependent necroptosis, which bypassed the block in mitochondrial apoptosis. This effect was associated with dissociation of the autophagy inducer beclin-1 from the antiapoptotic BCL-2 family member myeloid cell leukemia sequence 1 (MCL-1) and with a marked decrease in mammalian target of rapamycin (mTOR) activity. Consistent with a protective role for mTOR in glucocorticoid resistance in childhood ALL, combination of rapamycin with the glucocorticoid dexamethasone triggered autophagy-dependent cell death, with characteristic features of necroptosis. Execution of cell death, but not induction of autophagy, was strictly dependent on expression of receptor-interacting protein (RIP-1) kinase and cylindromatosis (turban tumor syndrome) (CYLD), two key regulators of necroptosis. Accordingly, both inhibition of RIP-1 and interference with CYLD restored glucocorticoid resistance completely. Together with evidence for a chemosensitizing activity of obatoclax in vivo, our data provide a compelling rationale for clinical translation of this pharmacological approach into treatments for patients with refractory ALL. PMID:20200450

  13. Indoleamine 2,3-dioxygenase 1 (IDO1) activity in leukemia blasts correlates with poor outcome in childhood acute myeloid leukemia.

    PubMed

    Folgiero, Valentina; Goffredo, Bianca M; Filippini, Perla; Masetti, Riccardo; Bonanno, Giuseppina; Caruso, Roberta; Bertaina, Valentina; Mastronuzzi, Angela; Gaspari, Stefania; Zecca, Marco; Torelli, Giovanni F; Testi, Anna M; Pession, Andrea; Locatelli, Franco; Rutella, Sergio

    2014-04-30

    Microenvironmental factors contribute to the immune dysfunction characterizing acute myeloid leukemia (AML). Indoleamine 2,3-dioxygenase 1 (IDO1) is an interferon (IFN)-γ-inducible enzyme that degrades tryptophan into kynurenine, which, in turn, inhibits effector T cells and promotes regulatory T-cell (Treg) differentiation. It is presently unknown whether childhood AML cells express IDO1 and whether IDO1 activity correlates with patient outcome. We investigated IDO1 expression and function in 37 children with newly diagnosed AML other than acute promyelocytic leukemia. Blast cells were cultured with exogenous IFN-γ for 24 hours, followed by the measurement of kynurenine production and tryptophan consumption. No constitutive expression of IDO1 protein was detected in blast cells from the 37 AML samples herein tested. Conversely, 19 out of 37 (51%) AML samples up-regulated functional IDO1 protein in response to IFN-γ. The inability to express IDO1 by the remaining 18 AML samples was not apparently due to a defective IFN-γ signaling circuitry, as suggested by the measurement of signal transducer and activator of transcription 3 (STAT3) phosphorylation. Co-immunoprecipitation assays indicated the occurrence of physical interactions between STAT3 and IDO1 in AML blasts. In line with this finding, STAT3 inhibitors abrogated IDO1 function in AML blasts. Interestingly, levels of IFN-γ were significantly higher in the bone marrow fluid of IDO-expressing compared with IDO-nonexpressing AMLs. In mixed tumor lymphocyte cultures (MTLC), IDO-expressing AML blasts blunted the ability of allogeneic naïve T cells to produce IFN-γ and promoted Treg differentiation. From a clinical perspective, the 8-year event-free survival was significantly worse in IDO-expressing children (16.4%, SE 9.8) as compared with IDO-nonexpressing ones (48.0%, SE 12.1; p=0.035). These data indicate that IDO1 expression by leukemia blasts negatively affects the prognosis of childhood AML. Moreover

  14. 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

  15. Decrease in cerebral metabolic rate of glucose after high-dose methotrexate in childhood acute lymphocytic leukemia

    SciTech Connect

    Komatsu, K.; Takada, G.; Uemura, K.; Shishido, F.; Kanno, I. )

    1990-09-01

    We measured changes in the regional cerebral metabolic rate of glucose (rCMRGlu) using {sup 18}F-fluorodeoxyglucose and positron emission tomography for the assessment of neurotoxicity in childhood acute lymphocytic leukemia treated with high-dose methotrexate (HD-MTX) therapy. We studied 8 children with acute lymphocytic leukemia (mean age: 9.6 years) treated with HD-MTX (200 mg/kg or 2,000 mg/M2) therapy. CMRGlu after HD-MTX therapy was most reduced (40%) in the patient who had central nervous system leukemia and was treated with the largest total doses of both intrathecal MTX (IT-MTX) and HD-MTX. CMRGlu in the whole brain after HD-MTX therapy was reduced by an average of 21% (P less than 0.05). The reductions of CMRGlu in 8 patients were correlated with total doses of both IT-MTX (r = 0.717; P less than 0.05) and systemic HD-MTX (r = 0.784; P less than 0.05). CMRGlu of the cerebral cortex, especially the frontal and occipital cortex, was reduced more noticeably than that of the basal ganglia and white matter. We suggest that the measurement of changes in rCMRGlu after HD-MTX therapy is useful for detecting accumulated MTX neurotoxicity.

  16. Combination Chemotherapy and Rituximab in Treating Young Patients With Recurrent or Refractory Non-Hodgkin's Lymphoma or Acute Lymphoblastic Leukemia

    ClinicalTrials.gov

    2013-10-07

    B-cell Childhood Acute Lymphoblastic Leukemia; Childhood Burkitt Lymphoma; Childhood Diffuse Large Cell Lymphoma; Childhood Immunoblastic Large Cell Lymphoma; L3 Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Small Noncleaved Cell Lymphoma

  17. Multiple extramedullary relapses without bone marrow involvement after second allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia.

    PubMed

    Yoo, Sang Woo; Chung, Eun Jin; Kim, Sun Young; Ko, Jeong Hee; Baek, Hey Sung; Lee, Hyun Ju; Oh, Sung Hee; Jeon, Seok Cheol; Lee, Woong Soo; Park, Chan Kum; Lee, Chul Hoon

    2012-06-01

    EMR without BM involvement after allogeneic HSCT is extremely rare, especially in children; only a few cases have been reported. A two-yr-old boy was diagnosed with AML (M4) and underwent allogeneic HSCT in first complete remission with BM from HLA-matched unrelated donor without GVHD. Four yr later, he had a BM relapse and after induction and consolidation chemotherapy, he received a second HSCT from an unrelated donor using peripheral blood stem cells. His second post-transplant course was complicated by extensive chronic GVHD involving the skin, oral cavity, and lungs, which was treated with tacrolimus and corticosteroid. Two yr later, he noticed a mild swelling in the right cheek area. The BM showed a complete remission marrow and a soft tissue biopsy was compatible with granulocytic sarcoma. PET-CT showed multifocal bone involvements. He received chemotherapy, and the chloromas decreased in size. We report a case of diffuse EMR of AML without BM involvement after a second allogeneic HSCT. PMID:21923886

  18. Molecular Cytogenetics in Childhood Acute Lymphoblastic Leukemia: A Hospital-Based Observational Study

    PubMed Central

    Pandita, Aakash; Harish, Rekha; Digra, Sanjeev K; Raina, Alok; Sharma, Annie Arvind; Koul, Ashwani

    2015-01-01

    OBJECTIVE This study was conducted to determine the frequency of chromosomal aberrations in children aged <19 years with newly diagnosed acute lymphoblastic leukemia (ALL), attending/admitted in the Department of Pediatrics and Radiotherapy, Government Medical College, Jammu. Furthermore, we aimed to study the correlation between the cytogenetic molecular abnormalities and the immediate clinical outcome (induction of remission). MATERIALS AND METHODS This was a prospective study conducted over a period of 2 years (May 2011 to May 2013) in a tertiary care hospital in India. Forty pediatric (1–19 years) patients (18 males, 22 females; M: F = 0.8 : 1) with newly diagnosed ALL were studied for molecular cytogenetic analysis. Written consent was obtained from the parents of the patients. Bone marrow aspiration was done for making the diagnosis of ALL. Children lost to follow-up and who failed to give consent were excluded from the survey. Host factors and clinical parameters were obtained from patients. RESULTS Bone marrow aspirate samples of 40 diagnosed cases of ALL were subjected to routine cytogenetic analysis, and reverse transcription-polymerase chain reaction (RT-PCR) technique was used for molecular analysis. Well-spread metaphase plates were obtained in 18/40 (45%) cases for analysis. RT-PCR revealed abnormal genes in 20/40 (50%) patients. The results of molecular cytogenetic analysis were correlated with patients’ clinical and hematological parameters for risk stratification and immediate outcome (induction of remission). Eighteen out of 40 (45%) cases revealed no abnormality. Among the remaining 22 cases, 8 had TEL–AML1 (20%), 6 had BCR–ABL (15%), 4 had MLL–AF4 (10%), 2 had E2A–PBX1 (5%) fusion genes, and 2 had hyperdiploidy. To conclude, a higher proportion of cases in this study showed adverse translocations such as t (9;22), t (4;11), and t (1;19) compared to that reported in literature. CONCLUSION RT-PCR assay was useful in detecting the

  19. Role of Radiation Dose in the Risk of Secondary Leukemia After a Solid Tumor in Childhood Treated Between 1980 and 1999

    SciTech Connect

    Allard, Aurore; Haddy, Nadia; Le Deley, Marie-Cecile; Rubino, Carole; Lassalle, Mathilde; Samsaldin, Akthar; Quiniou, Eric; Chompret, Agnes; Lefkopoulos, Dimitri; Diallo, Ibrahima; Vathaire, Florent de

    2010-12-01

    Purpose: The purpose of this study was to estimate the risk of secondary leukemia as a function of radiation dose, taking into account heterogeneous radiation dose distribution. Methods and Materials: We analyzed a case-control study that investigated the risk of secondary leukemia and myelodysplasia after a solid tumor in childhood; it included 61 patients with leukemia matched with 196 controls. Complete clinical, chemotherapy, and radiotherapy histories were recorded for each patient in the study. Average radiation dose to each of seven bone marrow components for each patient was incorporated into the models, and corresponding risks were summed up. Conditional maximum likelihood methods were used to estimate risk parameters. Results: Whatever the model, we failed to evidence a role for the radiation dose to active bone marrow in the risk of later leukemia, myelodysplasia, or myeloproliferative syndrome, when adjusting for epipodophyllotoxin and anthracycline doses. This result was confirmed when fitting models that included total dose of radiation delivered during radiotherapy, when fitting models taking into account dose per fraction, and when restricting the analysis to acute myeloid leukemia. Conclusions: In contrast to results found in similar studies that included children treated before the use of epipodophyllotoxins, this study failed to show a role for radiotherapy in the risk of secondary leukemia after childhood cancer in children treated between 1980 and 1999. This discrepancy was probably due to a competitive mechanism between these two carcinogens.

  20. [Acute leukemia in childhood: present status of 100 cases after 7 years of complete remission (author's transl)].

    PubMed

    Schaison, G; Jacquillat, C; Lemercier, N; Weil, M; Alby, N; Auclerc, M F; Boiron, M; Bernard, J

    1980-01-01

    Amongst 1,200 leukemie children treated between 1958 and 1971, 60 are in complete remission for more than 10 years and 100 for more than 7 years. There were 96 acute lymphoid and 4 acute myeloid leukemias. Ten patients who have relapsed in the past have not done so lately. The F/M sex ratio is 1.5. Poor prognostic features were initially absent in 2/3 of cases. In 1/3 there was associated hyperleucocytosis and/or tumours. 93 children are in remission, their treatment having been stopped for 1 to 12 years. Five children relapsed and 4 are in a second remission for more than 2 years. Two children died in remission: one from a hepatocarcinoma and one from cardiac failure. These patients have been shown to have the following: 1) normal growth; 2) normal puberty: 8 patients have been able to reproduce, giving 10 children, one with multiple malformations; 3) school achievement and later socioprofessional behaviour has been normal. The patients have often sought a medical or paramedical career. Sequelae are minimal, psychological problems being minimal in the child. With the protocols used, mean remission curve shows a plateau after 9 years and complete definitive care is achieved in 92 per cent of patients surviving at 7 years. The very distant future outlook is not known. No other malignant haematological disease has occurred but one child died from a carcinoma. PMID:6931627

  1. Familial history of cancer and childhood acute leukemia: a French population-based case-control study

    PubMed Central

    Ripert, Mahaut; Menegaux, Florence; Perel, Yves; Méchinaud, Françoise; Plouvier, Emmanuel; Gandemer, Virginie; Lutz, Patrick; Vannier, Jean-Pierre; Lamagnére, Jean-Pierre; Margueritte, Geneviève; Boutard, Patrick; Robert, Alain; Armari-Alla, Corinne; Munzer, Martine; Millot, Frédéric; de Lumley, Lionel; Berthou, Christian; Rialland, Xavier; Pautard, Brigitte; Clavel, Jacqueline

    2007-01-01

    Objective A case-control study was conducted to investigate the role of a familial history of cancer in the etiology of childhood acute leukemia (AL). Methods The history of cancer in the relatives of 472 cases was compared to that of 567 population-based controls. Recruitment was frequency matched on age, gender and region. The familial history of cancer in each child’s relatives was reported by the mother in response to a standardized self-administered questionnaire. Results A familial history of solid tumor in first- or second-degree relatives was associated with an increased risk of ALL (OR=1.6 [1.2–2.1]), while a familial history of hematopoietic malignancies in first- or second-degree relatives was associated with an increased risk of AML (OR=4.3 [1.4–13]). The ORs for the histories of cancer increased with the number of relatives with cancer (OR=1.5 [1.1–2.0] for one relative and OR=2.3 [1.3–3.8] for two relatives or more; ptrend<0.0001). Significant associations between childhood AL and familial history of genital cancers and brain tumor were also observed (OR=2.7 [1.2–5.8], OR=10.7 [1.3–86], respectively). Conclusion This study supports the hypothesis that a familial history of cancer may play a role in the etiology of childhood acute leukemia. It also evidences some specific associations that require further investigation. PMID:17923819

  2. Combination Chemotherapy With or Without PSC 833, Peripheral Stem Cell Transplantation, and/or Interleukin-2 in Treating Patients With Acute Myeloid Leukemia

    ClinicalTrials.gov

    2013-06-03

    Adult Acute Basophilic Leukemia; Adult Acute Eosinophilic Leukemia; Adult Acute Erythroid Leukemia (M6); Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monoblastic Leukemia and Acute Monocytic Leukemia (M5); 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); 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 Monoblastic Leukemia and Acute Monocytic Leukemia (M5); 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; Untreated Adult Acute Myeloid Leukemia; Untreated Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies

  3. Distance to high-voltage power lines and risk of childhood leukemia--an analysis of confounding by and interaction with other potential risk factors.

    PubMed

    Pedersen, Camilla; Bräuner, Elvira V; Rod, Naja H; Albieri, Vanna; Andersen, Claus E; Ulbak, Kaare; Hertel, Ole; Johansen, Christoffer; Schüz, Joachim; Raaschou-Nielsen, Ole

    2014-01-01

    We investigated whether there is an interaction between distance from residence at birth to nearest power line and domestic radon and traffic-related air pollution, respectively, in relation to childhood leukemia risk. Further, we investigated whether adjusting for potential confounders alters the association between distance to nearest power line and childhood leukemia. We included 1024 cases aged <15, diagnosed with leukemia during 1968-1991, from the Danish Cancer Registry and 2048 controls randomly selected from the Danish childhood population and individually matched by gender and year of birth. We used geographical information systems to determine the distance between residence at birth and the nearest 132-400 kV overhead power line. Concentrations of domestic radon and traffic-related air pollution (NOx at the front door) were estimated using validated models. We found a statistically significant interaction between distance to nearest power line and domestic radon regarding risk of childhood leukemia (p = 0.01) when using the median radon level as cut-off point but not when using the 75th percentile (p = 0.90). We found no evidence of an interaction between distance to nearest power line and traffic-related air pollution (p = 0.73). We found almost no change in the estimated association between distance to power line and risk of childhood leukemia when adjusting for socioeconomic status of the municipality, urbanization, maternal age, birth order, domestic radon and traffic-related air pollution. The statistically significant interaction between distance to nearest power line and domestic radon was based on few exposed cases and controls and sensitive to the choice of exposure categorization and might, therefore, be due to chance. PMID:25259740

  4. 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

  5. Association between CEBPE Variant and Childhood Acute Leukemia Risk: Evidence from a Meta-Analysis of 22 Studies

    PubMed Central

    Tang, Linjun; Healy, Jasmine; Sinnett, Daniel; Dai, Yue-e

    2015-01-01

    The CCAAT/enhancer binding proteins (CEBPs) have been involved in the etiology of acute leukemia (AL) and investigated in numerous genetic association studies, however, the results were inconclusive. The current meta-analysis was conducted to clarify the effect of CEBPE rs2239633 variant on childhood AL risk. Electronic literature search was performed on August 15, 2014, from databases of Medline, PubMed, Embase, and Web of Science. A total of 22 case-control studies were eligible for the pooled analysis. The results demonstrated that rs2239633 A allele was significantly associated with a decreased risk of childhood AL (A vs G: OR=0.87, 95%CI = 0.80, 0.94, p<0.001), especially in B-cell ALL subgroup (A vs G: OR = 0.79, 95%CI = 0.74, 0.83, p<0.001), but not among T-cell ALL or AML subgroups. In the stratified analysis by ethnicity, the association was observed in Europeans (A vs G: OR = 0.80, 95%CI = 0.76, 0.84, p<0.001) but not in Asian and mixed populations. Moreover, the results of sensitivity and cumulative meta-analysis indicated the robustness of our results. Also, Begg’s and Egger’s tests did not indicate any evidence of obvious asymmetry. In summary, our study provided evidence that CEBPE rs2239633 variant is associated with decreased risk of childhood B-cell ALL in Europeans. PMID:25938438

  6. 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.

  7. Childhood CT scans linked to leukemia and brain cancer later in life

    Cancer.gov

    Children and young adults scanned multiple times by computed tomography (CT), a commonly used diagnostic tool, have a small increased risk of leukemia and brain tumors in the decade following their first scan.

  8. 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

  9. Dose study of the multikinase inhibitor, LY2457546, in patients with relapsed acute myeloid leukemia to assess safety, pharmacokinetics, and pharmacodynamics

    PubMed Central

    Wacheck, Volker; Lahn, Michael; Dickinson, Gemma; Füreder, Wolfgang; Meyer, Renata; Herndlhofer, Susanne; Füreder, Thorsten; Dorfner, Georg; Pillay, Sada; André, Valérie; Burkholder, Timothy P; Akunda, Jacqueline K; Flye-Blakemore, Leann; Van Bockstaele, Dirk; Schlenk, Richard F; Sperr, Wolfgang R; Valent, Peter

    2011-01-01

    Background: Acute myeloid leukemia (AML) is a life-threatening malignancy with limited treatment options in chemotherapy-refractory patients. A first-in-human dose study was designed to investigate a safe and biologically effective dose range for LY2457546, a novel multikinase inhibitor, in patients with relapsed AML. Methods: In this nonrandomized, open-label, dose escalation Phase I study, LY2457546 was administered orally once a day. Safety, pharmacokinetics, changes in phosphorylation of target kinases in AML blasts, and risk of drug–drug interactions (DDI) were assessed. Results: Five patients were treated at the starting and predicted minimal biologically effective dose of 50 mg/day. The most commonly observed adverse events were febrile neutropenia, epistaxis, petechiae, and headache. The majority of adverse events (81%) were Grade 1 or 2. One patient had generalized muscle weakness (Grade 3), which was deemed to be a dose-limiting toxicity. Notably, the pharmacokinetic profile of LY2457546 showed virtually no elimination of LY2457546 within 24 hours, and thus prevented further dose escalation. No significant DDI were observed. Ex vivo flow cytometry studies showed downregulation of the phosphoproteins, pcKIT, pFLT3, and pS6, in AML blasts after LY2457546 administration. No medically relevant responses were observed in the five treated patients. Conclusion: No biologically effective dose could be established for LY2457546 in chemotherapy-resistant AML patients. Lack of drug clearance prevented safe dose escalation, and the study was terminated early. Future efforts should be made to develop derivatives with a more favorable pharmacokinetic profile. PMID:21625399

  10. Substantial Susceptibility of Chronic Lymphocytic Leukemia to BCL2 Inhibition: Results of a Phase I Study of Navitoclax in Patients With Relapsed or Refractory Disease

    PubMed Central

    Roberts, Andrew W.; Seymour, John F.; Brown, Jennifer R.; Wierda, William G.; Kipps, Thomas J.; Khaw, Seong Lin; Carney, Dennis A.; He, Simon Z.; Huang, David C.S.; Xiong, Hao; Cui, Yue; Busman, Todd A.; McKeegan, Evelyn M.; Krivoshik, Andrew P.; Enschede, Sari H.; Humerickhouse, Rod

    2012-01-01

    Purpose BCL2 overexpression is a hallmark of chronic lymphocytic leukemia (CLL). The novel BH3 mimetic navitoclax (ABT-263) specifically inhibits BCL2 and related proteins BCL-xl and BCL-w, potently inducing apoptosis of CLL cells in vitro. A phase I trial in patients with CLL was conducted to evaluate the safety, pharmacokinetics, and biologic activity of oral navitoclax. Patients and Methods Twenty-nine patients with relapsed or refractory CLL received daily navitoclax for 14 days (10, 110, 200, or 250 mg/d; n = 15) or 21 days (125, 200, 250, or 300 mg/d; n = 14) of each 21-day cycle. Dose escalation decisions were informed by continual reassessment methodology. Results Lymphocytosis was reduced by more than 50% in 19 of 21 patients with baseline lymphocytosis. Among 26 patients treated with navitoclax ≥ 110 mg/d, nine (35%) achieved a partial response and seven maintained stable disease for more than 6 months. Median treatment duration was 7 months (range, 1 to ≥ 29 months). Median progression-free survival was 25 months. Activity was observed in patients with fludarabine-refractory disease, bulky adenopathy, and del(17p) CLL. Thrombocytopenia due to BCL-xl inhibition was the major dose-limiting toxicity and was dose-related. Low MCL1 expression and high BIM:MCL1 or BIM:BCL2 ratios in leukemic cells correlated with response. We determined that the navitoclax dose of 250 mg/d in a continuous dosing schedule was optimal for phase II studies. Conclusion BCL2 is a valid therapeutic target in CLL, and its inhibition by navitoclax warrants further evaluation as monotherapy and in combination in this disease. PMID:22184378

  11. Re-induction Chemoimmunotherapy with Epratuzumab in Relapsed Acute Lymphoblastic Leukemia (ALL): Phase II Results from Children’s Oncology Group (COG) Study ADVL04P2

    PubMed Central

    Raetz, Elizabeth A.; Cairo, Mitchell S.; Borowitz, Michael J.; Lu, Xiaomin; Devidas, Meenakshi; Reid, Joel M.; Goldenberg, David M.; Wegener, William A.; Zeng, Hui; Whitlock, James A.; Adamson, Peter C.; Hunger, Stephen P.; Carroll, William L.

    2015-01-01

    Background Given the success of immunotherapeutic approaches in hematologic malignancies, the COG designed a phase I/II study to determine whether the addition of epratuzumab (anti-CD22) to an established chemotherapy platform improves rates of second remission (CR2) in pediatric patients with B-lymphoblastic leukemia (B-ALL) and early bone marrow relapse. Procedure Therapy consisted of 3 established blocks of re-induction chemotherapy. Epratuzumab (360 mg/m2/dose) was combined with chemotherapy on weekly × 4 (B1) and twice weekly × 4 [8 doses] (B2) schedules during the first re-induction block. Remission rates and minimal residual disease (MRD) status were compared to historical rates observed with the identical chemotherapy platform alone. Results CR2 was achieved in 65% and 66%, of the evaluable B1 (n=54) and B2 patients (n=60), respectively; unchanged from that observed historically without epratuzumab. Rates of MRD negativity (< 0.01%) were 31% in B1 (P=0.4128)and 39% in B2 patients (P=0.1731), compared to 25% in historical controls. The addition of epratuzumab was well tolerated, with a similar toxicity profile to that observed with the re-induction chemotherapy platform regimen alone. Conclusions Epratuzumab was well tolerated in combination with re-induction chemotherapy. While CR2 rates were not improved compared to historical controls treated with chemotherapy alone, there was a non-significant trend towards improvement in MRD response with the addition of epratuzumab (twice weekly for 8 doses) to re-induction chemotherapy. PMID:25732247

  12. Brain Function in Young Patients Receiving Methotrexate for Acute Lymphoblastic Leukemia

    ClinicalTrials.gov

    2016-04-08

    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

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

    ClinicalTrials.gov

    2016-08-10

    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

  14. Results of the Japan Association of Childhood Leukemia Study (JACLS) NHL-98 protocol for the treatment of B-cell non-Hodgkin lymphoma and mature B-cell acute lymphoblastic leukemia in childhood.

    PubMed

    Fujita, Naoto; Kobayashi, Ryoji; Takimoto, Tetsuya; Nakagawa, Atsuko; Ueda, Kazuhiro; Horibe, Keizo

    2011-02-01

    The Japan Association of Childhood Leukemia Study (JACLS) NHL-98 is a multicenter study designed to evaluate treatment outcomes in Japanese children with B-cell non-Hodgkin lymphoma (B-NHL) and mature B-cell acute lymphoblastic leukemia (B-ALL). The study was supported by a central pathology review system and used a new, standardized protocol with short, intensive treatment regimens. From April 1998 to May 2002, 69 patients with B-NHL and B-ALL up to 16 years of age were enrolled in the NHL-98 study. Treatment was stratified by risk group; patients with limited disease were in groups A and B, and those with extensive disease were in groups C and D. Patients in groups B, C, and D received consolidation phases with high-dose methotrexate (HDMTX) followed by other multi-agent chemotherapy. Patients in group A did not receive either MTX or etoposide. Only patients in group D received etoposide. The event-free survival rates were 100% in groups A and B, 75.1% in group C, and 66.2% in group D. Overall, patients with limited disease had favorable results. For patients with extensive disease, additional treatment options such as increased doses of anticancer drugs warrant further investigation. PMID:21261497

  15. Obesity is associated with residual leukemia following induction therapy for childhood B-precursor acute lymphoblastic leukemia.

    PubMed

    Orgel, Etan; Tucci, Jonathan; Alhushki, Waseem; Malvar, Jemily; Sposto, Richard; Fu, Cecilia H; Freyer, David R; Abdel-Azim, Hisham; Mittelman, Steven D

    2014-12-18

    Obesity is associated with poorer event-free survival (EFS) in pediatric acute lymphoblastic leukemia (ALL). Persistent minimal residual disease (MRD) in the bone marrow as measured by multidimensional flow cytometry (MDF) is a key early prognostic indicator and is strongly associated with EFS. We therefore hypothesized that obesity during induction would be associated with positive end-of-induction MRD (≥0.01%). We analyzed MDF of end-induction bone marrow samples from a historical cohort of 198 children newly diagnosed with B-precursor ALL (BP-ALL) and treated with Children's Oncology Group induction regimens. We assessed the influence of body mass index on risk for positive end-induction MRD in the bone marrow. In our cohort of BP-ALL, 30 children (15.2%) were overweight and 41 (20.7%) were obese at diagnosis. Independent of established predictors of treatment response, obesity during induction was associated with significantly greater risk for persistent MRD (odds ratio, 2.57; 95% confidence interval, 1.19 to 5.54; P = .016). Obesity and overweight were associated with poorer EFS irrespective of end-induction MRD (P = .012). Obese children with newly diagnosed BP-ALL are at increased risk for positive end-induction MRD and poorer EFS. PMID:25349177

  16. Confirmation of Childhood Acute Lymphoblastic Leukemia Variants, ARID5B and IKZF1, and Interaction with Parental Environmental Exposures

    PubMed Central

    Evans, Tiffany-Jane; Milne, Elizabeth; Anderson, Denise; de Klerk, Nicholas H.; Jamieson, Sarra E.; Talseth-Palmer, Bente A.; Bowden, Nikola A.; Holliday, Elizabeth G.; Rudant, Jérémie; Orsi, Laurent; Richardson, Ebony; Lavis, Laura; Catchpoole, Daniel; Attia, John R.; Armstrong, Bruce K.; Clavel, Jacqueline; Scott, Rodney J.

    2014-01-01

    Genome wide association studies (GWAS) have established association of ARID5B and IKZF1 variants with childhood acute lymphoblastic leukemia (ALL). Epidemiological studies suggest that environmental factors alone appear to make a relatively minor contribution to disease risk. The polygenic nature of childhood ALL predisposition together with the timing of environmental triggers may hold vital clues for disease etiology. This study presents results from an Australian GWAS of childhood ALL cases (n = 358) and population controls (n = 1192). Furthermore, we utilised family trio (n = 204) genotypes to extend our investigation to gene-environment interaction of significant loci with parental exposures before conception, and child’s sex and age. Thirteen SNPs achieved genome wide significance in the population based case/control analysis; ten annotated to ARID5B and three to IKZF1. The most significant SNPs in these regions were ARID5B rs4245595 (OR 1.63, CI 1.38–1.93, P = 2.13×10−9), and IKZF1 rs1110701 (OR 1.69, CI 1.42–2.02, p = 7.26×10−9). There was evidence of gene-environment interaction for risk genotype at IKZF1, whereby an apparently stronger genetic effect was observed if the mother took folic acid or if the father did not smoke prior to pregnancy (respective interaction P-values: 0.04, 0.05). There were no interactions of risk genotypes with age or sex (P-values >0.2). Our results evidence that interaction of genetic variants and environmental exposures may further alter risk of childhood ALL however, investigation in a larger population is required. If interaction of folic acid supplementation and IKZF1 variants holds, it may be useful to quantify folate levels prior to initiating use of folic acid supplements. PMID:25310577

  17. The long-term results of childhood acute lymphoblastic leukemia at two centers from Turkey: 15 years of experience with the ALL-BFM 95 protocol.

    PubMed

    Güneş, Adalet Meral; Oren, Hale; Baytan, Birol; Bengoa, Sebnem Yılmaz; Evim, Melike Sezgin; Gözmen, Salih; Tüfekçi, Ozlem; Karapınar, Tuba Hilkay; Irken, Gülersu

    2014-10-01

    Dramatic progress in the treatment of childhood acute lymphoblastic leukemia (ALL) has been achieved during the last two decades in Western countries, where the 5-year event-free survival (EFS) rate has risen from 30 to 85 %. However, similarly high cure rates have not always been achieved in all centers in developing countries due to limited sources. We evaluated the treatment results of the ALL-Berlin-Frankfurt-Münster (BFM) 95 protocol as used between 1995 and 2009 in the pediatric hematology departments of two university hospitals. A retrospective analysis of 343 children newly diagnosed with ALL (M/F 200/143, median age 6.8 years) was performed. The overall survival (OS) and EFS according to age, initial leukocyte count, immunophenotype, chemotherapy responses (on days 8, 15, and 33), and risk groups were analyzed by Kaplan-Meier survival analysis. Median follow-up time was 6.4 years. Complete remission was achieved in 97 % of children. Five-year EFS and OS were found to be 78.4 and 79.9 %, respectively. Children younger than 6 years old had significantly better EFS and OS (83.7 and 85.2 %) than children aged ≥6 years (71.4 and 72.8 %). Adolescents achieved 63 % EFS and 65 % OS. Patients who had initial leukocyte counts of <20 × 10(9)/L had better EFS and OS (82.2 and 84.6 %) than children with higher initial leukocyte counts (72.6 and 72.6 %). EFS for B-cell precursor and T-cell ALL was 81.5 and 66.7 %, respectively. Children with a good response to prednisolone on day 8 (87 %) achieved significantly better EFS and OS (81.2 and 81.9 % vs. 55.3 and 60.5 %). Children whose bone marrow on day 15 was in complete remission had higher EFS and OS (83.7 and 86.6.1 % vs. 56.4 and 61.5 %). Children in the standard-risk and medium-risk groups obtained statistically significantly higher EFS (95.5 and 82.7 %) and OS (97.7 and 82.3 %) compared to the high-risk group (EFS 56.3 %, OS 63.4 %). The relapse rate was 14.8 %. The median relapse time from diagnosis was 23

  18. Successful treatment of metastatic relapse of medulloblastoma in childhood with single session stereotactic radiosurgery: a report of 3 cases.

    PubMed

    King, David; Connolly, Daniel; Zaki, Hesham; Lee, Vicki; Yeomanson, Daniel

    2014-05-01

    Stereotactic radiosurgery (SRS) is an increasingly used treatment modality in adults, but its use and effectiveness in pediatric brain tumors is still uncertain. We describe 3 patients with metastatic relapse of medulloblastoma, who were treated with SRS, and achieved prolonged, progression-free survival. Tolerability of the treatment was excellent with no adverse effects reported. This work adds to the growing evidence that SRS may have an important role to play in the treatment of pediatric brain tumors. PMID:23459380

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

    ClinicalTrials.gov

    2016-02-23

    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

  20. Combination Chemotherapy in Treating Young Patients With Newly Diagnosed High-Risk Acute Lymphoblastic Leukemia

    ClinicalTrials.gov

    2016-08-23

    B Acute Lymphoblastic Leukemia; Bone Necrosis; Central Nervous System Leukemia; Cognitive Side Effects of Cancer Therapy; Neurotoxicity Syndrome; Pain; Testicular Leukemia; Therapy-Related Toxicity; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Childhood Acute Lymphoblastic Leukemia

  1. Purine metabolism enzyme pattern, cytochemical characteristics and clinicopathologic features of CD10-positive childhood T-cell leukemia.

    PubMed

    Babusíková, O; Cáp, J; Hrivnáková, A; Klobusická, M; Mesárosová, A; Koníková, E

    1991-01-01

    Purine metabolism enzyme pattern, cytochemical markers and clinicopathologic features of common acute lymphoblastic leukemia antigen (cALLA; CD10)-positive, CD10-negative T acute lymphoblastic leukemia (ALL), and cALLA-positive non-T, non-B ALL (common ALL; C ALL) of children were compared. The results of immunophenotyping of blast cells in 61 children with ALL who were treated and followed during the last 7 years at the Second Pediatric Clinic in Bratislava are presented. The aim of our study was to determine the correlation of CD10 marker expression with purine enzyme activities and clinical course in ALL of children. Immunologic phenotype performed by a panel of monoclonal antibodies in indirect immunofluorescence assay revealed 3 main ALL groups: Common ALL (C ALL), T ALL and CD10+ T ALL (C + T ALL). An additional exact cytochemical marker analysis was performed in these three ALL immunologic subtypes. Two enzymes of purine metabolism, i.e. adenosine deaminase (ADA) and purine nucleosidephosphorylase (PNP) were investigated in blast cells by paper radiochromatography. Life-table analysis revealed significant prognostic differences with regard to event-free survival and overall survival in followed groups of ALL patients. Our results showed a rather high frequency of mixed (C + T) ALL phenotype. The characteristic T ALL enzyme pattern (high ADA, low PNP) was present not only in T, but also in CD10+ T ALL blast cells. The T cell marker showed to be dominant in the determination of clinical course and prognostic significance in children with ALL; children with T and CD10+ T ALL phenotype, in contrast to C ALL phenotype, experienced more frequent relapses and a shorter event-free survival. PMID:1837333

  2. Metabolic syndrome in adults who received hematopoietic stem cell transplantation for acute childhood leukemia: an LEA study.

    PubMed

    Oudin, C; Auquier, P; Bertrand, Y; Contet, A; Kanold, J; Sirvent, N; Thouvenin, S; Tabone, M-D; Lutz, P; Ducassou, S; Plantaz, D; Dalle, J-H; Gandemer, V; Beliard, S; Berbis, J; Vercasson, C; Barlogis, V; Baruchel, A; Leverger, G; Michel, G

    2015-11-01

    We evaluated prospectively the incidence and risk factors of the metabolic syndrome (MS) and its components in 170 adult patients (mean age at evaluation: 24.8±5.4 years) who received an hematopoietic stem cell transplantation for childhood ALL, n=119, or AML, n=51. TBI was carried out in 124 cases; a busulfan-based conditioning was done in 30 patients. Twenty-nine patients developed a MS (17.1%, 95% confidence intervals: 11.7-23.6). The cumulative incidence was 13.4% at 25 years of age and 35.5% at 35 years of age. A higher body mass index (BMI) before transplantation and a growth hormone deficiency were associated with increased MS risk (P=0.002 and 0.01, respectively). MS risk was similar for patients who received TBI or busulfan-based conditioning. The TBI use increased the hyperglycemia risk (odds ratio (OR): 4.7, P=0.02). Women were at the risk of developing increased waist circumference (OR: 7.18, P=0.003) and low levels of high-density lipoprotein cholesterol (OR: 2.72, P=0.007). The steroid dose was not a risk factor. The MS occurs frequently among transplanted survivors of childhood leukemia. Its incidence increases with age. Both intrinsic (BMI, gender) and extrinsic factors (TBI, alkylating agents) contribute to its etiopathogenesis. PMID:26191949

  3. CCND1 G870A polymorphism is associated with toxicity of methotrexate in childhood acute lymphoblastic leukemia

    PubMed Central

    Xue, Yao; Rong, Liucheng; Tong, Na; Wang, Meilin; Zhang, Zhengdong; Fang, Yongjun

    2015-01-01

    CCND1 plays a key role in cell cycle progression and may cause methotrexate (MTX) resistance, as well as its cytotoxicity. CCND1 870A variant allele is associated with altered transcripts of this gene. We hypothesized that this polymorphism may contribute to the elimination rate and hepatotoxicity of MTX in childhood acute lymphoblastic leukemia (ALL). We genotyped the CCND1 G870A polymorphism in 125 childhood ALL patients treated with HDMTX. We found no notable associations between G870A polymorphism and the risk of delayed MTX elimination. However, this polymorphism was significantly associated with an increased risk of MTX hepatotoxicity [adjusted odds ratio (OR) = 4.44, 95% confidence interval (CI) = 1.35-14.63 for AG versus GG and adjusted OR = 6.39, 95% CI = 1.82-22.43 for AA versus GG]. Our results indicated that the CCND1 G870A polymorphism may be involved in the hepatotoxicity of MTX and act as a biological marker. PMID:26617896

  4. Neurocognitive Outcomes in Long-term Survivors of Childhood Acute Lymphoblastic Leukemia Treated on Contemporary Treatment Protocols: A Systematic Review

    PubMed Central

    Cheung, Yin Ting; Krull, Kevin R.

    2015-01-01

    The intensified administration of chemotherapeutic drugs has gradually replaced cranial radiation therapy (CRT) for the treatment of childhood acute lymphoblastic leukemia (ALL). While CRT is often implicated in neurocognitive impairment in ALL survivors, there is a paucity of literature that evaluates the persistence of neurocognitive deficits in long-term survivors of pediatric ALL who were treated with contemporary chemotherapy-only protocols. Results from this systematic review concurred to the probable cognitive-sparing effect of chemotherapy-based protocols over CRT in long-term survivors. However, coupled with multiple intrinsic and extrinsic factors, survivors who received chemotherapy treatment still suffered from apparent cognitive impairment, particularly in the attention and executive function domains. Notably, there is evidence to suggest that the late neurotoxic effect of methotrexate on survivors’ neurocognitive performance may be dose-related. This review also recommends future pharmacokinetic, neuroimaging and genetic studies to illuminate the multifactorial nature of this subject matter and discusses the potential value of neurochemical, physiological, inflammatory and genetic markers for the prediction of susceptibility to neurocognitive impairment in long-term survivors of childhood ALL. PMID:25857254

  5. School: The Normalizing Factor for Children with Childhood Leukemia. Perspectives of Young Survivors and Their Parents.

    ERIC Educational Resources Information Center

    Sullivan, Nanci A.; Fulmer, Deborah L.; Zigmond, Naomi

    2001-01-01

    A study of 8 children (ages 5-7) with Acute Lymphoblastic Leukemia found returning to school was a major milestone and that school serves as the mechanism by which young survivors approach the process of living each day. Attendance obstacles are discussed, along with guidelines for maintaining school as a priority. (Contains references.) (CR)

  6. News Note: New chemotherapy scheduling improves survival for most common form of childhood leukemia

    Cancer.gov

    New NCI-sponsored clinical trial results reported today at the annual American Society of Clinical Oncology meeting in Chicago show that, in a high-risk form of pediatric acute lymphoblastic leukemia (ALL), a high-dose schedule of a drug raises already high cure rates even higher.

  7. Hyperglycemia during induction therapy is associated with increased infectious complications in childhood acute lymphocytic leukemia

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Children with acute lymphocytic leukemia (ALL) are at high risk for developing hyperglycemia. Hyperglycemic adult ALL patients have shorter remissions, more infections, and increased mortality. No corresponding data are available in children. We hypothesized that children with ALL who become hypergl...

  8. Emotional Aspects of Childhood Cancer and Leukemia: A Handbook for Parents.

    ERIC Educational Resources Information Center

    Spinetta, John J.; And Others

    Written for parents of children with cancer and leukemia, the booklet considers the psychosocial aspect of the conditions as well as the effects on the family and child. Part I reviews emotions experienced by parents at the time of the initial diagnosis and through the course of the illness. Marriage strain, support sources, and relatives are…

  9. Educational Implications of the Subtle Late Effects of Childhood Leukemia Medical Treatment: A Case Study

    ERIC Educational Resources Information Center

    Lavach, John F.; Hart, Juliet E.

    2008-01-01

    This paper presents a four-year longitudinal case study of a nine-year-old student when he was diagnosed with leukemia. Cognitive, neuropsychological, and affective functioning both pre and post chemotherapy treatment were assessed. Full neuropsychological evaluation revealed difficulties with processing speed, concentration, and organization…

  10. The CPI Subscales as Predictors of Parental Coping with Childhood Leukemia.

    ERIC Educational Resources Information Center

    Kupst, Mary Jo; Schulman, Jerome L.

    1981-01-01

    Determined the role of the California Psychological Inventory (CPI) in prediction of parental coping with leukemia. None of the standard CPI subscales was a significant predictor of coping. Coping with the specific situation may be a better predictor of later coping with a similar situation than more global assessments. (Author)

  11. Radio-frequency radiation exposure from AM radio transmitters and childhood leukemia and brain cancer.

    PubMed

    Ha, Mina; Im, Hyoungjune; Lee, Mihye; Kim, Hyun Joo; Kim, Byung-Chan; Gimm, Yoon-Myoung; Pack, Jeong-Ki

    2007-08-01

    Leukemia and brain cancer patients under age 15 years, along with controls with respiratory illnesses who were matched to cases on age, sex, and year of diagnosis (1993-1999), were selected from 14 South Korean hospitals using the South Korean Medical Insurance Data System. Diagnoses were confirmed through the South Korean National Cancer Registry. Residential addresses were obtained from medical records. A newly developed prediction program incorporating a geographic information system that was modified by the results of actual measurements was used to estimate radio-frequency radiation (RFR) exposure from 31 amplitude modulation (AM) radio transmitters with a power of 20 kW or more. A total of 1,928 leukemia patients, 956 brain cancer patients, and 3,082 controls were analyzed. Cancer risks were estimated using conditional logistic regression adjusted for residential area, socioeconomic status, and community population density. The odds ratio for all types of leukemia was 2.15 (95% confidence interval (CI): 1.00, 4.67) among children who resided within 2 km of the nearest AM radio transmitter as compared with those resided more than 20 km from it. For total RFR exposure from all transmitters, odds ratios for lymphocytic leukemia were 1.39 (95% CI: 1.04, 1.86) and 1.59 (95% CI: 1.19, 2.11) for children in the second and third quartiles, respectively, versus the lowest quartile. Brain cancer and infantile cancer were not associated with AM RFR. PMID:17556764

  12. Childhood leukemia and residential exposure to weak extremely low frequency magnetic fields

    SciTech Connect

    Feychting, M.; Ahlbom, A.

    1995-03-01

    There is no known mechanism by which magnetic fields of the type generated by high voltage power lines can play a role in cancer development. Nevertheless, epidemiologic research has rather consistently found associations between residential magnetic field exposure and cancer. This is most evident for leukemia in children. 18 refs., 1 tab.

  13. Childhood Cancer Genomics (PDQ®)—Health Professional Version

    Cancer.gov

    Expert-reviewed information summary about the genomics of childhood cancer. The summary describes the molecular subtypes for specific pediatric cancers and their associated clinical characteristics, the recurring genomic alterations that characterize each subtype at diagnosis or relapse, and the therapeutic and prognostic significance of the genomic alterations. The genomic alterations associated with brain tumors, kidney tumors, leukemias, lymphomas, sarcomas, and other cancers are discussed.

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

    ClinicalTrials.gov

    2016-08-23

    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

  15. A phase I/II study examining pentostatin, chlorambucil, and theophylline in patients with relapsed chronic lymphocytic leukemia and non-Hodgkin's lymphoma.

    PubMed

    Willis, Carl R; Goodrich, Amy; Park, Kathy; Waselenko, Jamie K; Lucas, Margaret; Reese, Amy; Diehl, Louis F; Grever, Michael R; Byrd, John C; Flinn, Ian W

    2006-05-01

    In an attempt to exploit bcl-2 overexpression and aberrant p53 function, two frequently encountered aberrations that predict marked treatment resistance and worse prognosis in patients with chronic lymphocytic leukemia (CLL) and non-Hodgkin's lymphoma (NHL), we combined theophylline, pentostatin, and chlorambucil at two dose levels (cohort I: 30 mg/m(2); cohort II: 20 mg/m(2)) on a 21-day cycle for up to six courses. We employed a phase I/II design to determine feasibility, define the maximum tolerated dose (MTD), and explore the impact of biologic modulation on response and time to progression (TTP) in 20 patients with relapsed or refractory CLL and NHL. Eight patients were enrolled in cohort I. They demonstrated a response rate (RR) of 28% and a 16.5-month TTP after receiving a median of two cycles. A 50% RR was observed in this cohort when patients with adverse histologies were excluded. Because of myelotoxicity, this dose level defined the MTD, and de-escalation occurred. All 12 patients in cohort II received 20 mg/m(2) chlorambucil. A 50% RR and an 18-month TTP were observed after a median of 5.5 cycles. An RR of 47% and a complete remission (CR) of 5% were observed for the entire group, although responses and TTP varied greatly by histology. Significant activity was observed in patients with B-cell CLL and follicular lymphoma (FL). RR and TTP for fludarabine-sensitive/naïve and fludarabine-refractory (FR) B-cell CLL patients were 66 vs 25% and 20 vs 8.5 months, respectively. Both FL patients responded (one with partial remission and one with CR), with a 22.5-monthly median TTP. For responding patients, median TTP and overall survival (OS) was 21 and 69 months, respectively, compared to a median TTP of 2 months and an OS of 13.5 months for nonresponders. The combination of pentostatin, chlorambucil, and theophylline is the active regimen in patients with FL and B-cell CLL. PMID:16518606

  16. Clofarabine Plus Cytarabine Compared With Cytarabine Alone in Older Patients With Relapsed or Refractory Acute Myelogenous Leukemia: Results From the CLASSIC I Trial

    PubMed Central

    Faderl, Stefan; Wetzler, Meir; Rizzieri, David; Schiller, Gary; Jagasia, Madan; Stuart, Robert; Ganguly, Siddhartha; Avigan, David; Craig, Michael; Collins, Robert; Maris, Michael; Kovacsovics, Tibor; Goldberg, Stuart; Seiter, Karen; Hari, Parameswaran; Greiner, Jochen; Vey, Norbert; Recher, Christian; Ravandi, Farhad; Wang, Eunice S.; Vasconcelles, Michael; Huebner, Dirk; Kantarjian, Hagop M.

    2012-01-01

    Purpose To compare the receipt of clofarabine plus cytarabine (Clo+Ara-C arm) with cytarabine (Ara-C arm) in patients ≥ 55 years old with refractory or relapsed acute myelogenous leukemia (AML). Patients and Methods Patients were randomly assigned to receive either clofarabine (Clo) 40 mg/m2 or a placebo followed by Ara-C 1 g/m2 for five consecutive days. The primary end point was overall survival (OS). Secondary end points included event-free survival (EFS), 4-month EFS, overall remission rate (ORR; complete remission [CR] plus CR with incomplete peripheral blood count recovery), disease-free survival (DFS), duration of remission (DOR), and safety. Results Among 320 patients with confirmed AML (median age, 67 years), the median OS was 6.6 months in the Clo+Ara-C arm and 6.3 months in the Ara-C arm (hazard ratio [HR], 1.00; 95% CI, 0.78 to 1.28; P = 1.00). The ORR was 46.9% in the Clo+Ara-C arm (35.2% CR) versus 22.9% in the Ara-C arm (17.8% CR; P < .01). EFS (HR: 0.63; 95% CI, 0.49 to 0.80; P < .01) and 4-month EFS (37.7% v 16.6%; P < .01) favored the Clo+Ara-C arm compared with Ara-C arm, respectively. DFS and DOR were similar in both arms. Overall 30-day mortality was 16% and 5% for CLO+Ara-C and Ara-C arms, respectively. In the Clo+Ara-C and Ara-C arms, the most common grade 3 to 4 toxicities were febrile neutropenia (47% v 35%, respectively), hypokalemia (18% v 11%, respectively), thrombocytopenia (16% v 17%, respectively), pneumonia (14% v 10%, respectively), anemia (13% v 0%, respectively), neutropenia (11% v 9%, respectively), increased AST (11% v 2%, respectively), and increased ALT (10% v 3%, respectively). Conclusion Although the primary end point of OS did not differ between arms, Clo+Ara-C significantly improved response rates and EFS. Study follow-up continues, and the role of clofarabine in the treatment of adult patients with AML continues to be investigated. PMID:22585697

  17. Neurocognitive Outcomes Decades After Treatment for Childhood Acute Lymphoblastic Leukemia: A Report From the St Jude Lifetime Cohort Study

    PubMed Central

    Krull, Kevin R.; Brinkman, Tara M.; Li, Chenghong; Armstrong, Gregory T.; Ness, Kirsten K.; Srivastava, Deo Kumar; Gurney, James G.; Kimberg, Cara; Krasin, Matthew J.; Pui, Ching-Hon; Robison, Leslie L.; Hudson, Melissa M.

    2013-01-01

    Purpose To determine rates, patterns, and predictors of neurocognitive impairment in adults decades after treatment for childhood acute lymphoblastic leukemia (ALL). Patients and Methods Survivors of childhood ALL treated at St Jude Children's Research Hospital who were still alive at 10 or more years after diagnosis and were age ≥ 18 years were recruited for neurocognitive testing. In all, 1,014 survivors were eligible, 738 (72.8%) agreed to participate, and 567 (76.8%) of these were evaluated. Mean age was 33 years; mean time since diagnosis was 26 years. Medical record abstraction was performed for data on doses of cranial radiation therapy (CRT) and cumulative chemotherapy. Multivariable modeling was conducted and glmulti package was used to select the best model with minimum Akaike information criterion. Results Impairment rates across neurocognitive domains ranged from 28.6% to 58.9%, and those treated with chemotherapy only demonstrated increased impairment in all domains (all P values < .006). In survivors who received no CRT, dexamethasone was associated with impaired attention (relative risk [RR], 2.12; 95% CI, 1.11 to 4.03) and executive function (RR, 2.42; 95% CI, 1.20 to 4.91). The impact of CRT was dependent on young age at diagnosis for intelligence, academic, and memory functions. Risk for executive function problems increased with survival time in a CRT dose-dependent fashion. In all survivors, self-reported behavior problems increased by 5% (RR, 1.05; 95% CI, 1.01 to 1.09) with each year from diagnosis. Impairment was associated with reduced educational attainment and unemployment. Conclusion This study demonstrates persistent and significant neurocognitive impairment in adult survivors of childhood ALL and warrants ongoing monitoring of brain health to facilitate successful adult development and to detect early onset of decline as survivors mature. PMID:24190124

  18. 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

  19. Donor Stem Cell Transplant in Treating Patients With High Risk Acute Myeloid Leukemia

    ClinicalTrials.gov

    2015-08-29

    Adult Acute Megakaryoblastic Leukemia (M7); 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 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); 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

  20. Safety, Tolerability, and Pharmacokinetics of Idelalisib in Japanese Adults With Relapsed or Refractory Indolent B-Cell Non-Hodgkin Lymphomas or Chronic Lymphocytic Leukemia

    ClinicalTrials.gov

    2016-05-16

    Chronic Lymphocytic Leukemia; Indolent Non-Hodgkin Lymphoma; Follicular Lymphoma; Small Lymphocytic Lymphoma; Lymphoplasmacytic Lymphoma (With or Without Waldenstrom Macroglobulinemia); Marginal Zone Lymphoma

  1. 3-AP and Fludarabine in Treating Patients With Myeloproliferative Disorders, Chronic Myelomonocytic Leukemia, or Accelerated Phase or Blastic Phase Chronic Myelogenous Leukemia

    ClinicalTrials.gov

    2014-12-16

    Accelerated Phase Chronic Myelogenous Leukemia; Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative; Blastic Phase Chronic Myelogenous Leukemia; Chronic Eosinophilic Leukemia; Chronic Myelomonocytic Leukemia; Essential Thrombocythemia; Philadelphia Chromosome Negative Chronic Myelogenous Leukemia; Polycythemia Vera; Primary Myelofibrosis; Relapsing Chronic Myelogenous Leukemia

  2. Fatal adenovirus hepatitis during standard chemotherapy for childhood acute lymphoblastic leukemia.

    PubMed

    Hough, Rachael; Chetwood, Andrew; Sinfield, Rebecca; Welch, Jenny; Vora, Ajay

    2005-02-01

    Fulminant hepatitis is a rare complication of adenoviral infection that has not previously been reported in children receiving standard chemotherapy for acute leukemia. The authors have observed fatal adenovirus hepatitis in three children receiving first-line chemotherapy for acute lymphoblastic leukemia (ALL). The patients presented 10, 17, and 8 months into therapy according to the UKALL XI (third intensification), UKALL 97/99 (maintenance), and pilot UKALL 2003 (delayed intensification II) protocols, respectively. All patients received aggressive supportive care and intravenous immunoglobulins. The second and third patients were also treated with intravenous cidofovir. Despite these measures, all three children deteriorated rapidly and died of fulminant liver failure. Although rare, adenovirus infection should be considered in the differential diagnosis of acute hepatitis in children receiving standard chemotherapy for ALL. PMID:15701979

  3. Combination Chemotherapy With or Without Rituximab in Treating Younger Patients With Stage III-IV Non-Hodgkin Lymphoma or B-Cell Acute Leukemia

    ClinicalTrials.gov

    2015-10-20

    Childhood B Acute Lymphoblastic Leukemia; Childhood Burkitt Leukemia; Childhood Diffuse Large Cell Lymphoma; Mediastinal (Thymic) Large B-Cell Lymphoma; Stage III Childhood Large Cell Lymphoma; Stage IV Childhood Large Cell Lymphoma

  4. Improved relapse-free survival after autologous stem cell transplantation does not translate into better quality of life in chronic lymphocytic leukemia: lessons from the randomized European Society for Blood and Marrow Transplantation-Intergroup study.

    PubMed

    de Wreede, Liesbeth C; Watson, Maggie; van Os, Marleen; Milligan, Donald; van Gelder, Michel; Michallet, Mauricette; Dreger, Peter; Dearden, Claire E; Homewood, Janis; Dupuis, Jehan; Leporrier, Michel; Karas, Michal; Corront, Bernadette; Baerlocher, Gabriela M; Herr, Wolfgang; Choquet, Sylvain; Niederwieser, Dietger W; Sutton, Laurent; Kröger, Nicolaus; de Witte, Theo M; Schetelig On Behalf Of The Chronic Malignancies Working Party Of The Ebmt And The Uk Medical Research Council, Johannes

    2014-02-01

    In chronic lymphocytic leukemia (CLL) medical progress is driven by clinical studies with relapse-free survival (RFS) as the primary endpoint. The randomized EBMT-Intergroup trial compared high-dose therapy and autologous stem cell transplantation (ASCT) to observation and demonstrated a substantial improvement of RFS without showing improved overall survival for the transplant arm. Here we report quality of life (QoL) information of the first 3 years following randomization from that study. The main objective was to assess the impact of treatment on QoL over time. Two secondary analyses were performed to further investigate the impact of ASCT and relapse on QoL. In the primary analysis, we demonstrate an adverse impact of ASCT on QoL which was largest at 4 months and continued throughout the first year after randomization. Further, we demonstrated a sustained adverse impact of relapse on QoL which worsened over time. Despite better disease control by ASCT the side effects thus turned the net effect towards inferior QoL in the first year and comparable QoL in the following 2 years after randomization. This study emphasizes the importance of information concerning QoL impacts when patients are counseled about treatments aimed at improving RFS in the absence of a survival benefit. PMID:24123244

  5. Gonadal function after 12-Gy testicular irradiation in childhood acute lymphoblastic leukemia

    SciTech Connect

    Castillo, L.A.; Craft, A.W.; Kernahan, J.; Evans, R.G.; Aynsley-Green, A. )

    1990-01-01

    Gonadal function was assessed in 15 boys with acute lymphoblastic leukemia (ALL) who had received testicular irradiation. The dose to the testes was 12 Gy in 12, 15 Gy in 1, and 24 Gy in 2 cases. All of those who had received 12 or 15 Gy had normal Leydig cell function, although high levels of gonadotropins suggest subclinical Leydig cell damage. The 2 who had 24 Gy had Leydig cell failure. All who were old enough to produce a semen specimen were azoospermic.

  6. Prevalence of Gene Rearrangements in Mexican Children with Acute Lymphoblastic Leukemia: A Population Study—Report from the Mexican Interinstitutional Group for the Identification of the Causes of Childhood Leukemia

    PubMed Central

    Bekker-Méndez, Vilma Carolina; Miranda-Peralta, Enrique; Núñez-Enríquez, Juan Carlos; Olarte-Carrillo, Irma; Guerra-Castillo, Francisco Xavier; Pompa-Mera, Ericka Nelly; Ocaña-Mondragón, Alicia; Bernáldez-Ríos, Roberto; Medina-Sanson, Aurora; Jiménez-Hernández, Elva; Amador-Sánchez, Raquel; Peñaloza-González, José Gabriel; de Diego Flores-Chapa, José; Fajardo-Gutiérrez, Arturo; Flores-Lujano, Janet; Rodríguez-Zepeda, María del Carmen; Dorantes-Acosta, Elisa María; Bolea-Murga, Victoria; Núñez-Villegas, Nancy; Velázquez-Aviña, Martha Margarita; Torres-Nava, José Refugio; Reyes-Zepeda, Nancy Carolina; González-Bonilla, Cesar; Mejía-Aranguré, Juan Manuel

    2014-01-01

    Mexico has one of the highest incidences of childhood leukemia worldwide and significantly higher mortality rates for this disease compared with other countries. One possible cause is the high prevalence of gene rearrangements associated with the etiology or with a poor prognosis of childhood acute lymphoblastic leukemia (ALL). The aims of this multicenter study were to determine the prevalence of the four most common gene rearrangements [ETV6-RUNX1, TCF3-PBX1, BCR-ABL1, and MLL rearrangements] and to explore their relationship with mortality rates during the first year of treatment in ALL children from Mexico City. Patients were recruited from eight public hospitals during 2010–2012. A total of 282 bone marrow samples were obtained at each child's diagnosis for screening by conventional and multiplex reverse transcription polymerase chain reaction to determine the gene rearrangements. Gene rearrangements were detected in 50 (17.7%) patients. ETV6-RUNX1 was detected in 21 (7.4%) patients, TCF3-PBX1 in 20 (7.1%) patients, BCR-ABL1 in 5 (1.8%) patients, and MLL rearrangements in 4 (1.4%) patients. The earliest deaths occurred at months 1, 2, and 3 after diagnosis in patients with MLL, ETV6-RUNX1, and BCR-ABL1 gene rearrangements, respectively. Gene rearrangements could be related to the aggressiveness of leukemia observed in Mexican children. PMID:25692130

  7. Prevalence of gene rearrangements in Mexican children with acute lymphoblastic leukemia: a population study-report from the Mexican Interinstitutional Group for the identification of the causes of childhood leukemia.

    PubMed

    Bekker-Méndez, Vilma Carolina; Miranda-Peralta, Enrique; Núñez-Enríquez, Juan Carlos; Olarte-Carrillo, Irma; Guerra-Castillo, Francisco Xavier; Pompa-Mera, Ericka Nelly; Ocaña-Mondragón, Alicia; Rangel-López, Angélica; Bernáldez-Ríos, Roberto; Medina-Sanson, Aurora; Jiménez-Hernández, Elva; Amador-Sánchez, Raquel; Peñaloza-González, José Gabriel; de Diego Flores-Chapa, José; Fajardo-Gutiérrez, Arturo; Flores-Lujano, Janet; Rodríguez-Zepeda, María Del Carmen; Dorantes-Acosta, Elisa María; Bolea-Murga, Victoria; Núñez-Villegas, Nancy; Velázquez-Aviña, Martha Margarita; Torres-Nava, José Refugio; Reyes-Zepeda, Nancy Carolina; González-Bonilla, Cesar; Mejía-Aranguré, Juan Manuel

    2014-01-01

    Mexico has one of the highest incidences of childhood leukemia worldwide and significantly higher mortality rates for this disease compared with other countries. One possible cause is the high prevalence of gene rearrangements associated with the etiology or with a poor prognosis of childhood acute lymphoblastic leukemia (ALL). The aims of this multicenter study were to determine the prevalence of the four most common gene rearrangements [ETV6-RUNX1, TCF3-PBX1, BCR-ABL1, and MLL rearrangements] and to explore their relationship with mortality rates during the first year of treatment in ALL children from Mexico City. Patients were recruited from eight public hospitals during 2010-2012. A total of 282 bone marrow samples were obtained at each child's diagnosis for screening by conventional and multiplex reverse transcription polymerase chain reaction to determine the gene rearrangements. Gene rearrangements were detected in 50 (17.7%) patients. ETV6-RUNX1 was detected in 21 (7.4%) patients, TCF3-PBX1 in 20 (7.1%) patients, BCR-ABL1 in 5 (1.8%) patients, and MLL rearrangements in 4 (1.4%) patients. The earliest deaths occurred at months 1, 2, and 3 after diagnosis in patients with MLL, ETV6-RUNX1, and BCR-ABL1 gene rearrangements, respectively. Gene rearrangements could be related to the aggressiveness of leukemia observed in Mexican children. PMID:25692130

  8. Associations between Metabolic Risk Factors and the Hypothalamic Volume in Childhood Leukemia Survivors Treated with Cranial Radiotherapy

    PubMed Central

    Follin, Cecilia; Gabery, Sanaz; Petersén, Åsa; Sundgren, Pia C.; Björkman-Burtcher, Isabella; Lätt, Jimmy; Mannfolk, Peter; Erfurth, Eva Marie

    2016-01-01

    Metabolic complications are prevalent in individuals treated with cranial radiotherapy (CRT) for childhood acute lymphoblastic leukemia (ALL). The hypothalamus is a master regulator of endocrine and metabolic control. The aim of this study was to investigate whether the hypothalamic volume would be associated to metabolic parameters in ALL survivors. Thirty-eight (21 women) survivors participated in this study 34 years after diagnosis and with a median age of 38 (27–46) years. All were treated with a median CRT dose of 24 Gy and 11 years (3–13) of complete hormone supplementation. Comparisons were made to 31 matched controls. We performed analyses of fat mass, fat free mass, plasma (p)-glucose, p-insulin, Homa-Index (a measure of insulin resistance), serum (s)-leptin, s-ghrelin and of the hypothalamic volume in scans obtained by magnetic resonance imaging (MRI) at 3 Tesla. Serum leptin/kg fat mass (r = -0.4, P = 0.04) and fat mass (r = -0.4, P = 0.01) were negatively correlated with the HT volume among ALL survivors, but not among controls. We also detected significantly higher BMI, waist, fat mass, p-insulin, Homa-Index, leptin/kg fat mass and s-ghrelin and significantly lower fat free mass specifically among female ALL survivors (all P<0.01). Interestingly, s-ghrelin levels increased with time since diagnosis and with low age at diagnosis for childhood ALL. Our results showed that leptin/kg fat mass and fat mass were associated with a reduced HT volume 34 years after ALL diagnosis and that women treated with CRT after ALL are at high risk of metabolic abnormalities. Taken together our data suggest that the hypothalamus is involved in the metabolic consequences after CRT in ALL survivors. PMID:26824435

  9. Is there an increased risk of metabolic syndrome among childhood acute lymphoblastic leukemia survivors? A developing country experience.

    PubMed

    Mohapatra, Sonali; Bansal, Deepak; Bhalla, A K; Verma Attri, Savita; Sachdeva, Naresh; Trehan, Amita; Marwaha, R K

    2016-03-01

    Data on metabolic syndrome (MS) in survivors of childhood acute lymphoblastic leukemia (ALL) from developing countries are lacking. The purpose of this single-center, uncontrolled, observational study was to assess the frequency of MS in our survivors. The survivors of ALL ≤15 years at diagnosis, who had completed therapy ≥2 years earlier, were enrolled. Anthropometric measurements (weight, height, waist circumference), biochemistry (glucose, insulin, triglycerides, high-density lipoprotein [HDL], thyroid function tests, C-reactive protein [CRP], magnesium), measurement of blood pressure, and Tanner staging were performed. MS was defined by International Diabetes Federation (IDF) and the National Cholesterol Education Program Third Adult Treatment Panel guidelines (NCEP ATP III) criteria, modified by Cook et al. (Arch Pediatr Adolesc Med. 2003;157:821-827) and Ford et al. (Diabetes Care. 2005;28:878-881). The median age of 76 survivors was 11.9 years (interquartile range [IQR]: 9.6-13.5). Twenty-four (32%) survivors were obese or overweight. The prevalence of insulin resistance (17%), hypertension (7%), hypertriglyceridemia (20%), and low HDL (37%) was comparable to the prevalence in children/adolescents in historical population-based studies from India. The prevalence of MS ranged from 1.3% to 5.2%, as per different defining criteria. Cranial radiotherapy, age at diagnosis, sex, or socioeconomic status were not risk factors for MS. The prevalence of MS in survivors of childhood ALL, at a median duration of 3 years from completion of chemotherapy, was comparable to the reference population. The prevalence of being obese or overweight was, however, greater than historical controls. PMID:26984439

  10. The Genomic Landscape of Juvenile Myelomonocytic Leukemia

    PubMed Central

    Chang, Tiffany Y.; Gelston, Laura C.; Wang, Yong-Dong; Mazor, Tali; Esquivel, Emilio; Yu, Ariel; Seepo, Sara; Olsen, Scott; Rosenberg, Mara; Archambeault, Sophie L.; Abusin, Ghada; Beckman, Kyle; Brown, Patrick A.; Briones, Michael; Carcamo, Benjamin; Cooper, Todd; Dahl, Gary V.; Emanuel, Peter D.; Fluchel, Mark N.; Goyal, Rakesh K.; Hayashi, Robert J.; Hitzler, Johann; Hugge, Christopher; Liu, Y. Lucy; Messinger, Yoav H.; Mahoney, Donald H.; Monteleone, Philip; Nemecek, Eneida R.; Roehrs, Philip A.; Schore, Reuven J.; Stine, Kimo C.; Takemoto, Clifford M.; Toretsky, Jeffrey A.; Costello, Joseph F.; Olshen, Adam B.; Stewart, Chip; Li, Yongjin; Ma, Jing; Gerbing, Robert B.; Alonzo, Todd A.; Getz, Gad; Gruber, Tanja; Golub, Todd; Stegmaier, Kimberly; Loh, Mignon L.

    2015-01-01

    Juvenile myelomonocytic leukemia (JMML) is a myeloproliferative neoplasm (MPN) of childhood with a poor prognosis. Mutations in NF1, NRAS, KRAS, PTPN11 and CBL occur in 85% of patients, yet there are currently no risk stratification algorithms capable of predicting which patients will be refractory to conventional treatment and therefore be candidates for experimental therapies. In addition, there have been few other molecular pathways identified aside from the Ras/MAPK pathway to serve as the basis for such novel therapeutic strategies. We therefore sought to genomically characterize serial samples from patients at diagnosis through relapse and transformation to acute myeloid leukemia in order to expand our knowledge of the mutational spectrum in JMML. We identified recurrent mutations in genes involved in signal transduction, gene splicing, the polycomb repressive complex 2 (PRC2) and transcription. Importantly, the number of somatic alterations present at diagnosis appears to be the major determinant of outcome. PMID:26457647

  11. Acute leukemia in children: A review of the current Indian data

    PubMed Central

    Arora, Ramandeep Singh; Arora, Brijesh

    2016-01-01

    Acute leukemias are the most common diagnostic group of childhood cancer. This review summarizes the published literature on reported current outcomes of childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) from India. Overall survival in ALL ranged from 45% to 81% (commonly >60%) and event-free survival ranged from 41% to 70% (commonly >50%). Outcome data for AML was patchy with varying duration of follow-up, but it can be inferred that 50–80% of treated patients had experienced an event (toxic death, refractory disease or relapse). It is imperative that going forward focus should be on collaborative efforts, which promote treatment of patients on risk-stratified adapted protocols based on local infrastructure, improvement in supportive care and encourage prospective multi-center clinical trials. PMID:27606304

  12. Acute leukemia in children: A review of the current Indian data.

    PubMed

    Arora, Ramandeep Singh; Arora, Brijesh

    2016-01-01

    Acute leukemias are the most common diagnostic group of childhood cancer. This review summarizes the published literature on reported current outcomes of childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) from India. Overall survival in ALL ranged from 45% to 81% (commonly >60%) and event-free survival ranged from 41% to 70% (commonly >50%). Outcome data for AML was patchy with varying duration of follow-up, but it can be inferred that 50-80% of treated patients had experienced an event (toxic death, refractory disease or relapse). It is imperative that going forward focus should be on collaborative efforts, which promote treatment of patients on risk-stratified adapted protocols based on local infrastructure, improvement in supportive care and encourage prospective multi-center clinical trials. PMID:27606304

  13. Ethnicity and survival in childhood acute myeloid leukemia: a report from the Children's Oncology Group

    PubMed Central

    Aplenc, Richard; Alonzo, Todd A.; Gerbing, Robert B.; Smith, Franklin O.; Meshinchi, Soheil; Ross, Julie A.; Perentesis, John; Woods, William G.; Lange, Beverly J.; Davies, Stella M.

    2006-01-01

    We evaluated differences in outcome by ethnicity among children with acute myeloid leukemia (AML). We analyzed 791 children in the CCG 2891 trial and confirmed positive findings in 850 children in the CCG 2961 trial. Hispanic and black children treated with chemotherapy in CCG 2891 had significantly inferior overall survival (OS) from study entry compared with white children (37%± 9% vs 48%± 4% [P = .016] and 34% ± 10% vs 48% ± 4%, [P = .007], respectively). Significantly fewer black children had related donors. Analyses of CCG 2961 confirmed that black children had significantly decreased OS rates compared with white children (45% ± 12% vs 60% ± 4%; P = .007) The difference in OS rates between Hispanic and white children approached statistical significance (51% ± 8% vs 60% ± 4%; P = .065) Only 7.5% of black children on CCG 2961 had an available family donor. In conclusion, Hispanic and black children with AML have worse survival than white children. Access to chemotherapy, differences in supportive care or leukemia phenotype, and reduced compliance are unlikely explanations for this difference because therapy was given intravenously according to CCG protocols. Fewer black children than expected had an available family marrow donor. (Blood. 2006;108:74-80) PMID:16537811

  14. Effects of Race/Ethnicity and Socioeconomic Status on Outcome in Childhood Acute Lymphoblastic Leukemia.

    PubMed

    Acharya, Sahaja; Hsieh, Samantha; Shinohara, Eric T; DeWees, Todd; Frangoul, Haydar; Perkins, Stephanie M

    2016-07-01

    With modern therapy, overall survival (OS) for children with acute lymphoblastic leukemia approaches 90%. However, inferior outcomes for minority children have been reported. Data on the effects of ethnicity/race as it relates to socioeconomic status are limited. Using state cancer registry data from Texas and Florida, we evaluated the impact of neighborhood-level poverty rate and race/ethnicity on OS for 4719 children with acute lymphoblastic leukemia. On multivariable analysis, patients residing in neighborhoods with the highest poverty rate had a 1.8-fold increase in mortality compared with patients residing in neighborhoods with the lowest poverty rate (hazard ratio [HR], 1.8; 95% confidence interval [CI], 1.41-2.30). Hispanic and non-Hispanic black patients also had increased risk of mortality compared with non-Hispanic white patients (Hispanic: HR, 1.18; 95% CI, 1.01-1.39; non-Hispanic black: HR, 1.31; 95% CI, 1.03-1.66). On subgroup analysis, there was a 21.7% difference in 5-year OS when comparing non-Hispanic white children living in the lowest poverty neighborhoods (5-year OS, 91.2%; 95% CI, 88.6-93.2) to non-Hispanic black children living in the highest poverty neighborhoods (5-year OS, 69.5%; 95% CI, 61.5-76.1). To address such disparities in survival, further work is needed to identify barriers to cancer care in this pediatric population. PMID:27177145

  15. Health and Risk Behaviors in Survivors of Childhood Acute Myeloid Leukemia: A Report From the Children’s Oncology Group

    PubMed Central

    Schultz, Kris Ann P.; Chen, Lu; Chen, Zhengjia; Zeltzer, Lonnie K.; Nicholson, H. Stacy; Neglia, Joseph P.

    2011-01-01

    Background Survivors of childhood acute myeloid leukemia (AML) face increased risks of chronic disease and secondary malignancies. Substance exposure may compound these risks. Procedures Participants were diagnosed with AML at <21 years of age and survived ≥5 years following diagnosis. All underwent chemotherapy alone or followed by autologous BMT (chemo ± autoBMT) or underwent allogeneic BMT (alloBMT) if an HLA-matched related donor was available. Survivors completed a health questionnaire and a Youth Risk Behavior Survey (YRBS). Results Of eligible survivors, 117 were ≥18 years of age and completed a YRBS. Survivors were a mean age of 10 years at diagnosis and 24 years at interview. Of the substance exposures assessed by YRBS, tobacco, alcohol, and marijuana were most common. Twenty-two percent (22%) had smoked cigarettes in the last 30 days. One-quarter (25%) reported binge drinking in the last month. None of these exposures varied by treatment group. Less than 10% of survivors reported cocaine, heroin, or methamphetamine use. Men were more likely to report high substance exposure (P = 0.004). Sadness/suicidality score was associated with cancer-related anxiety (P = 0.006) and multiple health conditions (P = 0.006). Conclusions This analysis reveals exposure to tobacco, alcohol, and marijuana in young adults with few differences based on treatment received. Survivors with cancer-related anxiety or multiple health conditions were more likely to report sadness/hopelessness. PMID:20232426

  16. Stochastic modeling reveals an evolutionary mechanism underlying elevated rates of childhood leukemia.

    PubMed

    Rozhok, Andrii I; Salstrom, Jennifer L; DeGregori, James

    2016-01-26

    Young children have higher rates of leukemia than young adults. This fact represents a fundamental conundrum, because hematopoietic cells in young children should have fewer mutations (including oncogenic ones) than such cells in adults. Here, we present the results of stochastic modeling of hematopoietic stem cell (HSC) clonal dynamics, which demonstrated that early HSC pools were permissive to clonal evolution driven by drift. We show that drift-driven clonal expansions cooperate with faster HSC cycling in young children to produce conditions that are permissive for accumulation of multiple driver mutations in a single cell. Later in life, clonal evolution was suppressed by stabilizing selection in the larger young adult pools, and it was driven by positive selection at advanced ages in the presence of microenvironmental decline. Overall, our results indicate that leukemogenesis is driven by distinct evolutionary forces in children and adults. PMID:26755588

  17. Safety and tolerability of allogeneic dendritic cell vaccination with induction of Wilms tumor 1-specific T cells in a pediatric donor and pediatric patient with relapsed leukemia: a case report and review of the literature.

    PubMed

    Saito, Shoji; Yanagisawa, Ryu; Yoshikawa, Kentaro; Higuchi, Yumiko; Koya, Terutsugu; Yoshizawa, Kiyoshi; Tanaka, Miyuki; Sakashita, Kazuo; Kobayashi, Takashi; Kurata, Takashi; Hirabayashi, Koichi; Nakazawa, Yozo; Shiohara, Masaaki; Yonemitsu, Yoshikazu; Okamoto, Masato; Sugiyama, Haruo; Koike, Kenichi; Shimodaira, Shigetaka

    2015-03-01

    A 15-year-old girl with acute lymphoblastic leukemia received allogeneic dendritic cell vaccination, pulsed with Wilms tumor 1 (WT1) peptide, after her third hematopoietic stem cell transplantation (HSCT). The vaccines were generated from the third HSCT donor, who was her younger sister, age 12 years. The patient received 14 vaccines and had no graft-versus-host disease or systemic adverse effect, aside from grade 2 skin reaction at the injection site. WT1-specific immune responses were detected after vaccination by both WT1-tetramer analysis and enzyme-linked immunosorbent spot assay. This strategy may be safe, tolerable and even feasible for patients with a relapse after HSCT. PMID:25484308

  18. Postremission sequential monitoring of minimal residual disease by WT1 Q-PCR and multiparametric flow cytometry assessment predicts relapse and may help to address risk-adapted therapy in acute myeloid leukemia patients.

    PubMed

    Malagola, Michele; Skert, Cristina; Borlenghi, Erika; Chiarini, Marco; Cattaneo, Chiara; Morello, Enrico; Cancelli, Valeria; Cattina, Federica; Cerqui, Elisa; Pagani, Chiara; Passi, Angela; Ribolla, Rossella; Bernardi, Simona; Giustini, Viviana; Lamorgese, Cinzia; Ruggeri, Giuseppina; Imberti, Luisa; Caimi, Luigi; Russo, Domenico; Rossi, Giuseppe

    2016-02-01

    Risk stratification in acute myeloid leukemia (AML) patients using prognostic parameters at diagnosis is effective, but may be significantly improved by the use of on treatment parameters which better define the actual sensitivity to therapy in the single patient. Minimal residual disease (MRD) monitoring has been demonstrated crucial for the identification of AML patients at high risk of relapse, but the best method and timing of MRD detection are still discussed. Thus, we retrospectively analyzed 104 newly diagnosed AML patients, consecutively treated and monitored by quantitative polymerase chain reactions (Q-PCR) on WT1 and by multiparametric flow cytometry (MFC) on leukemia-associated immunophenotypes (LAIPs) at baseline, after induction, after 1st consolidation and after 1st intensification. By multivariate analysis, the factors independently associated with adverse relapse-free survival (RFS) were: bone marrow (BM)-WT1 ≥ 121/10(4) ABL copies (P = 0.02) and LAIP ≥ 0.2% (P = 0.0001) (after 1st consolidation) (RFS at the median follow up of 12.5 months: 51% vs. 82% [P < 0.0001] and 57% vs. 81%, respectively [P = 0.0003]) and PB-WT1 ≥ 16/10(4) ABL copies (P = 0.0001) (after 1st intensification) (RFS 43% vs. 95% [P < 0.0001]) Our data confirm the benefits of sequential MRD monitoring with both Q-PCR and MFC. If confirmed by further prospective trials, they may significantly improve the possibility of a risk-adapted, postinduction therapy of AML. PMID:26715369

  19. Role of glutathione S-transferase M1, T1 and P1 gene polymorphisms in childhood acute lymphoblastic leukemia susceptibility in a Turkish population.

    PubMed

    Guven, Mehmet; Unal, Selin; Erhan, Duygu; Ozdemir, Nihal; Baris, Safa; Celkan, Tiraje; Bostancı, Merve; Batar, Bahadir

    2015-09-01

    The variations between different individuals in the xenobiotic metabolizing enzymes' activity were shown to modify susceptibility to childhood acute lymphoblastic leukemia (ALL). Polymorphisms associated with genes coding for the glutathione S-transferase (GST) enzyme were known to affect the metabolism of different carcinogens. The aim of this study was to evaluate the influence of the GSTM1 and GSTT1 deletion polymorphisms, and the GSTP1 Ile105Val single nucleotide polymorphism (SNP) on the susceptibility to childhood ALL. The study was conducted in 95 children with ALL and 190 healthy control subjects from the Turkish population. The data revealed no difference in the prevalence of the GSTM1 and GSTT1 null genotypes between the childhood ALL patients and the controls. No association was found between GSTP1 Ile105Val variants and the susceptibility to childhood ALL, separately or in combination. Our findings suggested that the status of heritable GST polymorphism might not influence the risk of developing childhood ALL. Studies with a larger sample size are needed to evaluate and confirm the validity of our results. PMID:26137447

  20. Effective multi-agent chemotherapy for advanced abdominal lymphoma and FAB L3 leukemia of childhood.

    PubMed

    Toogood, I R; Tiedemann, K; Stevens, M; Smith, P J

    1993-01-01

    Between June 1981 and May 1988, 51 children with diffuse undifferentiated, advanced (Murphy Stage III and IV) intra-abdominal non-Hodgkin's lymphoma were treated on an intensive multi-drug chemotherapy protocol without irradiation to the primary tumour. Therapy was completed for Stage III disease at one year, but Stage IV patients continued with a further year of therapy until January 1986, when it was reduced to one year. Central nervous system (CNS) prophylaxis consisted of eight doses of intrathecal MTX for all children, and 24 Gy cranial irradiation for Stage IV patients only. There were 42 patients with Stage III disease (III A n = 29 and III B n = 13) and nine patients with Stage IV disease, of whom eight had extensive bone marrow and extramedullary disease (FAB L3 ALL). No patient had CNS disease at presentation. Forty-eight of 51 children (94%) achieved a complete remission. Two children died during remission induction therapy and eleven children relapsed, mostly within eight months of diagnosis. All patients have completed therapy. Failure free survival is 76% for Stage III and 67% for Stage IV patients, with a median followup of 90 and 64 months, respectively. Subdividing Stage III patients into Stage III A and III B did not show significantly different survival (P = 0.9), but the number of patients in Stage III B is small. These results compare favourably with the most effective published protocols, and toxicity has been manageable. PMID:8433675

  1. Glucocorticoid-induced alterations in mitochondrial membrane properties and respiration in childhood acute lymphoblastic leukemia.

    PubMed

    Eberhart, Karin; Rainer, Johannes; Bindreither, Daniel; Ritter, Ireen; Gnaiger, Erich; Kofler, Reinhard; Oefner, Peter J; Renner, Kathrin

    2011-06-01

    Mitochondria are signal-integrating organelles involved in cell death induction. Mitochondrial alterations and reduction in energy metabolism have been previously reported in the context of glucocorticoid (GC)-triggered apoptosis, although the mechanism is not yet clarified. We analyzed mitochondrial function in a GC-sensitive precursor B-cell acute lymphoblastic leukemia (ALL) model as well as in GC-sensitive and GC-resistant T-ALL model systems. Respiratory activity was preserved in intact GC-sensitive cells up to 24h under treatment with 100 nM dexamethasone before depression of mitochondrial respiration occurred. Severe repression of mitochondrial respiratory function was observed after permeabilization of the cell membrane and provision of exogenous substrates. Several mitochondrial metabolite and protein transporters and two subunits of the ATP synthase were downregulated in the T-ALL and in the precursor B-ALL model at the gene expression level under dexamethasone treatment. These data could partly be confirmed in ALL lymphoblasts from patients, dependent on the molecular abnormality in the ALL cells. GC-resistant cell lines did not show any of these defects after dexamethasone treatment. In conclusion, in GC-sensitive ALL cells, dexamethasone induces changes in membrane properties that together with the reduced expression of mitochondrial transporters of substrates and proteins may lead to repressed mitochondrial respiratory activity and lower ATP levels that contribute to GC-induced apoptosis. PMID:21237131

  2. Increased Body Mass Index during Therapy for Childhood Acute Lymphoblastic Leukemia: A Significant and Underestimated Complication.

    PubMed

    Atkinson, Helen C; Marsh, Julie A; Rath, Shoshana R; Kotecha, Rishi S; Gough, Hazel; Taylor, Mandy; Walwyn, Thomas; Gottardo, Nicholas G; Cole, Catherine H; Choong, Catherine S

    2015-01-01

    Objective & Design. We undertook a retrospective review of children diagnosed with acute lymphoblastic leukemia (ALL) and treated with modern COG protocols (n = 80) to determine longitudinal changes in body mass index (BMI) and the prevalence of obesity compared with a healthy reference population. Results. At diagnosis, the majority of patients (77.5%) were in the healthy weight category. During treatment, increases in BMI z-scores were greater for females than males; the prevalence of obesity increased from 10.3% to 44.8% (P < 0.004) for females but remained relatively unchanged for males (9.8% to 13.7%, P = 0.7). Longitudinal analysis using linear mixed-effects identified associations between BMI z-scores and time-dependent interactions with sex (P = 0.0005), disease risk (P < 0.0001), age (P = 0.0001), and BMI z-score (P < 0.0001) at diagnosis and total dose of steroid during maintenance (P = 0.01). Predicted mean BMI z-scores at the end of therapy were greater for females with standard risk ALL irrespective of age at diagnosis and for males younger than 4 years of age at diagnosis with standard risk ALL. Conclusion. Females treated on standard risk protocols and younger males may be at greatest risk of becoming obese during treatment for ALL. These subgroups may benefit from intervention strategies to manage BMI during treatment for ALL. PMID:26101530

  3. Feasibility and Initial Effectiveness of Home Exercise During Maintenance Therapy for Childhood Acute Lymphoblastic Leukemia

    PubMed Central

    Esbenshade, Adam J.; Friedman, Debra L.; Smith, Webb A.; Jeha, Sima; Pui, Ching-Hon; Robison, Leslie L.; Ness, Kirsten K.

    2014-01-01

    Purpose Children with acute lymphoblastic leukemia (ALL) are at increased risk of obesity and deconditioning from cancer therapy. This pilot study assessed feasibility/initial efficacy of an exercise intervention for ALL patients undergoing maintenance therapy. Methods Participants were children with ALL, age 5-10 years, receiving maintenance therapy, in first remission. A 6-month home-based intervention, with written and video instruction, was supervised with weekly calls from an exercise coach. Pre- and post-study testing evaluated strength, flexibility, fitness and motor function. Results Seventeen patients enrolled (participation 63%). Twelve (71%) finished the intervention, completing 81.7±7.2% of prescribed sessions. Improvements ≥5% occurred in 67% for knee and 75% for grip strength, 58% for hamstring/low-back and 83% for ankle flexibility, 75% for the 6-minute-walk-test, and 33% for performance on the Bruininks-Oseretsky Test of Motor Proficiency Version 2. Conclusions This pilot study demonstrated that exercise intervention during ALL therapy is feasible and has promise for efficacy. PMID:24979081

  4. Psychological Impact of Chemotherapy for Childhood Acute Lymphoblastic Leukemia on Patients and Their Parents

    PubMed Central

    Sherief, Laila M.; Kamal, Naglaa M.; Abdalrahman, Hadel M.; Youssef, Doaa M.; Alhady, Mohamed A Abd; Ali, Adel SA; Elbasset, Maha Aly Abd; Hashim, Hiatham M.

    2015-01-01

    Abstract To assess the self-esteem of pediatric patients on chemotherapy for acute lymphoblastic leukemia (ALL) and psychological status of their parents. The psychological status of 178 children receiving chemotherapy for ALL and their parents was assessed using parenting stress index (PSI) to determine the degree of stress the parents are exposed to using parent's and child's domains. Self-esteem Scale was used to determine the psychological status of patients. The study revealed signi