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

ClinicalTrials.gov

2018-04-13

Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome; Chronic Myelomonocytic Leukemia; Myelodysplastic Syndrome; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Refractory Adult Acute Lymphoblastic Leukemia

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

ClinicalTrials.gov

2018-04-20

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

Brain Function in Young Patients Receiving Methotrexate for Acute Lymphoblastic Leukemia

ClinicalTrials.gov

2017-07-19

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

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

Blinatumomab and Combination Chemotherapy or Dasatinib, Prednisone, and Blinatumomab in Treating Older Patients With Acute Lymphoblastic Leukemia

ClinicalTrials.gov

2018-06-01

Acute Lymphoblastic Leukemia; B Acute Lymphoblastic Leukemia; B Acute Lymphoblastic Leukemia With t(9;22)(q34.1;q11.2); BCR-ABL1; B Acute Lymphoblastic Leukemia, Philadelphia Chromosome Negative; Philadelphia Chromosome Positive; Recurrent Adult Acute Lymphoblastic Leukemia; Refractory Adult Acute Lymphoblastic Leukemia; Untreated Adult Acute Lymphoblastic Leukemia

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

PubMed Central

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

2016-01-01

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

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

PubMed

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

2016-08-01

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

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

ClinicalTrials.gov

2016-09-08

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

Pharmacogenetics in Acute Lymphoblastic Leukemia

PubMed Central

Cheok, Meyling H.; Pottier, Nicolas; Kager, Leo

2009-01-01

Progress in the treatment of acute leukemia in children has been remarkable, from a disease being lethal four decades ago to current cure rates exceeding 80%. This exemplary progress is largely due to the optimization of existing treatment modalities rather than the discovery of new antileukemic agents. However, despite these high cure rates, the annual number of children whose leukemia relapses after their initial therapy remains greater than that of new cases of most types of childhood cancers. The aim of pharmacogenetics is to develop strategies to personalize treatment and tailor therapy to individual patients, with the goal of optimizing efficacy and safety through better understanding of human genome variability and its influence on drug response. In this review, we summarize recent pharmacogenomic studies related to the treatment of pediatric acute lymphoblastic leukemia. These studies illustrate the promise of pharmacogenomics to further advance the treatment of human cancers, with childhood leukemia serving as a paradigm. PMID:19100367

Vincristine and fine motor function of children with acute lymphoblastic leukemia

PubMed

Sabarre, Cheryl L; Rassekh, Shahrad R; Zwicker, Jill G

2014-10-01

Children with acute lymphoblastic leukemia receive vincristine, a chemotherapy drug known to cause peripheral neuropathy. Yet, few studies have examined the association of vincristine to fine motor function. This study will describe the fine motor skills and function of children with acute lymphoblastic leukemia on maintenance vincristine. A prospective case series design assessed manual dexterity and parent-reported fine motor dysfunction of 15 children with acute lymphoblastic leukemia in relation to cumulative vincristine exposure. Almost half of the participants had below-average fine motor skills compared to age-related norms, and 57% of parents observed functional motor problems in their children. No significant associations were found between vincristine, manual dexterity, and functional motor skills. Early detection and intervention for fine motor difficulties is suggested. Research with a larger sample is necessary to further explore the association of vincristine and fine motor function in this clinical population.

Combination Chemotherapy With or Without Bortezomib in Treating Younger Patients With Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia or Stage II-IV T-Cell Lymphoblastic Lymphoma

ClinicalTrials.gov

2018-06-27

Adult T Acute Lymphoblastic Leukemia; Ann Arbor Stage II Adult Lymphoblastic Lymphoma; Ann Arbor Stage II Childhood Lymphoblastic Lymphoma; Ann Arbor Stage III Adult Lymphoblastic Lymphoma; Ann Arbor Stage III Childhood Lymphoblastic Lymphoma; Ann Arbor Stage IV Adult Lymphoblastic Lymphoma; Ann Arbor Stage IV Childhood Lymphoblastic Lymphoma; Childhood T Acute Lymphoblastic Leukemia; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Childhood Acute Lymphoblastic Leukemia

Nilotinib and Combination Chemotherapy in Treating Patients With Newly Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia or Blastic Phase Chronic Myelogenous Leukemia

ClinicalTrials.gov

2015-10-29

B-cell Adult Acute Lymphoblastic Leukemia; Blastic Phase Chronic Myelogenous Leukemia; Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Philadelphia Chromosome Positive Adult Precursor Acute Lymphoblastic Leukemia; Untreated Adult Acute Lymphoblastic Leukemia

Acute myelofibrosis and acute lymphoblastic leukemia in an elderly patient with previously treated multiple myeloma.

PubMed

Gonzalez, Maria M; Kidd, Laura; Quesada, Jorge; Nguyen, Nghia; Chen, Lei

2013-01-01

Multiple myeloma (MM) is a plasma cell neoplasm involving the bone marrow with organ damage and/or a monoclonal protein (M-spike in the serum and/or urine). This neoplasm typically affects adults over the age of 50. Acute lymphoblastic leukemia (ALL) is a hematological disorder involving at least 20% lymphoblasts in the bone marrow of the B-cell lineage. Acute lymphoblastic leukemia most commonly affects young children with 75% of cases occurring in children less than 6 years old. This case report describes a patient diagnosed with MM in 2000 who achieved a complete remission in 2006 after chemotherapy. Four years later, the patient presented with sudden pancytopenia. A bone marrow biopsy was obtained revealing a B lymphoblastic leukemia in an extensively fibrotic marrow without evidence of MM. A diagnosis of ALL with myelofibrosis is rare in the adult population, acute myelofibrosis (AMF) is more commonly associated with myeloproliferative disorders, and the development of acute leukemia in myeloma is rare. To the best of our knowledge, the presence of MM, ALL, and myelofibrosis in one patient has never been reported.

Pure erythroid leukemia following precursor B-cell lymphoblastic leukemia.

PubMed

Xu, Min; Finn, Laura S; Tsuchiya, Karen D; Thomson, Blythe; Pollard, Jessica; Rutledge, Joe

2012-01-01

Therapy-related acute myeloid leukemia is an unfortunate sequel to current multimodal intensive chemotherapy. The patient described was diagnosed with pure erythroleukemia, AML-M6b, during therapy for precursor B-cell acute lymphoblastic leukemia. To the best of our knowledge, this is the first report of this unusual association.

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

2017-03-27

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

Case-control study of childhood acute lymphoblastic leukemia and residential radon exposure.

PubMed

Lubin, J H; Linet, M S; Boice, J D; Buckley, J; Conrath, S M; Hatch, E E; Kleinerman, R A; Tarone, R E; Wacholder, S; Robison, L L

1998-02-18

Several ecologic analyses have shown significant positive associations between mean indoor radon concentrations and risk of leukemia at all ages (acute myeloid leukemia and chronic lymphocytic leukemia) and for children (all leukemia, acute myeloid leukemia, and acute lymphoblastic leukemia [ALL]). As part of an age-matched, case-control study of childhood ALL in the United States, we investigated the association between the incidence of ALL in children under age 15 years and indoor radon exposure. Radon detectors were placed in current and previous homes of subjects where they resided for 6 months or longer. Children were included in analyses if radon measurements covered 70% or more of the 5-year period prior to diagnosis for case subjects (or from birth for case subjects under age 5 years) and the corresponding reference dates for control subjects. Radon levels could be estimated for 97% of the exposure period for the eligible 505 case subjects and 443 control subjects. Mean radon concentration was lower for case subjects (65.4 becquerels per cubic meter [Bqm(-3)]) than for control subjects (79.1 Bqm(-3)). For categories less than 37, 37-73, 74-147, and 148 or more Bqm(-3) of radon exposure, relative risks based on matched case-control pairs were 1.00, 1.22, 0.82, and 1.02, respectively, and were similar to results from an unmatched analysis. There was no association between ALL and radon exposure within subgroups defined by categories of age, income, birth order, birth weight, sex, type of residence, magnetic field exposure, parental age at the subject's birth, parental occupation, or parental smoking habits. In contrast to prior ecologic studies, the results from this analytic study provide no evidence for an association between indoor radon exposure and childhood ALL.

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

Association of ARID5B gene variants with acute lymphoblastic leukemia in Yemeni children.

PubMed

Al-Absi, Boshra; Noor, Suzita M; Saif-Ali, Riyadh; Salem, Sameer D; Ahmed, Radwan H; Razif, Muhammad Fm; Muniandy, Sekaran

2017-04-01

Studies have shown an association between ARID5B gene polymorphisms and childhood acute lymphoblastic leukemia. However, the association between ARID5B variants and acute lymphoblastic leukemia among the Arab population still needs to be studied. The aim of this study was to investigate the association between ARID5B variants with acute lymphoblastic leukemia in Yemeni children. A total of 14 ARID5B gene single nucleotide polymorphisms (SNPs) were genotyped in 289 Yemeni children, of whom 136 had acute lymphoblastic leukemia and 153 were controls, using the nanofluidic Dynamic Array (Fluidigm 192.24 Dynamic Array). Using logistic regression adjusted for age and gender, the risks of acute lymphoblastic leukemia were presented as odds ratios and 95% confidence intervals. We found that nine SNPs were associated with acute lymphoblastic leukemia under additive genetic models: rs7073837, rs10740055, rs7089424, rs10821936, rs4506592, rs10994982, rs7896246, rs10821938, and rs7923074. Furthermore, the recessive models revealed that six SNPs were risk factors for acute lymphoblastic leukemia: rs10740055, rs7089424, rs10994982, rs7896246, rs10821938, and rs7923074. The gender-specific impact of these SNPs under the recessive genetic model revealed that SNPs rs10740055, rs10994982, and rs6479779 in females, and rs10821938 and rs7923074 in males were significantly associated with acute lymphoblastic leukemia risk. Under the dominant model, SNPs rs7073837, rs10821936, rs7896246, and rs6479778 in males only showed striking association with acute lymphoblastic leukemia. The additive model revealed that SNPs with significant association with acute lymphoblastic leukemia were rs10821936 (both males and females); rs7073837, rs10740055, rs10994982, and rs4948487 (females only); and rs7089424, rs7896246, rs10821938, and rs7923074 (males only). In addition, the ARID5B haplotype block (CGAACACAA) showed a higher risk for acute lymphoblastic leukemia. The haplotype (CCCGACTGC) was

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

ClinicalTrials.gov

2018-05-02

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

Obesity in patients with acute lymphoblastic leukemia in childhood

PubMed Central

2012-01-01

Acute lymphoblastic leukemia is the most common malignancy in childhood. Continuous progress in risk-adapted treatment for childhood acute lymphoblastic leukemia has secured 5-year event-free survival rates of approximately 80% and 8-year survival rates approaching 90%. Almost 75% of survivors, however, have a chronic health condition negatively impacting on cardiovascular morbidity and mortality. Obesity can be considered one of the most important health chronic conditions in the general population, with an increasing incidence in patients treated for childhood cancers and especially in acute lymphoblastic leukemia survivors who are, at the same time, more at risk of experiencing precocious cardiovascular and metabolic co-morbidities. The hypothalamic-pituitary axis damage secondary to cancer therapies (cranial irradiation and chemotherapy) or to primary tumor together with lifestyle modifications and genetic factors could affect long-term outcomes. Nevertheless, the etiology of obesity in acute lymphoblastic leukemia is not yet fully understood. The present review has the aim of summarizing the published data and examining the most accepted mechanisms and main predisposing factors related to weight gain in this particular population. PMID:22284631

Frequencies and prognostic impact of RAS mutations in MLL-rearranged acute lymphoblastic leukemia in infants

PubMed Central

Driessen, Emma M.C.; van Roon, Eddy H.J.; Spijkers-Hagelstein, Jill A.P.; Schneider, Pauline; de Lorenzo, Paola; Valsecchi, Maria Grazia; Pieters, Rob; Stam, Ronald W.

2013-01-01

Acute lymphoblastic leukemia in infants represents an aggressive malignancy associated with a high incidence (approx. 80%) of translocations involving the Mixed Lineage Leukemia (MLL) gene. Attempts to mimic Mixed Lineage Leukemia fusion driven leukemogenesis in mice raised the question whether these fusion proteins require secondary hits. RAS mutations are suggested as candidates. Earlier results on the incidence of RAS mutations in Mixed Lineage Leukemia-rearranged acute lymphoblastic leukemia are inconclusive. Therefore, we studied frequencies and relation with clinical parameters of RAS mutations in a large cohort of infant acute lymphoblastic leukemia patients. Using conventional sequencing analysis, we screened neuroblastoma RAS viral (v-ras) oncogene homolog gene (NRAS), v-Ki-ras Kirsten rat sarcoma viral oncogene homolog gene (KRAS), and v-raf murine sarcoma viral oncogene homolog B1 gene (BRAF) for mutations in a large cohort (n=109) of infant acute lymphoblastic leukemia patients and studied the mutations in relation to several clinical parameters, and in relation to Homeobox gene A9 expression and the presence of ALL1 fused gene 4-Mixed Lineage Leukemia (AF4-MLL). Mutations were detected in approximately 14% of all cases, with a higher frequency of approximately 24% in t(4;11)-positive patients (P=0.04). Furthermore, we identified RAS mutations as an independent predictor (P=0.019) for poor outcome in Mixed Lineage Leukemia-rearranged infant acute lymphoblastic leukemia, with a hazard ratio of 3.194 (95% confidence interval (CI):1.211–8.429). Also, RAS-mutated infants have higher white blood cell counts at diagnosis (P=0.013), and are more resistant to glucocorticoids in vitro (P<0.05). Finally, we demonstrate that RAS mutations, and not the lack of Homeobox gene A9 expression nor the expression of AF4-MLL are associated with poor outcome in t(4;11)-rearranged infants. We conclude that the presence of RAS mutations in Mixed Lineage Leukemia

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

ClinicalTrials.gov

2018-06-07

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

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

PubMed Central

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

2012-01-01

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

Expression of HER2/Neu in B-Cell Acute Lymphoblastic Leukemia.

PubMed

Rodriguez-Rodriguez, Sergio; Pomerantz, Alan; Demichelis-Gomez, Roberta; Barrera-Lumbreras, Georgina; Barrales-Benitez, Olga; Aguayo-Gonzalez, Alvaro

2016-01-01

The expression of HER2/neu in B-cell acute lymphoblastic leukemia has been reported in previous studies. The objective of this research was to study the expression of HER2/neu on the blasts of patients with acute leukemia from the Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran. From June 2015 to February 2016, a HER2/neu monoclonal antibody was added to the panel of antibodies that we routinely use in patients with acute leukemia. An expression of ≥ 30% was considered positive. We studied 33 patients: 19 had de novo leukemia (57.6%), three (9.1%) were in relapse, and in 11 (33.3%) their status could not be specified. Seventeen patients (51.5%) were classified as B-cell acute lymphoblastic leukemia with a median expression of HER2/neu of 0.3% (range 0-90.2). Three patients with B-cell acute lymphoblastic leukemia were positive for HER2/neu: 89.4%, 90.9%, and 62.4%. The first and third patient had de novo B-cell acute lymphoblastic leukemia. The second patient was in second relapse after allogeneic stem cell transplant. All three patients were categorized as high-risk at the time of diagnosis. In the studied Mexican population, we found a positive expression of HER2/neu in 17% of the B-cell acute lymphoblastic leukemia patients, similar to previous studies in which the expression was found in 15-50%.

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

ClinicalTrials.gov

2017-04-05

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

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

PubMed Central

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

2015-01-01

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

[Childhood acute lymphoblastic leukemia in Norway 1992-2000].

PubMed

Kolmannskog, Svein; Flaegstad, Trond; Helgestad, Jon; Hellebostad, Marit; Zeller, Bernward; Glomstein, Anders

2007-05-31

Acute lymphoblastic leukemia is the most common malignancy in childhood. The survival rate has increased steadily over the last 40 years. All children aged 0-15 years and diagnosed in Norway in the period 1992-2000, were included in the study (n = 301). The patients were followed up until 1.1. 2005. The diagnosis was made in 301 children, 33 new cases per year (range 24 to 40) on average. The peak incidence was between 2 and 5 years. Four of 6 infants with acute lymphoblastic leukemia and all 4 with mature B-cell leukemia are alive. Two of the remaining 291 children died before treatment was started. 289 were all treated according to the common Nordic NOPHO-ALL 1992 protocol. All children achieved remission (99.7%), except for one who died before remission was achieved. 55 children (19%) relapsed. Radiation to the brain as part of central nervous system prophylaxis was given to just 10% of the children. The 10-year event-free survival (p-EFS) was 76%, and 244 of 289 (84%) were alive 4-13 years after the diagnosis was made. The data are comparable with the best international results.

[Acute lymphoblastic leukemia in children: history of drug therapy management].

PubMed

Bauters, T; Benoit, Y

2014-12-01

The last forty years have witnessed major improvements in the survival of pediatric cancer patients with an evolution of acute tymphoblastic leukemia as an untreatable disease to acute lymphoblastic leukemia with a survival rate of more than 90%. This has become possible due to improvements in the various modalities of cancer therapy and supportive care. The aim of this commentary is to give an overview of the history of pharmacological treatment for children with acute Lymphoblastic leukemia.

Combination Chemotherapy in Treating Young Patients With Newly Diagnosed High-Risk B Acute Lymphoblastic Leukemia and Ph-Like TKI Sensitive Mutations

ClinicalTrials.gov

2018-06-25

B Acute Lymphoblastic Leukemia; Central Nervous System Leukemia; Ph-Like Acute Lymphoblastic Leukemia; Testicular Leukemia; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Childhood Acute Lymphoblastic Leukemia

Epigenetic inactivation of TWIST2 in acute lymphoblastic leukemia modulates proliferation, cell survival and chemosensitivity

PubMed Central

Thathia, Shabnam H.; Ferguson, Stuart; Gautrey, Hannah E.; van Otterdijk, Sanne D.; Hili, Michela; Rand, Vikki; Moorman, Anthony V.; Meyer, Stefan; Brown, Robert; Strathdee, Gordon

2012-01-01

Background Altered regulation of many transcription factors has been shown to be important in the development of leukemia. TWIST2 modulates the activity of a number of important transcription factors and is known to be a regulator of hematopoietic differentiation. Here, we investigated the significance of epigenetic regulation of TWIST2 in the control of cell growth and survival and in response to cytotoxic agents in acute lymphoblastic leukemia. Design and Methods TWIST2 promoter methylation status was assessed quantitatively, by combined bisulfite and restriction analysis (COBRA) and pyrosequencing assays, in multiple types of leukemia and TWIST2 expression was determined by quantitative reverse transcriptase polymerase chain reaction analysis. The functional role of TWIST2 in cell proliferation, survival and response to chemotherapy was assessed in transient and stable expression systems. Results We found that TWIST2 was inactivated in more than 50% of cases of childhood and adult acute lymphoblastic leukemia through promoter hypermethylation and that this epigenetic regulation was especially prevalent in RUNX1-ETV6-driven cases. Re-expression of TWIST2 in cell lines resulted in a dramatic reduction in cell growth and induction of apoptosis in the Reh cell line. Furthermore, re-expression of TWIST2 resulted in increased sensitivity to the chemotherapeutic agents etoposide, daunorubicin and dexamethasone and TWIST2 hypermethylation was almost invariably found in relapsed adult acute lymphoblastic leukemia (91% of samples hypermethylated). Conclusions This study suggests a dual role for epigenetic inactivation of TWIST2 in acute lymphoblastic leukemia, initially through altering cell growth and survival properties and subsequently by increasing resistance to chemotherapy. PMID:22058208

Tumor suppressors BTG1 and IKZF1 cooperate during mouse leukemia development and increase relapse risk in B-cell precursor acute lymphoblastic leukemia patients.

PubMed

Scheijen, Blanca; Boer, Judith M; Marke, René; Tijchon, Esther; van Ingen Schenau, Dorette; Waanders, Esmé; van Emst, Liesbeth; van der Meer, Laurens T; Pieters, Rob; Escherich, Gabriele; Horstmann, Martin A; Sonneveld, Edwin; Venn, Nicola; Sutton, Rosemary; Dalla-Pozza, Luciano; Kuiper, Roland P; Hoogerbrugge, Peter M; den Boer, Monique L; van Leeuwen, Frank N

2017-03-01

Deletions and mutations affecting lymphoid transcription factor IKZF1 (IKAROS) are associated with an increased relapse risk and poor outcome in B-cell precursor acute lymphoblastic leukemia. However, additional genetic events may either enhance or negate the effects of IKZF1 deletions on prognosis. In a large discovery cohort of 533 childhood B-cell precursor acute lymphoblastic leukemia patients, we observed that single-copy losses of BTG1 were significantly enriched in IKZF1 -deleted B-cell precursor acute lymphoblastic leukemia ( P =0.007). While BTG1 deletions alone had no impact on prognosis, the combined presence of BTG1 and IKZF1 deletions was associated with a significantly lower 5-year event-free survival ( P =0.0003) and a higher 5-year cumulative incidence of relapse ( P =0.005), when compared with IKZF1 -deleted cases without BTG1 aberrations. In contrast, other copy number losses commonly observed in B-cell precursor acute lymphoblastic leukemia, such as CDKN2A/B, PAX5, EBF1 or RB1 , did not affect the outcome of IKZF1 -deleted acute lymphoblastic leukemia patients. To establish whether the combined loss of IKZF1 and BTG1 function cooperate in leukemogenesis, Btg1 -deficient mice were crossed onto an Ikzf1 heterozygous background. We observed that loss of Btg1 increased the tumor incidence of Ikzf1 +/- mice in a dose-dependent manner. Moreover, murine B cells deficient for Btg1 and Ikzf1 +/- displayed increased resistance to glucocorticoids, but not to other chemotherapeutic drugs. Together, our results identify BTG1 as a tumor suppressor in leukemia that, when deleted, strongly enhances the risk of relapse in IKZF1 -deleted B-cell precursor acute lymphoblastic leukemia, and augments the glucocorticoid resistance phenotype mediated by the loss of IKZF1 function. Copyright© Ferrata Storti Foundation.

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

PubMed

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

2017-02-01

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

Acute lymphoblastic leukemia mimicking Wilms tumor at presentation.

PubMed

Singh, Amitabh; Mandal, Anirban; Guru, Vijay; Seth, Rachna

2016-09-01

Acute lymphoblastic leukemia (ALL), the commonest malignancy of childhood, is known to manifest with a myriad of atypical presentations. Nephromegaly is a rare presentation of childhood ALL with hepatic mass being even rarer. We present a 3 year-old child with unilateral renal mass and hepatic mass lesion with normal blood counts, initially suspected to have metastatic Wilms tumor based on clinical, radiological and WT1 positivity on immunocytochemistry of renal mass. He was later diagnosed as ALL with peripheral blood flowcytometry and bone marrow examination. Renomegaly at presentation of acute leukemia is not necessarily due to leukemic infiltration and rarely leads to renal impairment. The radiological differential of such a renal mass includes both benign and malignant entities including metastasis. Over-expression of WT1 mRNA has been found in a number of solid tumors and hematological malignancies and is far from being diagnostic of Wilms tumor. Again, a small number of children with acute leukemia may have a deceptively normal complete blood count at presentation. Though, initial all (clinical, radiological, hematological, and immunocytological) parameters pointed towards a diagnosis of Wilms tumor in our case, the subsequent development of thrombocytopenia and lymphocytic leukocytosis prompted further investigation and final diagnosis of ALL. WT1 positivity is a known phenomenon in childhood ALL and undifferentiated lymphoblasts may be positive for WT1 and negative for Leucocyte common antigen. Acute leukemia with renal and hepatic mass with normal blood counts at presentation is a diagnostic challenge.

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

ClinicalTrials.gov

2017-10-24

CD19-Positive Neoplastic Cells Present; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Chronic Lymphocytic Leukemia; Recurrent Diffuse Large B-Cell Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Non-Hodgkin Lymphoma; Recurrent Small Lymphocytic Lymphoma; Refractory Acute Lymphoblastic Leukemia; Refractory Chronic Lymphocytic Leukemia; Refractory Diffuse Large B-Cell Lymphoma; Refractory Mantle Cell Lymphoma; Refractory Non-Hodgkin Lymphoma; Refractory Small Lymphocytic Lymphoma

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

PubMed

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

2016-06-01

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

Nanomedicine approaches in acute lymphoblastic leukemia.

PubMed

Tatar, Andra-Sorina; Nagy-Simon, Timea; Tomuleasa, Ciprian; Boca, Sanda; Astilean, Simion

2016-09-28

Acute lymphoblastic leukemia (ALL) is the malignancy with the highest incidence amongst children (26% of all cancer cases), being surpassed only by the cancers of the brain and of the nervous system. The most recent research on ALL is focusing on new molecular therapies, like targeting specific biological structures in key points in the cell cycle, or using selective inhibitors for transmembranary proteins involved in cell signalling, and even aiming cell surface receptors with specifically designed antibodies for active targeting. Nanomedicine approaches, especially by the use of nanoparticle-based compounds for the delivery of drugs, cancer diagnosis or therapeutics may represent new and modern ways in the near future anti-cancer therapies. This review offers an overview on the recent role of nanomedicine in the detection and treatment of acute lymphoblastic leukemia as resulting from a thorough literature survey. A short introduction on the basics of ALL is presented followed by the description of the conventional methods used in the ALL detection and treatment. We follow our discussion by introducing some of the general nano-strategies used for cancer detection and treatment. The detailed role of organic and inorganic nanoparticles in ALL applications is further presented, with a special focus on gold nanoparticle-based nanocarriers of antileukemic drugs. Copyright © 2016 Elsevier B.V. All rights reserved.

Invasive fungal infection caused by geotrichum capitatum in patients with acute lymphoblastic leukemia: a case study and literature review

PubMed Central

Gao, Guang-Xun; Tang, Hai-Long; Zhang, Xuan; Xin, Xiao-Li; Feng, Juan; Chen, Xie-Qun

2015-01-01

Geotrichum capitatum infection has a very low incidence rate with atypical clinical symptoms, making diagnosis difficult, and it has a poor prognosis. The incidence is even more rare in China. This paper reports the first case of infection caused by G. capitatum during bone marrow suppression after chemotherapy in a Chinese patient with acute lymphoblastic leukemia. In addition, it reports a systematic literature review of diagnosis and treatment. The patient with acute lymphoblastic leukemia was confirmed to be infected with G. capitatum, involving lung, liver and skin, through a blood culture test. Caspofungin, amphotericin B loposome, and a combination therapy of amphotericin B liposome and voriconazole were used in succession for treatment. Despite normal body temperature and a slight improvement of clinical symptoms with the combination therapy treatment, the patient died 40 days after chemotherapy due to heart and lung failure. PMID:26550401

Inhibiting Polo-like kinase 1 causes growth reduction and apoptosis in pediatric acute lymphoblastic leukemia cells

PubMed Central

Hartsink-Segers, Stefanie A.; Exalto, Carla; Allen, Matthew; Williamson, Daniel; Clifford, Steven C.; Horstmann, Martin; Caron, Huib N.; Pieters, Rob; Den Boer, Monique L.

2013-01-01

This study investigated Polo-like kinase 1, a mitotic regulator often over-expressed in solid tumors and adult hematopoietic malignancies, as a potential new target in the treatment of pediatric acute lymphoblastic leukemia. Polo-like kinase 1 protein and Thr210 phosphorylation levels were higher in pediatric acute lymphoblastic leukemia (n=172) than in normal bone marrow mononuclear cells (n=10) (P<0.0001). High Polo-like kinase 1 protein phosphorylation, but not expression, was associated with a lower probability of event-free survival (P=0.042) and was a borderline significant prognostic factor (P=0.065) in a multivariate analysis including age and initial white blood cell count. Polo-like kinase 1 was necessary for leukemic cell survival, since short hairpin-mediated Polo-like kinase 1 knockdown in acute lymphoblastic leukemia cell lines inhibited cell proliferation by G2/M cell cycle arrest and induced apoptosis through caspase-3 and poly (ADP-ribose) polymerase cleavage. Primary patient cells with a high Polo-like kinase 1 protein expression were sensitive to the Polo-like kinase 1-specific inhibitor NMS-P937 in vitro, whereas cells with a low expression and normal bone marrow cells were resistant. This sensitivity was likely not caused by Polo-like kinase 1 mutations, since only one new mutation (Ser335Arg) was found by 454-sequencing of 38 pediatric acute lymphoblastic leukemia cases. This mutation did not affect Polo-like kinase 1 expression or NMS-P937 sensitivity. Together, these results indicate a pivotal role for Polo-like kinase 1 in pediatric acute lymphoblastic leukemia and show potential for Polo-like kinase 1-inhibiting drugs as an addition to current treatment strategies for cases expressing high Polo-like kinase 1 levels. PMID:23753023

An Initial Reintegration Treatment of Children with Acute Lymphoblastic Leukemia (ALL).

ERIC Educational Resources Information Center

Lurie, Michelle; Kaufman, Nadeen

2001-01-01

Evaluated the cognitive, psychological, and social adjustment of pediatric acute lymphoblastic leukemia (ALL) patients and assessed how their needs could best be met through reintegration programs focusing on learning/ educational needs. Findings from three case studies highlight the need for ALL patients to be provided with comprehensive programs…

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

PubMed

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

2017-04-07

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

Carfilzomib and Hyper-CVAD in Treating Patients With Newly Diagnosed Acute Lymphoblastic Leukemia or Lymphoma

ClinicalTrials.gov

2018-03-01

Contiguous Stage II Adult Lymphoblastic Lymphoma; Noncontiguous Stage II Adult Lymphoblastic Lymphoma; Stage I Adult Lymphoblastic Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Untreated Adult Acute Lymphoblastic Leukemia

211^At-BC8-B10 Before Donor Stem Cell Transplant in Treating Patients With High-Risk Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, or Myelodysplastic Syndrome

ClinicalTrials.gov

2018-02-21

Acute Lymphoblastic Leukemia in Remission; Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome; Acute Myeloid Leukemia in Remission; CD45-Positive Neoplastic Cells Present; Chronic Myelomonocytic Leukemia; Myelodysplastic Syndrome With Excess Blasts; Recurrent Adult Acute Myeloid Leukemia; Refractory Adult Acute Lymphoblastic Leukemia

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

IKAROS Gene Deleted B-Cell Acute Lymphoblastic Leukemia in Mexican Mestizos: Observations in Seven Patients and a Short Review of the Literature.

PubMed

Ruiz-Delgado, Guillermo José; Cantero-Fortiz, Yahveth; León-Peña, Andrés Aurelio; León-González, Mónica; Nuñez-Cortés, Ana Karen; Ruiz-Argüelles, Guillermo José

2016-01-01

In B-cell acute lymphoblastic leukemia, one of the most frequent cytogenetic alterations is the presence of the Philadelphia chromosome. Recently, newly identified genetic alterations have been studied, among them the IKZF1 deletion. IKZF1 encodes IKAROS, a zinc finger protein that plays an important role in hematopoiesis involving the regulation process of adhesion, cellular migration, and as a tumor suppressor. We aimed to study the impact of IKAROS deletion in the evolution and prognosis of B-cell acute lymphoblastic leukemia. At a single center we prospectively studied patients diagnosed with B-cell acute lymphoblastic leukemia and screened for IKZF1 deletion using the multiplex ligation-dependent probe amplification method. We did a descriptive analysis of patients positive for the IKZF1 deletion to determine its impact on the evolution of the disease and survival rate. Between 2010 and 2015, 16 Mexican mestizo patients with B-cell acute lymphoblastic leukemia were prospectively screened for IKZF1 deletion; seven (43%) were positive and were included for further analysis. The age range of patients was 13-60 years; six were males and one female. All cases had type B acute lymphoblastic leukemia. Of the seven patients, two died, three were lost to follow-up, and two continue in complete remission with treatment. Results are worse than those in a group of patients with non-mutated IKAROS B-cell acute lymphoblastic leukemia previously studied in our center. Although this is a small sample, the presence of IKAROS deletion in acute lymphoblastic leukemia patients could represent a poor-prognosis marker and was probably related to therapy failure. It is also possible that this variant of leukemia may be more prevalent in Mexico. More studies are needed to define the role of IKZF1 deletion in acute lymphoblastic leukemia and the real prevalence of the disease in different populations.

B cell markers in Ph1-positive acute lymphoblastic leukemia.

PubMed

Alimena, G; De Rossi, G; Gastaldi, R; Guglielmi, C; Mandelli, F

1980-01-01

A case of acute lymphoblastic leukemia (ALL) where the blast cells had B cell markers and displayed the presence of a typical Ph1 chromosome, originated by a standard t (9;22) translocation, is reported. Cytological and clinical aspects during the entire course of the disease were consistent with the diagnosis of ALL. Evidence of differentiation along a well-defined lymphoid cell line in a Ph1-positive cell confirms the presence of the Ph1 chromosome in conditions other than chronic granulocytic leukemia and shows that it possibly does not occur in an exclusively undifferentiated totipotent stem cell.

Blinatumomab and Nivolumab With or Without Ipilimumab in Treating Patients With Poor-Risk Relapsed or Refractory CD19+ Precursor B-Lymphoblastic Leukemia

ClinicalTrials.gov

2018-05-14

B Acute Lymphoblastic Leukemia; B Acute Lymphoblastic Leukemia With t(9;22)(q34.1;q11.2); BCR-ABL1; CD19-Positive Neoplastic Cells Present; Mixed Phenotype Acute Leukemia; Mixed Phenotype Acute Leukemia With t(9;22)(q34.1;q11.2); BCR-ABL1; Recurrent B Acute Lymphoblastic Leukemia; Refractory B Acute Lymphoblastic Leukemia

PS-341 in Treating Patients With Refractory or Relapsed Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, Chronic Myeloid Leukemia in Blast Phase, or Myelodysplastic Syndrome

ClinicalTrials.gov

2013-01-22

Adult Acute Promyelocytic Leukemia (M3); Blastic Phase Chronic Myelogenous Leukemia; 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

Immune thrombocytopenic purpura in a child with acute lymphoblastic leukemia and mumps.

PubMed

Kurekci, A Emin; Atay, A Avni; Demirkaya, Erkan; Sarici, S Umit; Ozcan, Okan

2006-03-01

Immune thrombocytopenic purpura in childhood is characterized by a typical history of acute development of purpura and bruising in an otherwise healthy child. In children it usually follows a viral infection (eg, mumps, rubella) or immunization. We report for the first time a child with acute lymphoblastic leukemia who developed immune thrombocytopenic purpura due to mumps during the maintenance phase of acute lymphoblastic leukemia treatment.

Textural characteristics of bone marrow blast nucleus images with different variants of acute lymphoblastic leukemia

NASA Astrophysics Data System (ADS)

Nikitaev, V. G.; Pronichev, A. N.; Polyakov, E. V.; Mozhenkova, A. V.; Tupitsin, N. N.; Frenkel, M. A.

2018-01-01

The paper describes the method of recognition of T - and B - variants of acute lymphoblastic leukemia in microscopic images of blood cells. The method is based on the use of texture characteristics of images. Experimental recognition accuracy evaluation is obtained from the sample of 38 patients (17 with T-ALL and 21 with B-ALL variants of acute lymphoblastic leukemia). The obtained results show the possibility of applying of the proposed approach to the differential diagnosis of T- and B- variants of acute lymphoblastic leukemia.

Bone involvement at diagnosis as a predictive factor in children with acute lymphoblastic leukemia.

PubMed

Tragiannidis, A; Vasileiou, E; Papageorgiou, M; Damianidou, L; Hatzipantelis, E; Gombakis, N; Giannopoulos, A

2016-01-01

Bone involvement represents a common symptom at diagnosis in children with acute lymphoblastic leukemia, and its prognostic value is not entirely clarified. The aim of this study was to evaluate bone involvement at diagnosis in children with acute lymphoblastic leukemia as a predictive factor and to correlate its presence with other demographic, clinical, and laboratory findings. We retrospectively reviewed the medical records of 97 children with acute lymphoblastic leukemia diagnosed from January 2005 to December 2014. The mean age of patients was 5.7 years, and 83 (85.6 %) of them were diagnosed with B-acute lymphoblastic leukemia. Among the 97 children, 46 (47.4 %) reported bone involvement at the time of diagnosis. Among children with B-acute lymphoblastic leukemia 43/83 (51.8 %) reported bone involvement, while among children with T-acute lymphoblastic leukemia only 3/14 (21.4 %) (p =0.04). Bone involvement was registered more frequently among males (30/59; 50.8 %) in comparison to females (16/38; 42.2 %) (p =0.414). The mean white blood cell count at diagnosis was lower among children with bone involvement (109,800/mm 3 vs. 184,700/mm 3 ) (p =0.092). The mean age of patients with bone involvement was four years, which differs significantly from those without bone involvement (p =0.029). Moreover, children with bone involvement at diagnosis were prednisone "good responders" (79.5 %) when compared with those without bone involvement (58.8 %) (p =0.046). Additionally, mean serum phosphate values were higher at diagnosis among children with bone involvement (5.3 mg/dl vs. 4.8 mg/dl, p =0.035). The presence of bone involvement at diagnosis is related with immunophenotype of B-acute lymphoblastic leukemia, lower mean age, lower mean white blood cell count and good prednisone response. According to presented data, we conclude that the presence of bone involvement at diagnosis represents a positive predictive factor for outcome/survival. Hippokratia 2016, 20(3): 227-230.

Bone involvement at diagnosis as a predictive factor in children with acute lymphoblastic leukemia

PubMed Central

Tragiannidis, A; Vasileiou, E; Papageorgiou, M; Damianidou, L; Hatzipantelis, E; Gombakis, N; Giannopoulos, A

2016-01-01

Background: Bone involvement represents a common symptom at diagnosis in children with acute lymphoblastic leukemia, and its prognostic value is not entirely clarified. The aim of this study was to evaluate bone involvement at diagnosis in children with acute lymphoblastic leukemia as a predictive factor and to correlate its presence with other demographic, clinical, and laboratory findings. Methods: We retrospectively reviewed the medical records of 97 children with acute lymphoblastic leukemia diagnosed from January 2005 to December 2014. The mean age of patients was 5.7 years, and 83 (85.6 %) of them were diagnosed with B-acute lymphoblastic leukemia. Results: Among the 97 children, 46 (47.4 %) reported bone involvement at the time of diagnosis. Among children with B-acute lymphoblastic leukemia 43/83 (51.8 %) reported bone involvement, while among children with T-acute lymphoblastic leukemia only 3/14 (21.4 %) (p =0.04). Bone involvement was registered more frequently among males (30/59; 50.8 %) in comparison to females (16/38; 42.2 %) (p =0.414). The mean white blood cell count at diagnosis was lower among children with bone involvement (109,800/mm3 vs. 184,700/mm3) (p =0.092). The mean age of patients with bone involvement was four years, which differs significantly from those without bone involvement (p =0.029). Moreover, children with bone involvement at diagnosis were prednisone “good responders” (79.5 %) when compared with those without bone involvement (58.8 %) (p =0.046). Additionally, mean serum phosphate values were higher at diagnosis among children with bone involvement (5.3 mg/dl vs. 4.8 mg/dl, p =0.035). Conclusions: The presence of bone involvement at diagnosis is related with immunophenotype of B-acute lymphoblastic leukemia, lower mean age, lower mean white blood cell count and good prednisone response. According to presented data, we conclude that the presence of bone involvement at diagnosis represents a positive predictive factor for

Flavopiridol in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, or Chronic Myelogenous Leukemia

ClinicalTrials.gov

2013-06-03

Adult Acute Basophilic Leukemia; Adult Acute Eosinophilic Leukemia; Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Blastic Phase Chronic Myelogenous Leukemia; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Relapsing Chronic Myelogenous Leukemia

Acute Central Nervous System Complications in Pediatric Acute Lymphoblastic Leukemia.

PubMed

Baytan, Birol; Evim, Melike Sezgin; Güler, Salih; Güneş, Adalet Meral; Okan, Mehmet

2015-10-01

The outcome of childhood acute lymphoblastic leukemia has improved because of intensive chemotherapy and supportive care. The frequency of adverse events has also increased, but the data related to acute central nervous system complications during acute lymphoblastic leukemia treatment are sparse. The purpose of this study is to evaluate these complications and to determine their long term outcome. We retrospectively analyzed the hospital reports of 323 children with de novo acute lymphoblastic leukemia from a 13-year period for acute neurological complications. The central nervous system complications of leukemic involvement, peripheral neuropathy, and post-treatment late-onset encephalopathy, and neurocognitive defects were excluded. Twenty-three of 323 children (7.1%) suffered from central nervous system complications during acute lymphoblastic leukemia treatment. The majority of these complications (n = 13/23; 56.5%) developed during the induction period. The complications included posterior reversible encephalopathy (n = 6), fungal abscess (n = 5), cerebrovascular lesions (n = 5), syndrome of inappropriate secretion of antidiuretic hormone (n = 4), and methotrexate encephalopathy (n = 3). Three of these 23 children (13%) died of central nervous system complications, one from an intracranial fungal abscess and the others from intracranial thrombosis. Seven of the survivors (n = 7/20; 35%) became epileptic and three of them had also developed mental and motor retardation. Acute central neurological complications are varied and require an urgent approach for proper diagnosis and treatment. Collaboration among the hematologist, radiologist, neurologist, microbiologist, and neurosurgeon is essential to prevent fatal outcome and serious morbidity. Copyright © 2015 Elsevier Inc. All rights reserved.

Mutational landscape, clonal evolution patterns, and role of RAS mutations in relapsed acute lymphoblastic leukemia

PubMed Central

Oshima, Koichi; Khiabanian, Hossein; da Silva-Almeida, Ana C.; Tzoneva, Gannie; Abate, Francesco; Ambesi-Impiombato, Alberto; Sanchez-Martin, Marta; Carpenter, Zachary; Penson, Alex; Perez-Garcia, Arianne; Eckert, Cornelia; Nicolas, Concepción; Balbin, Milagros; Sulis, Maria Luisa; Kato, Motohiro; Koh, Katsuyoshi; Paganin, Maddalena; Basso, Giuseppe; Gastier-Foster, Julie M.; Devidas, Meenakshi; Loh, Mignon L.; Kirschner-Schwabe, Renate; Palomero, Teresa; Rabadan, Raul; Ferrando, Adolfo A.

2016-01-01

Although multiagent combination chemotherapy is curative in a significant fraction of childhood acute lymphoblastic leukemia (ALL) patients, 20% of cases relapse and most die because of chemorefractory disease. Here we used whole-exome and whole-genome sequencing to analyze the mutational landscape at relapse in pediatric ALL cases. These analyses identified numerous relapse-associated mutated genes intertwined in chemotherapy resistance-related protein complexes. In this context, RAS-MAPK pathway-activating mutations in the neuroblastoma RAS viral oncogene homolog (NRAS), kirsten rat sarcoma viral oncogene homolog (KRAS), and protein tyrosine phosphatase, nonreceptor type 11 (PTPN11) genes were present in 24 of 55 (44%) cases in our series. Interestingly, some leukemias showed retention or emergence of RAS mutant clones at relapse, whereas in others RAS mutant clones present at diagnosis were replaced by RAS wild-type populations, supporting a role for both positive and negative selection evolutionary pressures in clonal evolution of RAS-mutant leukemia. Consistently, functional dissection of mouse and human wild-type and mutant RAS isogenic leukemia cells demonstrated induction of methotrexate resistance but also improved the response to vincristine in mutant RAS-expressing lymphoblasts. These results highlight the central role of chemotherapy-driven selection as a central mechanism of leukemia clonal evolution in relapsed ALL, and demonstrate a previously unrecognized dual role of RAS mutations as drivers of both sensitivity and resistance to chemotherapy. PMID:27655895

Adult Acute Lymphoblastic Leukemia Treatment (PDQ®)—Health Professional Version

Cancer.gov

Adult Acute Lymphoblastic Leukemia (ALL; also called acute lymphocytic leukemia) is an aggressive cancer that can progress quickly without treatment. Treatments include chemotherapy, radiation therapy, stem cell transplant, and targeted therapy. Get detailed information about the molecular genetics, prognosis, and treatment of ALL in this clinician summary.

Acute lymphoblastic leukemia: a comprehensive review and 2017 update

PubMed Central

Terwilliger, T; Abdul-Hay, M

2017-01-01

Acute lymphoblastic leukemia (ALL) is the second most common acute leukemia in adults, with an incidence of over 6500 cases per year in the United States alone. The hallmark of ALL is chromosomal abnormalities and genetic alterations involved in differentiation and proliferation of lymphoid precursor cells. In adults, 75% of cases develop from precursors of the B-cell lineage, with the remainder of cases consisting of malignant T-cell precursors. Traditionally, risk stratification has been based on clinical factors such age, white blood cell count and response to chemotherapy; however, the identification of recurrent genetic alterations has helped refine individual prognosis and guide management. Despite advances in management, the backbone of therapy remains multi-agent chemotherapy with vincristine, corticosteroids and an anthracycline with allogeneic stem cell transplantation for eligible candidates. Elderly patients are often unable to tolerate such regimens and carry a particularly poor prognosis. Here, we review the major recent advances in the treatment of ALL. PMID:28665419

Role of CD81 and CD58 in minimal residual disease detection in pediatric B lymphoblastic leukemia.

PubMed

Tsitsikov, E; Harris, M H; Silverman, L B; Sallan, S E; Weinberg, O K

2018-06-01

Minimal residual disease (MRD) in B lymphoblastic leukemia has been demonstrated to be a powerful predictor of clinical outcome in numerous studies in both children and adults. In this study, we evaluated 86 pediatric patients with both diagnostic and remission flow cytometry studies and compared expression of CD81, CD58, CD19, CD34, CD20, and CD38 in the detection of MRD. We evaluated 86 patients with B lymphoblastic leukemia who had both diagnostic studies and remission studies for the presence of MRD using multicolor flow cytometry. We established our detection limit for identifying abnormal lymphoblasts using serial dilutions. We also compared flow cytometry findings with molecular MRD detection in a subset of patients. We found that we can resolve differences between hematogones and lymphoblasts in 85 of 86 cases using a combination of CD45, CD19, CD34, CD10, CD20, CD38, CD58, and CD81. Our detection limit using flow cytometry is 0.002% for detecting a population of abnormal B lymphoblasts. Comparison with MRD assessment by molecular methods showed a high concordance rate with flow cytometry findings. Our study highlights importance of using multiple markers to detect MRD in B lymphoblastic leukemia. Our findings indicate that including both CD58 and CD81 markers in addition to CD19, CD34, CD20, CD38, and CD10 are helpful in MRD detection by flow cytometry. © 2018 John Wiley & Sons Ltd.

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

ClinicalTrials.gov

2016-12-16

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

Monoclonal Antibody Therapy in Treating Patients With Chronic Lymphocytic Leukemia, Lymphocytic Lymphoma, Acute Lymphoblastic Leukemia, or Acute Myeloid Leukemia

ClinicalTrials.gov

2013-06-03

Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Splenic Marginal Zone Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Small Lymphocytic Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Small Lymphocytic Lymphoma

CREBBP knockdown enhances RAS/RAF/MEK/ERK signaling in Ras pathway mutated acute lymphoblastic leukemia but does not modulate chemotherapeutic response.

PubMed

Dixon, Zach A; Nicholson, Lindsay; Zeppetzauer, Martin; Matheson, Elizabeth; Sinclair, Paul; Harrison, Christine J; Irving, Julie A E

2017-04-01

Relapsed acute lymphoblastic leukemia is the most common cause of cancer-related mortality in young people and new therapeutic strategies are needed to improve outcome. Recent studies have shown that heterozygous inactivating mutations in the histone acetyl transferase, CREBBP , are particularly frequent in relapsed childhood acute lymphoblastic leukemia and associated with a hyperdiploid karyotype and KRAS mutations. To study the functional impact of CREBBP haploinsufficiency in acute lymphoblastic leukemia, RNA interference was used to knock down expression of CREBBP in acute lymphoblastic leukemia cell lines and various primagraft acute lymphoblastic leukemia cells. We demonstrate that attenuation of CREBBP results in reduced acetylation of histone 3 lysine 18, but has no significant impact on cAMP-dependent target gene expression. Impaired induction of glucocorticoid receptor targets was only seen in 1 of 4 CREBBP knockdown models, and there was no significant difference in glucocorticoid-induced apoptosis, sensitivity to other acute lymphoblastic leukemia chemotherapeutics or histone deacetylase inhibitors. Importantly, we show that CREBBP directly acetylates KRAS and that CREBBP knockdown enhances signaling of the RAS/RAF/MEK/ERK pathway in Ras pathway mutated acute lymphoblastic leukemia cells, which are still sensitive to MEK inhibitors. Thus, CREBBP mutations might assist in enhancing oncogenic RAS signaling in acute lymphoblastic leukemia but do not alter response to MEK inhibitors. Copyright© Ferrata Storti Foundation.

Recognition of acute lymphoblastic leukemia cells in microscopic images using k-means clustering and support vector machine classifier.

PubMed

Amin, Morteza Moradi; Kermani, Saeed; Talebi, Ardeshir; Oghli, Mostafa Ghelich

2015-01-01

Acute lymphoblastic leukemia is the most common form of pediatric cancer which is categorized into three L1, L2, and L3 and could be detected through screening of blood and bone marrow smears by pathologists. Due to being time-consuming and tediousness of the procedure, a computer-based system is acquired for convenient detection of Acute lymphoblastic leukemia. Microscopic images are acquired from blood and bone marrow smears of patients with Acute lymphoblastic leukemia and normal cases. After applying image preprocessing, cells nuclei are segmented by k-means algorithm. Then geometric and statistical features are extracted from nuclei and finally these cells are classified to cancerous and noncancerous cells by means of support vector machine classifier with 10-fold cross validation. These cells are also classified into their sub-types by multi-Support vector machine classifier. Classifier is evaluated by these parameters: Sensitivity, specificity, and accuracy which values for cancerous and noncancerous cells 98%, 95%, and 97%, respectively. These parameters are also used for evaluation of cell sub-types which values in mean 84.3%, 97.3%, and 95.6%, respectively. The results show that proposed algorithm could achieve an acceptable performance for the diagnosis of Acute lymphoblastic leukemia and its sub-types and can be used as an assistant diagnostic tool for pathologists.

New decision support tool for acute lymphoblastic leukemia classification

NASA Astrophysics Data System (ADS)

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

2012-03-01

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

Cytomegalovirus Retinitis in Three Pediatric Cases with Acute Lymphoblastic Leukemia: Case Series and Review of the Literature.

PubMed

Demir, Sevliya Öcal; Çeliker, Hande; Karaaslan, Ayşe; Kadayifci, Eda Kepenekli; Akkoç, Gülşen; Atıcı, Serkan; Yakut, Nurhayat; Şenay, Emel; Kazokoğlu, Haluk; Koç, Ahmet; Bakır, Mustafa; Soysal, Ahmet

2016-11-22

Cytomegalovirus (CMV) retinitis is typically diagnosed in patient with AIDS and those who underwent allogeneic hematopoietic cell transplant. However, it may develop in patients with acute lymphoblastic leukemia (ALL) who have not undergone hematopoietic cell transplantation. To increase awareness of CMV retinitis in this group, we describe 3 patients ages 3, 9, and 12, with ALL who developed CMV retinitis. The diagnosis of CMV retinitis was made on the basis of ophthalmological findings suggesting typical retinal lesions. In 2 cases, CMV DNAemia was present, while in 1 patient CMV DNA was detected only in vitreous fluid using the PCR technique. All cases were treated with intravenous ganciclovir for 2 or 3 weeks as induction therapy, followed by oral valganciclovir prophylaxis. Initially, active retinitis lesions resolved in all cases; however, in 1 patient CMV retinitis relapsed 3 times during follow-up. In this case, by using foscarnet therapy, satisfactory responses were achieved and the progression of CMV retinitis lesions stopped and eventually regressed.

Delayed Neurotoxicity Associated with Therapy for Children with Acute Lymphoblastic Leukemia

ERIC Educational Resources Information Center

Cole, Peter D.; Kamen, Barton A.

2006-01-01

Most children diagnosed today with acute lymphoblastic leukemia (ALL) will be cured. However, treatment entails risk of neurotoxicity, causing deficits in neurocognitive function that can persist in the years after treatment is completed. Many of the components of leukemia therapy can contribute to adverse neurologic sequelae, including…

Acute lymphoblastic leukemia in children and adolescents: prognostic factors and analysis of survival

PubMed Central

Lustosa de Sousa, Daniel Willian; de Almeida Ferreira, Francisco Valdeci; Cavalcante Félix, Francisco Helder; de Oliveira Lopes, Marcos Vinicios

2015-01-01

Objective To describe the clinical and laboratory features of children and adolescents with acute lymphoblastic leukemia treated at three referral centers in Ceará and evaluate prognostic factors for survival, including age, gender, presenting white blood cell count, immunophenotype, DNA index and early response to treatment. Methods Seventy-six under 19-year-old patients with newly diagnosed acute lymphoblastic leukemia treated with the Grupo Brasileiro de Tratamento de Leucemia da Infância – acute lymphoblastic leukemia-93 and -99 protocols between September 2007 and December 2009 were analyzed. The diagnosis was based on cytological, immunophenotypic and cytogenetic criteria. Associations between variables, prognostic factors and response to treatment were analyzed using the chi-square test and Fisher's exact test. Overall and event-free survival were estimated by Kaplan–Meier analysis and compared using the log-rank test. A Cox proportional hazards model was used to identify independent prognostic factors. Results The average age at diagnosis was 6.3 ± 0.5 years and males were predominant (65%). The most frequently observed clinical features were hepatomegaly, splenomegaly and lymphadenopathy. Central nervous system involvement and mediastinal enlargement occurred in 6.6% and 11.8%, respectively. B-acute lymphoblastic leukemia was more common (89.5%) than T-acute lymphoblastic leukemia. A DNA index >1.16 was found in 19% of patients and was associated with favorable prognosis. On Day 8 of induction therapy, 95% of the patients had lymphoblast counts <1000/μL and white blood cell counts <5.0 × 109/L. The remission induction rate was 95%, the induction mortality rate was 2.6% and overall survival was 72%. Conclusion The prognostic factors identified are compatible with the literature. The 5-year overall and event-free survival rates were lower than those reported for developed countries. As shown by the multivariate analysis, age and baseline white

Altered brain function in new onset childhood acute lymphoblastic leukemia before chemotherapy: A resting-state fMRI study.

PubMed

Hu, Zhanqi; Zou, Dongfang; Mai, Huirong; Yuan, Xiuli; Wang, Lihong; Li, Yue; Liao, Jianxiang; Liu, Liwei; Liu, Guosheng; Zeng, Hongwu; Wen, Feiqiu

2017-10-01

Cognitive impairments had been reported in childhood acute lymphoblastic leukemia, what caused the impairments needed to be demonstrated, chemotherapy-related or the disease itself. The primary aim of this exploratory investigation was to determine if there were changes in brain function of children with acute lymphoblastic leukemia before chemotherapy. In this study, we advanced a measure named regional homogeneity to evaluate the resting-state brain activities, intelligence quotient test was performed at same time. Using regional homogeneity, we first investigated the resting state brain function in patients with new onset childhood acute lymphoblastic leukemia before chemotherapy, healthy children as control. The decreased ReHo values were mainly founded in the default mode network and left frontal lobe, bilateral inferior parietal lobule, bilateral temporal lobe, bilateral occipital lobe, precentral gyrus, bilateral cerebellum in the newly diagnosed acute lymphoblastic leukemia patients compared with the healthy control. While in contrast, increased ReHo values were mainly shown in the right frontal lobe (language area), superior frontal gyrus-R, middle frontal gyrus-R and inferior parietal lobule-R for acute lymphoblastic leukemia patients group. There were no significant differences for intelligence quotient measurements between the acute lymphoblastic leukemia patient group and the healthy control in performance intelligence quotient, verbal intelligence quotient, total intelligence quotient. The altered brain functions are associated with cognitive change and language, it is suggested that there may be cognition impairment before the chemotherapy. Regional homogeneity by functional magnetic resonance image is a sensitive way for early detection on brain damage in childhood acute lymphoblastic leukemia. Copyright © 2017 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

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

ClinicalTrials.gov

2017-11-20

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

T-cell acute lymphoblastic leukemia associated with complex karyotype and SET-NUP214 rearrangement: a case study and review of the literature.

PubMed

Lee, Sang-Guk; Park, Tae Sung; Cho, Sun Young; Lim, Gayoung; Park, Gwang Jin; Oh, Seung Hwan; Cho, Eun Hae; Chong, So Young; Huh, Ji Young

2011-01-01

SET-NUP214 rearrangements have been rarely reported in T-cell acute lymphoblastic leukemia (T-ALL), acute undifferentiated leukemia, and acute myeloid leukemia, and most documented cases have been associated with normal karyotypes in conventional cytogenetic analyses. Here, we describe a novel case of T-ALL associated with a mediastinal mass and a SET-NUP214 rearrangement, which was masked by a complex karyotype at the time of initial diagnosis. Using multiplex reverse transcriptase-polymerase chain reaction analysis, we detected a cryptic SET-NUP214 rearrangement in our patient. As only 11 cases (including the present study) of T-ALL with SET-NUP214 rearrangement have been reported, the clinical features and treatment outcomes have not been fully determined. Further studies are necessary to evaluate the incidence of SET-NUP214 rearrangement in T-ALL patients and the treatment responses as well as prognosis of these patients.

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

Cancer.gov

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

Acute lymphoblastic leukemia in a 2-year-old girl whose mother was previously diagnosed with antiphospholipid syndrome: a case report.

PubMed

Castro-Jiménez, Miguel Ángel; Cortés-Sánchez, Carlos Efraín; Rueda-Arenas, Ernesto; Tibaduiza-Buitrago, Lucy Adela

2015-04-15

The role of maternal exposures and conditions in the origin of childhood cancer has been a subject of growing interest, but current evidence is inconclusive. We present a case detected in a multicenter case-control study evaluating the association between parental risk factors and childhood acute lymphoblastic leukemia (ALL). The patient is a Colombian girl who was diagnosed with ALL-L1 when she was 2 years old. Her mother had been diagnosed with antiphospholipid syndrome before pregnancy and had also been treated with subcutaneous injections of heparin. Other potentially relevant maternal and patient exposures are also reported in this paper. We hypothesize that the maternal autoimmune disease could be a contributor in the causality network of the daughter's leukemia. However, the role of other exposures cannot be excluded.

Allopurinol Use During Maintenance Therapy for Acute Lymphoblastic Leukemia Avoids Mercaptopurine-related Hepatotoxicity.

PubMed

Giamanco, Nicole M; Cunningham, Bethany S; Klein, Laura S; Parekh, Dina S; Warwick, Anne B; Lieuw, Kenneth

2016-03-01

6-Mercaptopurine (6-MP) is the mainstay of treatment for acute lymphoblastic leukemia and lymphoblastic lymphoma. It is metabolized into the pharmacologically active, 6-thioguanine nucleotide (6-TGN), and 6-methyl mercaptopurine nucleotides (6-MMPN), which is associated with hepatotoxicity that jeopardizes antileukemic therapy. Allopurinol alters the metabolism of 6-MP to increase 6-TGN levels and decreases 6-methyl mercaptopurine nucleotides levels. We report 2 cases in which combination therapy of allopurinol with 6-MP was used successfully to avoid hepatotoxicity while delivering adequate 6-TGN levels. We suggest that this combination therapy can be used safely to change the metabolite production in patients who develop excessive hepatotoxicity.

Adult Acute Lymphoblastic Leukemia Treatment (PDQ®)—Health Professional Version

Cancer.gov

Adult acute lymphoblastic leukemia (ALL) treatment options include chemotherapy, radiation therapy, stem cell transplant, and targeted therapy. Get detailed information about the molecular genetics, prognosis, and treatment of ALL in this summary for clinicians.

Diagnosis of acute lymphoblastic leukemia from intracerebral hemorrhage and blast crisis. A case report and review of the literature.

PubMed

Naunheim, Matthew R; Nahed, Brian V; Walcott, Brian P; Kahle, Kristopher T; Soupir, Chad P; Cahill, Daniel P; Borges, Lawrence F

2010-09-01

Intracerebral hemorrhage (ICH) contributes significantly to the morbidity and mortality of patients suffering from acute leukemia. While ICH is often identified in autopsy studies of leukemic patients, it is rare for ICH to be the presenting sign that ultimately leads to the diagnosis of leukemia. We report a patient with previously undiagnosed acute precursor B-cell lymphoblastic leukemia (ALL) who presented with diffuse encephalopathy due to ICH in the setting of an acute blast crisis. The diagnosis of ALL was initially suspected, because of the hyperleukocytosis observed on presentation, then confirmed with a bone marrow biopsy and flow cytometry study of the peripheral blood. Furthermore, detection of the BCR/ABL Philadelphia translocation t(9:22)(q34:q11) in this leukemic patient by fluorescent in situ hybridization permitted targeted therapy of the blast crisis with imatinib (Gleevec). Understanding the underlying etiology of ICH is pivotal in its management. This case demonstrates that the presence of hyperleukocytosis in a patient with intracerebral hemorrhage should raise clinical suspicion for acute leukemia as the cause of the ICH.

[Long-term destiny of adolescents and young adults with de novo acute lymphoblastic leukemia treated with a pediatric protocol type].

PubMed

López-Hernández, Manuel Antonio; Alvarado-Ibarra, Martha; Álvarez-Veral, José Luis; Ortiz-Zepeda, Maricela; Guajardo-Leal, Martha Lilia; Cota-Range, Xochitl

The prognosis, in the long term, of adolescents and young adults with acute de novo lymphoblastic leukemia, treated with a pediatric type protocol. To analyze the efficacy and tolerability of a chemotherapy regimen of pediatric type on patients 15-35 years old with de novo acute lymphoblastic leukemia, Ph(-). A retrospective study of patients received from 2001 to 2013, without initial infiltration of the central nervous system. They received the regimen called LALÍN. Terminal goals: frequency of initial remission, probability of survival free of leukemia and event-free survival for five years. We included 101 patients; there were 29 relapses and 19 deaths. There was initial remission in 97% of the cases; survival free of leukemia of 0.58 and event-free survival 0.44. No difference in patients aged 16-21 years vs. 22-35 (p > 0.55). Negative prognostic factors: abnormal karyotypes, except hyperdiploids (p = 0.001); > 5% of blasts, on 14 day induction (p = 0. 0001); delay in the punctuality of the courses of the chemotherapy regimen (p = 0.0001). A pediatric type regimen is applicable to patients aged from 16 to 35 years with acute lymphoblastic leukemia, without greater toxicity and a best survival free of leukemia. The count of > 5% of blasts and the delay in the execution of the stages of the chemotherapy regimen are the stronger negative prognostic factors.

The use of optical microscope equipped with multispectral detector to distinguish different types of acute lymphoblastic leukemia

NASA Astrophysics Data System (ADS)

Pronichev, A. N.; Polyakov, E. V.; Tupitsyn, N. N.; Frenkel, M. A.; Mozhenkova, A. V.

2017-01-01

The article describes the use of a computer optical microscopy with multispectral camera to characterize the texture of blasts bone marrow of patients with different variants of acute lymphoblastic leukemia: B- and T- types. Specific characteristics of the chromatin of the nuclei of blasts for different types of acute lymphoblastic leukemia were obtained.

The significance of PTEN and AKT aberrations in pediatric T-cell acute lymphoblastic leukemia

PubMed Central

Zuurbier, Linda; Petricoin, Emanuel F.; Vuerhard, Maartje J.; Calvert, Valerie; Kooi, Clarissa; Buijs-Gladdines, Jessica G.C.A.M.; Smits, Willem K.; Sonneveld, Edwin; Veerman, Anjo J.P.; Kamps, Willem A.; Horstmann, Martin; Pieters, Rob; Meijerink, Jules P.P.

2012-01-01

Background PI3K/AKT pathway mutations are found in T-cell acute lymphoblastic leukemia, but their overall impact and associations with other genetic aberrations is unknown. PTEN mutations have been proposed as secondary mutations that follow NOTCH1-activating mutations and cause cellular resistance to γ-secretase inhibitors. Design and Methods The impact of PTEN, PI3K and AKT aberrations was studied in a genetically well-characterized pediatric T-cell leukemia patient cohort (n=146) treated on DCOG or COALL protocols. Results PTEN and AKT E17K aberrations were detected in 13% and 2% of patients, respectively. Defective PTEN-splicing was identified in incidental cases. Patients without PTEN protein but lacking exon-, splice-, promoter mutations or promoter hypermethylation were present. PTEN/AKT mutations were especially abundant in TAL- or LMO-rearranged leukemia but nearly absent in TLX3-rearranged patients (P=0.03), the opposite to that observed for NOTCH1-activating mutations. Most PTEN/AKT mutant patients either lacked NOTCH1-activating mutations (P=0.006) or had weak NOTCH1-activating mutations (P=0.011), and consequently expressed low intracellular NOTCH1, cMYC and MUSASHI levels. T-cell leukemia patients without PTEN/AKT and NOTCH1-activating mutations fared well, with a cumulative incidence of relapse of only 8% versus 35% for PTEN/AKT and/or NOTCH1-activated patients (P=0.005). Conclusions PI3K/AKT pathway aberrations are present in 18% of pediatric T-cell acute lymphoblastic leukemia patients. Absence of strong NOTCH1-activating mutations in these cases may explain cellular insensitivity to γ-secretase inhibitors. PMID:22491738

Advances in acute lymphoblastic leukemia.

PubMed

Randolph, Tim R

2004-01-01

Current literature. Acute lymphoblastic leukemia (ALL) is a stem cell disorder characterized by an overproduction of lymphoblasts in the bone marrow that eventually spill into circulation, producing lymphocytosis. As with the other acute leukemias, the most common symptoms experienced by patients include fatigue, bleeding, and recurrent infections resulting from the suppression of normal hematopoiesis in the bone marrow by the accumulating blasts. ALL primarily affects children and exhibits the best response to standard chemotherapy as compared to acute myeloblastic leukemias (AML). Further, remission rates are highest among ALL patients, many of whom are experiencing sustained remissions suggesting cure. In light of early treatment successes, researchers began to investigate modifications of standard treatment regimens to accommodate variability in weight, age, and response to therapy among children with ALL. Individualized treatment plans were implemented where some patients received a reduced intensity course of therapy to minimize drug toxicity while others received drug intensification to maximize response. More recently, research efforts have been directed at the elucidation of leukemogenic mechanisms implicated in ALL to identify specific protein mutants that can be used to design drugs tailored to interfere with the activity of these mutant protein targets. Identification of chimeric proteins produced from chromosomal translocations and gene expression profiles from microarray analyses are the primary techniques used to identify the potential therapeutic targets. Several reliable prognostic indicators have been identified and are being used to improve therapeutic planning and outcome prediction in ALL patients. Individualized treatment regimens have been developed based on the specific characteristics of each patient to minimize treatment related adverse events and maximize response. Through the use of cytogenetic, molecular, and microarray testing, ALL

Non-infectious chemotherapy-associated acute toxicities during childhood acute lymphoblastic leukemia therapy

PubMed Central

Schmiegelow, Kjeld; Müller, Klaus; Mogensen, Signe Sloth; Mogensen, Pernille Rudebeck; Wolthers, Benjamin Ole; Stoltze, Ulrik Kristoffer; Tuckuviene, Ruta; Frandsen, Thomas

2017-01-01

During chemotherapy for childhood acute lymphoblastic leukemia, all organs can be affected by severe acute side effects, the most common being opportunistic infections, mucositis, central or peripheral neuropathy (or both), bone toxicities (including osteonecrosis), thromboembolism, sinusoidal obstruction syndrome, endocrinopathies (especially steroid-induced adrenal insufficiency and hyperglycemia), high-dose methotrexate-induced nephrotoxicity, asparaginase-associated hypersensitivity, pancreatitis, and hyperlipidemia. Few of the non-infectious acute toxicities are associated with clinically useful risk factors, and across study groups there has been wide diversity in toxicity definitions, capture strategies, and reporting, thus hampering meaningful comparisons of toxicity incidences for different leukemia protocols. Since treatment of acute lymphoblastic leukemia now yields 5-year overall survival rates above 90%, there is a need for strategies for assessing the burden of toxicities in the overall evaluation of anti-leukemic therapy programs. PMID:28413626

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

CD22: A Promising Target for Acute Lymphoblastic Leukemia Treatment | Center for Cancer Research

Cancer.gov

There are about 4,000 new cases of acute lymphoblastic leukemia (ALL) in the United States each year. Great improvements have been made in the treatment of ALL, but many patients suffer from side effects of standard therapy and continue to die of this disease. One of the most promising therapeutic strategies includes engineering T cells with a chimeric antigen receptor (CAR)

Biology of acute lymphoblastic leukemia (ALL): clinical and therapeutic relevance.

PubMed

Graux, Carlos

2011-04-01

Acute lymphoblastic leukemia is a heterogeneous disease comprising several clinico-biological entities. Karyotyping of leukemic cells identifies recurrent chromosome rearrangements. These are usually translocations that activate genes encoding transcription factor regulating B- or T-cell differentiation. Gene expression-array confirms the prognostic relevance of ALL subgroups identified by specific chromosomal rearrangements and isolates new subgroups. Analysis of genomic copy number changes and high throughput sequencing reveal new cryptic deletions. The challenge is now to understand how these cooperative genetic lesions interact in order to have the molecular rationales needed to select new therapeutic targets and to develop and combine inhibitors with high levels of anti-leukemic specificity. The aim of this paper is to provide some data on the biology of acute lymphoblastic leukemia which are relevant in clinical practice. Copyright © 2011 Elsevier Ltd. All rights reserved.

Three case reports of radiation-induced glioblastoma after complete remission of acute lymphoblastic leukemia.

PubMed

Kajitani, Takumi; Kanamori, Masayuki; Saito, Ryuta; Watanabe, Yuko; Suzuki, Hiroyoshi; Watanabe, Mika; Kure, Shigeo; Tominaga, Teiji

2018-04-01

Radiation therapy is sometimes performed to control intracranial acute lymphoblastic leukemia (ALL), but may lead to radiation-induced malignant glioma. The clinical, radiological, histological, and molecular findings are described of three cases of radiation-induced glioblastoma after the treatment for ALL. They received radiation therapy at age 6-8 years. The latency from radiation therapy to the onset of radiation-induced glioblastoma was 5-10 years. Magnetic resonance imaging demonstrated diffuse lesions with multiple small enhanced lesions in all cases. Histological examination showed that the tumors consisted of mainly small round astrocytic atypical cells in one case, and astrocytic atypical cells with elongated cytoplasm and nuclear pleomorphism with small cell component in two cases. Microvascular proliferation was present in all cases. Immunohistochemical analysis for B-Raf V600E, and mutational analysis for the isocitrate dehydrogenase (IDH) 1, IDH2, and H3F3A gene revealed the wild-type alleles in all three cases. The integrated diagnoses were IDH wild-type glioblastoma, and local irradiation and concomitant temozolomide were performed. After the initial treatment, significant shrinkage of the diffuse lesion and enhanced lesion was found in all cases. Radiation-induced glioblastoma occurring after the treatment for ALL had unique clinical, radiological, histological, and molecular characteristics in our three cases.

Donor Peripheral Blood Stem Cell Transplant and Pretargeted Radioimmunotherapy in Treating Patients With High-Risk Advanced Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, or Myelodysplastic Syndrome

ClinicalTrials.gov

2017-08-28

Chronic Myelomonocytic Leukemia; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Previously Treated Myelodysplastic Syndrome; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Refractory Anemia With Excess Blasts; Refractory Cytopenia With Multilineage Dysplasia; Refractory Cytopenia With Multilineage Dysplasia and Ringed Sideroblasts; Secondary Acute Myeloid Leukemia

Vincristine-induced peripheral neuropathy in a neonate with congenital acute lymphoblastic leukemia.

PubMed

Baker, Steven K; Lipson, David M

2010-04-01

We report the case of a 46-day-old boy with a fulminant vincristine-induced peripheral neuropathy after treatment for congenital acute lymphoblastic leukemia. Flaccid paralysis developed at the end of the first phase of induction, requiring intubation and ventilation for 51 days. Treatment was initiated with levocarnitine, N-acetylcysteine, and pyridoxine and progressive reversal of the neuropathy occurred over the next 4 months. Potential differences in pathogenesis and presentation of vincristine neurotoxicity and Guillian-Barre syndrome in the neonate are discussed.

Neurodevelopmental Sequelae of Pediatric Acute Lymphoblastic Leukemia and Its Treatment

ERIC Educational Resources Information Center

Janzen, Laura A.; Spiegler, Brenda J.

2008-01-01

This review will describe the neurocognitive outcomes associated with pediatric acute lymphoblastic leukemia (ALL) and its treatment. The literature is reviewed with the aim of addressing methodological issues, treatment factors, risks and moderators, special populations, relationship to neuroimaging findings, and directions for future research.…

Childhood Acute Lymphoblastic Leukemia Treatment (PDQ®)—Health Professional Version

Cancer.gov

For acute lymphoblastic leukemia (ALL), the 5-year survival rate has improved significantly since 1975. Get information about risk factors, signs, diagnosis, molecular features, survival, risk-based treatment assignment, and induction and postinduction therapy for children and adolescents with newly diagnosed and recurrent ALL.

Methylenetetrahydrofolate reductase gene polymorphisms and risk of acute lymphoblastic leukemia in children.

PubMed

Sadananda Adiga, M N; Chandy, S; Ramachandra, N; Appaji, L; Aruna Kumari, B S; Ramaswamy, G; Savithri, H S; Krishnamoorthy, L

2010-01-01

Methylenetetrahydrofolate reductase (MTHFR) is a critical enzyme in folate metabolism and is involved in DNA synthesis, DNA repair and DNA methylation. Genetic polymorphisms of this enzyme have been shown to impact several diseases, including cancer. Leukemias are malignancies arising from rapidly proliferating hematopoietic cells having great requirement of DNA synthesis. This case-control study was undertaken to analyze the association of the MTHFR gene polymorphisms 677 C"T and 1298 A"C and the risk of acute lymphoblastic leukemia in children. Eighty-six patients aged below 15 years with a confirmed diagnosis of acute lymphoblastic leukemia (ALL) and 99 matched controls were taken for this study. Analysis of the polymorphisms was done using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Frequency of MTHFR 677 CC and CT were 85.9% and 14.1% in the controls, and 84.9% and 15.1% in the cases. The 'T' allele frequency was 7% and 7.5% in cases and controls respectively. The frequency of MTHFR 1298 AA, AC, and CC were 28.3%, 55.6% and 16.1% for controls and 23.3%, 59.3% and 17.4% for cases respectively. The 'C' allele frequency for 1298 A-->C was 43.9% and 47% respectively for controls and cases. The odds ratio (OR) for C677T was 1.08 (95% CI 0.48-2.45, p = 0.851) and OR for A1298C was 1.29 (95% CI 0.65-2.29, p = 0.46) and OR for 1298 CC was 1.31 (95% CI 0.53-3.26, p = 0.56). The OR for the combined heterozygous status (677 CT and 1298 AC) was 1.94 (95% CI 0.58-6.52, p = 0.286). The prevalence of 'T' allele for 677 MTHFR polymorphism was low in the population studied. There was no association between MTHFR 677 C-->T and 1298 A-->C gene polymorphisms and risk of ALL, which may be due to the small sample size.

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.

Leukemia cell-rhabdovirus vaccine: personalized immunotherapy for acute lymphoblastic leukemia.

PubMed

Conrad, David P; Tsang, Jovian; Maclean, Meaghan; Diallo, Jean-Simon; Le Boeuf, Fabrice; Lemay, Chantal G; Falls, Theresa J; Parato, Kelley A; Bell, John C; Atkins, Harold L

2013-07-15

Acute lymphoblastic leukemia (ALL) remains incurable in most adults. It has been difficult to provide effective immunotherapy to improve outcomes for the majority of patients. Rhabdoviruses induce strong antiviral immune responses. We hypothesized that mice administered ex vivo rhabdovirus-infected ALL cells [immunotherapy by leukemia-oncotropic virus (iLOV)] would develop robust antileukemic immune responses capable of controlling ALL. Viral protein production, replication, and cytopathy were measured in human and murine ALL cells exposed to attenuated rhabdovirus. Survival following injection of graded amounts of ALL cells was compared between cohorts of mice administered γ-irradiated rhabdovirus-infected ALL cells (iLOV) or multiple control vaccines to determine key immunotherapeutic components and characteristics. Host immune requirements were assessed in immunodeficient and bone marrow-transplanted mice or by adoptive splenocyte transfer from immunized donors. Antileukemic immune memory was ascertained by second leukemic challenge in long-term survivors. Human and murine ALL cells were infected and killed by rhabdovirus; this produced a potent antileukemia vaccine. iLOV protected mice from otherwise lethal ALL by developing durable leukemia-specific immune-mediated responses (P < 0.0001), which required an intact CTL compartment. Preexisting antiviral immunity augmented iLOV potency. Splenocytes from iLOV-vaccinated donors protected 60% of naïve recipients from ALL challenge (P = 0.0001). Injecting leukemia cells activated by, or concurrent with, multiple Toll-like receptor agonists could not reproduce the protective effect of iLOV. Similarly, injecting uninfected irradiated viable, apoptotic, or necrotic leukemia cells with/without concurrent rhabdovirus administration was ineffective. Rhabdovirus-infected leukemia cells can be used to produce a vaccine that induces robust specific immunity against aggressive leukemia.

Extramedullary Relapse of Acute Lymphoblastic Leukemia Presenting as Abnormal Uterine Bleeding: A Case Report.

PubMed

Robillard, Diana T; Kutny, Matthew A; Chewning, Joseph H; Arbuckle, Janeen L

2017-06-01

Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy. Relapse of ALL occurs in 15%-20% of patients, with 2%-6% occurring exclusively in extramedullary sites. Relapse of ALL in gynecologic organs is extremely rare. We present a case of a 12-year-old girl with a history of ALL who was referred to the pediatric gynecology clinic with abnormal uterine bleeding. She was determined to have an extramedullary uterine relapse of her ALL. Abnormal uterine bleeding in the setting of childhood malignancy is a frequent reason for consultation to pediatric and adolescent gynecology services. This bleeding is commonly attributed to thrombocytopenia due to bone marrow suppressive chemotherapeutic agents. However, as shown in this report, abnormal uterine bleeding might be a manifestation of an extramedullary relapse. Copyright © 2017 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. All rights reserved.

Donor Umbilical Cord Blood Transplant With or Without Ex-vivo Expanded Cord Blood Progenitor Cells in Treating Patients With Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, Chronic Myelogenous Leukemia, or Myelodysplastic Syndromes

ClinicalTrials.gov

2018-03-05

Acute Biphenotypic Leukemia; Acute Erythroid Leukemia; Acute Lymphoblastic Leukemia in Remission; Acute Megakaryoblastic Leukemia; Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome; Acute Myeloid Leukemia in Remission; Blasts Under 10 Percent of Bone Marrow Nucleated Cells; Blasts Under 5 Percent of Bone Marrow Nucleated Cells; Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Mixed Phenotype Acute Leukemia; Myelodysplastic Syndrome; Myelodysplastic Syndrome With Excess Blasts; Pancytopenia; Refractory Anemia; Secondary Acute Myeloid Leukemia

Bilateral parotid gland enlargement and palpable nephromegaly in infant acute lymphoblastic leukemia: case report and review of the literature.

PubMed

Saha, Aniket; Dandekar, Smita; Milla, Sarah; Roman, Elizabeth; Bhatla, Teena

2014-04-01

Acute lymphoblastic leukemia (ALL) in infants below 1 year of age accounts for 2.5% to 5% of childhood ALL. Most children with ALL present with fever, bruising, mucosal bleeding, bone pain, pallor, hepatosplenomegaly, and lymphadenopathy. Common sites of extramedullary involvement at diagnosis include liver, spleen, lymph nodes, brain, and testes. Nephromegaly has also been reported. We present a novel case of bilateral parotid enlargement along with bilateral palpable nephromegaly in a patient with newly diagnosed infant ALL. This unique presentation highlights the importance of considering ALL in the differential diagnosis of parotid enlargement especially when associated with abnormal blood counts.

Acute lymphoblastic leukemia terminating as histiocytic medullary reticulosis.

PubMed

Shreiner, D P

1975-02-24

A young man with acute lymphoblastic leukemia was treated with vincristine sulfate, prednisone, and intrathecally injected methotrexate sodium for central nervous system involvement. A good remission was induced, but three months later he had hepatosplenomegaly, an enlarging mediastinal mass, and progressive anemia. Histiocytic medullary reticulosis was confirmed by a bone marrow biopsy specimen. The patient died of respiratory failure because of infiltration of the lungs by malignant histiocytes.

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

Trisomy 13 in a patient with common acute lymphoblastic leukemia: description of a case and review of the literature.

PubMed

Spirito, Francesca R; Mancini, Marco; Derme, Valentina; Cimino, Giuseppe; Testi, Anna Maria; Tafuri, Agostino; Vitale, Antonella; Foà, Robin

2003-07-01

Trisomy 13 occurring as a single cytogenetic abnormality has been associated with undifferentiated or biphenotypic acute leukemias and with an adverse prognostic outcome. We describe for the first time a case of B-cell common acute lymphoblastic leukemia (ALL) with trisomy 13 at diagnosis in an 18-year-old boy. The leukemic cells did not express myelocytic or T-cell associated antigens and no molecular abnormalities were detected. Following treatment, according to the GIMEMA ALL 0496 protocol, the patient achieved a brief (2 months) complete remission. At relapse, cytogenetic analysis showed karyotypic evolution that included two novel subclones carrying a del(6q), a del(7q), and an add(17q) in association with trisomy 13. In addition, immunophenotypic analysis revealed the coexpression of the CD33 and CD7 antigens on common ALL blasts, in accordance with other reported cases that displayed a predominant biphenotypic leukemia profile. The patient failed to obtain a second remission and died soon after due to infective complications. This report indicates that trisomy 13 can be found also in B-lineage ALL and underlines that this cytogenetic abnormality may identify a subgroup of male patients with clonal evolution potential and an adverse clinical outcome.

Assessing Compliance With Mercaptopurine Treatment in Younger Patients With Acute Lymphoblastic Leukemia in First Remission | Division of Cancer Prevention

Cancer.gov

This randomized phase III trial studies compliance to a mercaptopurine treatment intervention compared to standard of care in younger patients with acute lymphoblastic leukemia in remission. Assessing ways to help patients who have acute lymphoblastic leukemia to take their medications as prescribed may help them in taking their medications more consistently and may improve

DEREGULATION OF DUX4 AND ERG IN ACUTE LYMPHOBLASTIC LEUKEMIA

PubMed Central

Zhang, Jinghui; McCastlain, Kelly; Yoshihara, Hiroki; Xu, Beisi; Chang, Yunchao; Churchman, Michelle L.; Wu, Gang; Li, Yongjin; Wei, Lei; Iacobucci, Ilaria; Liu, Yu; Qu, Chunxu; Wen, Ji; Edmonson, Michael; Payne-Turner, Debbie; Kaufmann, Kerstin B.; Takayanagi, Shin-ichiro; Wienholds, Erno; Waanders, Esmé; Ntziachristos, Panagiotis; Bakogianni, Sofia; Wang, Jingjing; Aifantis, Iannis; Roberts, Kathryn G.; Ma, Jing; Song, Guangchun; Easton, John; Mulder, Heather L.; Chen, Xiang; Newman, Scott; Ma, Xiaotu; Rusch, Michael; Gupta, Pankaj; Boggs, Kristy; Vadodaria, Bhavin; Dalton, James; Liu, Yanling; Valentine, Marcus L; Ding, Li; Lu, Charles; Fulton, Robert S.; Fulton, Lucinda; Tabib, Yashodhan; Ochoa, Kerri; Devidas, Meenakshi; Pei, Deqing; Cheng, Cheng; Yang, Jun; Evans, William E.; Relling, Mary V.; Pui, Ching-Hon; Jeha, Sima; Harvey, Richard C.; Chen, I-Ming L; Willman, Cheryl L.; Marcucci, Guido; Bloomfield, Clara D.; Kohlschmidt, Jessica; Mrózek, Krzysztof; Paietta, Elisabeth; Tallman, Martin S.; Stock, Wendy; Foster, Matthew C.; Racevskis, Janis; Rowe, Jacob M.; Luger, Selina; Kornblau, Steven M.; Shurtleff, Sheila A; Raimondi, Susana C.; Mardis, Elaine R.; Wilson, Richard K.; Dick, John E.; Hunger, Stephen P; Loh, Mignon L.; Downing, James R.; Mullighan, Charles G.

2016-01-01

Chromosomal rearrangements deregulating hematopoietic transcription factors are common in acute lymphoblastic leukemia (ALL).1,2 Here, we show that deregulation of the homeobox transcription factor gene DUX4 and the ETS transcription factor gene ERG are hallmarks of a subtype of B-progenitor ALL that comprises up to 7% of B-ALL. DUX4 rearrangement and overexpression was present in all cases, and was accompanied by transcriptional deregulation of ERG, expression of a novel ERG isoform, ERGalt, and frequent ERG deletion. ERGalt utilizes a non-canonical first exon whose transcription was initiated by DUX4 binding. ERGalt retains the DNA-binding and transactivating domains of ERG, but inhibits wild-type ERG transcriptional activity and is transforming. These results illustrate a unique paradigm of transcription factor deregulation in leukemia, in which DUX4 deregulation results in loss-of-function of ERG, either by deletion or induction of expression of an isoform that is a dominant negative inhibitor of wild type ERG function. PMID:27776115

Acute lymphoblastic leukemia in patients with Down syndrome with a previous history of acute myeloid leukemia.

PubMed

Tomizawa, Daisuke; Endo, Akifumi; Kajiwara, Michiko; Sakaguchi, Hirotoshi; Matsumoto, Kimikazu; Kaneda, Makoto; Taga, Takashi

2017-08-01

Patients with Down syndrome (DS) are predisposed to acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) in early and later childhood, respectively, but rarely experience both. We herein discuss four patients with DS with ALL and a history of AML who were treated with various chemotherapies, one of whom later received a bone marrow transplantation. Three patients survived and remain in remission. One patient died of fulminant hepatitis during therapy. No common cytogenetic abnormalities in AML and ALL besides constitutional +21 were identified, indicating that the two leukemia types were independent events. However, the underlying pathomechanism of these conditions awaits clarification. © 2016 Wiley Periodicals, Inc.

Characterization of leukemias with ETV6-ABL1 fusion

PubMed Central

Zaliova, Marketa; Moorman, Anthony V.; Cazzaniga, Giovanni; Stanulla, Martin; Harvey, Richard C.; Roberts, Kathryn G.; Heatley, Sue L.; Loh, Mignon L.; Konopleva, Marina; Chen, I-Ming; Zimmermannova, Olga; Schwab, Claire; Smith, Owen; Mozziconacci, Marie-Joelle; Chabannon, Christian; Kim, Myungshin; Frederik Falkenburg, J. H.; Norton, Alice; Marshall, Karen; Haas, Oskar A.; Starkova, Julia; Stuchly, Jan; Hunger, Stephen P.; White, Deborah; Mullighan, Charles G.; Willman, Cheryl L.; Stary, Jan; Trka, Jan; Zuna, Jan

2016-01-01

To characterize the incidence, clinical features and genetics of ETV6-ABL1 leukemias, representing targetable kinase-activating lesions, we analyzed 44 new and published cases of ETV6-ABL1-positive hematologic malignancies [22 cases of acute lymphoblastic leukemia (13 children, 9 adults) and 22 myeloid malignancies (18 myeloproliferative neoplasms, 4 acute myeloid leukemias)]. The presence of the ETV6-ABL1 fusion was ascertained by cytogenetics, fluorescence in-situ hybridization, reverse transcriptase-polymerase chain reaction and RNA sequencing. Genomic and gene expression profiling was performed by single nucleotide polymorphism and expression arrays. Systematic screening of more than 4,500 cases revealed that in acute lymphoblastic leukemia ETV6-ABL1 is rare in childhood (0.17% cases) and slightly more common in adults (0.38%). There is no systematic screening of myeloproliferative neoplasms; however, the number of ETV6-ABL1-positive cases and the relative incidence of acute lymphoblastic leukemia and myeloproliferative neoplasms suggest that in adulthood ETV6-ABL1 is more common in BCR-ABL1-negative chronic myeloid leukemia-like myeloproliferations than in acute lymphoblastic leukemia. The genomic profile of ETV6-ABL1 acute lymphoblastic leukemia resembled that of BCR-ABL1 and BCR-ABL1-like cases with 80% of patients having concurrent CDKN2A/B and IKZF1 deletions. In the gene expression profiling all the ETV6-ABL1-positive samples clustered in close vicinity to BCR-ABL1 cases. All but one of the cases of ETV6-ABL1 acute lymphoblastic leukemia were classified as BCR-ABL1-like by a standardized assay. Over 60% of patients died, irrespectively of the disease or age subgroup examined. In conclusion, ETV6-ABL1 fusion occurs in both lymphoid and myeloid leukemias; the genomic profile and clinical behavior resemble BCR-ABL1-positive malignancies, including the unfavorable prognosis, particularly of acute leukemias. The poor outcome suggests that treatment with

Characterization of leukemias with ETV6-ABL1 fusion.

PubMed

Zaliova, Marketa; Moorman, Anthony V; Cazzaniga, Giovanni; Stanulla, Martin; Harvey, Richard C; Roberts, Kathryn G; Heatley, Sue L; Loh, Mignon L; Konopleva, Marina; Chen, I-Ming; Zimmermannova, Olga; Schwab, Claire; Smith, Owen; Mozziconacci, Marie-Joelle; Chabannon, Christian; Kim, Myungshin; Frederik Falkenburg, J H; Norton, Alice; Marshall, Karen; Haas, Oskar A; Starkova, Julia; Stuchly, Jan; Hunger, Stephen P; White, Deborah; Mullighan, Charles G; Willman, Cheryl L; Stary, Jan; Trka, Jan; Zuna, Jan

2016-09-01

To characterize the incidence, clinical features and genetics of ETV6-ABL1 leukemias, representing targetable kinase-activating lesions, we analyzed 44 new and published cases of ETV6-ABL1-positive hematologic malignancies [22 cases of acute lymphoblastic leukemia (13 children, 9 adults) and 22 myeloid malignancies (18 myeloproliferative neoplasms, 4 acute myeloid leukemias)]. The presence of the ETV6-ABL1 fusion was ascertained by cytogenetics, fluorescence in-situ hybridization, reverse transcriptase-polymerase chain reaction and RNA sequencing. Genomic and gene expression profiling was performed by single nucleotide polymorphism and expression arrays. Systematic screening of more than 4,500 cases revealed that in acute lymphoblastic leukemia ETV6-ABL1 is rare in childhood (0.17% cases) and slightly more common in adults (0.38%). There is no systematic screening of myeloproliferative neoplasms; however, the number of ETV6-ABL1-positive cases and the relative incidence of acute lymphoblastic leukemia and myeloproliferative neoplasms suggest that in adulthood ETV6-ABL1 is more common in BCR-ABL1-negative chronic myeloid leukemia-like myeloproliferations than in acute lymphoblastic leukemia. The genomic profile of ETV6-ABL1 acute lymphoblastic leukemia resembled that of BCR-ABL1 and BCR-ABL1-like cases with 80% of patients having concurrent CDKN2A/B and IKZF1 deletions. In the gene expression profiling all the ETV6-ABL1-positive samples clustered in close vicinity to BCR-ABL1 cases. All but one of the cases of ETV6-ABL1 acute lymphoblastic leukemia were classified as BCR-ABL1-like by a standardized assay. Over 60% of patients died, irrespectively of the disease or age subgroup examined. In conclusion, ETV6-ABL1 fusion occurs in both lymphoid and myeloid leukemias; the genomic profile and clinical behavior resemble BCR-ABL1-positive malignancies, including the unfavorable prognosis, particularly of acute leukemias. The poor outcome suggests that treatment with

CD22: A Promising Target for Acute Lymphoblastic Leukemia Treatment | Center for Cancer Research

Cancer.gov

There are about 4,000 new cases of acute lymphoblastic leukemia (ALL) in the United States each year. Great improvements have been made in the treatment of ALL, but many patients suffer from side effects of standard therapy and continue to die of this disease. One of the most promising therapeutic strategies includes engineering T cells with a chimeric antigen receptor (CAR) that alters T cell specificity and function to recognize tumor antigens.

Letter regarding Zhao et al. entitled " DPYD gene polymorphisms are associated with risk and chemotherapy prognosis in pediatric patients with acute lymphoblastic leukemia".

PubMed

Deenen, Maarten J; Henricks, Linda M; Sonke, Gabe S; Schellens, Jan Hm; Meulendijks, Didier

2017-06-01

Zhao et al. investigated the association between germline genetic polymorphisms in DPYD, the gene encoding dihydropyrimidine dehydrogenase, and (1) the risk of developing pediatric acute lymphoblastic leukemia and (2) outcome of acute lymphoblastic leukemia following the treatment with 5-fluorouracil plus oxaliplatin (FOLFOX). The authors found that the common DPYD variant c.85T>C (rs1801265, DPYD*9A) was significantly associated with (1) risk of developing pediatric acute lymphoblastic leukemia, (2) complete response rate, (3) event-free survival, and (4) treatment-related toxicity. The authors conclude that patients carrying the c.85T>C C allele have an increased risk of developing acute lymphoblastic leukemia and have inferior outcome, and that DPYD c.85T>C can be used as a guide for individualized treatment and the decision to utilize 5-fluorouracil in acute lymphoblastic leukemia patients. In our view, the published article gives rise to multiple critical issues regarding the study's rationale and the methodology used, which strongly question the validity of the authors' conclusions.

Diagnosis of intrachromosomal amplification of chromosome 21 (iAMP21) by molecular cytogenetics in pediatric acute lymphoblastic leukemia.

PubMed

Duployez, Nicolas; Boudry-Labis, Elise; Decool, Gauthier; Grzych, Guillaume; Grardel, Nathalie; Abou Chahla, Wadih; Preudhomme, Claude; Roche-Lestienne, Catherine

2015-10-01

Intrachromosomal amplification of chromosome 21 (iAMP21) defines a distinct cytogenetic subgroup of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) with poor prognosis that should be investigated in routine practice. Single-nucleotide polymorphism (SNP)-array provides a useful method to detect such cases showing a highly characteristic profile.

Mitochondrial DNA in Residual Leukemia Cells in Cerebrospinal Fluid in Children with Acute Lymphoblastic Leukemia

PubMed Central

Egan, Kathryn; Kusao, Ian; Troelstrup, David; Agsalda, Melissa; Shiramizu, Bruce

2010-01-01

This feasibility study was designed to assess the ability to measure mitochondrial DNA (mtDNA) in cerebrospinal fluid (CSF) cells that contributed to minimal disease/persistent or residual disease (MD/PRD) from children with acute lymphoblastic leukemia (ALL). Increase in mtDNA copies in cancer cells has been suggested to play a role in MD/PRD. CSF as well as blood specimens from 6 children were assayed for MD/PRD and mtDNA copy numbers by quantitative real-time polymerase chain reaction. Of 7 MD/PRD-positive specimens, 6 had increased mtDNA copy numbers; while 11 MD/PRD-negative specimens had no increase in mtDNA copy numbers, p < 0.003. This is the first proof-of-concept study to measure mtDNA copy numbers in MD/PRD-positive CSF specimens from children with ALL. Increase of mtDNA copy numbers in MD/PRD childhood ALL cells and its significance as a mechanism for recurrence requires further investigation. Keywords Minimal residual disease; Acute lymphoblastic leukemia; Central nervous system; Cerebrospinal fluid; Mitochondria PMID:21331151

huJCAR014 CAR-T Cells in Treating Adult Patients With Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma or Acute Lymphoblastic Leukemia

ClinicalTrials.gov

2018-05-25

Adult B Acute Lymphoblastic Leukemia; BCL2 Gene Rearrangement; BCL6 Gene Rearrangement; CD19 Positive; Diffuse Large B-Cell Lymphoma, Not Otherwise Specified; MYC Gene Rearrangement; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent B-Cell Non-Hodgkin Lymphoma; Recurrent Diffuse Large B-Cell Lymphoma; Recurrent Mediastinal (Thymic) Large B-Cell Cell Lymphoma; Refractory Adult Acute Lymphoblastic Leukemia; Refractory B-Cell Non-Hodgkin Lymphoma; Refractory Diffuse Large B-Cell Lymphoma; Refractory Mediastinal (Thymic) Large B-Cell Cell Lymphoma; Transformed Recurrent Non-Hodgkin Lymphoma

Comparison between qualitative and real-time polymerase chain reaction to evaluate minimal residual disease in children with acute lymphoblastic leukemia.

PubMed

Paula, Francisco Danilo Ferreira; Elói-Santos, Silvana Maria; Xavier, Sandra Guerra; Ganazza, Mônica Aparecida; Jotta, Patricia Yoshioka; Yunes, José Andrés; Viana, Marcos Borato; Assumpção, Juliana Godoy

2015-01-01

Minimal residual disease is an important independent prognostic factor that can identify poor responders among patients with acute lymphoblastic leukemia. The aim of this study was to analyze minimal residual disease using immunoglobulin (Ig) and T-cell receptor (TCR) gene rearrangements by conventional polymerase chain reaction followed by homo-heteroduplex analysis and to compare this with real-time polymerase chain reaction at the end of the induction period in children with acute lymphoblastic leukemia. Seventy-four patients diagnosed with acute lymphoblastic leukemia were enrolled. Minimal residual disease was evaluated by qualitative polymerase chain reaction in 57 and by both tests in 44. The Kaplan-Meier and multivariate Cox methods and the log-rank test were used for statistical analysis. Nine patients (15.8%) were positive for minimal residual disease by qualitative polymerase chain reaction and 11 (25%) by real-time polymerase chain reaction considering a cut-off point of 1×10(-3) for precursor B-cell acute lymphoblastic leukemia and 1×10(-2) for T-cell acute lymphoblastic leukemia. Using the qualitative method, the 3.5-year leukemia-free survival was significantly higher in children negative for minimal residual disease compared to those with positive results (84.1%±5.6% versus 41.7%±17.3%, respectively; p-value=0.004). There was no significant association between leukemia-free survival and minimal residual disease by real-time polymerase chain reaction. Minimal residual disease by qualitative polymerase chain reaction was the only variable significantly correlated to leukemia-free survival. Given the difficulties in the implementation of minimal residual disease monitoring by real-time polymerase chain reaction in most treatment centers in Brazil, the qualitative polymerase chain reaction strategy may be a cost-effective alternative. Copyright © 2015 Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular. Published by Elsevier

Pharmacogenetics predictive of response and toxicity in acute lymphoblastic leukemia therapy.

PubMed

Mei, Lin; Ontiveros, Evelena P; Griffiths, Elizabeth A; Thompson, James E; Wang, Eunice S; Wetzler, Meir

2015-07-01

Acute lymphoblastic leukemia (ALL) is a relatively rare disease in adults accounting for no more than 20% of all cases of acute leukemia. By contrast with the pediatric population, in whom significant improvements in long term survival and even cure have been achieved over the last 30years, adult ALL remains a significant challenge. Overall survival in this group remains a relatively poor 20-40%. Modern research has focused on improved pharmacokinetics, novel pharmacogenetics and personalized principles to optimize the efficacy of the treatment while reducing toxicity. Here we review the pharmacogenetics of medications used in the management of patients with ALL, including l-asparaginase, glucocorticoids, 6-mercaptopurine, methotrexate, vincristine and tyrosine kinase inhibitors. Incorporating recent pharmacogenetic data, mainly from pediatric ALL, will provide novel perspective of predicting response and toxicity in both pediatric and adult ALL therapies. Copyright © 2015 Elsevier Ltd. All rights reserved.

Incidence and risk factors for central nervous system relapse in children and adolescents with acute lymphoblastic leukemia

PubMed Central

Cancela, Camila Silva Peres; Murao, Mitiko; Viana, Marcos Borato; de Oliveira, Benigna Maria

2012-01-01

Background Despite all the advances in the treatment of childhood acute lymphoblastic leukemia, central nervous system relapse remains an important obstacle to curing these patients. This study analyzed the incidence of central nervous system relapse and the risk factors for its occurrence in children and adolescents with acute lymphoblastic leukemia. Methods This study has a retrospective cohort design. The studied population comprised 199 children and adolescents with a diagnosis of acute lymphoblastic leukemia followed up at Hospital das Clinicas, Universidade Federal de Minas Gerais (HC-UFMG) between March 2001 and August 2009 and submitted to the Grupo Brasileiro de Tratamento de Leucemia da Infância - acute lymphoblastic leukemia (GBTLI-LLA-99) treatment protocol. Results The estimated probabilities of overall survival and event free survival at 5 years were 69.5% (± 3.6%) and 58.8% (± 4.0%), respectively. The cumulative incidence of central nervous system (isolated or combined) relapse was 11.0% at 8 years. The estimated rate of isolated central nervous system relapse at 8 years was 6.8%. In patients with a blood leukocyte count at diagnosis ≥ 50 x 109/L, the estimated rate of isolated or combined central nervous system relapse was higher than in the group with a count < 50 x 109/L (p-value = 0.0008). There was no difference in cumulative central nervous system relapse (isolated or combined) for the other analyzed variables: immunophenotype, traumatic lumbar puncture, interval between diagnosis and first lumbar puncture and place where the procedure was performed. Conclusions These results suggest that a leukocyte count > 50 x 109/L at diagnosis seems to be a significant prognostic factor for a higher incidence of central nervous system relapse in childhood acute lymphoblastic leukemia. PMID:23323068

Acute lymphoblastic leukemia of childhood monitored by bacteriocin and flowcytometry.

PubMed

Musclow, C E; Farkas-Himsley, H; Weitzman, S S; Herridge, M

1987-04-01

Bacteriocin and flowcytometric analysis of 106 blood samples from children with acute lymphoblastic leukemia were correlated with clinical stages of disease. Bacteriocins interacted selectively with malignant, and not with normal, lymphocytes causing cell cycle perturbation which was rapidly and objectively recorded by the flowcytometer. The patients were grouped as: (A) newly-diagnosed (15); (B) early induction (11); (C) remission with viral infection (7); (D) remission (64); (E) bone marrow relapsed (5); (F) extramedullary relapsed (3); (G) non-malignant pediatric controls (8). Bacteriocin reacted usually with groups A, B, C, E and not with groups D, F and G. Repeated testing correlated well with the clinical status. Blood from 7 patients in remission and from 3 normal individuals, each with transient viral infection, reacted with bacteriocin. A quantitative correlation between peripheral blood blasts or surface markers for ALL and bacteriocin reactivity was not established. Unexpected results were obtained only in 13% (false-positive 11% and false-negative 3%). This test can be recommended for preliminary diagnosis and possibly prognosis of lymphoblastic leukemia and provides means of monitoring progress during chemotherapy.

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

PubMed Central

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

2010-01-01

Background Mixed phenotype acute leukemia (MPAL) represents a diagnostic and therapeutic dilemma. The European Group for the Immunological Classification of Leukemias (EGIL) scoring system unambiguously defines MPAL expressing aberrant lineage markers. Discussions surrounding it have focused on scoring details, and information is limited regarding its biological, clinical and prognostic significance. The recent World Health Organization classification is simpler and could replace the EGIL scoring system after transformation into unambiguous guidelines. Design and Methods Simple immunophenotypic criteria were used to classify all cases of childhood acute leukemia in order to provide therapy directed against acute lymphoblastic leukemia or acute myeloid leukemia. Prognosis, genotype and immunoglobulin/T-cell receptor gene rearrangement status were analyzed. Results The incidences of MPAL were 28/582 and 4/107 for children treated with acute lymphoblastic leukemia and acute myeloid leukemia regimens, respectively. In immunophenotypic principal component analysis, MPAL treated as T-cell acute lymphoblastic leukemia clustered between cases of non-mixed T-cell acute lymphoblastic leukemia and acute myeloid leukemia, while other MPAL cases were included in the respective non-mixed B-cell progenitor acute lymphoblastic leukemia or acute myeloid leukemia clusters. Analogously, immunoglobulin/T-cell receptor gene rearrangements followed the expected pattern in patients treated as having acute myeloid leukemia (non-rearranged, 4/4) or as having B-cell progenitor acute lymphoblastic leukemia (rearranged, 20/20), but were missing in 3/5 analyzed cases of MPAL treated as having T-cell acute lymphobastic leukemia. In patients who received acute lymphoblastic leukemia treatment, the 5-year event-free survival of the MPAL cases was worse than that of the non-mixed cases (53±10% and 76±2% at 5 years, respectively, P=0.0075), with a more pronounced difference among B lineage cases

CD200/BTLA deletions in pediatric precursor B-cell acute lymphoblastic leukemia treated according to the EORTC-CLG 58951 protocol

PubMed Central

Ghazavi, Farzaneh; Clappier, Emmanuelle; Lammens, Tim; Suciu, Stefan; Caye, Aurélie; Zegrari, Samira; Bakkus, Marleen; Grardel, Nathalie; Benoit, Yves; Bertrand, Yves; Minckes, Odile; Costa, Vitor; Ferster, Alina; Mazingue, Françoise; Plat, Geneviève; Plouvier, Emmanuel; Poirée, Marilyne; Uyttebroeck, Anne; van der Werff-ten Bosch, Jutte; Yakouben, Karima; Helsmoortel, Hetty; Meul, Magali; Van Roy, Nadine; Philippé, Jan; Speleman, Frank; Cavé, Hélène; Van Vlierberghe, Pieter; De Moerloose, Barbara

2015-01-01

DNA copy number analysis has been instrumental for the identification of genetic alterations in B-cell precursor acute lymphoblastic leukemia. Notably, some of these genetic defects have been associated with poor treatment outcome and might be relevant for future risk stratification. In this study, we characterized recurrent deletions of CD200 and BTLA genes, mediated by recombination-activating genes, and used breakpoint-specific polymerase chain reaction assay to screen a cohort of 1154 cases of B-cell precursor acute lymphoblastic leukemia uniformly treated according to the EORTC-CLG 58951 protocol. CD200/BTLA deletions were identified in 56 of the patients (4.8%) and were associated with an inferior 8-year event free survival in this treatment protocol [70.2% ± 1.2% for patients with deletions versus 83.5% ± 6.4% for non-deleted cases (hazard ratio 2.02; 95% confidence interval 1.23–3.32; P=0.005)]. Genetically, CD200/BTLA deletions were strongly associated with ETV6-RUNX1-positive leukemias (P<0.0001), but were also identified in patients who did not have any genetic abnormality that is currently used for risk stratification. Within the latter population of patients, the presence of CD200/BTLA deletions was associated with inferior event-free survival and overall survival. Moreover, the multivariate Cox model indicated that these deletions had independent prognostic impact on event-free survival when adjusting for conventional risk criteria. All together, these findings further underscore the rationale for copy number profiling as an important tool for risk stratification in human B-cell precursor acute lymphoblastic leukemia. This trial was registered at www.ClinicalTrials.gov as #NCT00003728. PMID:26137961

CD200/BTLA deletions in pediatric precursor B-cell acute lymphoblastic leukemia treated according to the EORTC-CLG 58951 protocol.

PubMed

Ghazavi, Farzaneh; Clappier, Emmanuelle; Lammens, Tim; Suciu, Stefan; Caye, Aurélie; Zegrari, Samira; Bakkus, Marleen; Grardel, Nathalie; Benoit, Yves; Bertrand, Yves; Minckes, Odile; Costa, Vitor; Ferster, Alina; Mazingue, Françoise; Plat, Geneviève; Plouvier, Emmanuel; Poirée, Marilyne; Uyttebroeck, Anne; van der Werff-Ten Bosch, Jutte; Yakouben, Karima; Helsmoortel, Hetty; Meul, Magali; Van Roy, Nadine; Philippé, Jan; Speleman, Frank; Cavé, Hélène; Van Vlierberghe, Pieter; De Moerloose, Barbara

2015-10-01

DNA copy number analysis has been instrumental for the identification of genetic alterations in B-cell precursor acute lymphoblastic leukemia. Notably, some of these genetic defects have been associated with poor treatment outcome and might be relevant for future risk stratification. In this study, we characterized recurrent deletions of CD200 and BTLA genes, mediated by recombination-activating genes, and used breakpoint-specific polymerase chain reaction assay to screen a cohort of 1154 cases of B-cell precursor acute lymphoblastic leukemia uniformly treated according to the EORTC-CLG 58951 protocol. CD200/BTLA deletions were identified in 56 of the patients (4.8%) and were associated with an inferior 8-year event free survival in this treatment protocol [70.2% ± 1.2% for patients with deletions versus 83.5% ± 6.4% for non-deleted cases (hazard ratio 2.02; 95% confidence interval 1.23-3.32; P=0.005)]. Genetically, CD200/BTLA deletions were strongly associated with ETV6-RUNX1-positive leukemias (P<0.0001), but were also identified in patients who did not have any genetic abnormality that is currently used for risk stratification. Within the latter population of patients, the presence of CD200/BTLA deletions was associated with inferior event-free survival and overall survival. Moreover, the multivariate Cox model indicated that these deletions had independent prognostic impact on event-free survival when adjusting for conventional risk criteria. All together, these findings further underscore the rationale for copy number profiling as an important tool for risk stratification in human B-cell precursor acute lymphoblastic leukemia. This trial was registered at www.ClinicalTrials.gov as #NCT00003728. Copyright© Ferrata Storti Foundation.

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

PubMed

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

2012-01-01

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

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

PubMed Central

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

2013-01-01

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

Yttrium Y 90 Anti-CD45 Monoclonal Antibody BC8 Followed by Donor Stem Cell Transplant in Treating Patients With High-Risk Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, or Myelodysplastic Syndrome

ClinicalTrials.gov

2018-03-19

Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome; Chronic Myelomonocytic Leukemia; Previously Treated Myelodysplastic Syndrome; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Refractory Anemia With Excess Blasts; Secondary Acute Myeloid Leukemia

Diagnosis of intrachromosomal amplification of chromosome 21 (iAMP21) by molecular cytogenetics in pediatric acute lymphoblastic leukemia

PubMed Central

Duployez, Nicolas; Boudry-Labis, Elise; Decool, Gauthier; Grzych, Guillaume; Grardel, Nathalie; Abou Chahla, Wadih; Preudhomme, Claude; Roche-Lestienne, Catherine

2015-01-01

Key Clinical Message Intrachromosomal amplification of chromosome 21 (iAMP21) defines a distinct cytogenetic subgroup of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) with poor prognosis that should be investigated in routine practice. Single-nucleotide polymorphism (SNP)-array provides a useful method to detect such cases showing a highly characteristic profile. PMID:26509013

Phenotypic and genotypic analyses of blastic cell population suggest that pure B-lymphoblastic leukemia may arise from myelodysplastic syndrome.

PubMed

Pajor, L; Matolcsy, A; Vass, J A; Méhes, G; Marton, E; Szabó, F; Iványi, J L

1998-01-01

The case history of a 70-year-old man with myelodysplastic syndrome terminated into acute leukemia in 22 months is presented. The leukemic cells exhibited multifocal acid phosphatase positivity and expressed TdT, CD45, CD34 and HLA-DR but not myeloid, monocytic or megakaryocytic differentiation antigenes. The genotypic analysis revealed clonal immunoglobulin heavy chain gene rearrangement. These phenotypic and genotypic analyses of the blastic cell population suggest that myelodysplastic syndrome may transform to pure acute lymphoblastic leukemia of B-cell origin.

Image-based RNA interference screening reveals an individual dependence of acute lymphoblastic leukemia on stromal cysteine support

PubMed Central

Marovca, Blerim; Vonderheit, Andreas; Grotzer, Michael A.; Eckert, Cornelia; Cario, Gunnar; Wollscheid, Bernd; Horvath, Peter

2014-01-01

Interactions with the bone marrow microenvironment are essential for leukemia survival and disease progression. We developed an imaging-based RNAi platform to identify protective cues from bone marrow derived mesenchymal stromal cells (MSC) that promote survival of primary acute lymphoblastic leukemia (ALL) cells. Using a candidate gene approach, we detected distinct responses of individual ALL cases to RNA interference with stromal targets. The strongest effects were observed when interfering with solute carrier family 3 member 2 (SLC3A2) expression, which forms the cystine transporter xc− when associated with SLC7A11. Import of cystine and metabolism to cysteine by stromal cells provides the limiting substrate to generate and maintain glutathione in ALL. This metabolic interaction reduces oxidative stress in ALL cells that depend on stromal xc−. Indeed, cysteine depletion using cysteine dioxygenase resulted in leukemia cell death. Thus, functional evaluation of intercellular interactions between leukemia cells and their microenvironment identifies a selective dependency of ALL cells on stromal metabolism for a relevant subgroup of cases, providing new opportunities to develop more personalized approaches to leukemia treatment. PMID:25415224

Successful Single-Lung Transplant for Severe Lung Graft-Versus-Host Disease Two Years After Sibling Allograft for Acute Lymphoblastic Leukemia: A Case Report.

PubMed

Irhimeh, M R; Musk, M; Cooney, J P

2016-11-01

Bone marrow transplantation (BMT) has been performed as a successful life-saving treatment for hematological and neoplastic diseases. Despite the predictable long-term survival rates in BMT, pulmonary complications reduce the survival rates significantly mainly because of chronic graft-versus-host disease (GVHD). This report briefly discusses a successful lung transplantation case for severe lung GVHD after allograft for acute lymphoblastic leukemia. This case report supports the scarce evidence in the literature for the importance of lung transplantation as a therapeutic option for patients who develop respiratory failure secondary to BMT. Copyright © 2016. Published by Elsevier Inc.

Severe neurotoxicity following intrathecal methotrexate with nitrous oxide sedation in a child with acute lymphoblastic leukemia.

PubMed

Löbel, U; Trah, J; Escherich, G

2015-03-01

Systemic and intrathecal methotrexate is widely used in treatment protocols for childhood acute lymphoblastic leukemia. Its side effects vary in characteristics, intensity and time of onset, and depend on the administration route. Interactions with several drugs are known. Side effects of nitrous oxide sedation, often used for moderately painful procedures, typically occur after long time use and include neurological symptoms. We present a child who experienced a severe and long-lasting neurotoxicity after the third intrathecal application of methotrexate with short sedation by nitrous oxide during induction therapy for acute lymphoblastic leukemia. Symptoms completely resolved after 12 months. © 2014 Wiley Periodicals, Inc.

Childhood lymphoblastic leukemia adverse drug reactions: study of risk factors and therapy prognosis by optical methods

NASA Astrophysics Data System (ADS)

Zyubin, A.; Lavrova, A.; Babak, S.; Malaschenko, V.; Borisova, A.; Opryshko, N.

2016-10-01

The treatment of acute lymphoblastic leukemia (ALL) can result in the side-effects such as kidney affection, hepatic failure and tissue hypoxia. We study dynamics of special biochemical marker of these pathologies - adenosine triphosphate, that is well-known substance of energy metabolism. We use methods of confocal microscopy for determining the cellular and mitochondrial concentration of adenosine triphosphate (ATP). Quantitative values of adenosine triphosphate were calculated for each patient and correlation with degree of side-effects had been done. The application of confocal microscopy for studying of side-effects and therapy of lymphoblastic leukemia is discussed.

Loss of p19Arf in a Rag1−/− B-cell precursor population initiates acute B-lymphoblastic leukemia

PubMed Central

Hauer, Julia; Mullighan, Charles; Morillon, Estelle; Wang, Gary; Bruneau, Julie; Brousse, Nicole; Lelorc'h, Marc; Romana, Serge; Boudil, Amine; Tiedau, Daniela; Kracker, Sven; Bushmann, Frederic D.; Borkhardt, Arndt; Fischer, Alain; Hacein-Bey-Abina, Salima

2011-01-01

In human B-acute lymphoblastic leukemia (B-ALL), RAG1-induced genomic alterations are important for disease progression. However, given that biallelic loss of the RAG1 locus is observed in a subset of cases, RAG1's role in the development of B-ALL remains unclear. We chose a p19Arf−/−Rag1−/− mouse model to confirm the previously published results concerning the contribution of CDKN2A (p19ARF /INK4a) and RAG1 copy number alterations in precursor B cells to the initiation and/or progression to B-acute lymphoblastic leukemia (B-ALL). In this murine model, we identified a new, Rag1-independent leukemia-initiating mechanism originating from a Sca1+CD19+ precursor cell population and showed that Notch1 expression accelerates the cells' self-renewal capacity in vitro. In human RAG1-deficient BM, a similar CD34+CD19+ population expressed p19ARF. These findings suggest that combined loss of p19Arf and Rag1 results in B-cell precursor leukemia in mice and may contribute to the progression of precursor B-ALL in humans. PMID:21622646

Clinical updates in adult acute lymphoblastic leukemia.

PubMed

Al Ustwani, Omar; Gupta, Neha; Bakhribah, Hatoon; Griffiths, Elizabeth; Wang, Eunice; Wetzler, Meir

2016-03-01

Acute lymphoblastic leukemia (ALL) is a clonal disease characterized by B or T lineage. Here we cover the clinical manifestations, pathophysiology and therapy for ALL. Additionally, we will discuss the evidence for minimal residual disease assessment, novel molecular targets and newly developed targeted therapies. The separation of ALL into Philadelphia chromosome positive and recently into Philadelphia-like disease represents the most exciting developments in this disease. Finally, the advent of new immunotherapeutic approaches led us to predict that in few years, ALL therapy might be based heavily on non-chemotherapeutic approaches. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

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

PubMed Central

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

2014-01-01

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

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

PubMed

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

2014-01-01

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

Family Characteristics as Risk Factors for Childhood Acute Lymphoblastic Leukemia: A Population-Based Case-Control Study

PubMed Central

Zwahlen, Marcel; Brazzola, Pierluigi; Niggli, Felix; Kuehni, Claudia

2010-01-01

Background To date, few risk factors for childhood acute lymphoblastic leukemia (ALL) have been confirmed and the scientific literature is full of controversial “evidence.” We examined if family characteristics, particularly maternal and paternal age and number of older siblings, were risk factors for childhood acute lymphoblastic leukemia (ALL). Methodology/Principal Findings In this population-based nationwide matched case-control study, patients 0–14 years of age with ALL diagnosed 1991–2006 and registered in the Swiss Childhood Cancer Registry were linked with their census records of 1990 and 2000. Eight controls per case were selected from the census. The association between family characteristics and ALL was analyzed by conditional logistic regressions. We found that increasing maternal age was associated with incidence of ALL in the offspring (OR per 5-year increase in maternal age 1.18, 95% CI 1.05–1.31; p = 0.004), remaining stable (trend OR 1.14, 95% CI 0.99–1.31; p = 0.060) after adjustment for other risk factors. The association with paternal age was weaker (OR per 5-year increase 1.14, 95% CI 1.01–1.28, p = 0.032) and disappeared after adjustments. Number of older siblings was not associated with risk of ALL in the overall group of children aged 0–14 years at diagnosis. However, we found a negative trend between number of older siblings and ALL diagnosed at age 0–4 years (OR per sibling 0.85, 95% CI 0.68–1.06; p = 0.141) and a positive trend for ALL diagnosed at age 5–9 (OR 1.34, 95% CI 1.05–1.72; p = 0.019), with some evidence for an effect modification (p-value for interaction  = 0.040). Conclusions As in other studies, increasing maternal, but not paternal age was associated with risk of ALL. We found only a weak association with the number of older siblings, suggesting a delay in disease manifestation rather than a decrease in incidence. PMID:20957179

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

PubMed

Alter, D; Mark, H F

2000-10-01

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

High incidence of symptomatic hyperammonemia in children with acute lymphoblastic leukemia receiving pegylated asparaginase.

PubMed

Heitink-Pollé, Katja M J; Prinsen, Berthil H C M T; de Koning, Tom J; van Hasselt, Peter M; Bierings, Marc B

2013-01-01

Asparaginase is a mainstay of treatment of childhood acute lymphoblastic leukemia. Pegylation of asparaginase extends its biological half-life and has been introduced in the newest treatment protocols aiming to further increase treatment success. Hyperammonemia is a recognized side effect of asparaginase treatment, but little is known about its incidence and clinical relevance. Alerted by a patient with severe hyperammonemia after introduction of the new acute lymphoblastic leukemia protocol, we analyzed blood samples and clinical data of eight consecutive patients receiving pegylated asparaginase (PEG-asparaginase) during their treatment of acute lymphoblastic leukemia. All patients showed hyperammonemia (>50 μmol/L) and seven patients (88 %) showed ammonia concentrations > 100 μmol/L. Maximum ammonia concentrations ranged from 89 to 400 μmol/L. Symptoms varied from mild anorexia and nausea to headache, vomiting, dizziness, and lethargy and led to early interruption of PEG-asparaginase in three patients. No evidence of urea cycle malfunction was found, so overproduction of ammonia through hydrolysis of plasma asparagine and glutamine seems to be the main cause. Interestingly, ammonia concentrations correlated with triglyceride values (r = 0.68, p < 0.0001), suggesting increased overall toxicity.The prolonged half-life of PEG-asparaginase may be responsible for the high incidence of hyperammonemia and warrants future studies to define optimal dosing schedules based on ammonia concentrations and individual asparagine and asparaginase measurements.

Cerebral venous thrombosis in adult patients with acute lymphoblastic leukemia or lymphoblastic lymphoma during induction chemotherapy with l-asparaginase: The GRAALL experience.

PubMed

Couturier, Marie-Anne; Huguet, Françoise; Chevallier, Patrice; Suarez, Felipe; Thomas, Xavier; Escoffre-Barbe, Martine; Cacheux, Victoria; Pignon, Jean-Michel; Bonmati, Caroline; Sanhes, Laurence; Bories, Pierre; Daguindau, Etienne; Dorvaux, Véronique; Reman, Oumedaly; Frayfer, Jamile; Orvain, Corentin; Lhéritier, Véronique; Ifrah, Norbert; Dombret, Hervé; Hunault-Berger, Mathilde; Tanguy-Schmidt, Aline

2015-11-01

Central nervous system (CNS) thrombotic events are a well-known complication of acute lymphoblastic leukemia (ALL) induction therapy, especially with treatments including l-asparaginase (l-ASP). Data on risk factors and clinical evolution is still lacking in adult patients. We report on the clinical evolution of 22 CNS venous thrombosis cases occurring in 708 adults treated for ALL or lymphoblastic lymphoma (LL) with the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL)-induction protocol, which included eight L-ASP (6,000 IU/m(2) ) infusions. The prevalence of CNS thrombosis was 3.1%. CNS thrombosis occurred after a median of 18 days (range: 11-31) when patients had received a median of three l-ASP injections (range: 2-7). Patients with CNS thrombosis exhibited a median antithrombin (AT) nadir of 47.5% (range: 36-67%) at Day 17 (range: D3-D28), and 95% of them exhibited AT levels lower than 60%. There were no evident increase in hereditary thrombotic risk factors prevalence, and thrombosis occurred despite heparin prophylaxis which was performed in 90% of patients. Acquired AT deficiency was frequently detected in patients with l-ASP-based therapy, and patients with CNS thrombosis received AT prophylaxis (45%) less frequently than patients without CNS thrombosis (83%), P = 0.0002). CNS thrombosis was lethal in 5% of patients, while 20% had persistent sequelae. One patient received all planned l-ASP infusions without recurrence of CNS thrombotic whereas l-ASP injections were discontinued in 20 patients during the management of thrombosis without a significant impact on overall survival (P = 0.4). © 2015 Wiley Periodicals, Inc.

D-lactic acidosis mediated neuronal encephalopathy in acute lymphoblastic leukemia patient: an under diagnosis.

PubMed

Mendu, Damodara Rao; Fleisher, Martin; McCash, Samuel I; Pessin, Melissa S; Ramanathan, Lakshmi V

2015-02-20

D-lactic acidosis, also referred as D-lactate encephalopathy, has been reported in patients with short bowl syndrome (SBS). The neurologic symptoms include altered mental status, slurred speech, and ataxia. Onset of neurological symptoms is accompanied by metabolic acidosis and high anion gap. We present here a case of D-lactic acidosis in a patient with acute lymphoblastic leukemia (ALL) who developed severe neurological symptoms and metabolic acidosis due to vancomycin-resistant enterococci (VRE) infection, and elevated D-lactic acid. Copyright © 2014 Elsevier B.V. All rights reserved.

Gene expression overlap affects karyotype prediction in pediatric acute lymphoblastic leukemia

DOE PAGES

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

2007-04-05

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

Association between the methylenetetrahydrofolate reductase polymorphisms and risk of acute lymphoblastic leukemia in Serbian children.

PubMed

Damnjanovic, Tatjana; Milicevic, Radomir; Novkovic, Tanja; Jovicic, Olivera; Bunjevacki, Vera; Jekic, Biljana; Lukovic, Ljiljana; Novakovic, Ivana; Redzic, Danka; Milasin, Jelena

2010-05-01

Methylenetetrahydrofolate reductase (MTHFR) regulates the metabolism of folate and methionine, essential components of DNA synthesis and methylation. Polymorphisms in the MTHFR gene have been associated with susceptibility to some types of cancer. We investigated a possible association of MTHFR polymorphisms (677C>T and 1298A>C) and increased risk for acute lymphoblastic leukemia in 78 affected children. The frequencies of both MTHFR 677 genotypes and alleles were significantly different between patients and controls. A significant association between CT/TT individuals and reduced risk of acute lymphoblastic leukemia was found. The odds ratios were 0.53 (95% confidence interval, 032-0.89) and 0.30 (95% confidence interval, 0.12-0.81). Polymorphism 1298 did not show statistical difference between patients and controls.

Recent advances in acute lymphoblastic leukemia in children and adolescents: an expert panel discussion.

PubMed

Asselin, Barbara L; Gaynon, Paul; Whitlock, James A

2013-12-01

Acute lymphoblastic leukemia (ALL) is the most common form of childhood leukemia, representing 75% to 80% of cases of acute leukemia among children. Dramatic improvements in the cure rates and survival outcomes for children with ALL have been seen over the past several decades; currently the 5-year survival rate for childhood ALL is more than 80%. These improvements have come about because of advances in the understanding of the molecular genetics and pathogenesis of the disease, incorporation of risk-adapted therapy, and the advent of new targeted agents. Scientific advances have provided new insights into leukemogenesis, drug resistance, and host pharmacogenomics, identified novel subtypes of leukemia, and suggested potential targets for therapy. At the same time novel monoclonal antibodies, small molecule inhibitors, chemotherapeutics, and cell-based treatment strategies have been developed and investigated. In this article, experts will discuss some of the current challenges and future directions in the treatment of pediatric ALL. The authors will offer expert guidance to practicing oncologists on how to best incorporate newer treatment approaches into the care of children and adolescents with ALL. The most important ongoing clinical trials in the area will also be reviewed.

Oral Microbiota Distinguishes Acute Lymphoblastic Leukemia Pediatric Hosts from Healthy Populations

PubMed Central

Zhou, Xuedong; You, Meng; Du, Qin; Yang, Xue; He, Jingzhi; Zou, Jing; Cheng, Lei; Li, Mingyun; Li, Yuqing; Zhu, Yiping; Li, Jiyao; Shi, Wenyuan; Xu, Xin

2014-01-01

In leukemia, oral manifestations indicate aberrations in oral microbiota. Microbiota structure is determined by both host and environmental factors. In human hosts, how health status shapes the composition of oral microbiota is largely unknown. Taking advantage of advances in high-throughput sequencing, we compared the composition of supragingival plaque microbiota of acute lymphoblastic leukemia (ALL) pediatric patients with healthy controls. The oral microbiota of leukemia patients had lower richness and less diversity compared to healthy controls. Microbial samples clustered into two major groups, one of ALL patients and another of healthy children, with different structure and composition. Abundance changes of certain taxa including the Phylum Firmicutes, the Class Bacilli, the Order Lactobacillales, the Family Aerococcaceae and Carnobacteriaceae, as well as the Genus Abiotrophia and Granulicatella were associated with leukemia status. ALL patients demonstrated a structural imbalance of the oral microbiota, characterized by reduced diversity and abundance alterations, possibly involved in systemic infections, indicating the importance of immune status in shaping the structure of oral microbiota. PMID:25025462

Mutation of the NPM1 gene contributes to the development of donor cell-derived acute myeloid leukemia after unrelated cord blood transplantation for acute lymphoblastic leukemia.

PubMed

Rodríguez-Macías, Gabriela; Martínez-Laperche, Carolina; Gayoso, Jorge; Noriega, Víctor; Serrano, David; Balsalobre, Pascual; Muñoz-Martínez, Cristina; Díez-Martín, José L; Buño, Ismael

2013-08-01

Donor cell leukemia (DCL) is a rare but severe complication after allogeneic stem cell transplantation. Its true incidence is unknown because of a lack of correct recognition and reporting, although improvements in molecular analysis of donor-host chimerism are contributing to a better diagnosis of this complication. The mechanisms of leukemogenesis are unclear, and multiple factors can contribute to the development of DCL. In recent years, cord blood has emerged as an alternative source of hematopoietic progenitor cells, and at least 12 cases of DCL have been reported after unrelated cord blood transplantation. We report a new case of DCL after unrelated cord blood transplantation in a 44-year-old woman diagnosed as having acute lymphoblastic leukemia with t(1;19) that developed acute myeloid leukemia with normal karyotype and nucleophosmin (NPM1) mutation in donor cells. To our knowledge, this is the first report of NPM1 mutation contributing to DCL development. Copyright © 2013 Elsevier Inc. All rights reserved.

Avascular necrosis of the femoral head in children with acute lymphoblastic leukemia: a 4- to 9-year follow-up study.

PubMed

Madadi, Firooz; Shamsian, Bibi Shahin; Alavi, Samin; Madadi, Firoozeh; Eajazi, Alireza; Aslani, Afshin

2011-10-05

Avascular necrosis of the femoral head is usually seen in children aged 1.5 to 10 years, reaching a peak incidence between the ages of 4 and 9. Avascular necrosis of the femoral head is a known complication of corticosteroid therapy in acute lymphoblastic leukemia. There are few reports in the literature regarding the natural history of this condition, and there is no consensus on its management. This study examined the natural history of avascular necrosis of the femoral head in children with leukemia. From 1993 to 2006, a total of 865 children with acute lymphoblastic leukemia were admitted to the hematology-oncology ward of a children's hospital. The diagnosis of acute lymphoblastic leukemia was established by bone marrow aspiration. Based on clinical and radiographic findings, avascular necrosis of the femoral head was found in 7 patients; these patients underwent follow-up for 4 to 9 years. Avascular necrosis of the femoral head was clinically symptomatic in all of the children, and they had advanced radiographic collapse of the femoral head. However, the head of the femur was not at risk in any patient based on clinical and radiographic findings. Patients received supportive treatment such as abduction brace and physiotherapy. After 4 to 9 years of follow-up, clinical and radiographic results were satisfactory. Provided that the head of the femur is not at risk, avascular necrosis of the femoral head in children with acute lymphoblastic leukemia may be successfully managed with nonoperative care. Copyright 2011, SLACK Incorporated.

T-lymphoblastic leukemia/lymphoma in macedonian patients with Nijmegen breakage syndrome.

PubMed

Kocheva, S A; Martinova, K; Antevska-Trajkova, Z; Coneska-Jovanova, B; Eftimov, A; Dimovski, A J

2016-07-01

Nijmegen breakage syndrome (NBS) is a rare autosomal recessive chromosomal instability disorder characterized by microcephaly, immunodeficiency, radiosensitivity and a very high predisposition to malignancy. The gene responsible for the disease, NBS1 , is located on chromosome 8q21 and encodes a protein called nibrin. After identification of the gene, a truncating 5 bp deletion, 657-661delACAAA, was identified as the disease-causing mutation in patients with the NBS. In this report, we describe two patients with NBS and T-lymphoblastic leukemia/lymphoma in a Macedonian family. To the best of our knowledge, this is the first family with NBS reported from Macedonia. Both children presented with microcephaly, syndactyly and the development of T cell lymphoblastic lekemia/lymphoma at the age of 7 and 10 years, respectively. The molecular analysis of NBS1 genes in our patients showed homozygosity for the 657del5 mutation in the NBS1 gene. The parents were heterozygotes for the 657del5 mutation and they had no knowledge of a consanguineous relationship. The first child was treated with the International Berlin-Frankfurt-Münster (BFM)-Non Hodgkin lymphoma (NHL) protocol and achieved a complete remission that lasted for 21 months. Subsequently, he developed a medullar relapse with hyperleukocytosis and died due to lethal central nervous system (CNS) complications. The second child was treated according to the International Collaborative Treatment Protocol for Children and Adolescents with Acute Lymphoblastic Leukemia 2009 (AIOP-BFM ALL 2009) protocol. Unfortunately, remission was not achieved.

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

PubMed

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

2016-11-01

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

Cytomegalovirus retinitis diagnosed after completion of chemotherapy for acute lymphoblastic leukemia in an adolescent.

PubMed

Han, Seung Beom; Lee, Jin Hee; Lee, Jae Wook; Chung, Nack-Gyun; Cho, Bin; Kang, Jin Han; Kim, Hack-Ki; Lee, Jin Hae; Lee, Won Ki

2015-03-01

Although cytomegalovirus (CMV) retinitis is usually diagnosed in allogeneic hematopoietic cell transplantation recipients among patients with hematologic and oncologic disease, it can also occur in acute leukemia patients who have not received hematopoietic cell transplantation. However, CMV retinitis diagnosed after completion of chemotherapy for acute leukemia has not previously been reported. A 17-year-old boy was diagnosed with CMV retinitis 3 months after completion of chemotherapy for acute lymphoblastic leukemia, and his retinitis was assumed to be caused by a delayed immune reconstitution after chemotherapy. The patient was treated with intravenous and intravitreous ganciclovir therapy, and subsequently underwent surgery for retinal detachment.

[Acute lymphoblastic leukemia: a genomic perspective].

PubMed

Jiménez-Morales, Silvia; Hidalgo-Miranda, Alfredo; Ramírez-Bello, Julián

In parallel to the human genome sequencing project, several technological platforms have been developed that let us gain insight into the genome structure of human entities, as well as evaluate their usefulness in the clinical approach of the patient. Thus, in acute lymphoblastic leukemia (ALL), the most common pediatric malignancy, genomic tools promise to be useful to detect patients at high risk of relapse, either at diagnosis or during treatment (minimal residual disease), and they also increase the possibility to identify cases at risk of adverse reactions to chemotherapy. Therefore, the physician could offer patient-tailored therapeutic schemes. A clear example of the useful genomic tools is the identification of single nucleotide polymorphisms (SNPs) in the thiopurine methyl transferase (TPMT) gene, where the presence of two null alleles (homozygous or compound heterozygous) indicates the need to reduce the dose of mercaptopurine by up to 90% to avoid toxic effects which could lead to the death of the patient. In this review, we provide an overview of the genomic perspective of ALL, describing some strategies that contribute to the identification of biomarkers with potential clinical application. Copyright © 2017 Hospital Infantil de México Federico Gómez. Publicado por Masson Doyma México S.A. All rights reserved.

Aberrant Signaling Pathways in T-Cell Acute Lymphoblastic Leukemia

PubMed Central

Bongiovanni, Deborah; Saccomani, Valentina

2017-01-01

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

Postinduction minimal residual disease monitoring by polymerase chain reaction in children with acute lymphoblastic leukemia.

PubMed

Paganin, Maddalena; Fabbri, Giulia; Conter, Valentino; Barisone, Elena; Polato, Katia; Cazzaniga, Giovanni; Giraldi, Eugenia; Fagioli, Franca; Aricò, Maurizio; Valsecchi, Maria Grazia; Basso, Giuseppe

2014-11-01

Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer. Monitoring minimal residual disease (MRD) by using real-time quantitative polymerase chain reaction (RQ-PCR) provides information for patient stratification and individual risk-directed treatment. Cooperative studies have documented that measurement of blast clearance from the bone marrow during and after induction therapy identifies patient populations with different risk of relapse. We explored the possible contribution of measurements of MRD during the course of treatment. We used RQ-PCR to detect MRD in 110 unselected patients treated in Italy in the International Collaborative Treatment Protocol for Children and Adolescents With Acute Lymphoblastic Leukemia (AIEOP-BFM ALL 2000). The trial took place in AIEOP centers during postinduction chemotherapy. Results were categorized as negative, low positive (below the quantitative range [< 5 × 10(-4)]), or high positive (≥ 5 × 10(-4)). Patients with at least one low-positive or high-positive result were assigned to the corresponding subgroup. Patients who tested high positive, low positive, or negative had significantly different cumulative incidences of leukemia relapse: 83.3%, 34.8%, and 8.6%, respectively (P < .001). Two thirds of positive cases were identified within 4 months after induction-consolidation therapy, suggesting that this time frame may be most suitable for cost-effective MRD monitoring, particularly in patients who did not clear their disease at the end of consolidation. These findings provide further insights into the dynamic of MRD and the ongoing effort to define molecular relapse in childhood ALL. © 2014 by American Society of Clinical Oncology.

A reliable Raman-spectroscopy-based approach for diagnosis, classification and follow-up of B-cell acute lymphoblastic leukemia

NASA Astrophysics Data System (ADS)

Managò, Stefano; Valente, Carmen; Mirabelli, Peppino; Circolo, Diego; Basile, Filomena; Corda, Daniela; de Luca, Anna Chiara

2016-04-01

Acute lymphoblastic leukemia type B (B-ALL) is a neoplastic disorder that shows high mortality rates due to immature lymphocyte B-cell proliferation. B-ALL diagnosis requires identification and classification of the leukemia cells. Here, we demonstrate the use of Raman spectroscopy to discriminate normal lymphocytic B-cells from three different B-leukemia transformed cell lines (i.e., RS4;11, REH, MN60 cells) based on their biochemical features. In combination with immunofluorescence and Western blotting, we show that these Raman markers reflect the relative changes in the potential biological markers from cell surface antigens, cytoplasmic proteins, and DNA content and correlate with the lymphoblastic B-cell maturation/differentiation stages. Our study demonstrates the potential of this technique for classification of B-leukemia cells into the different differentiation/maturation stages, as well as for the identification of key biochemical changes under chemotherapeutic treatments. Finally, preliminary results from clinical samples indicate high consistency of, and potential applications for, this Raman spectroscopy approach.

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

PubMed Central

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

2018-01-01

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

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

PubMed

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

2018-01-01

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

Successful Treatment of Disseminated Cryptococcal Infection in a Pediatric Acute Lymphoblastic Leukemia Patient During Induction

PubMed Central

Heath, Jessica L.; Yin, Dwight E.; Wechsler, Daniel S.; Turner, David A.

2015-01-01

Disseminated cryptococcal infection is rarely reported in the setting of pediatric acute leukemia, despite the immunocompromised state of these patients. However, when present, disseminated cryptococcal infection poses treatment challenges and is associated with significant morbidity and mortality. Treatment of invasive fungal disease in a child with acute leukemia requires a delicate balance between anti-fungal and anti-neoplastic therapy. This balance is particularly important early in the course of leukemia, since both the underlying disease and overwhelming infection can be life threatening. We describe the successful management of life-threatening disseminated cryptococcosis in a child with acute lymphoblastic leukemia during induction therapy. PMID:22258349

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

Cannabis extract treatment for terminal acute lymphoblastic leukemia with a Philadelphia chromosome mutation.

PubMed

Singh, Yadvinder; Bali, Chamandeep

2013-09-01

Acute lymphoblastic leukemia (ALL) is a cancer of the white blood cells and is typically well treated with combination chemotherapy, with a remission state after 5 years of 94% in children and 30-40% in adults. To establish how aggressive the disease is, further chromosome testing is required to determine whether the cancer is myeloblastic and involves neutrophils, eosinophils or basophils, or lymphoblastic involving B or T lymphocytes. This case study is on a 14-year-old patient diagnosed with a very aggressive form of ALL (positive for the Philadelphia chromosome mutation). A standard bone marrow transplant, aggressive chemotherapy and radiation therapy were revoked, with treatment being deemed a failure after 34 months. Without any other solutions provided by conventional approaches aside from palliation, the family administered cannabinoid extracts orally to the patient. Cannabinoid resin extract is used as an effective treatment for ALL with a positive Philadelphia chromosome mutation and indications of dose-dependent disease control. The clinical observation in this study revealed a rapid dose-dependent correlation.

Life-threatening hypophosphatemia and/or phosphate depletion in a patient with acute lymphoblastic leukemia: a rare case report.

PubMed

Soyoral, Yasemin; Aslan, Mehmet; Ebinc, Senar; Dirik, Yaren; Demir, Cengiz

2014-11-01

Acute severe hypophosphatemia can be life threatening and is associated with mortality and impaired cardiac and respiratory function. Several conditions including decreased absorption or increased urinary phosphate excretion, shifts from the extracellular to intracellular compartments, and phosphate consumption by rapidly proliferating cells are known to induce moderate to severe acute hypophosphatemia. Although hypophosphatemia and/or phosphate depletion in patients with acute or chronic myeloid leukemia have been reported in the literature, hypophosphatemia due to acute lymphoblastic leukemia (ALL) is very rare. We report a case of history of ALL complicated by life-threatening hypophosphatemia manifesting as generalized muscle weakness, fatigue, acute shortness of breath, and difficulty in standing up and walking for 3 days. Serum inorganic phosphate levels were consistently low (0.06 mmol/L). The patient was hospitalized and thought to have a relapsed ALL.Anticancer agents and oral phosphate (660 mg twice daily) were administered. On the second day of treatment, the patient began to improve, and the patient gradually fully recovered within 5 days.We suggested that this hypophosphatemia was induced by a shift of phosphorus into leukemic cells that rapidly replicated in the tissues and excessive cellular phosphate consumption by rapidly proliferating cells. Serum phosphate levels should always be monitored,especially in suspected life-threatening manifestation in relapsed ALL.

Detection of a new heterozygous germline ETV6 mutation in a case with hyperdiploid acute lymphoblastic leukemia.

PubMed

Duployez, Nicolas; Abou Chahla, Wadih; Lejeune, Sophie; Marceau-Renaut, Alice; Letizia, Guillaume; Boyer, Thomas; Geffroy, Sandrine; Peyrouze, Pauline; Grardel, Nathalie; Nelken, Brigitte; Michel, Gérard; Bertrand, Yves; Preudhomme, Claude

2018-01-01

ETV6 is a target of recurrent aberrations in sporadic and familial acute lymphoblastic leukemia (ALL). Here, we report on a new pedigree with a germline ETV6 mutation in which the index patient and his father developed high hyperdiploid (HeH) ALL and polycythemia vera at age 13 and 51, respectively. The index patient achieved durable complete remission without transplantation but had persistent moderate thrombocytopenia without bleeding tendency. To determine the prevalence of ETV6 alterations in HeH-ALL, we screened 81 unrelated subjects with HeH-ALL by single nucleotide polymorphism array and high-throughput sequencing for the ETV6 gene. Overall, ETV6 microdeletions and mutations were identified in 9% of cases, all of which were somatic and considered as secondary events. Apart from the index patient, no germline ETV6 aberration was identified. Finally, we reviewed the literature for ETV6 germline aberrations and predispositions to ALL. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

The role of methylenetetrahydrofolate reductase in acute lymphoblastic leukemia in a Brazilian mixed population.

PubMed

Zanrosso, Crisiane Wais; Hatagima, Ana; Emerenciano, Mariana; Ramos, Flávio; Figueiredo, Alexandre; Félix, Têmis Maria; Segal, Sandra L; Giugliani, Roberto; Guigliani, Roberto; Muniz, Maria Tereza Cartaxo; Pombo-de-Oliveira, Maria S

2006-04-01

The polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene are associated with leukemogenesis. In order to investigate the influence of two polymorphisms in the MTHFR gene, 677C>T and 1298A>C, on the risk of acute lymphoblastic leukemia (ALL) we performed a case-control study in children from different Brazilians' regions. Genotyping of 176 ALL and 199 unselected healthy subjects was performed using PCR-RFLP assay. There was no association between the 677C>T or 1298A>C and risk of ALL in total case-control sample. However, 677T allele was linked to a decrease risk of ALL [odds ratio (OR), 0.43; 95% confidence interval (CI), 0.22-0.86], whereas the 1298A>C polymorphism presents an elevated risk factor [OR, 2.01; 95% CI, 1.01-3.99] in non-White children. Our investigation provides interesting data concerning the opposite effect of A1298C polymorphisms, particularly in the light of relatively scarce data regarding the MTHFR role in leukemia susceptibility in different populations.

Treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia.

PubMed

Milone, Jorge H; Enrico, Alicia

2009-12-01

The presence of the Philadelphia chromosome is a poor prognosis factor in acute lymphoblastic leukemia (ALL), in both children and adults. Using molecular techniques of the gen bcr/abl, it is possible to detect the abnormality, in up to the 40% of adult patients. The unsatisfactory results with conventional chemotherapy schemes have determined the intensification of the treatments and the consideration of allogenic bone marrow transplants as the best therapeutic instance. The development of tyrosine kinase inhibitors have become a therapeutic improvement in the treatment of Philadelphia chromosome-positive ALL, being combined with chemotherapy schemes, only in a selected group of patients, even in therapeutic programs that include transplant.

Veliparib and Temozolomide in Treating Patients With Acute Leukemia

ClinicalTrials.gov

2018-04-20

Accelerated Phase of Disease; Acute Lymphoblastic Leukemia; Acute Myeloid Leukemia; Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome; Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With t(8;21); (q22; q22.1); RUNX1-RUNX1T1; Adult Acute Myeloid Leukemia With t(9;11)(p22.3;q23.3); MLLT3-KMT2A; Adult Acute Promyelocytic Leukemia With PML-RARA; Adult B Acute Lymphoblastic Leukemia; Adult B Acute Lymphoblastic Leukemia With t(9;22)(q34.1;q11.2); BCR-ABL1; Adult T Acute Lymphoblastic Leukemia; Alkylating Agent-Related Acute Myeloid Leukemia; Blastic Phase; Chronic Myelomonocytic Leukemia; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Disease; Secondary Acute Myeloid Leukemia; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Adult Acute Myeloid Leukemia

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

Prosthetic Management of Hard Palate Perforation in a Child with Acute Lymphoblastic Leukemia

PubMed Central

Chouksey, Gunjan C; Dholam, Kanchan P

2017-01-01

Palatal perforation is an uncommon complication seen in children with acute lymphoblastic leukemia undergoing chemotherapy. This may impact basic functions, such as speech, swallowing, chewing, affecting the quality of life (QOL). Prosthetic rehabilitation of the palatal perforation with obturator can optimally restore function, thereby improving and enhancing the QOL of these patients. PMID:28900336

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

PubMed Central

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

2014-01-01

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

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

PubMed

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

2010-04-01

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. 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. 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%). 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.

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

Gene polymorphisms in folate metabolizing enzymes in adult acute lymphoblastic leukemia: effects on methotrexate-related toxicity and survival

PubMed Central

Ongaro, Alessia; De Mattei, Monica; Della Porta, Matteo Giovanni; Rigolin, GianMatteo; Ambrosio, Cristina; Di Raimondo, Francesco; Pellati, Agnese; Masieri, Federica Francesca; Caruso, Angelo; Catozzi, Linda; Gemmati, Donato

2009-01-01

Background The antifolate agent methotrexate is an important component of maintenance therapy in acute lymphoblastic leukemia, although methotrexate-related toxicity is often a reason for interruption of chemotherapy. Prediction of toxicity is difficult because of inter-individual variability susceptibility to antileukemic agents. Methotrexate interferes with folate metabolism leading to depletion of reduced folates. Design and Methods The aim of this study was to investigate the influence of polymorphisms for folate metabolizing enzymes with respect to toxicity and survival in adult patients with acute lymphoblastic leukemia treated with methotrexate maintenance therapy. To this purpose, we evaluated possible associations between genotype and hematologic and non-hematologic toxicity and effects on survival at 2 years of follow-up in patients with acute lymphoblastic leukemia. Results Polymorphisms in the genes encoding for methylenetetrahydrofolate reductase (MTHFR 677C>T) and in dihydrofolate reductase (DHFR 19 bp deletion) significantly increased the risk of hepatotoxicity in single (odds ratio 5.23, 95% confidence interval 1.13–21.95 and odds ratio 4.57, 95% confidence interval 1.01–20.77, respectively) and in combined analysis (odds ratio 6.82, 95% confidence interval 1.38–33.59). MTHFR 677C>T also increased the risk of leukopenia and gastrointestinal toxicity, whilst thymidylate synthase 28 bp repeat polymorphism increased the risk of anemia (odds ratio 8.48, 95% confidence interval 2.00–36.09). Finally, patients with MTHFR 677TT had a decreased overall survival rate (hazard ratio 2.37, 95% confidence interval 1.46–8.45). Conclusions Genotyping of folate polymorphisms might be useful in adult acute lymphoblastic leukemia to optimize methotrexate therapy, reducing the associated toxicity with possible effects on survival. PMID:19648163

Pediatric acute lymphoblastic leukemia.

PubMed

Carroll, William L; Bhojwani, Deepa; Min, Dong-Joon; Raetz, Elizabeth; Relling, Mary; Davies, Stella; Downing, James R; Willman, Cheryl L; Reed, John C

2003-01-01

The outcome for children with acute lymphoblastic leukemia (ALL) has improved dramatically with current therapy resulting in an event free survival exceeding 75% for most patients. However significant challenges remain including developing better methods to predict which patients can be cured with less toxic treatment and which ones will benefit from augmented therapy. In addition, 25% of patients fail therapy and novel treatments that are focused on undermining specifically the leukemic process are needed urgently. In Section I, Dr. Carroll reviews current approaches to risk classification and proposes a system that incorporates well-established clinical parameters, genetic lesions of the blast as well as early response parameters. He then provides an overview of emerging technologies in genomics and proteomics and how they might lead to more rational, biologically based classification systems. In Section II, Drs. Mary Relling and Stella Davies describe emerging findings that relate to host features that influence outcome, the role of inherited germline variation. They highlight technical breakthroughs in assessing germline differences among patients. Polymorphisms of drug metabolizing genes have been shown to influence toxicity and the best example is the gene thiopurine methyltransferase (TPMT) a key enzyme in the metabolism of 6-mercaptopurine. Polymorphisms are associated with decreased activity that is also associated with increased toxicity. The role of polymorphisms in other genes whose products play an important role in drug metabolism as well as cytokine genes are discussed. In Sections III and IV, Drs. James Downing and Cheryl Willman review their findings using gene expression profiling to classify ALL. Both authors outline challenges in applying this methodology to analysis of clinical samples. Dr. Willman describes her laboratory's examination of infant leukemia and precursor B-ALL where unsupervised approaches have led to the identification of

Fetal Growth and Childhood Acute Lymphoblastic Leukemia: Findings from the Childhood Leukemia International Consortium (CLIC)

PubMed Central

Milne, Elizabeth; Greenop, Kathryn R.; Metayer, Catherine; Schüz, Joachim; Petridou, Eleni; Pombo-de-Oliveira, Maria S.; Infante-Rivard, Claire; Roman, Eve; Dockerty, John D.; Spector, Logan G.; Koifman, Sérgio; Orsi, Laurent; Rudant, Jérémie; Dessypris, Nick; Simpson, Jill; Lightfoot, Tracy; Kaatsch, Peter; Baka, Margarita; Faro, Alessandra; Armstrong, Bruce K.; Clavel, Jacqueline; Buffler, Patricia A.

2013-01-01

Positive associations have been reported between measures of accelerated fetal growth and risk of childhood acute lymphoblastic leukemia (ALL). We investigated this association by pooling individual-level data from 12 case-control studies participating in the Childhood Leukemia International Consortium. Two measures of fetal growth – weight-for-gestational-age and proportion of optimal birth weight (POBW) – were analysed. Study-specific odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression, and combined in fixed effects meta-analyses. Pooled analyses of all data were also undertaken using multivariable logistic regression. Subgroup analyses were undertaken when possible. Data on weight for gestational age were available for 7,348 cases and 12,489 controls from all 12 studies and POBW data were available for 1,680 cases and 3,139 controls from three studies. The summary ORs from the meta-analyses were 1.24 (95% CI 1.13, 1.36) for children who were large for gestational age relative to appropriate for gestational age, and 1.16 (95% CI: 1.09, 1.24) for a one standard deviation increase in POBW. The pooled analyses produced similar results. The summary and pooled ORs for small-for-gestational-age children were 0.83 (95% CI: 0.75, 0.92) and 0.86 (95% CI 0.77, 0.95) respectively. Results were consistent across subgroups defined by sex, ethnicity and immunophenotype, and when the analysis was restricted to children who did not have high birth weight. The evidence that accelerated fetal growth is associated with a modest increased risk of childhood ALL is strong and consistent with known biological mechanisms involving insulin like growth factors. PMID:23754574

International reference analysis of outcomes in adults with B-precursor Ph-negative relapsed/refractory acute lymphoblastic leukemia

PubMed Central

Gökbuget, Nicola; Dombret, Hervè; Ribera, Jose-Maria; Fielding, Adele K.; Advani, Anjali; Bassan, Renato; Chia, Victoria; Doubek, Michael; Giebel, Sebastian; Hoelzer, Dieter; Ifrah, Norbert; Katz, Aaron; Kelsh, Michael; Martinelli, Giovanni; Morgades, Mireia; O’Brien, Susan; Rowe, Jacob M.; Stieglmaier, Julia; Wadleigh, Martha; Kantarjian, Hagop

2016-01-01

Adults with relapsed/refractory acute lymphoblastic leukemia have an unfavourable prognosis, which is influenced by disease and patient characteristics. To further evaluate these characteristics, a retrospective analysis of 1,706 adult patients with Ph-negative relapsed/refractory B-precursor acute lymphoblastic leukemia diagnosed between 1990–2013 was conducted using data reflecting the standard of care from 11 study groups and large centers in Europe and the United States. Outcomes included complete remission, overall survival, and realization of stem cell transplantation after salvage treatment. The overall complete remission rate after first salvage was 40%, ranging from 35%–41% across disease status categories (primary refractory, relapsed with or without prior transplant), and was lower after second (21%) and third or greater (11%) salvage. The overall complete remission rate was higher for patients diagnosed from 2005 onward (45%, 95% CI: 39%–50%). One- and three-year survival rates after first, second, and third or greater salvage were 26% and 11%, 18% and 6%, and 15% and 4%, respectively, and rates were 2%–5% higher among patients diagnosed from 2005. Prognostic factors included younger age, longer duration of first remission, and lower white blood cell counts at primary diagnosis. This large dataset can provide detailed reference outcomes for patients with relapsed/refractory Ph-negative B-precursor acute lymphoblastic leukemia. clinicaltrials.gov identifier: 02003612 PMID:27587380

Childhood Acute Lymphoblastic Leukemia: Integrating Genomics into Therapy

PubMed Central

Tasian, Sarah K; Loh, Mignon L; Hunger, Stephen P

2015-01-01

Acute lymphoblastic leukemia (ALL), the most common malignancy of childhood, is a genetically complex entity that remains a major cause of childhood cancer-related mortality. Major advances in genomic and epigenomic profiling during the past decade have appreciably enhanced knowledge of the biology of de novo and relapsed ALL and have facilitated more precise risk stratification of patients. These achievements have also provided critical insights regarding potentially targetable lesions for development of new therapeutic approaches in the era of precision medicine. This review delineates the current genetic landscape of childhood ALL with emphasis upon patient outcomes with contemporary treatment regimens, as well as therapeutic implications of newly identified genomic alterations in specific subsets of ALL. PMID:26194091

Acute lymphoblastic leukemia in adolescents and young adults.

PubMed

Ribera, Josep-Maria; Oriol, Albert

2009-10-01

Today, long-term survival is achieved in more than 80% of children 1 to 10 years old with acute lymphoblastic leukemia (ALL). However, cure rates for adults and adolescents and young adults (AYA) with ALL remain relatively low, at only 40% to 50%. Age is a continuous prognostic variable in ALL, with no single age at which prognosis deteriorates markedly. Within childhood ALL populations, older children have shown inferior outcomes, whereas younger adults have shown superior outcomes among adult ALL patients. The type of treatment (pediatric-based versus adult-based) for AYA has recently been a matter of debate. In this article the biology and treatment of ALL in AYA is reviewed.

Advances in adult acute lymphoblastic leukemia therapy.

PubMed

Aldoss, Ibrahim; Stein, Anthony S

2018-05-01

Progress in adult acute lymphoblastic leukemia (ALL) treatment has been met with challenge until recently. A steady improvement in outcomes is being witnessed among adults with ALL, and it will be enhanced further with early referral of newly diagnosed ALL patients to specialized centers, enrolling more ALL adults in clinical trials, adopting pediatric-inspired ALL regimens in younger adults, tailoring treatments according to minimal residual disease response and disease genetics, incorporating novel therapies and tyrosine kinase inhibitors in frontline regimens, early referral to transplant when indicated, expanding the donor pool, and developing more effective salvage therapies for relapsed/refractory ALL. In this review, we will discuss the most significant advances in treating adult ALL observed in the last five years that have the potential to enhance adult ALL treatment and outcome.

MLL duplication in a pediatric patient with B-cell lymphoblastic lymphoma.

PubMed

Mater, David Van; Goodman, Barbara K; Wang, Endi; Gaca, Ana M; Wechsler, Daniel S

2012-04-01

Lymphoblastic lymphoma is the second most common type of non-Hodgkin lymphoma seen in children. Approximately, 90% of lymphoblastic lymphomas arise from T cells, with the remaining 10% being B-cell-lineage derived. Although T-cell lymphoblastic lymphoma most frequently occurs in the anterior mediastinum (thymus), B-cell lymphoblastic lymphoma (B-LBL) predominates in extranodal sites such as skin and bone. Here, we describe a pediatric B-LBL patient who presented with extensive abdominal involvement and whose lymphoma cells displayed segmental duplication of the mixed lineage leukemia (MLL) gene. MLL duplication/amplification has been described primarily in acute myeloid leukemia and myelodysplastic syndrome with no published reports of discrete MLL duplication/amplification events in B-LBL. The MLL gene duplication noted in this case may represent a novel mechanism for tumorigenesis in B-LBL.

The molecular genetic makeup of acute lymphoblastic leukemia | Office of Cancer Genomics

Cancer.gov

Abstract: Genomic profiling has transformed our understanding of the genetic basis of acute lymphoblastic leukemia (ALL). Recent years have seen a shift from microarray analysis and candidate gene sequencing to next-generation sequencing. Together, these approaches have shown that many ALL subtypes are characterized by constellations of structural rearrangements, submicroscopic DNA copy number alterations, and sequence mutations, several of which have clear implications for risk stratification and targeted therapeutic intervention.

A disseminated infection with the antifungal-multiresistant teleomorphic fungus Neocosmospora vasinfecta in a patient with acute B-lymphoblastic leukemia.

PubMed

Gabriel, Frédéric; D'Almeida, Mahussi; Albert, Olivier; Fitton-Ouhabi, Valérie; Noël, Thierry; Accoceberry, Isabelle

2013-02-09

We report on a fatal invasive infection due to the ascomycetous fungus Neocosmospora vasinfecta, in a 20-year-old European patient suffering from an acute lymphoblastic leukemia. The infection could not be controlled by a bitherapy combining liposomal amphotericin B and voriconazole. This is the second case of disseminated infection reported with this unusual fungus, which develops under its teleomorphic state, is fully resistant to all systemic antifungals, and which is known to live in tropical countries.

A disseminated infection with the antifungal-multiresistant teleomorphic fungus Neocosmospora vasinfecta in a patient with acute B-lymphoblastic leukemia

PubMed Central

Gabriel, Frédéric; D’Almeida, Mahussi; Albert, Olivier; Fitton-Ouhabi, Valérie; Noël, Thierry; Accoceberry, Isabelle

2013-01-01

We report on a fatal invasive infection due to the ascomycetous fungus Neocosmospora vasinfecta, in a 20-year-old European patient suffering from an acute lymphoblastic leukemia. The infection could not be controlled by a bitherapy combining liposomal amphotericin B and voriconazole. This is the second case of disseminated infection reported with this unusual fungus, which develops under its teleomorphic state, is fully resistant to all systemic antifungals, and which is known to live in tropical countries. PMID:24432214

Diet-induced obesity accelerates acute lymphoblastic leukemia progression in two murine models.

PubMed

Yun, Jason P; Behan, James W; Heisterkamp, Nora; Butturini, Anna; Klemm, Lars; Ji, Lingyun; Groffen, John; Müschen, Markus; Mittelman, Steven D

2010-10-01

Obesity is associated with an increased incidence of many cancers, including leukemia, although it is unknown whether leukemia incidence is increased directly by obesity or rather by associated genetic, lifestyle, health, or socioeconomic factors. We developed animal models of obesity and leukemia to test whether obesity could directly accelerate acute lymphoblastic leukemia (ALL) using BCR/ABL transgenic and AKR/J mice weaned onto a high-fat diet. Mice were observed until development of progressive ALL. Although obese and control BCR/ABL mice had similar median survival, older obese mice had accelerated ALL onset, implying a time-dependent effect of obesity on ALL. Obese AKR mice developed ALL significantly earlier than controls. The effect of obesity was not explained by WBC count, thymus/spleen weight, or ALL phenotype. However, obese AKR mice had higher leptin, insulin, and interleukin-6 levels than controls, and these obesity-related hormones all have potential roles in leukemia pathogenesis. In conclusion, obesity directly accelerates presentation of ALL, likely by increasing the risk of an early event in leukemogenesis. This is the first study to show that obesity can directly accelerate the progression of ALL. Thus, the observed associations between obesity and leukemia incidence are likely to be directly related to biological effects of obesity. ©2010 AACR.

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

PubMed

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

2017-02-01

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

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

Cancer.gov

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

Dexamethasone exposure and asparaginase antibodies affect relapse risk in acute lymphoblastic leukemia

PubMed Central

Kawedia, Jitesh D.; Liu, Chengcheng; Pei, Deqing; Cheng, Cheng; Fernandez, Christian A.; Howard, Scott C.; Campana, Dario; Panetta, John C.; Bowman, W. Paul; Evans, William E.; Pui, Ching-Hon

2012-01-01

We have previously hypothesized that higher systemic exposure to asparaginase may cause increased exposure to dexamethasone, both critical chemotherapeutic agents for acute lymphoblastic leukemia. Whether interpatient pharmaco-kinetic differences in dexamethasone contribute to relapse risk has never been studied. The impact of plasma clearance of dexamethasone and anti–asparaginase antibody levels on risk of relapse was assessed in 410 children who were treated on a front-line clinical trial for acute lymphoblastic leukemia and were evaluable for all pharmacologic measures, using multivariate analyses, adjusting for standard clinical and biologic prognostic factors. Dexamethasone clearance (mean ± SD) was higher (P = 3 × 10−8) in patients whose sera was positive (17.7 ± 18.6 L/h per m2) versus nega-tive (10.6 ± 5.99 L/h per m2) for anti–asparaginase antibodies. In multivariate analyses, higher dexamethasone clearance was associated with a higher risk of any relapse (P = .01) and of central nervous system relapse (P = .014). Central nervous system relapse was also more common in patients with anti–asparaginase antibodies (P = .019). In conclusion, systemic clearance of dexamethasone is higher in patients with anti–asparaginase antibodies. Lower exposure to both drugs was associated with an increased risk of relapse. PMID:22117041

Fungal discitis due to Aspergillus terreus in a patient with acute lymphoblastic leukemia.

PubMed Central

Park, K. U.; Lee, H. S.; Kim, C. J.; Kim, E. C.

2000-01-01

We report a case of Aspergillus terreus discitis which developed in a patient with acute lymphoblastic leukemia following induction chemotherapy. A. terreus was isolated from sputum, one month earlier, but the physician did not consider it significant at the time. Magnetic resonance imaging study showed the involvement of L3-4, L4-5 and L5-S1 intervertebral discs. Etiology was established by means of histology and culturing a surgical specimen of disc materials. Our patient survived after a surgical debridement and amphotericin B administration with a total dose of 2.0 g. Discitis caused by Aspergillus terreus is a very rare event. A. terreus is one of the invasive Aspergillus species. The pathogenetic mechanism is discussed and the literature is reviewed. PMID:11194199

Fungal discitis due to Aspergillus terreus in a patient with acute lymphoblastic leukemia.

PubMed

Park, K U; Lee, H S; Kim, C J; Kim, E C

2000-12-01

We report a case of Aspergillus terreus discitis which developed in a patient with acute lymphoblastic leukemia following induction chemotherapy. A. terreus was isolated from sputum, one month earlier, but the physician did not consider it significant at the time. Magnetic resonance imaging study showed the involvement of L3-4, L4-5 and L5-S1 intervertebral discs. Etiology was established by means of histology and culturing a surgical specimen of disc materials. Our patient survived after a surgical debridement and amphotericin B administration with a total dose of 2.0 g. Discitis caused by Aspergillus terreus is a very rare event. A. terreus is one of the invasive Aspergillus species. The pathogenetic mechanism is discussed and the literature is reviewed.

Modern Immunotherapy of Adult B-Lineage Acute Lymphoblastic Leukemia with Monoclonal Antibodies and Chimeric Antigen Receptor Modified T Cells

PubMed Central

Maino, Elena; Scattolin, Anna Maria; Viero, Piera; Sancetta, Rosaria; Pascarella, Anna; Vespignani, Michele; Bassan, Renato

2015-01-01

The introduction of newer cytotoxic monoclonal antibodies and chimeric antigen receptor modified T cells is opening a new age in the management of B-lineage adult acute lymphoblastic leukemia. This therapeutic change must be very positively acknowledged because of the limits of intensive chemotherapy programs and allogeneic stem cell transplantation. In fact, with these traditional therapeutic tools the cure can be achieved in only 40–50% of the patients. The failure rates are particularly high in the elderly, in patients with post-induction persistence of minimal residual disease and especially in refractory/relapsed disease. The place of the novel immunotherapeutics in improving the outcome of adult patients with B-lineage acute lymphoblastic leukemia is reviewed. PMID:25574360

Therapy-related myeloid neoplasm in an 18-year-old boy with B-lymphoblastic leukemia.

PubMed

Qing, Xin; Panosyan, Eduard; Yue, Changjun; Ji, Ping; Gotesman, Moran; French, Samuel; Cai, Junchao

2017-12-01

Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. Acute myeloid leukemia or myelodysplastic syndrome during the course of ALL is a rare entity. Some of these cases are therapy-related while the others occur due to lineage switch. The correct diagnosis relies on comparing the immunophenotypes and cytogenetic/molecular alterations of the myeloid neoplasm and the ALL. We present the clinical, pathologic and cytogenetic features of a case of an 18-year-old male with prior treatment for B-lymphoblastic leukemia (B-ALL) who developed therapy-related myeloid neoplasm (t-MN) 4-5years after his initial diagnosis of B-ALL. A 13-year-old boy with no significant past medical history presented to Harbor-UCLA Medical Center (HUMC) in November 2012 with night sweats, fevers and chills, nausea, vomiting, diarrhea, fatigue, weakness, and weight loss. Peripheral blood flow cytometric analysis disclosed B-ALL. The blasts expressed CD10, CD19, CD22 (dim), CD34, CD38, HLA-DR, and TdT, and were negative for CD20, CD13, CD33, CD117, and cytoplasmic MPO. Chromosomal analysis and a supplemental fluorescence in situ hybridization (FISH) study performed on the bone marrow aspirate showed an abnormal karyotype (47,XY,+X,del(9)(p21p21)[4]/46,XY[16]). He achieved remission after induction chemotherapy and remained in remission until March 2016 when bilateral testicular masses were noted. Biopsy of the left testicular mass showed relapsed B-ALL. Cerebrospinal fluid (CSF) contained rare TdT-positive blasts, suggestive of minimal/early involvement by B-ALL. However, there was no evidence of acute leukemia in his bone marrow at this time. He was then treated with COG protocol AALL1331 randomized to blinatumomab arm and achieved second remission. In June 2017, the patient's peripheral blood smear showed 11% circulating monoblasts. By flow cytometry, the blasts expressed CD4, CD11b, CD13, CD15, CD33, CD38, CD56, and CD64. In addition, a few TdT-positive blasts were seen in

Iodine I 131 Monoclonal Antibody BC8, Fludarabine Phosphate, Cyclophosphamide, Total-Body Irradiation and Donor Bone Marrow Transplant in Treating Patients With Advanced Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, or High-Risk Myelodysplastic Syndrome

ClinicalTrials.gov

2018-05-14

Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; CD45-Positive Neoplastic Cells Present; Chronic Myelomonocytic Leukemia; Previously Treated Myelodysplastic Syndrome; Refractory Anemia With Excess Blasts; Refractory Anemia With Ring Sideroblasts; Refractory Cytopenia With Multilineage Dysplasia; Refractory Cytopenia With Multilineage Dysplasia and Ring Sideroblasts

Acute lymphoblastic leukemia relapsing after first-line pediatric-inspired therapy: a retrospective GRAALL study.

PubMed

Desjonquères, A; Chevallier, P; Thomas, X; Huguet, F; Leguay, T; Bernard, M; Bay, J-O; Tavernier, E; Charbonnier, A; Isnard, F; Hunault, M; Turlure, P; Renaud, M; Bastié, J-N; Himberlin, C; Lepretre, S; Lioure, B; Lhéritier, V; Asnafi, V; Beldjord, K; Lafage-Pochitaloff, M; Béné, M C; Ifrah, N; Dombret, H

2016-12-09

The outcome of adult patients with Philadelphia chromosome-negative acute lymphoblastic leukemia (Ph- ALL) relapsing after pediatric-inspired front-line therapy is ill known. Here 229 relapsing Ph- ALL younger adults (18-63 years) treated within the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL)-2003/-2005 trials were considered. Salvage regimens consisted of potentially curative therapies in 194 cases, low-intensity therapies in 21, allogeneic stem cell transplant (allo-SCT) in 6 and best supportive care in 8. Overall, 77 patients received allo-SCT after relapse. The median follow-up was 3.1 years. A second complete remission (CR2) was achieved in 121 patients (53%). In multivariate analysis, only younger age <45 years (P=0.008) and CR1 duration ⩾18 months (P=0.009) predicted CR2. Overall survival (OS) at 2 and 5 years was 19.3% (14-24%) and 13.3% (8-18%), respectively. In CR2 patients, disease-free survival (DFS) at 2 and 5 years was 29.0% (21-38%) and 25% (17-33%). In multivariate analysis, CR1 duration ⩾18 months and allo-SCT after relapse were associated with longer DFS (P<0.009 and P=0.004, respectively) and longer OS (P=0.004 and P<0.0001, respectively). In conclusion, although younger adults relapsing after pediatric-inspired ALL therapies retain a poor outcome, some of them may be cured if CR1 duration ⩾18 months and if allo-SCT can be performed in CR2. New therapies are definitely needed for these patients.

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.

Dietary resveratrol does not delay engraftment, sensitize to vincristine, or inhibit growth of high-risk acute lymphoblastic leukemia cells in NOD/SCID mice

USDA-ARS?s Scientific Manuscript database

Acute lymphoblastic leukemia (ALL) with translocation t(4;11) is a high-risk leukemia found in 60-85% of infants with ALL and is often refractory to conventional chemotherapeutics after relapse. Although resveratrol is able to kill high-risk leukemia in vitro, this agent has not been evaluated agai...

Deletion of IKZF1 and Prognosis in Acute Lymphoblastic Leukemia | Office of Cancer Genomics

Cancer.gov

NCI's TARGET Initiative reported the discovery of a novel genetic marker for children with acute lymphoblastic leukemia (ALL) in the January 7, 2009, advance online edition of The New England Journal of Medicine. The genetic alteration identified, IKZF1, should improve clinicians' ability to identify high-risk patients and better assign these patients to appropriate therapy.

Osteolytic bone lesions, severe hypercalcemia without circulating blasts: unusual presentation of childhood acute lymphoblastic leukemia

PubMed Central

Bechir, Achour; Haifa, Regaieg; Atef, Ben Abdelkader; Emna, Bouslema; Asma, Achour; Nesrine, Ben Sayed; Yosra, Ben Youssef; Abdrrahim, Khelif

2017-01-01

Hypercalcemia and severe osteolytic lesions are rare complications of acute lymphoblastic leukemia (ALL) in childhood. We report a case of a 3 years old boy who presented with prolonged fever, nausea, vomiting and increasing lower limbs pain. Skeletal X-rays and CT scan showed severe osteolytic lesions of the skull and extremities. Her physical examination showed multiple cervical lymph nodes. In laboratory tests, he had severe hypercalcemia. Parathyroid hormone (PTH) was not elevated. Despite the absence of circulating blasts, bone marrow biopsy revealed B-precursor (ALL). Hypercalcemia was initially treated with intravenous isotonic sodium chloride solution and diuretics but the serum calcium level normalized only after the beginning of corticosteroids and chemotherapy. The child responded initially to chemotherapy and eventually relapsed and died of septic shock. Acute leukemia must be considered in differential diagnosis in patients with hypercalcemia. A detailed examination even when there no circulating blasts in their peripheral blood smear, and if in doubt bone marrow aspiration should must be taken into consideration. PMID:28690758

Febrile neutropenia in children with acute lymphoblastic leukemia: single center experience

PubMed Central

Özdemir, Nihal; Tüysüz, Gülen; Çelik, Nigar; Yantri, Leman; Erginöz, Ethem; Apak, Hilmi; Özkan, Alp; Yıldız, İnci; Celkan, Tiraje

2016-01-01

Aim: An important life-threatening complication of intensive chemotherapy administered in children with leukemia is febrile neutropenia. The objective of this study was to evaluate the clinical features and consequences of febrile neutropenia attacks in children who were treated for acute lymphoblastic leukemia. Material and Methods: Nighty-six children who received chemotherapy for acute lymphoblastic leukemia in our center between January 1995 and December 2010 were included in the study. The data related to demographic characteristics, treatment features, relapse and febrile neutropenia incidences, risk factors, culture results and prognosis were retrospectively evaluated from the patients’ files. Results: A total of two hundred-ninety nine febrile neutropenia attacks observed in the patients during initial treatment and relapse treatment were evaluated. When the incidence of febrile neutropenia was evaluated by years, it was observed that the patients treated after year 2000 had statistically significantly more febrile neutopenia attacks compared to the patients treated before year 2000. When the incidences of febrile neutropenia during initial treatment and during relapse treatment were compared, it was observed that more febrile neutropenia attacks occured during relapse treatment. Fifty-nine percent of all febrile neutropenia attacks were fever of unknown origin. Eighty microorganisms grew in cultures during febrile neutropenia throughout treatment in 75 patients; 86% were bacterial infections (50% gram positive and 50% gram negative), 8% were viral infections and 6% were fungal infections. Coagulase negative staphylococcus (n=17) was the most frequent gram positive pathogen; E. Coli (n=17) was the most commonly grown gram negative pathogen. Conclusions: In this study, it was found that an increase in the incidence of febrile neutropenia occured in years. Increments in treatment intensities increase the incidence of febrile neutropenia while improving

B-cell acute lymphoblastic leukemia with mature phenotype and MLL rearrangement: report of five new cases and review of the literature.

PubMed

Sajaroff, Elisa Olga; Mansini, Adrian; Rubio, Patricia; Alonso, Cristina Noemí; Gallego, Marta S; Coccé, Mariela C; Eandi-Eberle, Silvia; Bernasconi, Andrea Raquel; Ampatzidou, Maria; Paterakis, George; Papadhimitriou, Stefanos I; Petrikkos, Loizos; Papadakis, Vassilios; Polychronopoulou, Sophia; Rossi, Jorge G; Felice, Maria Sara

2016-10-01

The association between mature-B phenotype and MLL abnormalities in acute lymphoblastic leukemia (ALL) is a very unusual finding; only 14 pediatric cases have been reported so far. We describe the clinical and biological characteristics and outcome of five pediatric cases of newly diagnosed B lineage ALL with MLL abnormalities and mature immunophenotype based on light chain restriction and surface Ig expression. Blasts showed variable expression of CD10/CD34/TdT. MLL abnormalities with no MYC involvement were detected in all patients by G-banding, FISH, and/or RT-PCR. Three patients were treated according to Interfant protocol, one to ALLIC-09, and one received B-NHL-BFM-2004. All patients achieved complete remission and three of them relapsed. Despite the small cohort size, it could be postulated that B lineage ALL with MLL abnormalities and mature phenotype is a distinct entity that differs both from the typical Pro B ALL observed in infants and mature B-ALL with high MYC expression.

Management of Concurrent Pregnancy and Acute Lymphoblastic Malignancy in Teenaged Patients: Two Illustrative Cases and Review of the Literature

PubMed Central

Johnson, Liza-Marie; Church, Christopher L.; Gomez-Garcia, Wendy C.; Popescu, Marcela I.; Margolin, Judith F.; Ribeiro, Raul C.

2014-01-01

The usual age range of acute lymphoblastic malignancies (acute lymphoblastic leukemia and advanced-stage lymphoblastic lymphoma) includes teenagers and young adults (<22 years of age) and coincides with the age of fertility. Concurrence of acute lymphoblastic malignancy with pregnancy is therefore most likely to happen during the younger childbearing ages. However, the therapeutic challenges posed by the dual diagnosis of lymphoblastic malignancy and pregnancy have not specifically been studied in the context of age, and management guidelines for pregnant young patients are lacking. Inconsistency in defining the legal decision-making rights of pregnant teenaged patients adds a further level of complexity in this age group. Management of this challenging combination in the young patient therefore entails unique ethical considerations. Here we present two illustrative cases of teenage pregnancy complicated by acute lymphoblastic malignancy, review the available literature, and offer suggestions for the therapeutic management of such cases in adolescent and young adult patients. Importantly, practical management recommendations are provided in the context of clinical ethics principles that are universally applicable, including in developing countries, where the highest incidence of adolescent pregnancies has been documented. PMID:25538861

Absence of Genomic Ikaros/IKZF1 Deletions in Pediatric B-Precursor Acute Lymphoblastic Leukemia

PubMed Central

Qazi, Sanjive; Ma, Hong; Uckun, Fatih M

2013-01-01

Here we report the results of gene expression analyses using multiple probesets aimed at determining the incidence of Ikaros/IKZF1 deletions in pediatric B-precursor acute lymphoblastic leukemia (BPL). Primary leukemia cells from 122 Philadelphia chromosome (Ph)+ BPL patients and 237 Ph− BPL patients as well as normal hematopoietic cells from 74 normal non-leukemic bone marrow specimens were organized according to expression levels of IKZF1 transcripts utilizing two-way hierarchical clustering technique to identify specimens with low IKZF1 expression for the 10 probesets interrogating Exons 1 through 4 and Exon 8. Our analysis demonstrated no changes in expression that would be expected from homozygous or heterozygous deletions of IKZF1 in primary leukemic cells. Similar results were obtained in gene expression analysis of primary leukemic cells from 20 Ph+ positive and 155 Ph− BPL patients in a validation dataset. Taken together, our gene expression analyses in 534 pediatric BPL cases, including 142 cases with Ph+ BPL, contradict previous reports that were based on SNP array data and suggested that Ph+ pediatric BPL is characterized by a high frequency of homozygous or heterozygous IKZF1 deletions. Further, exon-specific genomic PCR analysis of primary leukemia cells from 21 high-risk pediatric BPL patients and 11 standard-risk pediatric BPL patients, and 8 patients with infant BPL did not show any evidence for homozygous IKZF1 locus deletions. Nor was there any evidence for homozygous or heterozygous intragenic IKZF1 deletions. PMID:24478816

Acute lymphoblastic leukemia in adults

PubMed Central

Ribera, Josep-Maria

2011-01-01

Acute lymphoblastic leukemia (ALL) is the most frequent neoplastic disease in children, being a rare disease in adults. Many of the advances in pediatric ALL have been through modifications in the doses and schedules of available agents as opposed to the introduction of new compounds. In recent years some improvements in the outcome of ALL in adults have occurred. Application of pediatric regimens to young and middle-aged adults shows promise to improve outcome. Advances in the supportive care of patients undergoing allogeneic stem cell transplantation (SCT), the use of alternative sources of hematopoietic stem cells and the use of reduced-intensity conditioning regimens will expand the number of patients who can benefit from this therapeutic modality. The evaluation of minimal residual disease will further stratify risk classification and redefine the role of therapeutic modalities such as SCT or biologic agents. New drugs such as thyrosin kinase inhibitors or monoclonal antibodies have led to incremental improvements in outcome. Advances in the genetic and epigenetic mechanisms of the disease provide hope that targeted therapies can more effectively treat the disease with less toxicity. PMID:22053271

Molecular characterization of acute lymphoblastic leukemia with high CRLF2 gene expression in childhood.

PubMed

Schmäh, Juliane; Fedders, Birthe; Panzer-Grümayer, Renate; Fischer, Susanna; Zimmermann, Martin; Dagdan, Elif; Bens, Susanne; Schewe, Denis; Moericke, Anja; Alten, Julia; Bleckmann, Kirsten; Siebert, Reiner; Schrappe, Martin; Stanulla, Martin; Cario, Gunnar

2017-10-01

A high-level expression of the CRLF2 gene is frequent in precursor B-cell acute lymphoblastic leukemia (pB-ALL) and can be caused by different genetic aberrations. The presence of the most frequent alteration, the P2RY8/CRLF2 fusion, was shown to be associated with a high relapse incidence in children treated according to ALL-Berlin-Frankfurt-Münster (BFM) protocols, which is poorly understood. Moreover, the frequency of other alterations has not been systematically analyzed yet. CRLF2 mRNA expression and potential genetic aberrations causing a CRLF2 high expression were prospectively assessed in 1,105 patients treated according to the Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP)-BFM ALL 2009 protocol. Additionally, we determined copy number alterations in selected B-cell differentiation genes for all CRLF2 high-expressing pB-ALL cases, as well as JAK2 and CRLF2 mutations. A CRLF2 high expression was detected in 26/178 (15%) T-cell acute lymphoblastic leukemia (T-ALL) cases, 21 of them (81%) had been stratified as high-risk patients by treatment response. In pB-ALL, a CRLF2 high expression was determined in 91/927 (10%) cases; the P2RY8/CRLF2 rearrangement in 44/91 (48%) of them, supernumerary copies of CRLF2 in 18/91 (20%), and, notably, the IGH/CRLF2 translocation was detected in 16/91 (18%). Remarkably, 7 of 16 (44%) patients with IGH/CRLF2 translocation had already relapsed. P2RY8/CRLF2- and IGH/CRLF2-positive samples (70 and 94%, respectively) were characterized by a high frequency of additional deletions in B-cell differentiation genes such as IKZF1 or PAX5. Our data suggest that this high frequency of genetic aberrations in the context of a high CRLF2 expression could contribute to the high risk of relapse in P2RY8/CRLF2- and IGH/CRLF2-positive ALL. © 2017 Wiley Periodicals, Inc.

Combined 677CC/1298AC genotypes of methylenetetrahydrofolate reductase (MTHFR ) reduce susceptibility to precursor B lymphoblastic leukemia in a Chinese population.

PubMed

Lv, Ling; Wu, Cuie; Sun, Henjuan; Zhu, Saijuan; Yang, Yongchen; Chen, Xi; Fu, Hua; Bao, Liming

2010-06-01

The methylenetetrahydrofolate reductase (MTHFR) encodes a major enzyme in folate metabolism. It has been suggested that two MTHFR polymorphisms, 677C>T and 1298A>C, influence risk of acute lymphoblastic leukemia (ALL). Most studies on relation of MTHFR polymorphisms to ALL susceptibility have been in pediatric populations because ALL is relatively rare in adults. Here, we report a case-control study of 127 Chinese patients with adult precursor B lymphoblastic leukemia (B-ALL) to examine correlation between the MTHFR polymorphisms and B-ALL susceptibility in adults. Our data show that although the prevalence of genotype 1298CC was significantly higher in the female patients than in the controls (P = 0.04), the differences in distributions of combined genotypes of 1298CC with either 677CC or 677CT between the cases and the controls were statistically insignificant. Haplotype analysis revealed no significant difference between the cases and the controls. The prevalence for joint MTHFR genotypes 677CC/1298AC was significantly lower in the female B-ALL cases than in the controls [odds ratio (OR) = 0.06, 95% CI = 0.00-0.53, P = 0.0033] and no differences among the men [OR = 0.71, 95% CI = 0.20-2.53, P = 0.55], suggesting that protective effects of combined MTHFR 677CC/1298AC genotypes on susceptibility of adult B-ALL are gender bias toward women with 677CC/1298AC women being at a 17-fold reduced odds to develop B-ALL.

Management of acute lymphoblastic leukemia in young adults.

PubMed

Muffly, Lori S; Reizine, Natalie; Stock, Wendy

2018-02-01

Substantial interest in acute lymphoblastic leukemia (ALL) in young adults (YAs) and investigations focused on this patient population have resulted in therapeutic advancements that are changing the management paradigm and improving outcomes. The pediatric ALL approach is feasible and effective when administered by medical oncologists. Advanced diagnostics and minimal residual disease measurements aid in prognostication and have resulted in shifting recommendations regarding allogeneic hematopoietic cell transplant in first remission. Blinatumomab, inotuzumab, and chimeric antigen receptor T-cell therapies are transforming the treatment of relapsed/refractory ALL. This comprehensive review of the current management of ALL in YAs summarizes recent scientific developments and clinical trial findings related to ALL biology, frontline management approaches, novel therapies, and supportive care specific to this patient population. Finally, a practical guide to modern YA management for practicing clinicians is provided.

Impact of cytogenetic abnormalities in adults with Ph-negative B-cell precursor acute lymphoblastic leukemia.

PubMed

Lafage-Pochitaloff, Marina; Baranger, Laurence; Hunault, Mathilde; Cuccuini, Wendy; Lefebvre, Christine; Bidet, Audrey; Tigaud, Isabelle; Eclache, Virginie; Delabesse, Eric; Bilhou-Nabéra, Chrystèle; Terré, Christine; Chapiro, Elise; Gachard, Nathalie; Mozziconacci, Marie-Joelle; Ameye, Geneviève; Porter, Sarah; Grardel, Nathalie; Béné, Marie C; Chalandon, Yves; Graux, Carlos; Huguet, Françoise; Lhéritier, Véronique; Ifrah, Norbert; Dombret, Hervé

2017-10-19

Multiple cytogenetic subgroups have been described in adult Philadelphia chromosome (Ph)-negative B-cell precursor (BCP) acute lymphoblastic leukemia (ALL), often comprising small numbers of patients. In this study, we aimed to reassess the prognostic value of cytogenetic abnormalities in a large series of 617 adult patients with Ph-negative BCP-ALL (median age, 38 years), treated in the intensified Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL)-2003/2005 trials. Combined data from karyotype, DNA index, fluorescence in situ hybridization, and polymerase chain reaction screening for relevant abnormalities were centrally reviewed and were informative in 542 cases (88%), allowing classification in 10 exclusive primary cytogenetic subgroups and in secondary subgroups, including complex and monosomal karyotypes. Prognostic analyses focused on cumulative incidence of failure (including primary refractoriness and relapse), event-free survival, and overall survival. Only 2 subgroups, namely t(4;11)/ KMT2A-AFF1 and 14q32/ IGH translocations, displayed a significantly worse outcome in this context, still observed after adjustment for age and after censoring patients who received allogeneic stem cell transplantation (SCT) in first remission at SCT time. A worse outcome was also observed in patients with low hypodiploidy/near triploidy, but this was likely related to their higher age and worse tolerance to therapy. The other cytogenetic abnormalities, including complex and monosomal karyotypes, had no prognostic value in these intensive protocols designed for adult patients up to the age of 60 years. © 2017 by The American Society of Hematology.

Methylenetetrahydrofolate reductase gene polymorphisms and acute lymphoblastic leukemia risk: a meta-analysis based on 28 case-control studies.

PubMed

Tong, Na; Sheng, Xiaojing; Wang, Meilin; Fang, Yongjun; Shi, Danni; Zhang, Zhizhong; Zhang, Zhengdong

2011-10-01

Methylenetetrahydrofolate reductase (MTHFR) is involved in DNA methylation and nucleotide synthesis. Accumulated evidence has demonstrated that C677T and A1298C polymorphisms of the MTHFR gene are associated with acute lymphoblastic leukemia (ALL) risk, but the results have been inconclusive. To determine a more precise estimation, we performed a meta-analysis of 28 studies with 4240 cases and 9289 controls. We found that the 677TT genotype showed a reduced risk of ALL compared with the 677CC genotype in the overall population (odds ratio [OR] 0.76, 95% confidence interval [CI] 0.61-0.92). The reduced risk was pronounced only among the Caucasian population (OR 0.68, 95% CI 0.51-0.90), not the Asian (OR 0.89, 95% CI 0.75-1.05). For the MTHFR A1298C polymorphism, no significant association with ALL susceptibility was observed in the pooled analyses. However, significantly increased ALL risk was found in childhood in the comparison of 1298CA versus AA genotype. This study provides evidence that MTHFR polymorphisms may play an important role in the development of ALL.

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

ClinicalTrials.gov

2018-02-28

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

Effect of Pre-treatment Nutritional Status, Folate and Vitamin B12 Levels on Induction Chemotherapy in Children with Acute Lymphoblastic Leukemia.

PubMed

Tandon, Sneha; Moulik, Nirmalya Roy; Kumar, Archana; Mahdi, Abbas Ali; Kumar, Ashutosh

2015-05-01

To evaluate pre-treatment undernutrition, and folate and B12 deficiency in children with acute lymphoblastic leukemia, and their correlation with complications and outcome of induction chemotherapy. Observational study. Tertiary care teaching hospital in Northern India. 50 children with acute lymphoblastic leukemia. Children were assessed for nutritional status (Weight for age Z-score, serum albumin, folate and B12) at presentation, and were followed-up during induction for bone marrow response, counts and outcome. Folate and B12 were repeated twice at monthly intervals after induction. Univariate and multivariate analyses were done to determine the association of nutritional parameters with the outcome variables. Baseline undernutrition was observed in 66%, hypo-albuminemia in 32.6%, folate deficiency in 41.3% and B12 deficiency in 36.9% of included children. Significant decline in folate levels was noted on serial assays during chemotherapy (P=0.001). Folate deficient children had higher risk for delayed marrow recovery and counts on day 14 (P=0.007 and P=0.001). Hypoalbuminemia (P=0.04), B12 deficiency (P=0.001) and folate (P=0.03) deficiency were associated with toxic deaths during induction. Baseline nutritional deficiencies negatively influence the outcome and occurrence of complications during induction chemotherapy in children with acute lymphoblastic leukemia.

Characterization of CD22 Expression in Acute Lymphoblastic Leukemia

PubMed Central

Shah, Nirali N.; Stetler-Stevenson, Maryalice; Yuan, Constance M.; Richards, Kelly; Delbrook, Cindy; Kreitman, Robert J.; Pastan, Ira; Wayne, Alan S.

2015-01-01

Background CD22 is a B-lineage differentiation antigen that has emerged as a leading therapeutic target in acute lymphoblastic leukemia (ALL). Procedure Properties of CD22 expression relevant to therapeutic targeting were characterized in primary samples obtained from children and young adults with relapsed and chemotherapy refractory B-precursor (pre-B) ALL. Results CD22 expression was demonstrated in all subjects (n=163) with detection on at least 90% of blasts in 155 cases. Median antigen site density of surface CD22 was 3,470 sites/cell (range 349 – 19,653, n=160). Blasts from patients with known 11q23 (MLL) rearrangement had lower site density (median 1,590 sites/cell, range 349-3,624, n=20 versus 3,853 sites/cell, range 451-19,653, n=140; p=<0.0001) and 6 of 21 cases had sub-populations of blasts lacking CD22 expression (22% – 82% CD22+). CD22 expression was maintained in serial studies of 73 subjects, including those treated with anti-CD22 targeted therapy. The levels of soluble CD22 in blood and marrow by ELISA were low and not expected to influence the pharmacokinetics of anti-CD22 directed agents. Conclusions These characteristics make CD22 an excellent potential therapeutic target in patients with relapsed and chemotherapy-refractory ALL, although cases with MLL rearrangement require close study to exclude the presence of a CD22-negative blast population. PMID:25728039

Eosinophilic folliculitis occurring after stem cell transplant for acute lymphoblastic leukemia: a case report and review.

PubMed

Zitelli, Kristine; Fernandes, Neil; Adams, Brian B

2015-07-01

Eosinophilic folliculitis (EF) comprises classic eosinophilic pustular folliculitis (EPF), human immunodeficiency virus (HIV)-related EF, and infantile EPF subtypes. A fourth proposed subtype describes EF associated with hematologic malignancy. Recently, EF has occurred after bone marrow or stem cell transplantation (SCT). We report a unique case of EF after haploidentical allogeneic SCT for acute lymphoblastic leukemia (ALL) and review the literature for similar cases. A 56-year-old, HIV-negative ALL patient presented with an intensely pruritic papulopustular eruption. He had undergone haploidentical allogeneic SCT 65 days earlier, which he had tolerated well. Histopathology revealed a moderately dense perifollicular and perivascular lymphocytic infiltrate with many eosinophils extending from the superficial dermis to the subcutaneous fat. Fungal stains were negative. These findings were highly consistent with EF. Therapy with a class II topical corticosteroid ointment, oral doxepin, and emollients achieved near-resolution of the lesions within eight weeks. Transition to topical tacrolimus 0.1% ointment applied twice daily to residual lesions yielded complete clearance by 12 weeks with mild post-inflammatory hyperpigmentation. The patient's ALL remains in remission. A fourth proposed subtype of EF is associated with HIV-negative hematologic disease. This subtype is distinguished by a predictable timeframe to presentation and a relatively rapid response to therapy. Although EF is an important consideration in all patients with hematologic malignancy, clinically heightened suspicion is warranted during the 2-3 months after transplant. © 2014 The International Society of Dermatology.

Ultrastructural cytochemical prospective study of adult acute lymphoblastic leukemia: detection of peroxidase activity in patients failing to respond to treatment.

PubMed

Reiffers, J; Darmendrail, V; Larrue, J; Villenave, I; Bernard, P; Boisseau, M; Broustet, A

1981-08-15

Ultrastructural cytochemical studies revealed peroxidase activity in five of 25 adult patients with apparent null lymphoblastic leukemia (ALL) in whom the peroxidase reaction studied with light microscopy was negative. None of these 5 patients responded to a chemotherapy regimen used for adult ALL. The importance of ultrastructural cytochemistry which allows the recognition of myeloblastic differentiation in undifferentiated blast cells is also demonstrated. The correct classification of such cases may be important for prognosis because they appear to be resistant to the chemotherapy used in treating ALL.

Mutations in RIT1 cause Noonan syndrome with possible juvenile myelomonocytic leukemia but are not involved in acute lymphoblastic leukemia.

PubMed

Cavé, Hélène; Caye, Aurélie; Ghedira, Nehla; Capri, Yline; Pouvreau, Nathalie; Fillot, Natacha; Trimouille, Aurélien; Vignal, Cédric; Fenneteau, Odile; Alembik, Yves; Alessandri, Jean-Luc; Blanchet, Patricia; Boute, Odile; Bouvagnet, Patrice; David, Albert; Dieux Coeslier, Anne; Doray, Bérénice; Dulac, Olivier; Drouin-Garraud, Valérie; Gérard, Marion; Héron, Delphine; Isidor, Bertrand; Lacombe, Didier; Lyonnet, Stanislas; Perrin, Laurence; Rio, Marlène; Roume, Joëlle; Sauvion, Sylvie; Toutain, Annick; Vincent-Delorme, Catherine; Willems, Marjorie; Baumann, Clarisse; Verloes, Alain

2016-08-01

Noonan syndrome is a heterogeneous autosomal dominant disorder caused by mutations in at least eight genes involved in the RAS/MAPK signaling pathway. Recently, RIT1 (Ras-like without CAAX 1) has been shown to be involved in the pathogenesis of some patients. We report a series of 44 patients from 30 pedigrees (including nine multiplex families) with mutations in RIT1. These patients display a typical Noonan gestalt and facial phenotype. Among the probands, 8.7% showed postnatal growth retardation, 90% had congenital heart defects, 36% had hypertrophic cardiomyopathy (a lower incidence compared with previous report), 50% displayed speech delay and 52% had learning difficulties, but only 22% required special education. None had major skin anomalies. One child died perinatally of juvenile myelomonocytic leukemia. Compared with the canonical Noonan phenotype linked to PTPN11 mutations, patients with RIT1 mutations appear to be less severely growth retarded and more frequently affected by cardiomyopathy. Based on our experience, we estimate that RIT1 could be the cause of 5% of Noonan syndrome patients. Because mutations found constitutionally in Noonan syndrome are also found in several tumors in adulthood, we evaluated the potential contribution of RIT1 to leukemogenesis in Noonan syndrome. We screened 192 pediatric cases of acute lymphoblastic leukemias (96 B-ALL and 96 T-ALL) and 110 cases of juvenile myelomonocytic leukemias (JMML), but detected no variation in these tumoral samples, suggesting that Noonan patients with germline RIT1 mutations are not at high risk to developing JMML or ALL, and that RIT1 has at most a marginal role in these sporadic malignancies.

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

PubMed

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

2018-05-14

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

Nephrogenic diabetes insipidus in initial stage of acute lymphoblastic leukemia and relapse after haploidentical hematopoietic stem-cell transplantation: A case report.

PubMed

Li, Dezhi; Liu, Qian; Feng, Zhifang; Zhang, Qi; Feng, Saran

2018-06-01

Nephrogenic diabetes insipidus (NDI) rarely presents in the initial stage of acute lymphoblastic leukemia (ALL) and relapse due to renal infiltration is also rare. A 19-year-old man presented with weakness, polydipsia, and polyuria for 1 month. NDI was diagnosed with insignificant response to a water deprivation test after stimulation with vasopressin injection. Bone marrow examination combined with immunophenotypic analysis, cerebrospinal cytology, and abdominal ultrasonography confirmed the diagnoses of precursor B cell ALL with renal infiltration. The patient accepted standardized combination chemotherapy and ultimately had sustained remission, and his polydipsia and polyuria disappeared after 3 days of treatment. The ALL relapsed 1 year later and he received haploidentical stem cell transplantation (haplo-SCT) from his father. One year later, he again developed NDI, with bilateral renal enlargement because of extramedullary relapse, leading to subsequent death. This case demonstrates unusual early renal involvement in ALL presenting with initial NDI. Interestingly, the NDI returned with the relapse of renal infiltration 1 year after haplo-SCT. This case suggests that NDI was probably secondary to renal leukemic infiltration.

Genetic loss of SH2B3 in acute lymphoblastic leukemia.

PubMed

Perez-Garcia, Arianne; Ambesi-Impiombato, Alberto; Hadler, Michael; Rigo, Isaura; LeDuc, Charles A; Kelly, Kara; Jalas, Chaim; Paietta, Elisabeth; Racevskis, Janis; Rowe, Jacob M; Tallman, Martin S; Paganin, Maddalena; Basso, Giuseppe; Tong, Wei; Chung, Wendy K; Ferrando, Adolfo A

2013-10-03

The SH2B adaptor protein 3 (SH2B3) gene encodes a negative regulator of cytokine signaling with a critical role in the homeostasis of hematopoietic stem cells and lymphoid progenitors. Here, we report the identification of germline homozygous SH2B3 mutations in 2 siblings affected with developmental delay and autoimmunity, one in whom B-precursor acute lymphoblastic leukemia (ALL) developed. Mechanistically, loss of SH2B3 increases Janus kinase-signal transducer and activator of transcription signaling, promotes lymphoid cell proliferation, and accelerates leukemia development in a mouse model of NOTCH1-induced ALL. Moreover, extended mutation analysis showed homozygous somatic mutations in SH2B3 in 2 of 167 ALLs analyzed. Overall, these results demonstrate a Knudson tumor suppressor role for SH2B3 in the pathogenesis of ALL and highlight a possible link between genetic predisposition factors in the pathogenesis of autoimmunity and leukemogenesis.

Genetic alterations activating kinase and cytokine receptor signaling in high-risk acute lymphoblastic leukemia

PubMed Central

Roberts, Kathryn G.; Morin, Ryan D.; Zhang, Jinghui; Hirst, Martin; Zhao, Yongjun; Su, Xiaoping; Chen, Shann-Ching; Payne-Turner, Debbie; Churchman, Michelle; Harvey, Richard C.; Chen, Xiang; Kasap, Corynn; Yan, Chunhua; Becksfort, Jared; Finney, Richard P.; Teachey, David T.; Maude, Shannon L.; Tse, Kane; Moore, Richard; Jones, Steven; Mungall, Karen; Birol, Inanc; Edmonson, Michael N.; Hu, Ying; Buetow, Kenneth E.; Chen, I-Ming; Carroll, William L.; Wei, Lei; Ma, Jing; Kleppe, Maria; Levine, Ross L.; Garcia-Manero, Guillermo; Larsen, Eric; Shah, Neil P.; Devidas, Meenakshi; Reaman, Gregory; Smith, Malcolm; Paugh, Steven W.; Evans, William E.; Grupp, Stephan A.; Jeha, Sima; Pui, Ching-Hon; Gerhard, Daniela S.; Downing, James R.; Willman, Cheryl L.; Loh, Mignon; Hunger, Stephen P.; Marra, Marco; Mullighan, Charles G.

2012-01-01

SUMMARY Genomic profiling has identified a subtype of high-risk B-progenitor acute lymphoblastic leukemia (B-ALL) with alteration of IKZF1, a gene expression profile similar to BCR-ABL1-positive ALL and poor outcome (Ph-like ALL). The genetic alterations that activate kinase signaling in Ph-like ALL are poorly understood. We performed transcriptome and whole genome sequencing on 15 cases of Ph-like ALL, and identified rearrangements involving ABL1, JAK2, PDGFRB, CRLF2 and EPOR, activating mutations of IL7R and FLT3, and deletion of SH2B3, which encodes the JAK2 negative regulator LNK. Importantly, several of these alterations induce transformation that is attenuated with tyrosine kinase inhibitors, suggesting the treatment outcome of these patients may be improved with targeted therapy. PMID:22897847

Clinical and Genetic Risk Factors for Acute Pancreatitis in Patients With Acute Lymphoblastic Leukemia

PubMed Central

Liu, Chengcheng; Yang, Wenjian; Devidas, Meenakshi; Cheng, Cheng; Pei, Deqing; Smith, Colton; Carroll, William L.; Raetz, Elizabeth A.; Bowman, W. Paul; Larsen, Eric C.; Maloney, Kelly W.; Martin, Paul L.; Mattano, Leonard A.; Winick, Naomi J.; Mardis, Elaine R.; Fulton, Robert S.; Bhojwani, Deepa; Howard, Scott C.; Jeha, Sima; Pui, Ching-Hon; Hunger, Stephen P.; Evans, William E.; Loh, Mignon L.

2016-01-01

Purpose Acute pancreatitis is one of the common causes of asparaginase intolerance. The mechanism is unknown, and genetic predisposition to asparaginase-induced pancreatitis has not been previously identified. Methods To determine clinical risk factors for asparaginase-induced pancreatitis, we studied a cohort of 5,185 children and young adults with acute lymphoblastic leukemia, including 117 (2.3%) who were diagnosed with at least one episode of acute pancreatitis during therapy. A genome-wide association study was performed in the cohort and in an independent case-control group of 213 patients to identify genetic risk factors. Results Risk factors associated with pancreatitis included genetically defined Native American ancestry (P < .001), older age (P < .001), and higher cumulative dose of asparaginase (P < .001). No common variants reached genome-wide significance in the genome-wide association study, but a rare nonsense variant rs199695765 in CPA2, encoding carboxypeptidase A2, was highly associated with pancreatitis (hazard ratio, 587; 95% CI, 66.8 to 5166; P = 9.0 × 10−9). A gene-level analysis showed an excess of additional CPA2 variants in patients who did versus those who did not develop pancreatitis (P = .001). Sixteen CPA2 single-nucleotide polymorphisms were associated (P < .05) with pancreatitis, and 13 of 24 patients who carried at least one of these variants developed pancreatitis. Biologic functions that were overrepresented by common variants modestly associated with pancreatitis included purine metabolism and cytoskeleton regulation. Conclusion Older age, higher exposure to asparaginase, and higher Native American ancestry were independent risk factors for pancreatitis in patients with acute lymphoblastic leukemia. Those who inherit a nonsense rare variant in the CPA2 gene had a markedly increased risk of asparaginase-induced pancreatitis. PMID:27114598

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

ClinicalTrials.gov

2018-03-27

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

The molecular genetic makeup of acute lymphoblastic leukemia.

PubMed

Mullighan, Charles G

2012-01-01

Genomic profiling has transformed our understanding of the genetic basis of acute lymphoblastic leukemia (ALL). Recent years have seen a shift from microarray analysis and candidate gene sequencing to next-generation sequencing. Together, these approaches have shown that many ALL subtypes are characterized by constellations of structural rearrangements, submicroscopic DNA copy number alterations, and sequence mutations, several of which have clear implications for risk stratification and targeted therapeutic intervention. Mutations in genes regulating lymphoid development are a hallmark of ALL, and alterations of the lymphoid transcription factor gene IKZF1 (IKAROS) are associated with a high risk of treatment failure in B-ALL. Approximately 20% of B-ALL cases harbor genetic alterations that activate kinase signaling that may be amenable to treatment with tyrosine kinase inhibitors, including rearrangements of the cytokine receptor gene CRLF2; rearrangements of ABL1, JAK2, and PDGFRB; and mutations of JAK1 and JAK2. Whole-genome sequencing has also identified novel targets of mutation in aggressive T-lineage ALL, including hematopoietic regulators (ETV6 and RUNX1), tyrosine kinases, and epigenetic regulators. Challenges for the future are to comprehensively identify and experimentally validate all genetic alterations driving leukemogenesis and treatment failure in childhood and adult ALL and to implement genomic profiling into the clinical setting to guide risk stratification and targeted therapy.

Secondary EML4-ALK-positive lung adenocarcinoma in a patient previously treated for acute lymphoblastic leukemia in childhood: a case report.

PubMed

Nakamura, Yoichi; Taniguchi, Hirokazu; Mizoguchi, Kosuke; Ikeda, Takaya; Motoshima, Kohei; Yamaguchi, Hiroyuki; Nagashima, Seiji; Nakatomi, Katsumi; Soda, Manabu; Mano, Hiroyuki; Kohno, Shigeru

2014-06-01

It is widely recognized that the risk of secondary neoplasms increases as childhood cancer survivors progress through adulthood. These are mainly hematological malignancies, and recurrent chromosome translocations are commonly detected in such cases. On the other hand, while secondary epithelial malignancies have sometimes been reported, chromosome translocations in these epithelial malignancies have not. A 33-year-old man who had been diagnosed with acute lymphoblastic leukemia and treated with chemotherapy almost 20 years earlier was diagnosed with lung adenocarcinoma. After chromosomal rearrangement of echinoderm microtubule-associated protein-like 4 gene and the anaplastic lymphoma kinase gene was detected in this adenocarcinoma, he responded to treatment with crizotinib. It was therefore concluded that this echinoderm microtubule-associated protein-like 4 gene-anaplastic lymphoma kinase gene-positive lung adenocarcinoma was a secondary epithelial malignancy. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Interphase FISH for BCR-ABL1 rearrangement on neutrophils: A decisive tool to discriminate a lymphoid blast crisis of chronic myeloid leukemia from a de novo BCR-ABL1 positive acute lymphoblastic leukemia.

PubMed

Balducci, Estelle; Loosveld, Marie; Rahal, Ilhem; Boudjarane, John; Alazard, Emilie; Missirian, Chantal; Lafage-Pochitaloff, Marina; Michel, Gérard; Zattara, Hélène

2018-02-01

Discrimination between lymphoid blast crisis of chronic myeloid leukemia (CML) and de novo BCR-ABL1 positive acute lymphoblastic leukemia (ALL) represents a diagnostic challenge because this distinction has a major incidence on the management of patients. Here, we report an uncommon pediatric case of ALL with cryptic ins(22;9)(q11;q34q34) and p190-type BCR-ABL1 transcript. We performed interphase fluorescence in situ hybridization (FISH) for BCR-ABL1 rearrangement on blood neutrophils, which was positive consistent with the diagnosis of lymphoid blast crisis of CML. This case illustrates the major interest of interphase FISH for BCR-ABL1 rearrangement on blood neutrophils as a decisive method to discriminate a lymphoid blast crisis of CML from a de novo BCR-ABL1 positive ALL. Copyright © 2017 John Wiley & Sons, Ltd.

Measuring Vincristine-Induced Peripheral Neuropathy in Children with Acute Lymphoblastic Leukemia

PubMed Central

Lavoie Smith, Ellen M.; Li, Lang; Hutchinson, Raymond J.; Ho, Richard; Burnette, W. Bryan; Wells, Elizabeth; Bridges, Celia; Renbarger, Jamie

2014-01-01

Background Vincristine-induced peripheral neuropathy (VIPN) is difficult to quantify in children. Objective The study objective was to examine the reliability, validity, and clinical feasibility of several VIPN measures for use in children with acute lymphoblastic leukemia. Interventions/Methods Children (N = 65) aged 1–18 years receiving vincristine at four academic centers participated in the study. Baseline and pre-vincristine VIPN assessments were obtained using the Total Neuropathy Score-Pediatric Vincristine (TNS-PV), the National Cancer Institute Common Terminology Criteria for Adverse Events, the Balis grading scale, and the FACES pain scale. TNS-PV scores (n = 806) were obtained over 15 weeks. Blood was obtained at several time-points to quantify pharmacokinetic parameters. Results Cronbach’s alpha for a reduced TNS-PV scale was 0.84. TNS-PV scores correlated with cumulative vincristine dosage (r = 0.53, p = 0.01), pharmacokinetic parameters (r = 0.41, p = 0.05), and grading scale scores (r = 0.46 – 0.52; p = 0.01). FACES scores correlated with the TNS-PV neuropathic pain item (r = 0.48; p = 0.01), and were attainable in all ages. A 2-item V-Rex score (vibration and reflex items) was the most responsive to change (es 0.65, p < 0.001). TNS-PV scores were attainable in 95% of children ≥ 6 years. Conclusions The TNS-PV is reliable and valid for measuring VIPN. It is sensitive to change over time (15 weeks) and feasible for use in children ≥ 6 years of age. Implications for Practice The TNS-PV may be a useful tool for assessing vincristine toxicity in children with acute lymphoblastic leukemia. PMID:23842524

Methylenetetrahydrofolate reductase gene polymorphisms: association with risk for pediatric acute lymphoblastic leukemia in north Indians.

PubMed

Sood, Swati; Das, Reena; Trehan, Amita; Ahluwalia, Jasmina; Sachdeva, Man Updesh; Varma, Neelam; Bansal, Deepak; Marwaha, Ram Kumar

2010-05-01

Genetic polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene have been associated with the development of acute leukemias and various malignancies. We conducted a case-control study in 95 north Indian children with acute lymphoblastic leukemia (ALL) and 255 controls, to investigate the role of MTHFR C677T and A1298C polymorphisms as risk factors in the development of ALL. PCR-RFLP on genomic DNA was carried out to determine C677T and A1298C genotypes. The frequency of MTHFR C677T for the T allele was found to be 23.2% among patients and 18.2% among controls. The frequency of the C allele in MTHFR A1298C was 44.2% among cases and 48.2% in controls. Patients showed a higher frequency of heterozygosity for the MTHFR C677T polymorphism as compared to controls (40% vs 27.8%; OR = 1.73, 95% CI 1.02-2.91, p = 0.02), and the A1298C polymorphism did not show any difference in genotype frequency between cases and controls. MTHFR 677CC/1298AC genotype frequencies showed a statistically significant difference between cases and controls (OR = 0.58, 95% CI 0.34-1.01, p = 0.04). In conclusion, our study in north Indian controls and patients with pediatric ALL showed increased frequency for MTHFR C677T in the heterozygous state and no significant difference in the frequency of A1298C genotype between the two groups.

Comparison of long-term outcome between white and Vietnamese children treated for acute lymphoblastic leukemia according to the FRALLE 2000 protocol.

PubMed

Vu Hoang, Phuong Thu; Ambroise, Jérôme; Dang Chi, Vu Luan; Dekairelle, Anne-France; Dupont, Sophie; Huynh, Nghia; Nguyen, Tan Binh; Robert, Annie; Gala, Jean-Luc; Vermylen, Christiane

2014-10-01

To compare the relapse-free survival (RFS) in Vietnamese (n=141) and white (n=94) children living in Vietnam and Belgium, respectively, and treated in their own country for acute lymphoblastic leukemia according to the same FRALLE 2000 protocol. RFS was significantly worse in Vietnamese children (hazards ratio=4.48; 95% confidence interval [CI], 2.16-9.3; P<0.01). The 5-year RFS was 83.8% (95% CI, 76.3%-92.0%) and 47.8% (95% CI, 35.6%-64.2%) for white and Vietnamese children, respectively. In the latter group, relapses occurred in bone marrow and cerebrospinal fluid at a much earlier stage. The outcome was compared at first relapse only because of different treatments afterward, according to the country. Both series were similar for sex, age at diagnosis, initial white blood cell count, cytogenetic abnormalities, and corticosensitivity at day 8. Higher frequency of L2-acute lymphoblastic leukemia (P<0.001) but lower frequency of T-acute lymphoblastic leukemia (P=0.004) were observed in Vietnamese children. Several factors may contribute to the poor RFS in Vietnamese children, which include the time interval before the first intrathecal therapy and differences in the management of drug-related toxicity. However, additional contribution of socioeconomic factors and/or variations in pharmacogenetic polymorphisms in Vietnamese patients cannot currently be ruled out.

Characterization of CD22 expression in acute lymphoblastic leukemia.

PubMed

Shah, Nirali N; Stevenson, Maryalice Stetler; Yuan, Constance M; Richards, Kelly; Delbrook, Cindy; Kreitman, Robert J; Pastan, Ira; Wayne, Alan S

2015-06-01

CD22 is a B-lineage differentiation antigen that has emerged as a leading therapeutic target in acute lymphoblastic leukemia (ALL). Properties of CD22 expression relevant to therapeutic targeting were characterized in primary samples obtained from children and young adults with relapsed and chemotherapy refractory B-precursor (pre-B) ALL. CD22 expression was demonstrated in all subjects (n = 163) with detection on at least 90% of blasts in 155 cases. Median antigen site density of surface CD22 was 3,470 sites/cell (range 349-19,653, n = 160). Blasts from patients with known 11q23 (MLL) rearrangement had lower site density (median 1,590 sites/cell, range 349-3,624, n = 20 versus 3,853 sites/cell, range 451-19,653, n = 140; P = <0.0001) and 6 of 21 cases had sub-populations of blasts lacking CD22 expression (22%-82% CD22 +). CD22 expression was maintained in serial studies of 73 subjects, including those treated with anti-CD22 targeted therapy. The levels of soluble CD22 in blood and marrow by ELISA were low and not expected to influence the pharmacokinetics of anti-CD22 directed agents. These characteristics make CD22 an excellent potential therapeutic target in patients with relapsed and chemotherapy-refractory ALL, although cases with MLL rearrangement require close study to exclude the presence of a CD22-negative blast population. Published 2015. This article is a U.S. Government work and is in the public domain in the USA.

Growth factor independence-1 antagonizes a p53-induced DNA damage response pathway in lymphoblastic leukemia

PubMed Central

Khandanpour, Cyrus; Phelan, James D.; Vassen, Lothar; Schütte, Judith; Chen, Riyan; Horman, Shane R.; Gaudreau, Marie-Claude; Krongold, Joseph; Zhu, Jinfang; Paul, William E.; Dührsen, Ulrich; Göttgens, Bertie; Grimes, H. Leighton; Möröy, Tarik

2013-01-01

Summary Most patients with acute lymphoblastic leukemia (ALL) fail current treatments highlighting the need for better therapies. Since oncogenic signaling activates a p53-dependent DNA-damage response and apoptosis, leukemic cells must devise appropriate countermeasures. We show here that growth factor independence 1 (Gfi1) can serve such a function, since Gfi1 ablation exacerbates p53 responses, and lowers the threshold for p53-induced cell death. Specifically, Gfi1 restricts p53 activity and expression of pro-apoptotic p53 targets such as Bax, Noxa (Pmaip1) and Puma (Bbc3). Subsequently, Gfi1 ablation cures mice from leukemia and limits the expansion of primary human T-ALL xenografts in mice. This suggests that targeting Gfi1 could improve the prognosis of patients with T-ALL or other lymphoid leukemias. PMID:23410974

Detection of central nervous system leukemia in children with acute lymphoblastic leukemia by real-time polymerase chain reaction.

PubMed

Pine, Sharon R; Yin, Changhong; Matloub, Yousif H; Sabaawy, Hatem E; Sandoval, Claudio; Levendoglu-Tugal, Oya; Ozkaynak, M Fevzi; Jayabose, Somasundaram

2005-02-01

Accurate detection of central nervous system (CNS) involvement in children with newly diagnosed acute lymphoblastic leukemia (ALL) could have profound prognostic and therapeutic implications. We examined various cerebrospinal fluid (CSF) preservation methods to yield adequate DNA stability for polymerase chain reaction (PCR) analysis and developed a quantitative real-time PCR assay to detect occult CNS leukemia. Sixty CSF specimens were maintained in several storage conditions for varying amounts of time, and we found that preserving CSF in 1:1 serum-free RPMI tissue culture medium offers the best stability of DNA for PCR analysis. Sixty CSF samples (30 at diagnosis and 30 at the end of induction therapy) from 30 children with ALL were tested for CNS leukemic involvement by real-time PCR using patient-specific antigen receptor gene rearrangement primers. Six of thirty patient diagnosis samples were PCR-positive at levels ranging from 0.5 to 66% leukemic blasts in the CSF. Four of these patients had no clinical or cytomorphological evidence of CNS leukemia involvement at that time. All 30 CSF samples drawn at the end of induction therapy were PCR-negative. The data indicate that real-time PCR analysis of CSF is an excellent tool to assess occult CNS leukemia involvement in patients with ALL and can possibly be used to refine CNS status classification.

Detection of Central Nervous System Leukemia in Children with Acute Lymphoblastic Leukemia by Real-Time Polymerase Chain Reaction

PubMed Central

Pine, Sharon R.; Yin, Changhong; Matloub, Yousif H.; Sabaawy, Hatem E.; Sandoval, Claudio; Levendoglu-Tugal, Oya; Ozkaynak, M. Fevzi; Jayabose, Somasundaram

2005-01-01

Accurate detection of central nervous system (CNS) involvement in children with newly diagnosed acute lymphoblastic leukemia (ALL) could have profound prognostic and therapeutic implications. We examined various cerebrospinal fluid (CSF) preservation methods to yield adequate DNA stability for polymerase chain reaction (PCR) analysis and developed a quantitative real-time PCR assay to detect occult CNS leukemia. Sixty CSF specimens were maintained in several storage conditions for varying amounts of time, and we found that preserving CSF in 1:1 serum-free RPMI tissue culture medium offers the best stability of DNA for PCR analysis. Sixty CSF samples (30 at diagnosis and 30 at the end of induction therapy) from 30 children with ALL were tested for CNS leukemic involvement by real-time PCR using patient-specific antigen receptor gene rearrangement primers. Six of thirty patient diagnosis samples were PCR-positive at levels ranging from 0.5 to 66% leukemic blasts in the CSF. Four of these patients had no clinical or cytomorphological evidence of CNS leukemia involvement at that time. All 30 CSF samples drawn at the end of induction therapy were PCR-negative. The data indicate that real-time PCR analysis of CSF is an excellent tool to assess occult CNS leukemia involvement in patients with ALL and can possibly be used to refine CNS status classification. PMID:15681484

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

ClinicalTrials.gov

2018-04-09

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

Supporting Caregivers of Children With Acute Lymphoblastic Leukemia via a Smartphone App: A Pilot Study of Usability and Effectiveness.

PubMed

Wang, Jingting; Yao, Nengliang; Shen, Min; Zhang, Xiaoyan; Wang, Yuanyuan; Liu, Yanyan; Geng, Zhaohui; Yuan, Changrong

2016-11-01

Smartphone applications are widely used for self-help interventions in adult cancer survivors. However, applications for parents of pediatric cancer patients are limited. We developed an applications to assist parents of children with acute lymphoblastic leukemia. The aim of this study is to evaluate the app's usability and effectiveness in a preliminary way. A stepwise approach and mixed methods were used. The application was initially tested by healthcare providers, and their comments and suggestions were used to develop an updated version. This version was tested by parents of children with acute lymphoblastic leukemia. Comments and nonverbal expressions of parents were recorded during a 2-week pilot test. The qualitative study was followed by a quantitative study using audit log data from the administration portal to understand how parents use the application. Six healthcare providers and 15 parents participated. Parents gained a greater knowledge of leukemia, confidence in caregiving, social support, and information on how to reduce stress. Over usability was rated as stable, useful, simple, and self-explanatory. No software failure occurred. Applications have the potential to support caregivers of pediatric cancer patients. We plan to address limitations and perform an empirical interventional study to examine its clinical effectiveness.

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

Identification of CD34+ and CD34− leukemia-initiating cells in MLL-rearranged human acute lymphoblastic leukemia

PubMed Central

Aoki, Yuki; Watanabe, Takashi; Saito, Yoriko; Kuroki, Yoko; Hijikata, Atsushi; Takagi, Masatoshi; Tomizawa, Daisuke; Eguchi, Mariko; Eguchi-Ishimae, Minenori; Kaneko, Akiko; Ono, Rintaro; Sato, Kaori; Suzuki, Nahoko; Fujiki, Saera; Koh, Katsuyoshi; Ishii, Eiichi; Shultz, Leonard D.; Ohara, Osamu; Mizutani, Shuki

2015-01-01

Translocation of the mixed-lineage leukemia (MLL) gene with AF4, AF9, or ENL results in acute leukemia with both lymphoid and myeloid involvement. We characterized leukemia-initiating cells (LICs) in primary infant MLL-rearranged leukemia using a xenotransplantation model. In MLL-AF4 patients, CD34+CD38+CD19+ and CD34−CD19+ cells initiated leukemia, and in MLL-AF9 patients, CD34−CD19+ cells were LICs. In MLL-ENL patients, either CD34+ or CD34− cells were LICs, depending on the pattern of CD34 expression. In contrast, in patients with these MLL translocations, CD34+CD38−CD19−CD33− cells were enriched for normal hematopoietic stem cells (HSCs) with in vivo long-term multilineage hematopoietic repopulation capacity. Although LICs developed leukemic cells with clonal immunoglobulin heavy-chain (IGH) rearrangement in vivo, CD34+CD38−CD19−CD33− cells repopulated recipient bone marrow and spleen with B cells, showing broad polyclonal IGH rearrangement and recipient thymus with CD4+ single positive (SP), CD8+ SP, and CD4+CD8+ double-positive (DP) T cells. Global gene expression profiling revealed that CD9, CD32, and CD24 were over-represented in MLL-AF4, MLL-AF9, and MLL-ENL LICs compared with normal HSCs. In patient samples, these molecules were expressed in CD34+CD38+ and CD34− LICs but not in CD34+CD38−CD19−CD33− HSCs. Identification of LICs and LIC-specific molecules in primary human MLL-rearranged acute lymphoblastic leukemia may lead to improved therapeutic strategies for MLL-rearranged leukemia. PMID:25538041

New targeted therapies for relapsed pediatric acute lymphoblastic leukemia.

PubMed

Pierro, Joanna; Hogan, Laura E; Bhatla, Teena; Carroll, William L

2017-08-01

The improvement in outcomes for children with acute lymphoblastic leukemia (ALL) is one of the greatest success stories of modern oncology however the prognosis for patients who relapse remains dismal. Recent discoveries by high resolution genomic technologies have characterized the biology of relapsed leukemia, most notably pathways leading to the drug resistant phenotype. These observations open the possibility of targeting such pathways to prevent and/or treat relapse. Likewise, early experiences with new immunotherapeutic approaches have shown great promise. Areas covered: We performed a literature search on PubMed and recent meeting abstracts using the keywords below. We focused on the biology and clonal evolution of relapsed disease highlighting potential new targets of therapy. We further summarized the results of early trials of the three most prominent immunotherapy agents currently under investigation. Expert commentary: Discovery of targetable pathways that lead to drug resistance and recent breakthroughs in immunotherapy show great promise towards treating this aggressive disease. The best way to treat relapse, however, is to prevent it which makes incorporation of these new approaches into frontline therapy the best approach. Challenges remain to balance efficacy with toxicity and to prevent the emergence of resistant subclones which is why combining these newer agents with conventional chemotherapy will likely become standard of care.

Cytogenetic Profile of Moroccan Pediatric Acute Lymphoblastic Leukemia: Analysis of 155 Cases With a Review of the Literature.

PubMed

Chebihi, Zahra Takki; Belkhayat, Aziza; Chadli, Elbekkay; Hilal, Latifa; Skhoun, Hanaa; Hessissen, Laila; El Khorassani, Mohamed; El Kababri, Maria; Kili, Amina; Khattab, Mohammed; Bakri, Youssef; Dakka, Nadia

2018-04-25

Acute lymphoblastic leukemia (ALL) is the most common malignancy in children, with a peak incidence at 2 to 3 years of age and accounting for almost 30% of all cancers in this age group. It is well established that the identification of cytogenetic abnormalities is highly relevant for the prognosis of and therapeutic decisions in ALL. The purpose of the present study was to define the frequency of recurrent chromosomal abnormalities of ALL in Moroccan patients referred exclusively to the BIOLAB Laboratory of the Children's Hospital of Rabat during a 4-year period and compare our findings to the reported data. We performed conventional karyotyping of 155 ALL cases, with a successful cell culture rate of 94%. We identified chromosomal abnormalities in 66% of the total studied cases, of which 70% revealed important recurrent abnormalities with high prognostic value, such as hyperdiploidy, hypodiploidy, t(9;22), t(8;14), t(1;19), and MLL rearrangements. In total agreement with the reported data, most of the patients (56%) in the present study were aged 1 to 5 years, with a male predominance, and B-ALL was the most common blast phenotype (85%). The frequency of most chromosomal rearrangements successfully identified in our study and their lineage correlated with those reported in the published data. Copyright © 2018 Elsevier Inc. All rights reserved.

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

PubMed

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

2014-07-01

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

Secondary histiocytic sarcoma may cause apparent persistence or recurrence of minimal residual disease in childhood acute lymphoblastic leukemia.

PubMed

Alten, Julia; Klapper, Wolfram; Leuschner, Ivo; Eckert, Cornelia; Beier, Rita; Vallo, Elisabeth; Krause, Martin; Claviez, Alexander; Vieth, Simon; Bleckmann, Kirsten; Möricke, Anja; Schrappe, Martin; Cario, Gunnar

2015-09-01

Histiocytic sarcoma (HS) is a rare disease with poor prognosis which may develop subsequent to acute lymphoblastic leukemia (ALL). Here we report two children treated within the AIEOP-BFM ALL 2009 trial: one patient succumbed to fulminant hemophagocytic lymphohistiocytosis triggered by HS during ALL maintenance therapy, the other patient had a smoldering course of HS for over 2 years, and subsequently died after allogeneic stem cell transplantation. In both cases, HS and ALL were clonally related and apparent return of minimal residual disease (MRD) was detected by qPCR in bone marrow. Thus, HS should be considered in ALL when MRD appears to persist or reappear. © 2015 Wiley Periodicals, Inc.

Children’s Oncology Group’s 2013 Blueprint for Research: Acute Lymphoblastic Leukemia

PubMed Central

Hunger, Stephen P.; Loh, Mignon L.; Whitlock, James A.; Winick, Naomi J.; Carroll, William L.; Devidas, Meenakshi; Raetz, Elizabeth A.

2014-01-01

Approximately 90% of the 2,000 children, adolescents, and young adults enrolled each year in Children’s Oncology Group acute lymphoblastic leukemia (ALL) trials will be cured. However, high-risk subsets with significantly inferior survival remain, including infants, newly diagnosed patients with age ≥10 years, white blood count ≥50,000/µl, poor early response or T-cell ALL, and relapsed ALL patients. Effective strategies to improve survival include better risk stratification, optimizing standard chemotherapy and combining targeted therapies with cytotoxic chemotherapy, the latter of which is dependent upon identification of key driver mutations present in ALL. PMID:23255467

Treatment of Young Adults with Acute Lymphoblastic Leukemia.

PubMed

Kansagra, Ankit; Litzow, Mark

2017-06-01

Young adults with acute lymphoblastic leukemia are a distinctive category of patients, with substantial difference in disease biology and response to therapy; hence, they pose unique challenges and issues beyond those faced by children and older adults. Despite inferior survival compared to children, there is growing evidence to suggest that young adults have improved outcomes when treated with pediatric-based approaches. With better supportive care and toxicity management and multidisciplinary team and approach, we have made great improvement in outcomes of young adults with ALL. However, despite significant progress, patients with persistence of minimal residual disease have a poor prognosis. This review discusses current controversies in the management of young adults with ALL, outcomes following pediatric and adult protocols, and the role of allogeneic stem cell transplantation. We also explore recent advances in disease monitoring and highlight our approach to incorporation of novel therapies in the management of young adults with ALL.

Adolescents and young adults with acute lymphoblastic leukemia.

PubMed

Stock, Wendy

2010-01-01

During the last decade, increasing attention has been paid to a unique group of patients with acute lymphoblastic leukemia (ALL) who lie at the crossroad of therapeutic care by pediatric and adult hematologists/oncologists. ALL is a disease that affects infants, children, adolescents, and adult patients. With current therapies, the vast majority of children with ALL are now long-term survivors; unfortunately, the same good results have not yet been obtained for adults with ALL. This review will describe current controversies surrounding the treatment of adolescents and young adults with ALL--a group who finds themselves in the transition from "pediatric" to "adult" treatment approaches. The review focuses on recent insights into disease biology, prognostic factors, and treatment outcomes that have led to a series of prospective clinical trials specifically designed for adolescents and younger adults (AYAs) with ALL. These trials have been designed to provide important new clinical, psychosocial, and biological insights, and to further improve the survival of this challenging and unique group of patients.

Extreme Spindles and Leukoencephalopathy after Acute Lymphoblastic Leukemia Treatment: An Undescribed Association.

PubMed

Kanda, Paulo Afonso Medeiros; Kanda, Rafael Guimarães; Mei, Paulo Afonso; Cury, Ivan José

2015-12-01

We report a case of a child whose EEG demonstrated extreme spindles (ES) after acute lymphoblastic leukemia treatment. This finding has not been reported previously. In 1962, Gibbs and Gibbs described the ES EEG pattern due to its high amplitude (200 to 400 μV). ES are a rare spindle variant that is found in EEGs of 0.05% of normal children (average age, 3 years, with a range of 1 to 12 years), and are even rarer after 11 years. Moreover due to changes in the white matter of the frontal lobe, ES have been associated with such conditions as cerebral palsy and mental retardation, residual brain damage, undefined infections, infantile neuroaxonal dystrophy, Menkes' kinky-hair syndrome, congenital muscular dystrophy, hydrocephalus, porencephaly, epilepsy, progressive cerebellar degeneration, and mycoplasma encephalitis. Methotrexate has a notably toxic effect on the central nervous system, with leukoencephalopathy being the most common form. In our case, frontocentral ES were associated with hyperintense lesions in the white matter of the frontal lobe. Lesional deafferentation can be the substrate for an almost continuous ES, since both initiation and termination of spindle oscillations are thought to originate in thalamocortical neurons. Thus, we postulate that in some cases a partial functional cortical differentiation could generate ES.

Clonal selection in xenografted human T cell acute lymphoblastic leukemia recapitulates gain of malignancy at relapse.

PubMed

Clappier, Emmanuelle; Gerby, Bastien; Sigaux, François; Delord, Marc; Touzri, Farah; Hernandez, Lucie; Ballerini, Paola; Baruchel, André; Pflumio, Françoise; Soulier, Jean

2011-04-11

Genomic studies in human acute lymphoblastic leukemia (ALL) have revealed clonal heterogeneity at diagnosis and clonal evolution at relapse. In this study, we used genome-wide profiling to compare human T cell ALL samples at the time of diagnosis and after engraftment (xenograft) into immunodeficient recipient mice. Compared with paired diagnosis samples, the xenograft leukemia often contained additional genomic lesions in established human oncogenes and/or tumor suppressor genes. Mimicking such genomic lesions by short hairpin RNA-mediated knockdown in diagnosis samples conferred a selective advantage in competitive engraftment experiments, demonstrating that additional lesions can be drivers of increased leukemia-initiating activity. In addition, the xenograft leukemias appeared to arise from minor subclones existing in the patient at diagnosis. Comparison of paired diagnosis and relapse samples showed that, with regard to genetic lesions, xenograft leukemias more frequently more closely resembled relapse samples than bulk diagnosis samples. Moreover, a cell cycle- and mitosis-associated gene expression signature was present in xenograft and relapse samples, and xenograft leukemia exhibited diminished sensitivity to drugs. Thus, the establishment of human leukemia in immunodeficient mice selects and expands a more aggressive malignancy, recapitulating the process of relapse in patients. These findings may contribute to the design of novel strategies to prevent or treat relapse.

[Androgens and prolonged complete remissions in acute non lymphoblastic leukemias. Results of a systematic treatment with stanozolol associated with chemotherapy (author's transl)].

PubMed

Sotto, J J; Hollard, D; Schaerer, R; Bensa, J C; Seigneurin, D

1975-01-01

An androgen (stanozolol: 0,15 mg/kg/d) was systematically associated to the treatment of acute non lymphoblastic leukemias, since the beginning of induction therapy (vincristin, daunorubicin, prednisone) and throughout the maintenance period (6-mercaptopurine and methotrexate). Thirty-six patients less than 60 years old (median age: 44 years) presenting with acute non-lymphoblastic leukemia were entered to the study. Sixteen achieved complete remission (C.R.), i.e. 44% of the whole and 53% of treated patients. Out of 16 patients with complete remission, 4 relapsed during the observation period which lasted 4-1/2 years. The stability of the hematologic equilibrium in patients in C.R. is the main finding of the present study. The actuarial curve of the duration of the first complete remission reaches a "plateau"; after the 8th month only one relapse was observed in 9 patients. The rate of C.R. at 2 years is 76 +/- 23%. As compared to the results from other schedules of treatment, this rate appears significantly better, specially in the case of immunotherapy (p less than 0,001). A prospective randomized study is now suggested as to confirm this result; its therapeutic and theoretical basis and perspectives are discussed.

Can we incorporate geriatric assessment in the management of acute lymphoblastic leukemia in older adults?

PubMed

Loh, Kah Poh; Liesveld, Jane L; O'Dwyer, Kristen M

2018-04-05

Acute lymphoblastic leukemia (ALL) is an uncommon disease. Approximately 14% of new ALL cases occur in adults aged 60 and over, and the three-year overall survival in this population is poor at 12.8%. Older adults with ALL are heterogeneous in terms of their underlying health status, which can make treatment selection challenging given the disease rarity and limited inclusion of older patients in clinical trials. A comprehensive geriatric assessment (CGA) is a compilation of tools to assess multiple domains such as physical function and cognition, and may assist in guiding treatment selection and supportive care interventions. However, studies on the use of CGA are limited in older adults with ALL. In this review, we discuss the utility of CGA in patients with various hematologic malignancies. Using two patient cases of ALL, we also describe how CGA may be use to guide treatment and supportive care interventions. Copyright © 2018 Elsevier Inc. All rights reserved.

Acrophialophora fusispora Brain Abscess in a Child with Acute Lymphoblastic Leukemia: Review of Cases and Taxonomy

PubMed Central

Al-Mohsen, I. Z.; Sutton, D. A.; Sigler, L.; Almodovar, E.; Mahgoub, N.; Frayha, H.; Al-Hajjar, S.; Rinaldi, M. G.; Walsh, T. J.

2000-01-01

A 12-year-old girl with acute lymphoblastic leukemia was referred to King Faisal Specialist Hospital and Research Center. The diagnosis without central nervous system (CNS) involvement was confirmed on admission, and chemotherapy was initiated according to the Children Cancer Group (CCG) 1882 protocol for high-risk-group leukemia. During neutropenia amphotericin B (AMB) (1 mg/kg of body weight/day) was initiated for presumed fungal infection when a computed tomography (CT) scan of the chest revealed multiple nodular densities. After 3 weeks of AMB therapy, a follow-up chest CT revealed progression of the pulmonary nodules. The patient subsequently suffered a seizure, and a CT scan of the brain was consistent with infarction or hemorrhage. Because of progression of pulmonary lesions while receiving AMB, antifungal therapy was changed to liposomal AMB (LAMB) (6 mg/kg/day). Despite 26 days of LAMB, the patient continued to have intermittent fever, and CT and magnetic resonance imaging of the brain demonstrated findings consistent with a brain abscess. Aspiration of brain abscess was performed and the Gomori methenamine silver stain was positive for hyphal elements. Culture of this material grew Acrophialophora fusispora. Lung biopsy showed necrotizing fungal pneumonia with negative culture. The dosage of LAMB was increased, and itraconazole (ITRA) was added; subsequently LAMB was discontinued and therapy was continued with ITRA alone. The patient demonstrated clinical and radiological improvement. In vitro, the isolate was susceptible to low concentrations of AMB and ITRA. A. fusispora is a thermotolerant, fast-growing fungus with neurotropic potential. We report the first case of human infection involving the CNS. Acrophialophora resembles Paecilomyces but differs in having colonies that become dark and in the development of phialides along the sides or at the tips of echinulate brown conidiophores. Conidia are borne in long chains and are smooth or ornamented with

Genomic and transcriptional landscape of P2RY8-CRLF2-positive childhood acute lymphoblastic leukemia

PubMed Central

Vesely, C; Frech, C; Eckert, C; Cario, G; Mecklenbräuker, A; zur Stadt, U; Nebral, K; Kraler, F; Fischer, S; Attarbaschi, A; Schuster, M; Bock, C; Cavé, H; von Stackelberg, A; Schrappe, M; Horstmann, M A; Mann, G; Haas, O A; Panzer-Grümayer, R

2017-01-01

Children with P2RY8-CRLF2-positive acute lymphoblastic leukemia have an increased relapse risk. Their mutational and transcriptional landscape, as well as the respective patterns at relapse remain largely elusive. We, therefore, performed an integrated analysis of whole-exome and RNA sequencing in 41 major clone fusion-positive cases including 19 matched diagnosis/relapse pairs. We detected a variety of frequently subclonal and highly instable JAK/STAT but also RTK/Ras pathway-activating mutations in 76% of cases at diagnosis and virtually all relapses. Unlike P2RY8-CRLF2 that was lost in 32% of relapses, all other genomic alterations affecting lymphoid development (58%) and cell cycle (39%) remained stable. Only IKZF1 alterations predominated in relapsing cases (P=0.001) and increased from initially 36 to 58% in matched cases. IKZF1’s critical role is further corroborated by its specific transcriptional signature comprising stem cell features with signs of impaired lymphoid differentiation, enhanced focal adhesion, activated hypoxia pathway, deregulated cell cycle and increased drug resistance. Our findings support the notion that P2RY8-CRLF2 is dispensable for relapse development and instead highlight the prominent rank of IKZF1 for relapse development by mediating self-renewal and homing to the bone marrow niche. Consequently, reverting aberrant IKAROS signaling or its disparate programs emerges as an attractive potential treatment option in these leukemias. PMID:27899802

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

PubMed

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

2016-11-01

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

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

USDA-ARS?s Scientific Manuscript database

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

RAG-mediated recombination is the predominant driver of oncogenic rearrangement in ETV6-RUNX1 acute lymphoblastic leukemia

PubMed Central

Papaemmanuil, Elli; Rapado, Inmaculada; Li, Yilong; Potter, Nicola E; Wedge, David C; Tubio, Jose; Alexandrov, Ludmil B; Van Loo, Peter; Cooke, Susanna L; Marshall, John; Martincorena, Inigo; Hinton, Jonathan; Gundem, Gunes; van Delft, Frederik W; Nik-Zainal, Serena; Jones, David R; Ramakrishna, Manasa; Titley, Ian; Stebbings, Lucy; Leroy, Catherine; Menzies, Andrew; Gamble, John; Robinson, Ben; Mudie, Laura; Raine, Keiran; O’Meara, Sarah; Teague, Jon W; Butler, Adam P; Cazzaniga, Giovanni; Biondi, Andrea; Zuna, Jan; Kempski, Helena; Muschen, Markus; Ford, Anthony M; Stratton, Michael R; Greaves, Mel; Campbell, Peter J

2014-01-01

The ETV6-RUNX1 fusion gene, found in 25% of childhood acute lymphoblastic leukemia (ALL), is acquired in utero but requires additional somatic mutations for overt leukemia. We used exome and low-coverage whole-genome sequencing to characterize secondary events associated with leukemic transformation. RAG-mediated deletions emerge as the dominant mutational process, characterized by recombination signal sequence motifs near the breakpoints; incorporation of non-templated sequence at the junction; ~30-fold enrichment at promoters and enhancers of genes actively transcribed in B-cell development and an unexpectedly high ratio of recurrent to non-recurrent structural variants. Single cell tracking shows that this mechanism is active throughout leukemic evolution with evidence of localized clustering and re-iterated deletions. Integration of point mutation and rearrangement data identifies ATF7IP and MGA as two new tumor suppressor genes in ALL. Thus, a remarkably parsimonious mutational process transforms ETV6-RUNX1 lymphoblasts, targeting the promoters, enhancers and first exons of genes that normally regulate B-cell differentiation. PMID:24413735

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

2017-06-16

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

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

ClinicalTrials.gov

2018-04-30

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

Population pharmacokinetics of intravenous Erwinia asparaginase in pediatric acute lymphoblastic leukemia patients.

PubMed

Sassen, Sebastiaan D T; Mathôt, Ron A A; Pieters, Rob; Kloos, Robin Q H; de Haas, Valérie; Kaspers, Gertjan J L; van den Bos, Cor; Tissing, Wim J E; Te Loo, Maroeska; Bierings, Marc B; Kollen, Wouter J W; Zwaan, Christian M; van der Sluis, Inge M

2017-03-01

Erwinia asparaginase is an important component in the treatment of pediatric acute lymphoblastic leukemia. A large variability in serum concentrations has been observed after intravenous Erwinia asparaginase. Currently, Dutch Childhood Oncology Group protocols dose alterations are based on trough concentrations to ensure adequate asparaginase activity (≥100 IU/L). The aim of this study was to describe the population pharmacokinetics of intravenous Erwinia asparaginase to quantify and gather insight into inter-individual and inter-occasion variability. The starting dose was evaluated on the basis of the derived population pharmacokinetic parameters. In a multicenter prospective observational study, a total of 714 blood samples were collected from 51 children (age 1-17 years) with acute lymphoblastic leukemia. The starting dose was 20,000 IU/m 2 three times a week and adjusted according to trough levels from week three onwards. A population pharmacokinetic model was developed using NONMEM ® A 2-compartment linear model with allometric scaling best described the data. Inter-individual and inter-occasion variability of clearance were 33% and 13%, respectively. Clearance in the first month of treatment was 14% higher ( P <0.01). Monte Carlo simulations with our pharmacokinetic model demonstrated that patients with a low weight might require higher doses to achieve similar concentrations compared to patients with high weight. The current starting dose of 20,000 IU/m 2 might result in inadequate concentrations, especially for smaller, lower weight patients, hence dose adjustments based on individual clearance are recommended. The protocols were approved by the institutional review boards. (Registered at NTR 3379 Dutch Trial Register; www.trialregister.nl). Copyright© Ferrata Storti Foundation.

Predicting the neurobehavioral side effects of dexamethasone in pediatric acute lymphoblastic leukemia.

PubMed

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

2016-10-01

Although dexamethasone is an effective treatment for acute lymphoblastic leukemia (ALL), it can induce a variety of serious neurobehavioral side effects. We hypothesized that these side effects are influenced by glucocorticoid sensitivity at the tissue level. We therefore prospectively studied whether we could predict the occurrence of these side effects using the very low-dose dexamethasone suppression test (DST) or by measuring trough levels of dexamethasone. Fifty pediatric patients (3-16 years of age) with acute lymphoblastic leukemia (ALL) were initially included during the maintenance phase (with dexamethasone) of the Dutch ALL treatment protocol. As a marker of glucocorticoid sensitivity, the salivary very low-dose DST was used. A post-dexamethasone cortisol level <2.0nmol/L was considered a hypersensitive response. The neurobehavioral endpoints consisted of questionnaires regarding psychosocial and sleeping problems administered before and during the course of dexamethasone (6mg/m(2)), and dexamethasone trough levels were measured during dexamethasone treatment. Patients with a hypersensitive response to dexamethasone had more behavioral problems (N=11), sleeping problems, and/or somnolence (N=12) (P<0.05 for all three endpoints). The positive predictive values of the DST for psychosocial problems and sleeping problems were 50% and 30%, respectively. Dexamethasone levels were not associated with neurobehavioral side effects. We conclude that neither the very low-dose DST nor measuring dexamethasone trough levels can accurately predict dexamethasone-induced neurobehavioral side effects. However, patients with glucocorticoid hypersensitivity experienced significantly more symptoms associated with dexamethasone-induced depression. Future studies should elucidate further the mechanisms by which neurobehavioral side effects are influenced by glucocorticoid sensitivity. Copyright © 2016 Elsevier Ltd. All rights reserved.

[Treatment results with ALL-BFM-95 protocol in children with acute lymphoblastic leukemia in Hungary].

PubMed

Müller, Judit; Kovács, Gábor; Jakab, Zsuzsanna; Rényi, Imre; Galántai, Ilona; Békési, Andrea; Kiss, Csongor; Nagy, Kálmán; Kajtár, Pál; Bartyik, Katalin; Masát, Péter; Magyarosy, Edina

2005-01-09

In Hungary children (from 1 to 18 years of age) with de novo acute lymphoblastic leukemia were treated from January 1996 to October 2002, according to protocol ALL-BFM-95. The aim of this study was to evaluate the experience with this protocol, the treatment results according to the risk groups and to compare the Hungarian data with the international results. Patients were stratified into 3 risk groups, based on initial white blood cell count, age, immunology, cytogenetics and response to treatment: standard, medium and high risk group. Three hundred sixty eight children entered the study (male-female ratio was 1.27:1, median age 6 years and 4 months). 110 (29.9%) children were in the standard, 210 (57.1%) in the medium and 48 (13%) in the high risk group. Duration of the chemotherapy was 2 years, except of the boys in the standard risk group, their maintenance therapy was 1 year longer. The overall complete remission rate was 93.2%. 20 (5.4%) children died in induction and 5 (1.4%) were non-responders. The 5-year overall survival for all patients was 78.5%, in the standard risk group 93.2%, in the medium risk group 78.4% and in the high risk group 44.5% with a minimum follow up of 1.19 years and median follow up of 4.85 years. From the 368 patients 272 (73.9%) are still in their first complete clinical remission and other 18 children are alive after relapse. In 14.7% of the patients relapse was diagnosed; the most common site was the bone marrow. In one patient second malignancy occurred. The 5-year event free survival for all patients was 72.6%, in the standard risk group 87.6%, in the medium risk group 72.1% and in the high risk group 39.9%. The treatment outcome of children with acute lymphoblastic leukemia improved remarkably over the last decades. 78% of children suffering from acute lymphoblastic leukemia could be cured with the ALL-BFM-95 protocol. The Hungarian results are comparable to those achieved by other leukaemia study groups in the world regarding

Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia | Office of Cancer Genomics

Cancer.gov

Publication Abstract:  Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is characterized by a gene-expression profile similar to that of BCR-ABL1-positive ALL, alterations of lymphoid transcription factor genes, and a poor outcome. The frequency and spectrum of genetic alterations in Ph-like ALL and its responsiveness to tyrosine kinase inhibition are undefined, especially in adolescents and adults. We performed genomic profiling of 1725 patients with precursor B-cell ALL and detailed genomic analysis of 154 patients with Ph-like ALL.

Prediction of intellectual deficits in children with acute lymphoblastic leukemia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Trautman, P.D.; Erickson, C.; Shaffer, D.

1988-06-01

Possible predictors of reported lower cognitive functioning in irradiated children with acute lymphoblastic leukemia (ALL) were investigated. Thirty-four subjects, 5-14 years old, with ALL in continuous complete remission and without evidence of current or past central nervous system disease, were examined 9-110 months after diagnosis, using standard measures of intelligence and academic achievement. Subjects with a history of post-irradiation somnolence syndrome were significantly older at diagnosis than nonsomnolent subjects. Intelligence (IQ) was found to be unrelated to history of somnolence syndrome. IQ and achievement were unrelated to age at irradiation, irradiation-examination interval, and radiation dosages. The strongest predictor of IQmore » by far is parental social class. The importance of controlling for social class differences when searching for treatment effects on IQ and achievement is stressed.« less

Spectral karyotyping reveals a comprehensive karyotype in an adult acute lymphoblastic leukemia

PubMed Central

Guo, Bo; Zhu, Hong Li; Li, Su Xia; Lu, Xue Chun; Fan, Hui; Da, Wan Ming

2012-01-01

Cytogenetic abnormalities are frequently detected in patients with acute lymphoblastic leukemia (ALL). Comprehensive karyotype was related to poor prognosis frequently in ALL. We present a comprehensive karyotype in an adult ALL by spectral karyotyping (SKY) and R-banding. SKY not only confirmed the abnormalities previously seen by R-banding but also improved comprehensive karyotype analysis with the following result 47,XY,+9, ins(1;5)(q23;q23q34) t(6;7)(q23;p13). Our report demonstrated that SKY is able to provide more information accurately for prediction of disease prognosis in adult ALL with comprehensive karyotype. PMID:27298606

Nosocomial legionellosis and invasive aspergillosis in a child with T-lymphoblastic leukemia.

PubMed

Furtwängler, Rhoikos; Schlotthauer, Uwe; Gärtner, Barbara; Graf, Norbert; Simon, Arne

2017-07-01

Invasive aspergillosis of the lungs and the central nervous system and Legionella pneumophilia serotype 1 infection of the lungs were diagnosed in a 22-month old child during inpatient induction treatment for T-lymphoblastic leukemia. Environmental investigations i.e. samples from the hospital water system did not reveal any Legionella. The patient may have been exposed to waterborne pathogens despite terminal water filtration due to a technical device to release residual tap water from the hose after showering. A sodium chloride nose spray was found to be contaminated with the A. fumigatus isolate of the patient. Copyright © 2017 Elsevier GmbH. All rights reserved.

Chronic Myelogenous Leukemia (CML)

MedlinePlus

... del paciente Transplant process Diseases treated by transplant Acute myeloid leukemia Adrenoleukodystrophy (ALD) Chronic Lymphocytic Leukemia (CLL) ... SCID) Sickle cell disease (SCD) Wiskott-Aldrich syndrome Acute lymphoblastic leukemia (ALL) Other diseases Treatment decisions Learn ...

Effects of Acute Lymphoblastic Leukemia on Ceruloplasmin Oxidase, Copper and Several Markers of Oxidative Damage, in Children.

PubMed

Mehdi, Wesen Adel; Yusof, Faridah; Mehde, Atheer Awad; Zainulabdeen, Jwan Abdulmohsin; Raus, Raha Ahmed; Abdulbari, Alaa Shawqi

2015-01-01

Acute leukaemia is characterized by fast growth of abnormal clones of haemopoietic precursor cells inside bone marrow leading to undue accumulation in the bone marrow. Acute lymphoblastic leukemia (ALL) is the most common form of childhood cancer. The study concerned 50 children diagnosed with ALL (mean age, 8.55±2.54) compared to 40 healthy controls (mean age, 8.00±1.85). The Hb, serum copper, ceruloplasmin oxidase, advanced oxidation protein products (AOPPs), total antioxidant activity (TAA) and protein were measured in all groups. One proteinous component was isolated by gel filtration chromatography from the precipitate produced by polyethylene glycol. Significantly higher levels of AOPP, copper and decrease in total antioxidant activity were noted in the cases. Statistical analysis also showed a significant increase (p<0.01) in the activity of serum ceruloplasmin oxidase in patients with ALL compared to normal subjects. The maximum velocity (Vmax) and Michaelis constant had values of 104.2 U/L and 11.7 mM, respectively. The ΔH* values for ceruloplasmin oxidase in ALL patients were positive, confirming the reaction to be endothermic. The results from this study showed a significant increase in AOPP, ceruloplasmine oxidase and decrease in total antioxidant activity .These parameters may play a role in development of DNA damage in childhood patients with acute lymphoblastic leukemia (ALL). The ΔS* and ΔG* values were negative, these refer that the reaction of ES formation is spontaneous, but needs energy in a so-called endergonic reaction. Also the negative ΔS* value of ceruloplasmin oxidase indicates that the complex [ES*] is further modulated through increasing structure arrangement.

Brain Activity Associated With Attention Deficits Following Chemotherapy for Childhood Acute Lymphoblastic Leukemia.

PubMed

Fellah, Slim; Cheung, Yin T; Scoggins, Matthew A; Zou, Ping; Sabin, Noah D; Pui, Ching-Hon; Robison, Leslie L; Hudson, Melissa M; Ogg, Robert J; Krull, Kevin R

2018-05-21

The impact of contemporary chemotherapy treatment for childhood acute lymphoblastic leukemia on central nervous system activity is not fully appreciated. Neurocognitive testing and functional magnetic resonance imaging (fMRI) were obtained in 165 survivors five or more years postdiagnosis (average age = 14.4 years, 7.7 years from diagnosis, 51.5% males). Chemotherapy exposure was measured as serum concentration of methotrexate following high-dose intravenous injection. Neurocognitive testing included measures of attention and executive function. fMRI was obtained during completion of two tasks, the continuous performance task (CPT) and the attention network task (ANT). Image analysis was performed using Statistical Parametric Mapping software, with contrasts targeting sustained attention, alerting, orienting, and conflict. All statistical tests were two-sided. Compared with population norms, survivors demonstrated impairment on number-letter switching (P < .001, a measure of cognitive flexibility), which was associated with treatment intensity (P = .048). Task performance during fMRI was associated with neurocognitive dysfunction across multiple tasks. Regional brain activation was lower in survivors diagnosed at younger ages for the CPT (bilateral parietal and temporal lobes) and the ANT (left parietal and right hippocampus). With higher serum methotrexate exposure, CPT activation decreased in the right temporal and bilateral frontal and parietal lobes, but ANT alerting activation increased in the ventral frontal, insula, caudate, and anterior cingulate. Brain activation during attention and executive function tasks was associated with serum methotrexate exposure and age at diagnosis. These findings provide evidence for compromised and compensatory changes in regional brain function that may help clarify the neural substrates of cognitive deficits in acute lymphoblastic leukemia survivors.

Impact of a Vitamin D Replacement Algorithm in Children and Young Adults With Acute Lymphoblastic Leukemia.

PubMed

Young, Jennifer; Welin, Elizabeth; Braeutigam, Carina; Gilger, Elizabeth; Lane, Adam; Salloum, Ralph

2018-05-04

Pediatric cancer patients have a high prevalence of vitamin D deficiency. Children and young adults with acute lymphoblastic leukemia are at high risk for associated poor bone outcomes due to contributing effects of chemotherapy and supportive care. Evidence-based vitamin D guidelines are lacking in this population. This is a retrospective study following the implementation of an institutional guideline for standardized monitoring and supplementing vitamin D based on 25-hydroxyvitamin D levels and patient age. Goal 25-hydroxyvitamin D level was defined as ≥30 ng/mL and levels were checked every 3 months. Over a period of 22 months, 69 patients (median age, 6.7 y) were included. At diagnosis, 42 patients (60.8%) were insufficient. Among insufficient patients at diagnosis, 83.3% became sufficient at first repeat level following supplementation. At completion of the study 95.6% of patients were sufficient. Insufficiency was more common in winter than summer at baseline (74.3% vs. 47.1%, P=0.03), though the impact of seasonality was overcome following the algorithm. Throughout the study 4 patients had supratherapeutic but nontoxic levels. Vitamin D replacement guidelines implemented in the pediatric and young adult acute lymphoblastic leukemia population markedly increased the percentage of vitamin D sufficient patients in a short period of time.

Current Concepts in Pediatric Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

PubMed Central

Bernt, Kathrin M.; Hunger, Stephen P.

2014-01-01

The t(9;22)(q34;q11) or Philadelphia chromosome creates a BCR–ABL1 fusion gene encoding for a chimeric BCR–ABL1 protein. It is present in 3–4% of pediatric acute lymphoblastic leukemia (Ph+ ALL), and about 25% of adult ALL cases. Prior to the advent of tyrosine kinase inhibitors (TKI), Ph+ ALL was associated with a very poor prognosis despite the use of intensive chemotherapy and frequently hematopoietic stem-cell transplantation (HSCT) in first remission. The development of TKIs revolutionized the therapy of Ph+ ALL. Addition of the first generation ABL1 class TKI imatinib to intensive chemotherapy dramatically increased the survival for children with Ph+ ALL and established that many patients can be cured without HSCT. In parallel, the mechanistic understanding of Ph+ ALL expanded exponentially through careful mapping of pathways downstream of BCR–ABL1, the discovery of mutations in master regulators of B-cell development such as IKZF1 (Ikaros), PAX5, and early B-cell factor (EBF), the recognition of the complex clonal architecture of Ph+ ALL, and the delineation of genomic, epigenetic, and signaling abnormalities contributing to relapse and resistance. Still, many important basic and clinical questions remain unanswered. Current clinical trials are testing second generation TKIs in patients with newly diagnosed Ph+ ALL. Neither the optimal duration of therapy nor the optimal chemotherapy backbone are currently defined. The role of HSCT in first remission and post-transplant TKI therapy also require further study. In addition, it will be crucial to continue to dig deeper into understanding Ph+ ALL at a mechanistic level, and translate findings into complementary targeted approaches. Expanding targeted therapies hold great promise to decrease toxicity and improve survival in this high-risk disease, which provides a paradigm for how targeted therapies can be incorporated into treatment of other high-risk leukemias. PMID:24724051

[Acute hybrid leukemia. Review of the literature and presentation of a case].

PubMed

Guzzini, F; Angelopoulos, N; Banfi, L; Coppetti, D; Ceppi, M; Camerone, G

1990-03-01

In the last years, the development of immunophenotypic and molecular analyses allowed to recognize several cases of hybrid acute leukemia (AL), whose blast cell display both lymphoid and myeloid features. Hybrid, or mixed-lineage, AL seems to have distinct clinical manifestations and hematological findings, and is mainly characterized by resistance to chemotherapy and poor prognosis. We report on a patient with AL, which showed a very rapid switch from the lymphoblastic phenotype exhibited at presentation to a myelomonoblastic one, appeared at first relapse, and lastly progressed to an undifferentiated leukemia in the terminal phase. Together with this morphologic and cytochemical evolution, leukemic cells expressed, besides the primary early-B antigens, new immunological markers related to T-lymphocytic and myeloid lineages. Based on this observation and current understanding of the ontogenesis of hematologic malignancies, we discuss biological mechanisms which are likely to underlie hybrid leukemia.

Dental anomalies and dental age assessment in treated children with acute lymphoblastic leukemia.

PubMed

Khojastepour, L; Zareifar, S; Ebrahimi, M

2014-01-01

This cross sectional study was performed to evaluate dental ages and incidence of dental anomalies in children treated for acute lymphoblastic leukemia (ALL). A total of 25 ALL patient who passed at least 2 years of chemotherapy and 25 healthy sex and age matched children were evaluated. Dental age as well as dental anomalies in shape, size, number, and structure was recorded based on their panoramic radiographies which were taken for dental purposes. The number of dental anomalies significantly increased in ALL treated children. Seven ALL cases (28%) in compression to only one (4%) in control group had at least one dental anomaly. However, there was neither statistically significant differences between the mean of dental (p=0.32) and chronologic age (p=0.12) in both groups, nor between dental age of cases and control group (p=0.62).The age at the onset of treatment as well as treatment durations has not affected dental age and the incidence of dental anomalies significantly (p<0.05). Chemotherapy in children results in emergence of dental anomaly. Dental age, maturity, and development process however seems to be independent from chemotherapy.

EphB4-HSA Fusion Protein and Cytarabine /or Liposomal Vincristine in Patients With Recurrent or Refractory Acute Leukemia

ClinicalTrials.gov

2018-05-08

Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome; Blasts 5 Percent or More of Bone Marrow Nucleated Cells; Myelodysplastic/Myeloproliferative Neoplasm; Philadelphia Chromosome Positive; Recurrent Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Refractory Acute Lymphoblastic Leukemia; Refractory Acute Myeloid Leukemia; Refractory Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Secondary Acute Myeloid Leukemia; T Acute Lymphoblastic Leukemia

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

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

PubMed

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

2016-01-19

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.

Philadelphia chromosome-positive lymphoblastic lymphoma-Is it rare or underdiagnosed?

PubMed

Alshomar, Ahmad; El Fakih, Riad

2018-06-15

Lymphoblastic lymphomas (LBLs) are neoplasms of precursor B and T cells; they are considered in the same spectrum as precursor B and T cell acute lymphoblastic leukemia (ALL). The World Health Organization classification classifies both LBL and ALL as one disease entity. While chromosome abnormalities are well defined with all of their therapeutic and prognostic implications in ALL, these are not well studied in LBL. Here, we describe a case of Philadelphia chromosome-positive LBL and review the available literature regarding this entity. Copyright © 2018. Published by Elsevier Ltd.

Living near overhead high voltage transmission power lines as a risk factor for childhood acute lymphoblastic leukemia: a case-control study.

PubMed

Sohrabi, Mohammad-Reza; Tarjoman, Termeh; Abadi, Alireza; Yavari, Parvin

2010-01-01

This study aimed to investigate association of living near high voltage power lines with occurrence of childhood acute lymphoblastic leukemia (ALL). Through a case-control study 300 children aged 1-18 years with confirmed ALL were selected from all referral teaching centers for cancer. They interviewed for history of living near overhead high voltage power lines during at least past two years and compared with 300 controls which were individually matched for sex and approximate age. Logistic regression, chi square and paired t-tests were used for analysis when appropriate. The case group were living significantly closer to power lines (P<0.001). More than half of the cases were exposed to two or three types of power lines (P<0.02). Using logistic regression, odds ratio of 2.61 (95%CI: 1.73 to 3.94) calculated for less than 600 meters far from the nearest lines against more than 600 meters. This ratio estimated as 9.93 (95%CI: 3.47 to 28.5) for 123 KV, 10.78 (95%CI: 3.75 to 31) for 230 KV and 2.98 (95%CI: 0.93 to 9.54) for 400 KV lines. Odds of ALL decreased 0.61 for every 600 meters from the nearest power line. This study emphasizes that living close to high voltage power lines is a risk for ALL.

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

PubMed

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

2015-03-09

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

Transplantation Outcomes for Children with Hypodiploid Acute Lymphoblastic Leukemia.

PubMed

Mehta, Parinda A; Zhang, Mei-Jie; Eapen, Mary; He, Wensheng; Seber, Adriana; Gibson, Brenda; Camitta, Bruce M; Kitko, Carrie L; Dvorak, Christopher C; Nemecek, Eneida R; Frangoul, Haydar A; Abdel-Azim, Hisham; Kasow, Kimberly A; Lehmann, Leslie; Gonzalez Vicent, Marta; Diaz Pérez, Miguel A; Ayas, Mouhab; Qayed, Muna; Carpenter, Paul A; Jodele, Sonata; Lund, Troy C; Leung, Wing H; Davies, Stella M

2015-07-01

Children with hypodiploid acute lymphoblastic leukemia (ALL) have inferior outcomes despite intensive risk-adapted chemotherapy regimens. We describe 78 children with hypodiploid ALL who underwent hematopoietic stem cell transplantation between 1990 and 2010. Thirty-nine (50%) patients had ≤ 43 chromosomes, 12 (15%) had 44 chromosomes, and 27 (35%) had 45 chromosomes. Forty-three (55%) patients underwent transplantation in first remission (CR1) and 35 (45%) underwent transplantation in ≥ second remission (CR2). Twenty-nine patients (37%) received a graft from a related donor and 49 (63%) from an unrelated donor. All patients received a myeloablative conditioning regimen. The 5-year probabilities of leukemia-free survival, overall survival, relapse, and treatment-related mortality for the entire cohort were 51%, 56%, 27%, and 22%, respectively. Multivariate analysis confirmed that mortality risks were higher for patients who underwent transplantation in CR2 (hazard ratio, 2.16; P = .05), with number of chromosomes ≤ 43 (hazard ratio, 2.15; P = .05), and for those who underwent transplantation in the first decade of the study period (hazard ratio, 2.60; P = .01). Similarly, treatment failure risks were higher with number of chromosomes ≤ 43 (hazard ratio, 2.28; P = .04) and the earlier transplantation period (hazard ratio, 2.51; P = .01). Although survival is better with advances in donor selection and supportive care, disease-related risk factors significantly influence transplantation outcomes. Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Infection and childhood leukemia: review of evidence

PubMed Central

Maia, Raquel da Rocha Paiva; Wünsch, Victor

2013-01-01

OBJECTIVE To analyze studies that evaluated the role of infections as well as indirect measures of exposure to infection in the risk of childhood leukemia, particularly acute lymphoblastic leukemia. METHODS A search in Medline, Lilacs, and SciELO scientific publication databases initially using the descriptors "childhood leukemia" and "infection" and later searching for the words "childhood leukemia" and "maternal infection or disease" or "breastfeeding" or "daycare attendance" or "vaccination" resulted in 62 publications that met the following inclusion criteria: subject aged ≤ 15 years; specific analysis of cases diagnosed with acute lymphoblastic leukemia or total leukemia; exposure assessment of mothers' or infants' to infections (or proxy of infection), and risk of leukemia. RESULTS Overall, 23 studies that assessed infections in children support the hypothesis that occurrence of infection during early childhood reduces the risk of leukemia, but there are disagreements within and between studies. The evaluation of exposure to infection by indirect measures showed evidence of reduced risk of leukemia associated mainly with daycare attendance. More than 50.0% of the 16 studies that assessed maternal exposure to infection observed increased risk of leukemia associated with episodes of influenza, pneumonia, chickenpox, herpes zoster, lower genital tract infection, skin disease, sexually transmitted diseases, Epstein-Barr virus, and Helicobacter pylori. CONCLUSIONS Although no specific infectious agent has been identified, scientific evidence suggests that exposure to infections has some effect on childhood leukemia etiology. PMID:24626555

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

PubMed

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

2017-10-01

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

AZD1775 sensitizes T cell acute lymphoblastic leukemia cells to cytarabine by promoting apoptosis over DNA repair.

PubMed

Ford, James B; Baturin, Dmitry; Burleson, Tamara M; Van Linden, Annemie A; Kim, Yong-Mi; Porter, Christopher C

2015-09-29

While some children with acute lymphoblastic leukemia (ALL) have excellent prognoses, the prognosis for adults and children with T cell ALL is more guarded. Treatment for T-ALL is heavily dependent upon antimetabolite chemotherapeutics, including cytarabine. Targeted inhibition of WEE1 with AZD1775 has emerged as a strategy to sensitize cancer cells to cytarabine and other chemotherapeutics. We sought to determine if this strategy would be effective for T-ALL with clinically relevant anti-leukemia agents. We found that AZD1775 sensitizes T-ALL cells to several traditional anti-leukemia agents, acting synergistically with cytarabine by enhancing DNA damage and apoptosis. In addition to increased phosphorylation of H2AX at serine 139 (γH2AX), AZD1775 led to increased phosphorylation of H2AX at tyrosine 142, a signaling event associated with promotion of apoptosis over DNA repair. In a xenograft model of T-ALL, the addition of AZD1775 to cytarabine slowed leukemia progression and prolonged survival. Inhibition of WEE1 with AZD1775 sensitizes T-ALL to several anti-leukemia agents, particularly cytarabine and that mechanistically, AZD1775 promotes apoptosis over DNA repair in cells treated with cytarabine. These data support the development of clinical trials including AZD1775 in combination with conventional chemotherapy for acute leukemia.

AZD1775 sensitizes T cell acute lymphoblastic leukemia cells to cytarabine by promoting apoptosis over DNA repair

PubMed Central

Burleson, Tamara M.; Van Linden, Annemie A.; Kim, Yong-Mi; Porter, Christopher C.

2015-01-01

While some children with acute lymphoblastic leukemia (ALL) have excellent prognoses, the prognosis for adults and children with T cell ALL is more guarded. Treatment for T-ALL is heavily dependent upon antimetabolite chemotherapeutics, including cytarabine. Targeted inhibition of WEE1 with AZD1775 has emerged as a strategy to sensitize cancer cells to cytarabine and other chemotherapeutics. We sought to determine if this strategy would be effective for T-ALL with clinically relevant anti-leukemia agents. We found that AZD1775 sensitizes T-ALL cells to several traditional anti-leukemia agents, acting synergistically with cytarabine by enhancing DNA damage and apoptosis. In addition to increased phosphorylation of H2AX at serine 139 (γH2AX), AZD1775 led to increased phosphorylation of H2AX at tyrosine 142, a signaling event associated with promotion of apoptosis over DNA repair. In a xenograft model of T-ALL, the addition of AZD1775 to cytarabine slowed leukemia progression and prolonged survival. Inhibition of WEE1 with AZD1775 sensitizes T-ALL to several anti-leukemia agents, particularly cytarabine. Mechanistically, AZD1775 promotes apoptosis over DNA repair in cells treated with cytarabine. These data support the development of clinical trials including AZD1775 in combination with conventional chemotherapy for acute leukemia. PMID:26334102

Protracted Administration of L-Asparaginase in Maintenance Phase Is the Risk Factor for Hyperglycemia in Older Patients with Pediatric Acute Lymphoblastic Leukemia

PubMed Central

Yoshida, Hideki; Imamura, Toshihiko; Saito, Akiko M.; Takahashi, Yoshihiro; Suenobu, So-ichi; Hasegawa, Daiichiro; Deguchi, Takao; Hashii, Yoshiko; Kawasaki, Hirohide; Endo, Mikiya; Hori, Hiroki; Suzuki, Nobuhiro; Kosaka, Yoshiyuki; Kato, Koji; Yumura-Yagi, Keiko; Hara, Junichi; Oda, Megumi; Sato, Atsushi; Horibe, Keizo

2015-01-01

Although L-asparaginase related hyperglycemia is well known adverse event, it is not studied whether the profile of this adverse event is affected by intensification of L-asparaginase administration. Here, we analyzed the profile of L-asparaginase related hyperglycemia in a 1,176 patients with pediatric acute lymphoblastic leukemia treated according to the Japan Association of Childhood Leukemia Study ALL-02 protocol using protracted L-asparaginase administration in maintenance phase. We determined that a total of 75 L-asparaginase related hyperglycemia events occurred in 69 patients. Although 17 events (17/1176, 1.4%) developed in induction phase, which was lower incidence than those (10–15%) in previous reports, 45 events developed during the maintenance phase with protracted L-asparaginase administration. Multivariate analysis showed that older age at onset (≥10 years) was a sole independent risk factor for L-asparaginase-related hyperglycemia (P<0.01), especially in maintenance phase. Contrary to the previous reports, obesity was not associated with L-asparaginase-related hyperglycemia. These findings suggest that protracted administration of L-asparaginase is the risk factor for hyperglycemia when treating adolescent and young adult acute lymphoblastic leukemia patients. PMID:26317422

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

Living on a farm, contact with farm animals and pets, and childhood acute lymphoblastic leukemia: pooled and meta-analyses from the Childhood Leukemia International Consortium.

PubMed

Orsi, Laurent; Magnani, Corrado; Petridou, Eleni T; Dockerty, John D; Metayer, Catherine; Milne, Elizabeth; Bailey, Helen D; Dessypris, Nick; Kang, Alice Y; Wesseling, Catharina; Infante-Rivard, Claire; Wünsch-Filho, Victor; Mora, Ana M; Spector, Logan G; Clavel, Jacqueline

2018-06-01

The associations between childhood acute lymphoblastic leukemia (ALL) and several factors related to early stimulation of the immune system, that is, farm residence and regular contacts with farm animals (livestock, poultry) or pets in early childhood, were investigated using data from 13 case-control studies participating in the Childhood Leukemia International Consortium. The sample included 7847 ALL cases and 11,667 controls aged 1-14 years. In all studies, the data were obtained from case and control parents using standardized questionnaires. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by unconditional logistic regression adjusted for age, sex, study, maternal education, and maternal age. Contact with livestock in the first year of life was inversely associated with ALL (OR = 0.65, 95% CI: 0.50, 0.85). Inverse associations were also observed for contact with dogs (OR = 0.92, 95% CI: 0.86, 0.99) and cats (OR = 0.87, 95% CI: 0.80, 0.94) in the first year of life. There was no evidence of a significant association with farm residence in the first year of life. The findings of these large pooled and meta-analyses add additional evidence to the hypothesis that regular contact with animals in early childhood is inversely associated with childhood ALL occurrence which is consistent with Greaves' delayed infection hypothesis. © 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Prognostic Value of Cd95, Active Caspase-3, and Bcl-2 Expression in Adult Patients With De Novo Acute Lymphoblastic Leukemia.

PubMed

Montiel-Cervantes, Laura Arcelia; Reyes-Maldonado, Elba; Garcia-Chavez, Jaime; Hernandez-Caballero, Alvaro; Molina-Aguilar, Rubiraida; Garcia-Ruiz Esparza, Miriam America; Vela-Ojeda, Jorge

2018-04-18

Acute lymphoblastic leukemia is an aggressive malignant disease with high mortality rates in adults. The expression levels of CD95, active caspase-3, and Bcl-2 were determined in 111 patients with de novo acute lymphoblastic leukemia (ALL) and correlated with overall survival (OS) and disease-free survival (DFS). The immunophenotyped ok leukemia and the expression of CD95, active caspase-3, and Bcl-2, were determined by flow cytometry. Apoptotic variables were correlated by Spearman test, and survival by Kaplan-Meier method. Log-rank test was used to compare survival curves. From a total of 111 patients, 56 cases were B-ALL, 16 T-ALL, 16 B-ALL/CD33 + , and 23 ambiguous lineage-AL (AmbLin-AL). The median expression of CD95 (61.5%) and active-caspase-3 (19.4%) was higher in T-ALL (p < 0.05), whereas Bcl-2 was lower in T-ALL (p < 0.038). There was a highly significant correlation in B-ALL, B-ALL/CD33 + and AmbLin-AL between CD95 and Bcl-2, CD95-Active caspase-3, and Bcl-2-Active caspase-3; while in T-ALL, there was only a correlation between CD95-Active caspase-3, and Bcl-2-Active caspase-3. OS and DFS were better for T-ALL than the other groups, especially in patients having higher values of CD95 and active caspase 3, and lower values of Bcl-2. The worse survival rates were observed in patients with B-ALL/CD33 + , and AmbLin-AL. The prognosis of ALL in adults is influenced by the expression levels of Bcl-2, active-caspase-3, and CD95. Copyright © 2018 IMSS. Published by Elsevier Inc. All rights reserved.

Apatinib exhibits anti-leukemia activity in preclinical models of acute lymphoblastic leukemia.

PubMed

Deng, Manman; Zha, Jie; Jiang, Zhiwu; Jia, Xian; Shi, Yuanfei; Li, Peng; Chen, Xiao Lei; Fang, Zhihong; Du, Zhiqiang; Xu, Bing

2018-02-28

Acute lymphoblastic leukemia (ALL) is a clonal malignant disorder characterized by an uncontrolled proliferation of immature B or T lymphocytes. Extensive studies have suggested an involvement of angiogenesis signaling in ALL progression and resistance to treatment. Thus, targeting angiogenesis with anti-angiogenic drugs may be a promising approach for ALL treatment. In this study, we investigated the effectiveness of Apatinib, a novel receptor tyrosine kinase inhibitor selectively targeting VEGFR-2 in ALL cells. ALL cell lines were treated with different concentration of Apatinib and then CCK8 assay, flow cytometry were used to determine the IC 50 value and cell apoptosis, respectively. The effect of Apatinib against primary ALL cells from 11 adult patients and normal counterparts were also analyzed by apoptosis with flow cytometry. Next, we used western bolting and mass cytometry (CyTOF) assay to explore the underlying mechanism of the cytotoxicity of Apatinib. Finally, the anti-leukemia activity was further evaluated in an in vivo xenograft model of ALL. Our results showed that Apatinib significantly inhibited cell growth and promoted apoptosis in both B and T lineage ALL cell lines in a dose- and time-dependent manner. The IC 50 values of Apatinib against Nalm6, Reh, Jurkat and Molt4 for 48 h were 55.76 ± 13.19, 51.53 ± 10.74, 32.43 ± 5.58, 39.91 ± 9.88 μmol/L, and for 72 h were 30.34 ± 2.65, 31.96 ± 3.92, 17.62 ± 5.90, and 17.65 ± 2.17 μmol/L respectively. Similarly, Apatinib shows cytotoxic activity against primary adult ALL cells while sparing their normal counterparts in vitro. Moreover, Apatinib suppressed ALL growth and progression in an in vivo xenograft model. Mechanistically, Apatinib-induced cytotoxicity was closely associated with inhibition of VEGFR2 and its downstream signaling cascades, including the PI3 K, MAPK and STAT3 pathways. Our study indicates that Apatinib exerts its anti-leukemia effect by inducing

Childhood Acute Lymphoblastic Leukemia: Progress Through Collaboration

PubMed Central

Yang, Jun J.; Hunger, Stephen P.; Pieters, Rob; Schrappe, Martin; Biondi, Andrea; Vora, Ajay; Baruchel, André; Silverman, Lewis B.; Schmiegelow, Kjeld; Escherich, Gabriele; Horibe, Keizo; Benoit, Yves C.M.; Izraeli, Shai; Yeoh, Allen Eng Juh; Liang, Der-Cherng; Downing, James R.; Evans, William E.; Relling, Mary V.; Mullighan, Charles G.

2015-01-01

Purpose To review the impact of collaborative studies on advances in the biology and treatment of acute lymphoblastic leukemia (ALL) in children and adolescents. Methods A review of English literature on childhood ALL focusing on collaborative studies was performed. The resulting article was reviewed and revised by the committee chairs of the major ALL study groups. Results With long-term survival rates for ALL approaching 90% and the advent of high-resolution genome-wide analyses, several international study groups or consortia were established to conduct collaborative research to further improve outcome. As a result, treatment strategies have been improved for several subtypes of ALL, such as infant, MLL-rearranged, Philadelphia chromosome–positive, and Philadelphia chromosome–like ALL. Many recurrent genetic abnormalities that respond to tyrosine kinase inhibitors and multiple genetic determinants of drug resistance and toxicities have been identified to help develop targeted therapy. Several genetic polymorphisms have been recognized that show susceptibility to developing ALL and that help explain the racial/ethnic differences in the incidence of ALL. Conclusion The information gained from collaborative studies has helped decipher the heterogeneity of ALL to help improve personalized treatment, which will further advance the current high cure rate and the quality of life for children and adolescents with ALL. PMID:26304874

Childhood Acute Lymphoblastic Leukemia: Progress Through Collaboration.

PubMed

Pui, Ching-Hon; Yang, Jun J; Hunger, Stephen P; Pieters, Rob; Schrappe, Martin; Biondi, Andrea; Vora, Ajay; Baruchel, André; Silverman, Lewis B; Schmiegelow, Kjeld; Escherich, Gabriele; Horibe, Keizo; Benoit, Yves C M; Izraeli, Shai; Yeoh, Allen Eng Juh; Liang, Der-Cherng; Downing, James R; Evans, William E; Relling, Mary V; Mullighan, Charles G

2015-09-20

To review the impact of collaborative studies on advances in the biology and treatment of acute lymphoblastic leukemia (ALL) in children and adolescents. A review of English literature on childhood ALL focusing on collaborative studies was performed. The resulting article was reviewed and revised by the committee chairs of the major ALL study groups. With long-term survival rates for ALL approaching 90% and the advent of high-resolution genome-wide analyses, several international study groups or consortia were established to conduct collaborative research to further improve outcome. As a result, treatment strategies have been improved for several subtypes of ALL, such as infant, MLL-rearranged, Philadelphia chromosome-positive, and Philadelphia chromosome-like ALL. Many recurrent genetic abnormalities that respond to tyrosine kinase inhibitors and multiple genetic determinants of drug resistance and toxicities have been identified to help develop targeted therapy. Several genetic polymorphisms have been recognized that show susceptibility to developing ALL and that help explain the racial/ethnic differences in the incidence of ALL. The information gained from collaborative studies has helped decipher the heterogeneity of ALL to help improve personalized treatment, which will further advance the current high cure rate and the quality of life for children and adolescents with ALL. © 2015 by American Society of Clinical Oncology.

JAK2 aberrations in childhood B-cell precursor acute lymphoblastic leukemia

PubMed Central

de Goffau-Nobel, Willemieke; Hoogkamer, Alex Q.; Boer, Judith M.; Boeree, Aurélie; van de Ven, Cesca; Koudijs, Marco J.; Besselink, Nicolle J.M.; de Groot-Kruseman, Hester A.; Zwaan, Christian Michel; Horstmann, Martin A.; Pieters, Rob; den Boer, Monique L.

2017-01-01

JAK2 abnormalities may serve as target for precision medicines in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL). In the current study we performed a screening for JAK2 mutations and translocations, analyzed the clinical outcome and studied the efficacy of two JAK inhibitors in primary BCP-ALL cells. Importantly, we identify a number of limitations of JAK inhibitor therapy. JAK2 mutations mainly occurred in the poor prognostic subtypes BCR-ABL1-like and non- BCR-ABL1-like B-other (negative for sentinel cytogenetic lesions). JAK2 translocations were restricted to BCR-ABL1-like cases. Momelotinib and ruxolitinib were cytotoxic in both JAK2 translocated and JAK2 mutated cells, although efficacy in JAK2 mutated cells highly depended on cytokine receptor activation by TSLP. However, our data also suggest that the effect of JAK inhibition may be compromised by mutations in alternative survival pathways and microenvironment-induced resistance. Furthermore, inhibitors induced accumulation of phosphorylated JAK2Y1007, which resulted in a profound re-activation of JAK2 signaling upon release of the inhibitors. This preclinical evidence implies that further optimization and evaluation of JAK inhibitor treatment is necessary prior to its clinical integration in pediatric BCP-ALL. PMID:29163799

Detection and management of minimal residual disease in acute lymphoblastic leukemia.

PubMed

Schrappe, Martin

2014-12-05

The detection of minimal residual disease (MRD) has become part of the state-of-the-art diagnostics to guide treatment both in pediatric and adult acute lymphoblastic leukemia (ALL). This applies to the treatment of de novo and recurrent ALL. In high-risk ALL, MRD detection is considered an important tool to adjust therapy before and after hematopoietic stem cell transplantation. Precise quantification and quality control is instrumental to avoid false treatment assignment. A new methodological approach to analyzing MRD has become available and is based on next-generation sequencing. In principle, this technique will be able to detect a large number of leukemic subclones at a much higher speed than before. Carefully designed prospective studies need to demonstrate concordance or even superiority compared with those techniques in use right now: detection of aberrant expression of leukemia-specific antigens by flow cytometry of blood or bone marrow, or detection of specific rearrangements of the T-cell receptor or immunoglobulin genes by real-time quantitative polymerase chain reaction using DNA of leukemic cells. In some cases with known fusion genes, such as BCR/ABL, reverse transcriptase-polymerase chain reaction has been used as additional method to identify leukemic cells by analyzing RNA in patient samples. MRD detection may be used to modulate treatment intensity once it has been demonstrated at well-defined informative checkpoints that certain levels of MRD can reliably predict the risk of relapse. In addition, MRD is used as end point to determine the activity of a given agent or treatment protocol. If activity translates into antileukemic efficacy, MRD may be considered a surrogate clinical end point. © 2014 by The American Society of Hematology. All rights reserved.

Association between MTHFR C677T polymorphism and risk of acute lymphoblastic leukemia: a meta-analysis based on 51 case-control studies.

PubMed

Li, Su-yi; Ye, Jie-yu; Liang, En-yu; Zhou, Li-xia; Yang, Mo

2015-03-12

Studies and systematic reviews have reached inconsistent conclusions on the role of 5, 10-methylenetetrahydrofolate reductase (MTHFR) polymorphism C677T in acute lymphoblastic leukemia (ALL) risk. The present meta-analysis comprising of 51 case-control studies, including 7892 cases and 14 280 controls was performed to reevaluate the association between MTHFR C677T polymorphism and ALL risk. Statistical differences were found in the dominant model (TT+CT vs. CC, odd ratio (OR)=0.89, 95% CI, 0.79-1.00, P=0.04) and the CT vs. CC (OR=0.89, 95% CI, 0.80-1.00, P=0.05), but not in the allele contrast model (T vs. C, OR=0.92, 95% CI, 0.84-1.01, P=0.08), additive model (TT vs. CC, OR=0.87, 95% CI, 0.73-1.05, P=0.15), or recessive model (TT vs. CT+CC, OR=0.94, 95% CI, 0.81-1.10, P=0.44) in overall populations. In the subgroup analyses stratified by age (children and adults) and ethnicity (Asian and Caucasian), no significant associations between MTHFR C677T polymorphism and ALL risk were observed. The current study found no sufficient evidence of a protective role of MTHFR C677T polymorphism in ALL susceptibility.

[Epigenetic alterations in acute lymphoblastic leukemia].

PubMed

Navarrete-Meneses, María Del Pilar; Pérez-Vera, Patricia

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. It is well-known that genetic alterations constitute the basis for the etiology of ALL. However, genetic abnormalities are not enough for the complete development of the disease, and additional alterations such as epigenetic modifications are required. Such alterations, like DNA methylation, histone modifications, and noncoding RNA regulation have been identified in ALL. DNA hypermethylation in promoter regions is one of the most frequent epigenetic modifications observed in ALL. This modification frequently leads to gene silencing in tumor suppressor genes, and in consequence, contributes to leukemogenesis. Alterations in histone remodeling proteins have also been detected in ALL, such as the overexpression of histone deacetylases enzymes, and alteration of acetyltransferases and methyltransferases. ALL also shows alteration in the expression of miRNAs, and in consequence, the modification in the expression of their target genes. All of these epigenetic modifications are key events in the malignant transformation since they lead to the deregulation of oncogenes as BLK, WNT5B and WISP1, and tumor suppressors such as FHIT, CDKN2A, CDKN2B, and TP53, which alter fundamental cellular processes and potentially lead to the development of ALL. Both genetic and epigenetic alterations contribute to the development and evolution of ALL. Copyright © 2017 Hospital Infantil de México Federico Gómez. Publicado por Masson Doyma México S.A. All rights reserved.

Treatment of acute lymphoblastic leukemia in children and adolescents: peaks and pitfalls.

PubMed

Seibel, Nita L

2008-01-01

Survival of children with acute lymphoblastic leukemia (ALL) is often described as the success story for oncology. The improvements in the treatment of ALL represent the work of cooperative groups at their best. Fifty years ago a pediatric oncologist would have never considered using the term "cure" in a discussion with a family whose child was diagnosed with ALL. Today the term is not only used in the initial discussion but referred to frequently thereafter. However, as we all know, cure is not assured and is not obtained without sequelae. This review will focus on the improvements in treatment for newly diagnosed ALL in children and adolescents according to risk group and some of the challenges that remain despite the improved outcome.

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

PubMed

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

2017-10-01

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

The genomic landscape of acute lymphoblastic leukemia in children and young adults.

PubMed

Mullighan, Charles G

2014-12-05

Our understanding of the genetic basis of childhood acute lymphoblastic leukemia (ALL) has been greatly advanced by genomic profiling and sequencing studies. These efforts have characterized the genetic basis of recently described and poorly understood subtypes of ALL, including early T-cell precursor ALL, Philadelphia chromosome-like (Ph-like) ALL, and ALL with intrachromosomal amplification of chromosome 21, and have identified several rational therapeutic targets in high-risk ALL, notably ABL1-class and JAK-STAT inhibitors in Ph-like ALL. Deep sequencing studies are also refining our understanding of the genetic basis of clonal heterogeneity and relapse. These studies have elucidated the nature of clonal evolution during disease progression and identified genetic changes that confer resistance to specific therapeutic agents, including CREBBP and NT5C2. Genomic profiling has also identified common and rare inherited genetic variants that influence the risk of developing leukemia. These efforts are now being extended to ALL in adolescents and adults with the goal of fully defining the genetic landscape of ALL to further improve treatment outcomes in high-risk populations. © 2014 by The American Society of Hematology. All rights reserved.

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

PubMed

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

1978-05-01

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

Acute lymphoblastic leukemia in adolescents and young adults.

PubMed

Burke, Patrick W; Douer, Dan

2014-01-01

The cure rate of acute lymphoblastic leukemia (ALL) in children is 80%, compared to less than half in adults. A major proportion of this cure rate drop occurs in adolescents and young adults (AYAs). The age range defining this population varies between studies, biological characteristics are different from both younger children and older adults, and AYAs are treated either by pediatric or adult oncologists, who often apply different treatment approaches to the same ALL patient population. The outcome of AYAs aged 15-21 years treated by more contemporary pediatric protocols is similar to that of younger children but is inferior when using adult regimens. This motivated studying AYA patients, including those above the age of 21 years, with pediatric or 'pediatrics-inspired' regimens that intensified nonmyelosuppressive drugs such as vincristine, steroids and asparaginase, with very promising preliminary results. Discovering new mutations in AYA ALL will help stratify patients into risk subgroups and identify targets for novel agents. This, together with fine-tuning pediatric chemotherapy principles will hopefully finally decrease the cure rate gap between children and AYAs - and even older adults. © 2014 S. Karger AG, Basel.

Systemic Exposure to Thiopurines and Risk of Relapse in Children with Acute Lymphoblastic Leukemia: A Children’s Oncology Group Study

PubMed Central

Bhatia, Smita; Landier, Wendy; Hageman, Lindsey; Chen, Yanjun; Kim, Heeyoung; Sun, Can-Lan; Kornegay, Nancy; Evans, William E; Angiolillo, Anne L; Bostrom, Bruce; Casillas, Jacqueline; Lew, Glen; Maloney, Kelly W; Mascarenhas, Leo; Ritchey, A. Kim; Termuhlen, Amanda M; Carroll, William L; Wong, F Lennie; Relling, Mary V

2015-01-01

Importance Variability in prescribed 6-mercaptopurine and lack of adherence to 6-mercaptopurine could result in intra-individual variability in systemic exposure to 6-mercaptopurine (measured as erythrocyte thioguanine nucleotide levels) in children with acute lymphoblastic leukemia. The impact of intra-individual variability in systemic exposure to 6-mercaptopurine on relapse risk is unknown. Objective To determine impact of high intra-individual variability in 6-mercaptopurine systemic exposure on relapse risk in children with acute lymphoblastic leukemia. Design Prospective longitudinal design; daily adherence monitoring, 6-mercaptopurine dose-intensity and erythrocyte thioguanine nucleotide levels (pmol/8*10^8 erythrocytes) measured for 6 consecutive months per patient; cohort followed for a median of 6.7 years from diagnosis. Setting Children’s Oncology Group study (COG-AALL03N1); 94 participating institutions; ambulatory care setting. Participants Participants included 742 children meeting the following eligibility criteria: diagnosis of acute lymphoblastic leukemia at ≤21 years; in first continuous remission at study entry; receiving self/parent/caregiver-administered oral 6-mercaptopurine during maintenance. Median age at diagnosis: 5 years; 68% were male; 43% with NCI-based high-risk disease. Main Outcome Measures Adherence measured electronically using Medication Event Monitoring System that recorded date/time of each 6-mercaptopurine bottle opening; adherence rate defined as ratio of days of 6-mercaptopurine bottle opened to days when 6-mercaptopurine prescribed. 6-mercaptopurine doses actually prescribed were divided by planned protocol doses (75mg/m2/day) to compute average monthly dose-intensity. Electronically-monitored adherence (68,716 person-days), 6-mercaptopurine dose-intensity (120,439 person-days) and monthly erythrocyte thioguanine nucleotide levels (n=3,944 measurements) contributed to the analysis. Using intra-individual coefficients of

The biology, pathogenesis and clinical aspects of acute lymphoblastic leukemia in children with Down syndrome.

PubMed

Lee, P; Bhansali, R; Izraeli, S; Hijiya, N; Crispino, J D

2016-09-01

Children with Down syndrome (DS) are at a 20-fold increased risk for acute lymphoblastic leukemia (DS-ALL). Although the etiology of this higher risk of developing leukemia remains largely unclear, the recent identification of CRLF2 (cytokine receptor like factor 2) and JAK2 mutations and study of the effect of trisomy of Hmgn1 and Dyrk1a (dual-specificity tyrosine phosphorylation-regulated kinase 1A) on B-cell development have shed significant new light on the disease process. Here we focus on the clinical features, biology and genetics of ALL in children with DS. We review the unique characteristics of DS-ALL on both the clinical and molecular levels and discuss the differences in treatments and outcomes in ALL in children with DS compared with those without DS. The identification of new biological insights is expected to pave the way for novel targeted therapies.

Plasma Hsp90 Level as a Marker of Early Acute Lymphoblastic Leukemia Engraftment and Progression in Mice

PubMed Central

de Vasconcellos, Jaíra Ferreira; Brandalise, Silvia Regina; Nowill, Alexandre Eduardo; Yunes, José Andrés

2015-01-01

Current monitoring of acute lymphoblastic leukemia (ALL) in living mice is based on FACS analysis of blood hCD45+ cells. In this work, we evaluated the use of human IGFBP2, B2M or Hsp90 as soluble markers of leukemia. ELISA for B2M and IGFBP2 resulted in high background levels in healthy animals, precluding its use. Conversely, plasma levels of Hsp90 showed low background and linear correlation to FACS results. In another experiment, we compared Hsp90 levels with percentage of hCD45+ cells in blood, bone marrow, liver and spleen of animals weekly sacrificed. Hsp90 levels proved to be a superior method for the earlier detection of ALL engraftment and correlated linearly to ALL burden and progression in all compartments, even at minimal residual disease levels. Importantly, the Hsp90/hCD45+ ratio was not altered when animals were treated with dexamethasone or a PI3K inhibitor, indicating that chemotherapy does not directly interfere with leukemia production of Hsp90. In conclusion, plasma Hsp90 was validated as a soluble biomarker of ALL, useful for earlier detection of leukemia engraftment, monitoring leukemia kinetics at residual disease levels, and pre-clinical or mouse avatar evaluations of anti-leukemic drugs. PMID:26068922

The role of 18F-FDG PET/CT in pediatric lymph-node acute lymphoblastic leukemia involvement.

PubMed

Cistaro, Angelina; Saglio, Francesco; Asaftei, Sebastian; Fania, Piercarlo; Berger, Massimo; Fagioli, Franca

2011-01-01

In pediatric oncology, positron emission tomography/computed tomography (PET/CT) is emerging as an essential diagnostic tool in characterizing suspicious neoplastic lesions and staging malignant diseases. Most studies regarding the possible role of FDG-PET/CT in the management of acute lymphoblastic leukemia (ALL) patients are limited to adults. Here we report a pediatric patient with recurrent ALL, in which FDG-PET/CT was used both to define more precisely the cause of lymphadenopathy and to assess the effect of the second-line therapy.

Generation of human acute lymphoblastic leukemia xenografts for use in oncology drug discovery

PubMed Central

Holmfeldt, Linda

2015-01-01

The establishment of reproducible mouse models of acute lymphoblastic leukemia (ALL) is necessary to provide in vivo therapeutic models that recapitulate human ALL, and for amplification of limiting amounts of primary tumor material. A frequently used model is the primary xenograft model that utilizes immunocompromised mice and involves injection of primary patient tumor specimens into mice, and subsequent serial passaging of the tumors by retransplants of cells harvested from the mouse bone marrow and spleen. The tumors generated can then be used for genomic profiling, ex vivo compound testing, mechanistic studies and retransplantation. This unit describes detailed procedures for the establishment and maintenance of primary ALL xenograft panels for potential use in basic research or translational studies. PMID:25737157

Blinatumomab activity in a patient with Down syndrome B-precursor acute lymphoblastic leukemia.

PubMed

Wadhwa, Aman; Kutny, Matthew A; Xavier, Ana C

2018-02-01

Persistent minimal residual disease (MRD) after consolidation may indicate chemotherapy insensitivity in B-precursor acute lymphoblastic leukemia (BP-ALL). Given the strong association of MRD and outcome in non-Down syndrome (non-DS) BP-ALL, it is likely that MRD levels are also of prognostic significance in DS BP-ALL. We report here the successful use of blinatumomab, a bispecific T-cell engager antibody construct, in a patient with DS BP-ALL and persistent MRD at the end of consolidation. Blinatumomab has been shown to have excellent results in patients with relapsed/refractory BP-ALL. This patient had no significant toxicity and achieved MRD negativity after only one cycle of blinatumomab. © 2017 Wiley Periodicals, Inc.

Mapping of four distinct BCR-related loci to chromosome region 22q11: order of BCR loci relative to chronic myelogenous leukemia and acute lymphoblastic leukemia breakpoints

DOE Office of Scientific and Technical Information (OSTI.GOV)

Croce, C.M.; Huebner, K.; Isobe, M.

1987-10-01

A probe derived from the 3' region of the BCR gene (breakpoint cluster region gene) detects four distinct loci in the human genome. One of the loci corresponds to the complete BCR gene, whereas the other contain a 3' segment of the gene. After HindIII cleavage of human DNA, these four loci are detected as 23-, 19-, 13-, and 9-kikobase-pair fragments, designated BCR4, BCR3, BCR2, and BCR1, respectively, with BCR1 deriving from the original complete BCR gene. All four BCR loci segregate 100% concordantly with human chromosome 22 in a rodent-human somatic cell hybrid panel and are located at chromosomemore » region 22q11.2 by chromosomal in situ hybridization. The BCR2 and BCR4 loci are amplified in leukemia cell line K562 cells, indicating that they fall within the amplification unit that includes immunoglobulin lambda light chain locus (IGL) and ABL locus on the K562 Philadelphia chromosome (Ph/sup 1/). Similarly, in mouse-human hybrids retaining a Ph/sup 1/ chromosome derived from an acute lymphoblastic leukemia-in the absence of the 9q/sup +/ and 22, only BCR2 and BCR4 loci are retained. Thus, the order of loci on chromosome 22 is centromere ..-->.. BCR2, BCR4, and IGL ..-->.. BCR1 ..-->.. BCR3 ..-->.. SIS, possibly eliminating BCR2 and BCR4 loci as candidate targets for juxtaposition to the ABL gene in the acute lymphoblastic leukemia Ph/sup 1/ chromosome.« less

Heterogeneous breakpoints in patients with acute lymphoblastic leukemia and the dic(9;20)(p11~13;q11) show recurrent involvement of genes at 20q11.21

PubMed Central

An, Qian; Wright, Sarah L.; Moorman, Anthony V.; Parker, Helen; Griffiths, Mike; Ross, Fiona M.; Davies, Teresa; Harrison, Christine J.; Strefford, Jon C.

2009-01-01

The dic(9;20)(p11~13;q11) is a recurrent chromosomal abnormality in patients with acute lymphoblastic leukemia. Although it results in loss of material from 9p and 20q, the molecular targets on both chromosomes have not been fully elucidated. From an initial cohort of 58 with acute lymphoblastic leukemia patients with this translocation, breakpoint mapping with fluorescence in situ hybridization on 26 of them revealed breakpoint heterogeneity of both chromosomes. PAX5 has been proposed to be the target gene on 9p, while for 20q, FISH analysis implicated the involvement of the ASXL1 gene, either by a breakpoint within (n=4) or centromeric (deletion, n=12) of the gene. Molecular copy-number counting, long-distance inverse PCR and direct sequence analysis identified six dic(9;20) breakpoint sequences. In addition to the three previously reported: PAX5-ASXL1, PAX5-C20ORF112 and PAX5-KIF3B; we identified three new ones in this study: sequences 3’ of PAX5 disrupting ASXL1, and ZCCHC7 disrupted by sequences 3’ of FRG1B and LOC1499503. This study provides insight into the breakpoint complexity underlying dicentric chromosomal formation in acute lymphoblastic leukemia and highlights putative target gene loci. PMID:19586940

Heterogeneous breakpoints in patients with acute lymphoblastic leukemia and the dic(9;20)(p11-13;q11) show recurrent involvement of genes at 20q11.21.

PubMed

An, Qian; Wright, Sarah L; Moorman, Anthony V; Parker, Helen; Griffiths, Mike; Ross, Fiona M; Davies, Teresa; Harrison, Christine J; Strefford, Jon C

2009-08-01

The dic(9;20)(p11-13;q11) is a recurrent chromosomal abnormality in patients with acute lymphoblastic leukemia. Although it results in loss of material from 9p and 20q, the molecular targets on both chromosomes have not been fully elucidated. From an initial cohort of 58 with acute lymphoblastic leukemia patients with this translocation, breakpoint mapping with fluorescence in situ hybridization on 26 of them revealed breakpoint heterogeneity of both chromosomes. PAX5 has been proposed to be the target gene on 9p, while for 20q, FISH analysis implicated the involvement of the ASXL1 gene, either by a breakpoint within (n=4) or centromeric (deletion, n=12) of the gene. Molecular copy-number counting, long-distance inverse PCR and direct sequence analysis identified six dic(9;20) breakpoint sequences. In addition to the three previously reported: PAX5-ASXL1, PAX5-C20ORF112 and PAX5-KIF3B; we identified three new ones in this study: sequences 3' of PAX5 disrupting ASXL1, and ZCCHC7 disrupted by sequences 3' of FRG1B and LOC1499503. This study provides insight into the breakpoint complexity underlying dicentric chromosomal formation in acute lymphoblastic leukemia and highlights putative target gene loci.

Molecular detection of BCR/ABL fusion gene in Saudi acute lymphoblastic leukemia patients.

PubMed

El-Sissy, Azza; El-Mashari, May; Bassuni, Wafaa; El-Swaayed, Aziza

2006-06-01

Molecular cytogenetics is becoming one of the most useful tools targeting some genes which are generally considered to lead to leukemic transformation (as well as for numerical abnormalities). A fraction of acute lymphoblastic leukemia (ALL) cases carry the translocation t(9;22) (q34;q11.2) which juxtaposes the ABL proto-oncogene to the BCR gene generating a chimeric gene, BCR/ABL. This aberration is more frequent in adult ALL (20%-40%) than in pediatric ALL (<5%), and predicts poor clinical outcome. AIM OF OUR WORK: Is to study BCR/ABL fusion gene in ALL cases using fluorescent in situ hybridization. Twenty newly diagnosed ALL patients, 16 adult and 4 paediatric cases, were included in the study, 11 cases (55%) were of precursor B phenotype, 8 cases (40%) belonged to T lineage, while one case was biphenotypic expressing mainly precursor B cell markers tether with CD13, CD33, CD117, Detection of BCR/ABL fusion gene was done using interphase FISH technique and was confirmed molecularly using the RT-PCR technique. BCR/ABL fusion gene was negative in all the examined cases, yet abnormality involving 9q34, ABL gene, either by addition or deletion was detected in three cases (15%). Two of these cases were associated with BCR gene extra copies (three and four copies, respectively). This may reflect the frequency of association of ABL gene and BCR gene abnormality in our cases, and that absence of fusion gene BCR/ABL does not exclude their role in the leukomogenic process, yet a larger study is required to confirm and detect the prevalence of these gene disturbances in ALL and their association.

Impact of single nucleotide polymorphisms of cytarabine metabolic genes on drug toxicity in childhood acute lymphoblastic leukemia.

PubMed

Gabor, Krisztina Mita; Schermann, Geza; Lautner-Csorba, Orsolya; Rarosi, Ferenc; Erdelyi, Daniel J; Endreffy, Emoke; Berek, Krisztina; Bartyik, Katalin; Bereczki, Csaba; Szalai, Csaba; Semsei, Agnes F

2015-04-01

Cytarabine (cytosine arabinoside, ara-C) is a chemotherapeutical agent used in the treatment of pediatric acute lymphoblastic leukemia (ALL). Adverse drug reactions, such as interpatient variability in sensitivity to ara-C, are considerable and may cause difficulties during chemotherapy. Single nucleotide polymorphisms (SNPs) can play a significant role in modifying nucleoside-drug pharmacokinetics and pharmacodynamics and thus the development of adverse effects. Our aim was to determine whether polymorphisms in genes encoding transporters and enzymes responsible for the metabolism of ara-C are associated with toxicity and clinical outcome in a patient population with childhood ALL. We studied 8 SNPs in the CDA, DCK, DCTD, SLC28A3, and SLC29A1 genes in 144 patients with childhood acute lymphoblastic leukemia treated according to ALLIC BFM 1990, 1995 and 2002 protocols. DCK rs12648166 and DCK rs4694362 SNPs were associated with hematologic toxicity (OR = 2.63, CI 95% = 1.37-5.04, P = 0.0036 and OR = 2.53, CI 95% = 1.34-4.80, P = 0.0044, respectively). Our results indicate that DCK polymorphisms might be important genetic risk factors for hematologic toxicity during ALL treatment with ara-C. Individualized chemotherapy based on genetic profiling may help to optimize ara-C dosing, leading to improvements in clinical outcome and reduced toxicity. © 2015 Wiley Periodicals, Inc.

Clofarabine and Melphalan Before Donor Stem Cell Transplant in Treating Patients With Myelodysplasia, Acute Leukemia in Remission, or Chronic Myelomonocytic Leukemia

ClinicalTrials.gov

2018-03-22

Adult Acute Lymphoblastic Leukemia in Remission; Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome; Adult Acute Myeloid Leukemia in Remission; Myelodysplastic Syndrome; Secondary Myelodysplastic Syndrome; Chronic Myelomonocytic Leukemia; Therapy-Related Myelodysplastic Syndrome

Morphological and immunological criteria of minimal residual disease detection in children with B-cell precursors acute lymphoblastic leukemia

NASA Astrophysics Data System (ADS)

Beznos, O. A.; Grivtsova, L. Yu; Popa, A. V.; Shervashidze, M. A.; Serebtyakova, I. N.; Tupitsyn, N. N.; Selchuk, V. U.; Grebennikova, O. P.; Titova, G. V.

2018-01-01

One of the key factors of prognosis and risk stratification in patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is minimal residual disease (MRD). Identification of MRD on the day 15th is one of the most significant in prognosis of the disease. We compared data of a morphological and flow cytometry results of assessment of a bone marrow (BM) at the day 15th of induction chemotherapy in children with BCP-ALL.

Juvenile Myelomonocytic Leukemia (JMML) (For Parents)

MedlinePlus

... Radiation Chemotherapy Acute Lymphoblastic Leukemia (ALL) Leukemia Neutropenia Stem Cell Transplants Caring for a Seriously Ill Child Acute Myeloid Leukemia (AML) Cancer Center Chemotherapy Some Kinds of Cancer Kids Get When Cancer Keeps You Home Cancer: Readjusting ...

Parvovirus B19 infection in a child with acute lymphoblastic leukemia during induction therapy.

PubMed

McNall, R Y; Head, D R; Pui, C H; Razzouk, B I

2001-01-01

Immunocompromised children, including those undergoing chemotherapy treatment of malignant disease, are at particular risk for infection with parvovirus B19. However, these patients' attenuated immune responses may obscure the serologic and clinical manifestations of the infection. The authors describe a patient undergoing induction therapy for acute lymphoblastic leukemia whose parvovirus B19 infection was identified by the incidental detection of giant pronormoblasts and absence of normal mature erythroid precursors, characteristic of parvovirus infection, on a routine bone marrow examination. Intravenous immunoglobulin was administered and the patient's aplastic anemia resolved completely within 3 weeks. This highlights the importance of alertness to the possibility of parvovirus infection in children with cancer.

A scanning electron microscopic study of 34 cases of acute granulocytic, myelomonocytic, monoblastic and histiocytic leukemia.

PubMed

Polliack, A; McKenzie, S; Gee, T; Lampen, N; de Harven, E; Clarkson, B D

1975-09-01

This report describes the surface architecture of leukemic cells, as seen by scanning electron microscopy in 34 patients with acute nonlymphoblastic leukemia. Six patients with myeloblastic, 4 with promyelocytic, 10 with myelomonocytic, 8 with monocytic, 4 with histiocytic and 2 with undifferentiated leukemia were studied. Under the scanning electron microscope most leukemia histiocytes and monocytes appeared similar and were characterized by the presence of large, well developed broad-based ruffled membranes or prominent raised ridge-like profiles, resembling ithis respect normal monocytes. Most cells from patients with acute promyelocytic or myeloblastic leukemia exhibited narrower ridge-like profiles whereas some showed ruffles or microvilli. Patients with myelomonocytic leukemia showed mixed populations of cells with ridge-like profiles and ruffled membranes whereas cells from two patients with undifferentiated leukemia had smooth surfaces, similar to those encountered in cells from patients with acute lymphoblastic leukemia. It appears that nonlymphoblastic and lymphoblastic leukemia cells (particularly histiocytes and monocytes) can frequently be distinquished on the basis of their surface architecture. The surface features of leukemic histiocytes and monocytes are similar, suggesting that they may belong to the same cell series. The monocytes seem to have characteristic surface features recognizable with the scanning electron microscope and differ from most cells from patients with acute granulocytic leukemia. Although overlap of surface features and misidentification can occur, scanning electron microscopy is a useful adjunct to other modes of microscopy in the study and diagnosis of acute leukemia.

Targeting connective tissue growth factor (CTGF) in acute lymphoblastic leukemia preclinical models: anti-CTGF monoclonal antibody attenuates leukemia growth.

PubMed

Lu, Hongbo; Kojima, Kensuke; Battula, Venkata Lokesh; Korchin, Borys; Shi, Yuexi; Chen, Ye; Spong, Suzanne; Thomas, Deborah A; Kantarjian, Hagop; Lock, Richard B; Andreeff, Michael; Konopleva, Marina

2014-03-01

Connective tissue growth factor (CTGF/CCN2) is involved in extracellular matrix production, tumor cell proliferation, adhesion, migration, and metastasis. Recent studies have shown that CTGF expression is elevated in precursor B-acute lymphoblastic leukemia (ALL) and that increased expression of CTGF is associated with inferior outcome in B-ALL. In this study, we characterized the functional role and downstream signaling pathways of CTGF in ALL cells. First, we utilized lentiviral shRNA to knockdown CTGF in RS4;11 and REH ALL cells expressing high levels of CTGF mRNA. Silencing of CTGF resulted in significant suppression of leukemia cell growth compared to control vector, which was associated with AKT/mTOR inactivation and increased levels of cyclin-dependent kinase inhibitor p27. CTGF knockdown sensitized ALL cells to vincristine and methotrexate. Treatment with an anti-CTGF monoclonal antibody, FG-3019, significantly prolonged survival of mice injected with primary xenograft B-ALL cells when co-treated with conventional chemotherapy (vincristine, L-asparaginase and dexamethasone). Data suggest that CTGF represents a targetable molecular aberration in B-ALL, and blocking CTGF signaling in conjunction with administration of chemotherapy may represent a novel therapeutic approach for ALL patients.

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

PubMed Central

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

2017-01-01

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

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

PubMed

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

2017-05-23

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

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

PubMed

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

1987-01-01

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

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

USDA-ARS?s Scientific Manuscript database

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

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

PubMed Central

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

2016-01-01

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

Recurrent DUX4 fusions in B cell acute lymphoblastic leukemia of adolescents and young adults.

PubMed

Yasuda, Takahiko; Tsuzuki, Shinobu; Kawazu, Masahito; Hayakawa, Fumihiko; Kojima, Shinya; Ueno, Toshihide; Imoto, Naoto; Kohsaka, Shinji; Kunita, Akiko; Doi, Koichiro; Sakura, Toru; Yujiri, Toshiaki; Kondo, Eisei; Fujimaki, Katsumichi; Ueda, Yasunori; Aoyama, Yasutaka; Ohtake, Shigeki; Takita, Junko; Sai, Eirin; Taniwaki, Masafumi; Kurokawa, Mineo; Morishita, Shinichi; Fukayama, Masashi; Kiyoi, Hitoshi; Miyazaki, Yasushi; Naoe, Tomoki; Mano, Hiroyuki

2016-05-01

The oncogenic mechanisms underlying acute lymphoblastic leukemia (ALL) in adolescents and young adults (AYA; 15-39 years old) remain largely elusive. Here we have searched for new oncogenes in AYA-ALL by performing RNA-seq analysis of Philadelphia chromosome (Ph)-negative AYA-ALL specimens (n = 73) with the use of a next-generation sequencer. Interestingly, insertion of D4Z4 repeats containing the DUX4 gene into the IGH locus was frequently identified in B cell AYA-ALL, leading to a high level of expression of DUX4 protein with an aberrant C terminus. A transplantation assay in mice demonstrated that expression of DUX4-IGH in pro-B cells was capable of generating B cell leukemia in vivo. DUX4 fusions were preferentially detected in the AYA generation. Our data thus show that DUX4 can become an oncogenic driver as a result of somatic chromosomal rearrangements and that AYA-ALL may be a clinical entity distinct from ALL at other ages.

Profile of blinatumomab and its potential in the treatment of relapsed/refractory acute lymphoblastic leukemia

PubMed Central

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

2015-01-01

The CD19 marker is expressed on the surface of normal and malignant immature or mature B-cells. On the other hand, immunotherapy involving T-cells is a promising modality of treatment for many neoplastic diseases including leukemias and lymphomas. The CD19/CD3-bispecific T-cell-engaging (BiTE®) monoclonal antibody blinatumomab can transiently engage cytotoxic T-cells to CD19+ target B-cells inducing serial perforin-mediated lysis. In the first clinical trial, blinatumomab showed efficacy in non-Hodgkin’s lymphomas, but the most important trials have been conducted in relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) and in ALL with minimal residual disease. Encouraging reports on the activity of blinatumomab in R/R Philadelphia chromosome-negative B-cell precursor ALL led to its approval by the US Food and Drug Administration on December 3, 2014 after an accelerated review process. This review focuses on the profile of blinatumomab and its activity in R/R ALL. PMID:26170691

Whole-exome sequencing of a rare case of familial childhood acute lymphoblastic leukemia reveals putative predisposing mutations in Fanconi anemia genes.

PubMed

Spinella, Jean-François; Healy, Jasmine; Saillour, Virginie; Richer, Chantal; Cassart, Pauline; Ouimet, Manon; Sinnett, Daniel

2015-07-23

Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer. While the multi-step model of pediatric leukemogenesis suggests interplay between constitutional and somatic genomes, the role of inherited genetic variability remains largely undescribed. Nonsyndromic familial ALL, although extremely rare, provides the ideal setting to study inherited contributions to ALL. Toward this goal, we sequenced the exomes of a childhood ALL family consisting of mother, father and two non-twinned siblings diagnosed with concordant pre-B hyperdiploid ALL and previously shown to have inherited a rare form of PRDM9, a histone H3 methyltransferase involved in crossing-over at recombination hotspots and Holliday junctions. We postulated that inheritance of additional rare disadvantaging variants in predisposing cancer genes could affect genomic stability and lead to increased risk of hyperdiploid ALL within this family. Whole exomes were captured using Agilent's SureSelect kit and sequenced on the Life Technologies SOLiD System. We applied a data reduction strategy to identify candidate variants shared by both affected siblings. Under a recessive disease model, we focused on rare non-synonymous or frame-shift variants in leukemia predisposing pathways. Though the family was nonsyndromic, we identified a combination of rare variants in Fanconi anemia (FA) genes FANCP/SLX4 (compound heterozygote - rs137976282/rs79842542) and FANCA (rs61753269) and a rare homozygous variant in the Holliday junction resolvase GEN1 (rs16981869). These variants, predicted to affect protein function, were previously identified in familial breast cancer cases. Based on our in-house database of 369 childhood ALL exomes, the sibs were the only patients to carry this particularly rare combination and only a single hyperdiploid patient was heterozygote at both FANCP/SLX4 positions, while no FANCA variant allele carriers were identified. FANCA is the most commonly mutated gene in FA and is essential for

Constitutional abnormalities of IDH1 combined with secondary mutations predispose a patient with Maffucci syndrome to acute lymphoblastic leukemia.

PubMed

Hirabayashi, Shinsuke; Seki, Masafumi; Hasegawa, Daisuke; Kato, Motohiro; Hyakuna, Nobuyuki; Shuo, Takuya; Kimura, Shunsuke; Yoshida, Kenichi; Kataoka, Keisuke; Fujii, Yoichi; Shiraishi, Yuichi; Chiba, Kenichi; Tanaka, Hiroko; Kiyokawa, Nobutaka; Miyano, Satoru; Ogawa, Seishi; Takita, Junko; Manabe, Atsushi

2017-12-01

Maffucci syndrome is a nonhereditary disorder caused by somatic mosaic isocitrate dehydrogenase 1 or 2 (IDH1 or IDH2) mutations and is characterized by multiple enchondromas along with hemangiomas. Malignant transformation of enchondromas to chondrosarcomas and secondary neoplasms, such as brain tumors or acute myeloid leukemia, are serious complications. A 15-year-old female with Maffucci syndrome developed B-cell precursor acute lymphoblastic leukemia (BCP-ALL). A somatic mutation in IDH1 was detected in hemangioma and leukemic cells. KRAS mutation and deletion of IKZF1 were detected in leukemic cells. Patients with Maffucci syndrome may, therefore, be at risk of BCP-ALL associated with secondary genetic events that affect lymphocyte differentiation. © 2017 Wiley Periodicals, Inc.

Anti-CD22-chimeric antigen receptors targeting B-cell precursor acute lymphoblastic leukemia.

PubMed

Haso, Waleed; Lee, Daniel W; Shah, Nirali N; Stetler-Stevenson, Maryalice; Yuan, Constance M; Pastan, Ira H; Dimitrov, Dimiter S; Morgan, Richard A; FitzGerald, David J; Barrett, David M; Wayne, Alan S; Mackall, Crystal L; Orentas, Rimas J

2013-02-14

Immune targeting of B-cell malignancies using chimeric antigen receptors (CARs) is a promising new approach, but critical factors impacting CAR efficacy remain unclear. To test the suitability of targeting CD22 on precursor B-cell acute lymphoblastic leukemia (BCP-ALL), lymphoblasts from 111 patients with BCP-ALL were assayed for CD22 expression and all were found to be CD22-positive, with median CD22 expression levels of 3500 sites/cell. Three distinct binding domains targeting CD22 were fused to various TCR signaling domains ± an IgG heavy chain constant domain (CH2CH3) to create a series of vector constructs suitable to delineate optimal CAR configuration. CARs derived from the m971 anti-CD22 mAb, which targets a proximal CD22 epitope demonstrated superior antileukemic activity compared with those incorporating other binding domains, and addition of a 4-1BB signaling domain to CD28.CD3 constructs diminished potency, whereas increasing affinity of the anti-CD22 binding motif, and extending the CD22 binding domain away from the membrane via CH2CH3 had no effect. We conclude that second-generation m971 mAb-derived anti-CD22 CARs are promising novel therapeutics that should be tested in BCP-ALL.

How I treat acute lymphoblastic leukemia in older adolescents and young adults

PubMed Central

Curran, Emily

2015-01-01

At the intersection between children and older adults, the care of adolescent and young adult (AYA) patients with acute lymphoblastic leukemia (ALL) poses unique challenges and issues beyond those faced by other age groups. Although the survival of AYA patients is inferior to younger children, growing evidence suggests that AYA patients have improved outcomes, with disease-free survival rates of 60% to 70%, when treated with pediatric-based approaches. A holistic approach, incorporating a multidisciplinary team, is a key component of successful treatment of these AYA patients. With the appropriate support and management of toxicities during and following treatment, these regimens are well tolerated in the AYA population. Even with the significant progress that has been made during the last decade, patients with persistence of minimal residual disease (MRD) during intensive therapy still have a poor prognosis. With new insights into disease pathogenesis in AYA ALL and the availability of disease-specific kinase inhibitors and novel targeted antibodies, future studies will focus on individualized therapy to eradicate MRD and result in further improvements in survival. This case-based review will discuss the biology, pharmacology, and psychosocial aspects of AYA patients with ALL, highlighting our current approach to the management of these unique patients. PMID:25805810

How I treat acute lymphoblastic leukemia in older adolescents and young adults.

PubMed

Curran, Emily; Stock, Wendy

2015-06-11

At the intersection between children and older adults, the care of adolescent and young adult (AYA) patients with acute lymphoblastic leukemia (ALL) poses unique challenges and issues beyond those faced by other age groups. Although the survival of AYA patients is inferior to younger children, growing evidence suggests that AYA patients have improved outcomes, with disease-free survival rates of 60% to 70%, when treated with pediatric-based approaches. A holistic approach, incorporating a multidisciplinary team, is a key component of successful treatment of these AYA patients. With the appropriate support and management of toxicities during and following treatment, these regimens are well tolerated in the AYA population. Even with the significant progress that has been made during the last decade, patients with persistence of minimal residual disease (MRD) during intensive therapy still have a poor prognosis. With new insights into disease pathogenesis in AYA ALL and the availability of disease-specific kinase inhibitors and novel targeted antibodies, future studies will focus on individualized therapy to eradicate MRD and result in further improvements in survival. This case-based review will discuss the biology, pharmacology, and psychosocial aspects of AYA patients with ALL, highlighting our current approach to the management of these unique patients. © 2015 by The American Society of Hematology.

Genomic characterization of pediatric T-cell acute lymphoblastic leukemia reveals novel recurrent driver mutations

PubMed Central

Spinella, Jean-François; Cassart, Pauline; Richer, Chantal; Saillour, Virginie; Ouimet, Manon; Langlois, Sylvie; St-Onge, Pascal; Sontag, Thomas; Healy, Jasmine; Minden, Mark D.; Sinnett, Daniel

2016-01-01

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy with variable prognosis. It represents 15% of diagnosed pediatric ALL cases and has a threefold higher incidence among males. Many recurrent alterations have been identified and help define molecular subgroups of T-ALL, however the full range of events involved in driving transformation remain to be defined. Using an integrative approach combining genomic and transcriptomic data, we molecularly characterized 30 pediatric T-ALLs and identified common recurrent T-ALL targets such as FBXW7, JAK1, JAK3, PHF6, KDM6A and NOTCH1 as well as novel candidate T-ALL driver mutations including the p.R35L missense mutation in splicesome factor U2AF1 found in 3 patients and loss of function mutations in the X-linked tumor suppressor genes MED12 (frameshit mutation p.V167fs, splice site mutation g.chrX:70339329T>C, missense mutation p.R1989H) and USP9X (nonsense mutation p.Q117*). In vitro functional studies further supported the putative role of these novel T-ALL genes in driving transformation. U2AF1 p.R35L was shown to induce aberrant splicing of downstream target genes, and shRNA knockdown of MED12 and USP9X was shown to confer resistance to apoptosis following T-ALL relevant chemotherapy drug treatment in Jurkat leukemia cells. Interestingly, nearly 60% of novel candidate driver events were identified among immature T-ALL cases, highlighting the underlying genomic complexity of pediatric T-ALL, and the need for larger integrative studies to decipher the mechanisms that contribute to its various subtypes and provide opportunities to refine patient stratification and treatment. PMID:27602765

IKZF1 deletion is an independent predictor of outcome in pediatric acute lymphoblastic leukemia treated according to the ALL-BFM 2000 protocol.

PubMed

Dörge, Petra; Meissner, Barbara; Zimmermann, Martin; Möricke, Anja; Schrauder, André; Bouquin, Jean-Pierre; Schewe, Denis; Harbott, Jochen; Teigler-Schlegel, Andrea; Ratei, Richard; Ludwig, Wolf-Dieter; Koehler, Rolf; Bartram, Claus R; Schrappe, Martin; Stanulla, Martin; Cario, Gunnar

2013-03-01

IKZF1 gene deletions have been associated with a poor outcome in pediatric precursor B-cell acute lymphoblastic leukemia. To assess the prognostic relevance of IKZF1 deletions for patients treated on Berlin-Frankfurt-Münster Study Group trial ALL-BFM 2000, we screened 694 diagnostic acute lymphoblastic leukemia samples by Multiplex Ligation-dependent Probe Amplification. Patients whose leukemic cells bore IKZF1 deletions had a lower 5-year event-free survival (0.69±0.05 vs. 0.85±0.01; P<0.0001) compared to those without, mainly due to a higher cumulative incidence of relapses (0.21±0.04 vs. 0.10±0.01; P=0.001). Although IKZF1 deletions were significantly associated with the P2RY8-CRLF2 rearrangement, their prognostic value was found to be independent from this association. Thus, IKZF1 deletion is an independent predictor of treatment outcome and a strong candidate marker for integration in future treatment stratification strategies on ALL-BFM protocols. Clinicaltrials.gov identifier: NCT00430118.

Association between MTHFR C677T Polymorphism and Risk of Acute Lymphoblastic Leukemia: A Meta-Analysis Based on 51 Case-Control Studies

PubMed Central

Li, Su-yi; Ye, Jie-yu; Liang, En-yu; Zhou, Li-xia; Yang, Mo

2015-01-01

Background Studies and systematic reviews have reached inconsistent conclusions on the role of 5, 10-methylenetetrahydrofolate reductase (MTHFR) polymorphism C677T in acute lymphoblastic leukemia (ALL) risk. Material/Methods The present meta-analysis comprising of 51 case-control studies, including 7892 cases and 14 280 controls was performed to reevaluate the association between MTHFR C677T polymorphism and ALL risk. Results Statistical differences were found in the dominant model (TT+CT vs. CC, odd ratio (OR)=0.89, 95% CI, 0.79–1.00, P=0.04) and the CT vs. CC (OR=0.89, 95% CI, 0.80–1.00, P=0.05), but not in the allele contrast model (T vs. C, OR=0.92, 95% CI, 0.84–1.01, P=0.08), additive model (TT vs. CC, OR=0.87, 95% CI, 0.73–1.05, P=0.15), or recessive model (TT vs. CT+CC, OR=0.94, 95% CI, 0.81–1.10, P=0.44) in overall populations. In the subgroup analyses stratified by age (children and adults) and ethnicity (Asian and Caucasian), no significant associations between MTHFR C677T polymorphism and ALL risk were observed. Conclusions The current study found no sufficient evidence of a protective role of MTHFR C677T polymorphism in ALL susceptibility. PMID:25761797

Germline mutations in ETV6 are associated with thrombocytopenia, red cell macrocytosis and predisposition to lymphoblastic leukemia

PubMed Central

Lee-Sherick, Alisa B.; Callaghan, Michael; Noris, Patrizia; Savoia, Anna; Rajpurkar, Madhvi; Jones, Kenneth; Gowan, Katherine; Balduini, Carlo; Pecci, Alessandro; Gnan, Chiara; De Rocco, Daniela; Doubek, Michael; Li, Ling; Lu, Lily; Leung, Richard; Landolt-Marticorena, Carolina; Hunger, Stephen; Heller, Paula; Gutierrez-Hartmann, Arthur; Xiayuan, Liang; Pluthero, Fred G.; Rowley, Jesse W.; Weyrich, Andrew S.

2015-01-01

Some familial platelet disorders are associated with predisposition to leukemia, myelodysplastic syndrome (MDS) or dyserythropoietic anemia.1,2 We identified a family with autosomal dominant thrombocytopenia, high erythrocyte mean corpuscular volume (MCV) and two occurrences of B-cell precursor acute lymphoblastic leukemia (ALL). Whole exome sequencing identified a heterozygous single nucleotide change in ETV6 (Ets Variant Gene 6), c.641C>T, encoding a p.Pro214Leu substitution in the central domain, segregating with thrombocytopenia and elevated MCV. A screen of 23 families with similar phenotype found two with ETV6 mutations. One family had the p.Pro214Leu mutation and one individual with ALL. The other family had a c.1252A>G transition producing a p.Arg418Gly substitution in the DNA binding domain, with alternative splicing and exon-skipping. Functional characterization of these mutations showed aberrant cellular localization of mutant and endogenous ETV6, decreased transcriptional repression and altered megakaryocyte maturation. Our findings underscore a key role for ETV6 in platelet formation and leukemia predisposition. PMID:25807284

Combination therapeutics of Nilotinib and radiation in acute lymphoblastic leukemia as an effective method against drug-resistance.

PubMed

Kaveh, Kamran; Takahashi, Yutaka; Farrar, Michael A; Storme, Guy; Guido, Marcucci; Piepenburg, Jamie; Penning, Jackson; Foo, Jasmine; Leder, Kevin Z; Hui, Susanta K

2017-07-01

Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) is characterized by a very poor prognosis and a high likelihood of acquired chemo-resistance. Although tyrosine kinase inhibitor (TKI) therapy has improved clinical outcome, most ALL patients relapse following treatment with TKI due to the development of resistance. We developed an in vitro model of Nilotinib-resistant Ph+ leukemia cells to investigate whether low dose radiation (LDR) in combination with TKI therapy overcome chemo-resistance. Additionally, we developed a mathematical model, parameterized by cell viability experiments under Nilotinib treatment and LDR, to explain the cellular response to combination therapy. The addition of LDR significantly reduced drug resistance both in vitro and in computational model. Decreased expression level of phosphorylated AKT suggests that the combination treatment plays an important role in overcoming resistance through the AKT pathway. Model-predicted cellular responses to the combined therapy provide good agreement with experimental results. Augmentation of LDR and Nilotinib therapy seems to be beneficial to control Ph+ leukemia resistance and the quantitative model can determine optimal dosing schedule to enhance the effectiveness of the combination therapy.

SYK as a New Therapeutic Target in B-Cell Precursor Acute Lymphoblastic Leukemia

PubMed Central

Uckun, Fatih M.; Qazi, Sanjive

2014-01-01

The identification of SYK as a master regulator of apoptosis controlling the activation of the PI3-K/AKT, NFκB, and STAT3 pathways—three major anti-apoptotic signaling pathways in B-lineage leukemia/lymphoma cells—prompts the hypothesis that rationally designed inhibitors targeting SYK may overcome the resistance of malignant B-lineage lymphoid cells to apoptosis and thereby provide the foundation for more effective multi-modality treatment regimens for poor prognosis B-precursor acute lymphoblastic leukemia (BPL). In recent preclinical proof-of-concept studies, a liposomal nanoparticle (LNP) formulation of a SYK substrate-binding site inhibitor, known as C61, has been developed as a nanomedicine candidate against poor prognosis and relapsed BPL. This nanoscale formulation of C61 exhibited a uniquely favorable pharmacokinetics and safety profile in mice, induced apoptosis in radiation-resistant primary leukemic cells taken directly from BPL patients as well as in vivo clonogenic BPL xenograft cells, destroyed the leukemic stem cell fraction of BPL blasts, and exhibited potent in vivo anti-leukemic activity in xenograft models of aggressive BPL. Further development of C61-LNP may provide the foundation for new and effective treatment strategies against therapy-refractory BPL. PMID:24851191

Acute Lymphoblastic Leukemia (ALL) (For Parents)

MedlinePlus

... October 2012 More on this topic for: Parents Kids Teens Acute Myeloid Leukemia (AML) Chronic Myelogenous Leukemia (CML) Cancer Center Leukemia Neutropenia Stem Cell Transplants Cancer Center Chemotherapy When Cancer Keeps ...

Inhibition of IRAK1/4 sensitizes T cell acute lymphoblastic leukemia to chemotherapies

PubMed Central

Li, Zhaoyang; Younger, Kenisha; Gartenhaus, Ronald; Joseph, Ann Mary; Hu, Fang; Baer, Maria R.; Brown, Patrick; Davila, Eduardo

2015-01-01

Signaling via the MyD88/IRAK pathway in T cells is indispensable for cell survival; however, it is not known whether this pathway functions in the progression of T acute lymphoblastic leukemia (T-ALL). Here, we determined that compared with thymic and peripheral T cells, T-ALL cells from patients have elevated levels of IRAK1 and IRAK4 mRNA as well as increased total and phosphorylated protein. Targeted inhibition of IRAK1 and IRAK4, either with shRNA or with a pharmacological IRAK1/4 inhibitor, dramatically impeded proliferation of T-ALL cells isolated from patients and T-ALL cells in a murine leukemia model; however, IRAK1/4 inhibition had little effect on cell death. We screened several hundred FDA-approved compounds and identified a set of drugs that had enhanced cytotoxic activity when combined with IRAK inhibition. Administration of an IRAK1/4 inhibitor or IRAK knockdown in combination with either ABT-737 or vincristine markedly reduced leukemia burden in mice and prolonged survival. IRAK1/4 signaling activated the E3 ubiquitin ligase TRAF6, increasing K63-linked ubiquitination and enhancing stability of the antiapoptotic protein MCL1; therefore, IRAK inhibition reduced MCL1 stability and sensitized T-ALL to combination therapy. These studies demonstrate that IRAK1/4 signaling promotes T-ALL progression through stabilization of MCL1 and suggest that impeding this pathway has potential as a therapeutic strategy to enhance chemotherapeutic efficacy. PMID:25642772

Pro-apoptotic effect of Persea americana var. Hass (avocado) on Jurkat lymphoblastic leukemia cells.

PubMed

Bonilla-Porras, Angelica R; Salazar-Ospina, Andrea; Jimenez-Del-Rio, Marlene; Pereañez-Jimenez, Andres; Velez-Pardo, Carlos

2013-11-05

Abstract Context: Therapy for leukemia has a limited efficacy. There is a need to search for alternative anti-leukemia therapies. Persea americana Mill var. Hass (Lauraceae) is a tropical fruit (avocado) that might be used against cancer. Objective: To investigate whether P. americana induces death in Jurkat lymphoblastic leukemia cells. Materials and methods: Four ethanol extracts (0.1, 0.5, 1, 2 and 5 mg/mL) from avocado fruit (endocarp, whole seed, seed and leaves) were analyzed against Jurkat cells. Hydrogen peroxide generation by oxidation of 2',7'-dichlorodihydrofluorescein diacetate to the fluorescent compound 2',7'-dichlorfluorescein assay, acridine orange/ethidium bromide staining, flow cytometry analysis of annexin-V/7-amino-actinomycin, mitochondrial membrane potential and immunocytochemistry detection of transcription factor p53, caspase-3 and apoptosis-inducing factor (AIF) were evaluated. Results: Endocarp, seed, whole seed, and leaf (0.1 mg/mL) extracts induced significant apoptosis in Jurkat cells (p < 0.001) in an oxidative stress-dependent fashion via mitochondrial membrane depolarization (52-87%), activation of transcription factor p53 (6.3-25.4%), protease caspase-3 (8.3-20%) and predominance of AIF reactivity (20.6-36%) in all extracts. Similar results were obtained with 0.5 mg/mL extracts. However, extract ≥1 mg/mL concentration induced necrosis (100%). Conclusions: P. americana extracts function as a pro-apoptotic compound. Leukemic cells are eliminated through an oxidative stress mechanism. This study contributes to the understanding of the molecular mechanism of the avocado and its therapeutic action on leukemia.

K-RasG12D–induced T-cell lymphoblastic lymphoma/leukemias harbor Notch1 mutations and are sensitive to γ-secretase inhibitors

PubMed Central

Cornejo, Melanie G.; Scholl, Claudia; Liu, Jianing; Leeman, Dena S.; Haydu, J. Erika; Fröhling, Stefan; Lee, Benjamin H.; Gilliland, D. Gary

2008-01-01

To study the impact of oncogenic K-Ras on T-cell leukemia/lymphoma development and progression, we made use of a conditional K-RasG12D murine knockin model, in which oncogenic K-Ras is expressed from its endogenous promoter. Transplantation of whole bone marrow cells that express oncogenic K-Ras into wild-type recipient mice resulted in a highly penetrant, aggressive T-cell leukemia/lymphoma. The lymphoblasts were composed of a CD4/CD8 double-positive population that aberrantly expressed CD44. Thymi of primary donor mice showed reduced cellularity, and immunophenotypic analysis demonstrated a block in differentiation at the double-negative 1 stage. With progression of disease, approximately 50% of mice acquired Notch1 mutations within the PEST domain. Of note, primary lymphoblasts were hypersensitive to γ-secretase inhibitor treatment, which is known to impair Notch signaling. This inhibition was Notch-specific as assessed by down-regulation of Notch1 target genes and intracellular cleaved Notch. We also observed that the oncogenic K-Ras-induced T-cell disease was responsive to rapamycin and inhibitors of the RAS/MAPK pathway. These data indicate that patients with T-cell leukemia with K-Ras mutations may benefit from therapies that target the NOTCH pathway alone or in combination with inhibition of the PI3K/AKT/MTOR and RAS/MAPK pathways. PMID:18663146

Use of allopurinol in children with acute lymphoblastic leukemia to reduce skewed thiopurine metabolism.

PubMed

Brackett, Julienne; Schafer, Eric S; Leung, Daniel H; Bernhardt, M Brooke

2014-06-01

Mercaptopurine (6-MP), a critical component of acute lymphoblastic leukemia (ALL) therapy, is metabolized to 6-thioguanine (6-TGN) which is responsible for its anti-leukemic effect, and to 6-methylmercaptopurine nucleotides (6-MMPN/6-MMP) which can be hepatotoxic. Some patients preferentially metabolize 6-MP to 6-MMPN which may increase the risk of liver injury, reduce serum levels of 6-TGN and potentially increase the risk of relapse. The addition of allopurinol to oral 6-MP has been shown to optimize metabolism towards 6-TGN in patients with inflammatory bowel disease (IBD); however, this use has not been reported in patients undergoing treatment for ALL. © 2013 Wiley Periodicals, Inc.

Evaluation of Structural Factors Potentially Implicated in Acute Lymphoblastic Leukemia: A report of the MIGICCL.

PubMed

López-Sánchez, Dulce María; Méndez-Tenorio, Alfonso; Roacho-Pérez, Jorge Alberto; Rangel-López, Angélica

2016-10-01

Acute lymphoblastic leukemia (ALL) is the most common cancer in the pediatric population; ∼80% of the cases show some translocation. Translocations that result in ALL are due to chromosome breaks. However, the exact mechanisms that cause these breaks have not been well studied. A detailed search of the breakpoints associated with ALL reported in the NCBI database shows that some are concentrated in limited regions of the chromosome, whereas others are scattered throughout. Therefore, the objective of this study was to identify the structural factors involved in chromosomal breaks in ALL. We performed several bioinformatic studies on the sequences where chromosomal breakpoints have been reported in search of rearrangements: areas of high similarity, thermodynamic stability, composition and conformation of the DNA. Certain factors may influence chromosome breaks and are capable of predicting the propensity towards these types of events. These findings may be useful in the design of molecular techniques able to detect these changes in ALL. Copyright © 2016 IMSS. Published by Elsevier Inc. All rights reserved.

Essential role for cyclic-AMP responsive element binding protein 1 (CREB) in the survival of acute lymphoblastic leukemia.

PubMed

van der Sligte, Naomi E; Kampen, Kim R; ter Elst, Arja; Scherpen, Frank J G; Meeuwsen-de Boer, Tiny G J; Guryev, Victor; van Leeuwen, Frank N; Kornblau, Steven M; de Bont, Eveline S J M

2015-06-20

Acute lymphoblastic leukemia (ALL) relapse remains a leading cause of cancer related death in children, therefore, new therapeutic options are needed. Recently, we showed that a peptide derived from Cyclic-AMP Responsive Element Binding Protein (CREB) was highly phosphorylated in pediatric leukemias. In this study, we determined CREB phosphorylation and mRNA levels showing that CREB expression was significantly higher in ALL compared to normal bone marrow (phosphorylation: P < 0.0001, mRNA: P = 0.004). High CREB and phospho-CREB expression was correlated with a lower median overall survival in a cohort of 140 adult ALL patients. ShRNA mediated knockdown of CREB in ALL cell lines blocked leukemic cell growth by inducing cell cycle arrest and apoptosis. Gene expression array analysis showed downregulation of CREB target genes regulating cell proliferation and glucose metabolism and upregulation of apoptosis inducing genes. Similar to CREB knockdown, the CREB inhibitor KG-501 decreased leukemic cell viability and induced apoptosis in ALL cell lines, as well as primary T-ALL samples, with cases showing high phospho-CREB levels being more sensitive than those with lower phospho-CREB levels. Together, these in vitro findings support an important role for CREB in the survival of ALL cells and identify this transcription factor as a potential target for treatment.

Total Marrow and Lymphoid Irradiation, Fludarabine, and Melphalan Before Donor Stem Cell Transplant in Treating Participants With High-Risk Acute Leukemia or Myelodysplastic Syndrome

ClinicalTrials.gov

2018-06-01

Acute Lymphoblastic Leukemia; Acute Lymphoblastic Leukemia in Remission; Acute Myeloid Leukemia; Acute Myeloid Leukemia in Remission; Hematopoietic Cell Transplantation Recipient; Minimal Residual Disease; Myelodysplastic Syndrome; Secondary Acute Myeloid Leukemia

Circular RNA PVT1 expression and its roles in acute lymphoblastic leukemia.

PubMed

Hu, Jiaojiao; Han, Qi; Gu, Yan; Ma, Jinlong; McGrath, Mary; Qiao, Fengchang; Chen, Baoan; Song, Chunhua; Ge, Zheng

2018-04-25

The roles of circular RNA PVT1 (circPVT1) are explored in the patients with acute lymphoblastic leukemia (ALL). The circPVT1 level was detected by qRT-PCR and western blot. The apoptotic cells were examined by the annexin V assay in lentiviral shRNA knockdown cells. circPVT1 was highly expressed in ALL compared with normal bone marrow samples. circPVT1 expression was also significantly higher in ALL cell lines. circPVT1 knockdown inhibited cell proliferation and induced cell apoptosis through suppression of its neighbor gene c-Myc, and antiapoptotic Bcl-2 protein expression. circPVT1 is upregulated in ALL. Silencing circPVT1 results in cell growth arrest and apoptosis of the cells. Our results also suggested a therapeutic potential of targeting circPVT1 in ALL.

Recent advances in the management of pediatric acute lymphoblastic leukemia

PubMed Central

Starý, Jan; Hrušák, Ondřej

2016-01-01

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

Suppressed neutrophil function in children with acute lymphoblastic leukemia.

PubMed

Tanaka, Fumiko; Goto, Hiroaki; Yokosuka, Tomoko; Yanagimachi, Masakatsu; Kajiwara, Ryosuke; Naruto, Takuya; Nishimaki, Shigeru; Yokota, Shumpei

2009-10-01

Infection is a major obstacle in cancer chemotherapy. Neutropenia has been considered to be the most important risk factor for severe infection; however, other factors, such as impaired neutrophil function, may be involved in susceptibility to infection in patients undergoing chemotherapy. In this study, we analyzed neutrophil function in children with acute lymphoblastic leukemia (ALL). Whole blood samples were obtained from 16 children with ALL at diagnosis, after induction chemotherapy, and after consolidation chemotherapy. Oxidative burst and phagocytic activity of neutrophils were analyzed by flow cytometry. Oxidative burst of neutrophils was impaired in ALL patients. The percentage of neutrophils with normal oxidative burst after PMA stimulation was 59.0 +/- 13.2 or 70.0 +/- 21.0% at diagnosis or after induction chemotherapy, respectively, which was significantly lower compared with 93.8 +/- 6.1% in healthy control subjects (P = 0.00004, or 0.002, respectively); however, this value was normal after consolidation chemotherapy. No significant differences were noted in phagocytic activity in children with ALL compared with healthy control subjects. Impaired oxidative burst of neutrophils may be one risk factor for infections in children with ALL, especially in the initial periods of treatment.

Researchers Identify Genomic Alterations Associated with Drug-Targetable Kinase Activation in Ph-like Acute Lymphoblastic Leukemia | Office of Cancer Genomics

Cancer.gov

Acute lymphoblastic leukemia (ALL) is the most prevalent cancer among children and young adults, and standard treatments within this population generally result in favorable outcomes. By contrast, one particular subtype of this disease, Philadelphia chromosome-like ALL (Ph-like ALL), is associated with inferior outcomes. Ph-like ALL exhibits a gene expression profile similar to chromosome 9:22 translocation positive ALL, yet it lacks the characteristic BCR-ABL fusion protein.

EZH2 mutations and promoter hypermethylation in childhood acute lymphoblastic leukemia.

PubMed

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

2016-07-01

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

Relapsed or refractory pediatric acute lymphoblastic leukemia: current and emerging treatments.

PubMed

Martin, Alissa; Morgan, Elaine; Hijiya, Nobuko

2012-12-01

Relapsed acute lymphoblastic leukemia (ALL) represents a major cause of morbidity and mortality in pediatrics. With contemporary chemotherapy, >85% of patients with newly diagnosed ALL survive. Unfortunately, 20% of these patients will relapse and for these children, outcomes remain poor despite our best known chemotherapy protocols. Most of these children will achieve a second complete remission, but maintaining this remission remains difficult. Because relapsed ALL is such a significant cause of morbidity and mortality, it is the focus of much research interest. Efforts have been made and continue to focus on understanding the underlying biology that drives relapse. The role of hematopoietic stem cell transplantation in relapsed ALL remains unclear, but many clinicians still favor this for high-risk patients given the poor prognosis with current chemotherapy alone. It is important to use new drugs with little cross-resistance in the treatment of relapsed ALL. New classes of agents are currently being studied. We also discuss prognostic factors and the biology of relapsed ALL.

Flow cytometric characterization of phenotype, DNA indices and p53 gene expression in 55 cases of acute leukemia.

PubMed

Powari, Manish; Varma, Neelam; Varma, Subhash; Marwaha, Ram Kumar; Sandhu, Harpreet; Ganguly, Nirmal Kumar

2002-06-01

To characterize the phenotype of acute leukemia cases using flow cytometry, to detect mixed lineage cases and to use DNA index determination, including S-phase fraction (SPF) and p53 detection, to find if there was any correlation of SPF and p53 expression with outcome. Fifty-five cases of acute leukemia were enrolled in this study. A complete hemogram and routine bone marrow examination, including cytochemistry, was done. Mycloperoxidase-negative cases were evaluated on a flow cytometer using monoclonal antibodies. DNA indices were determined by flow cytometry in all cases, and p53 was detected immunohistochemically using the alkaline phosphatase/antialkaline phosphatase technique. Acute myeloblastic leukemia (AML) was diagnosed in 32 cases; acute lymphoblastic leukemia (ALL) was diagnosed in 18 (14 B lineage and 4 T line age). Four cases showed mixed lineage leukemia, and undifferentiated acute leukemia was diagnosed in one case. The mean/range of SPF for these groups were 3.76/0.33-6.91, 6.25/0.15-21.4, 2.89/0.35-10.64, 2.60/0.72-6.94 and 7.34, respectively. Aneuploidy was detected in two cases of B-lineage ALL and tetraploidy in a case of AML-M7, while all others were diploid p53. Was detected in 6 of 55 cases (10.90%). Follow-up was available for 24 patients. Five patients relapsed, and four had B-cell type ALL and were diploid and expressed no p53 gene. SPF% did not show any correlation with outcome. These data suggest that within acute leukemia subtypes, there is a wide variation in SPF. SPF does not seem to correlate with outcome. Immunophenotyping is essential to determine the lineage in myeloperoxidase-negative cases. It is perhaps the only way to diagnose mixed lineage leukemia and aberrant expression of markers presently. The p53 gene was detected less frequently. However, more studies are required from different centers with longer follow-up to evaluate prognostic significance.

Genotype-Specific Minimal Residual Disease Interpretation Improves Stratification in Pediatric Acute Lymphoblastic Leukemia

PubMed Central

O’Connor, David; Enshaei, Amir; Bartram, Jack; Hancock, Jeremy; Harrison, Christine J.; Hough, Rachael; Samarasinghe, Sujith; Schwab, Claire; Vora, Ajay; Wade, Rachel; Moppett, John; Moorman, Anthony V.; Goulden, Nick

2018-01-01

Purpose Minimal residual disease (MRD) and genetic abnormalities are important risk factors for outcome in acute lymphoblastic leukemia. Current risk algorithms dichotomize MRD data and do not assimilate genetics when assigning MRD risk, which reduces predictive accuracy. The aim of our study was to exploit the full power of MRD by examining it as a continuous variable and to integrate it with genetics. Patients and Methods We used a population-based cohort of 3,113 patients who were treated in UKALL2003, with a median follow-up of 7 years. MRD was evaluated by polymerase chain reaction analysis of Ig/TCR gene rearrangements, and patients were assigned to a genetic subtype on the basis of immunophenotype, cytogenetics, and fluorescence in situ hybridization. To examine response kinetics at the end of induction, we log-transformed the absolute MRD value and examined its distribution across subgroups. Results MRD was log normally distributed at the end of induction. MRD distributions of patients with distinct genetic subtypes were different (P < .001). Patients with good-risk cytogenetics demonstrated the fastest disease clearance, whereas patients with high-risk genetics and T-cell acute lymphoblastic leukemia responded more slowly. The risk of relapse was correlated with MRD kinetics, and each log reduction in disease level reduced the risk by 20% (hazard ratio, 0.80; 95% CI, 0.77 to 0.83; P < .001). Although the risk of relapse was directly proportional to the MRD level within each genetic risk group, absolute relapse rate that was associated with a specific MRD value or category varied significantly by genetic subtype. Integration of genetic subtype–specific MRD values allowed more refined risk group stratification. Conclusion A single threshold for assigning patients to an MRD risk group does not reflect the response kinetics of the different genetic subtypes. Future risk algorithms should integrate genetics with MRD to accurately identify patients with the

Anti-CD22–chimeric antigen receptors targeting B-cell precursor acute lymphoblastic leukemia

PubMed Central

Haso, Waleed; Lee, Daniel W.; Shah, Nirali N.; Stetler-Stevenson, Maryalice; Yuan, Constance M.; Pastan, Ira H.; Dimitrov, Dimiter S.; Morgan, Richard A.; FitzGerald, David J.; Barrett, David M.; Wayne, Alan S.; Mackall, Crystal L.

2013-01-01

Immune targeting of B-cell malignancies using chimeric antigen receptors (CARs) is a promising new approach, but critical factors impacting CAR efficacy remain unclear. To test the suitability of targeting CD22 on precursor B-cell acute lymphoblastic leukemia (BCP-ALL), lymphoblasts from 111 patients with BCP-ALL were assayed for CD22 expression and all were found to be CD22-positive, with median CD22 expression levels of 3500 sites/cell. Three distinct binding domains targeting CD22 were fused to various TCR signaling domains ± an IgG heavy chain constant domain (CH2CH3) to create a series of vector constructs suitable to delineate optimal CAR configuration. CARs derived from the m971 anti-CD22 mAb, which targets a proximal CD22 epitope demonstrated superior antileukemic activity compared with those incorporating other binding domains, and addition of a 4-1BB signaling domain to CD28.CD3ζ constructs diminished potency, whereas increasing affinity of the anti-CD22 binding motif, and extending the CD22 binding domain away from the membrane via CH2CH3 had no effect. We conclude that second-generation m971 mAb-derived anti-CD22 CARs are promising novel therapeutics that should be tested in BCP-ALL. PMID:23243285

Outcome of acute lymphoblastic leukemia in children with down syndrome-Polish pediatric leukemia and lymphoma study group report.

PubMed

Zawitkowska, Joanna; Odój, Teresa; Drabko, Katarzyna; Zaucha-Prażmo, Agnieszka; Rudnicka, Julia; Romiszewski, Michał; Matysiak, Michał; Kwiecińska, Kinga; Ćwiklińska, Magdalena; Balwierz, Walentyna; Owoc-Lempach, Joanna; Derwich, Katarzyna; Wachowiak, Jacek; Niedźwiecki, Maciej; Adamkiewicz-Drożyńska, Elżbieta; Trelińska, Joanna; Młynarski, Wojciech; Kołtan, Andrzej; Wysocki, Mariusz; Tomaszewska, Renata; Szczepański, Tomasz; Płonowski, Marcin; Krawczuk-Rybak, Maryna; Ociepa, Tomasz; Urasiński, Tomasz; Mizia-Malarz, Agnieszka; Sobol-Milejska, Grażyna; Karolczyk, Grażyna; Kowalczyk, Jerzy

2017-05-01

Children with Down syndrome (DS) have a 20-fold increased risk of developing leukemia compared with the general population. The aim of the study was to analyze the outcome of patients diagnosed with Down syndrome and acute lymphoblastic leukemia (ALL) in Poland between the years 2003 and 2010. A total of 1848 children were diagnosed with ALL (810 females and 1038 males). Of those, 41 (2.2%) had DS. The children were classified into three risk groups: a standard-risk group-14 patients, an intermediate-risk group-24, a high-risk group-3. All patients were treated according to ALLIC 2002 protocol. The median observation time of all patients was 6.1 years, and in patients with DS 5.3 years. Five-year overall survival (OS) was the same in all patients (86% vs 86%, long-rank test, p = .9). The relapse-free survival (RFS) was calculated as 73% in patients with DS and 81% in patients without DS during a median observation time (long-rank test, p = .3). No statistically significant differences were found in the incidence of nonrelapse mortality between those two groups of patients (p = .72). The study was based on children with ALL and Down syndrome who were treated with an identical therapy schedule as ALL patients without DS, according to risk group. This fact can increase the value of the presented results.

The MTHFR C677T polymorphism and risk of acute lymphoblastic leukemia: an updated meta-analysis based on 37 case-control studies.

PubMed

Jiang, Yuan; Hou, Jing; Zhang, Qiang; Jia, Shu-Ting; Wang, Bo-Yuan; Zhang, Ji-Hong; Tang, Wen-Ru; Luo, Ying

2013-01-01

The C677T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) has been associated with acute lymphoblastic leukemia (ALL). However, results were conflicting. The aim of this study was to quantitatively summarize the evidence for the MTHFRC677T polymorphism and ALL risk. Electronic searches of PubMed and the Chinese Biomedicine database were conducted to select case-control studies containing available genotype frequencies of C677T and the odds ratio (OR) with 95% confidence interval (CI) was used to assess the strength of any association. Case-control studies including 6,371 cases and 10,850 controls were identified. The meta-analysis stratified by ethnicity showed that individuals with the homozygous TT genotype had decreased risk of ALL (OR= 0.776, 95% CI: 0.687~0.877, p< 0.001) in Caucasians (OR= 0.715, 95% CI: 0.655~0.781, p= 0.000). However, results among Asians (OR=0.711, 95% CI: 0.591~1.005, p= 0.055) and others (OR=0.913, 95% CI: 0.656~1.271, p= 0. 590) did not suggest an association. A symmetric funnel plot, the Egger's test (P=0.093), and the Begg- test (P=0.072) were all suggestive of the lack of publication bias. This meta-analysis supports the idea that the MTHFR C677T genotype is associated with risk of ALL in Caucasians. To draw comprehensive and true conclusions, further prospective studies with larger numbers of participants worldwide are needed to examine associations between the MTHFRC677T polymorphism and ALL.

Cell cycle regulatory gene abnormalities are important determinants of leukemogenesis and disease biology in adult acute lymphoblastic leukemia.

PubMed

Stock, W; Tsai, T; Golden, C; Rankin, C; Sher, D; Slovak, M L; Pallavicini, M G; Radich, J P; Boldt, D H

2000-04-01

To test the hypothesis that cell cycle regulatory gene abnormalities are determinants of clinical outcome in adult acute lymphoblastic leukemia (ALL), we screened lymphoblasts from patients on a Southwest Oncology Group protocol for abnormalities of the genes, retinoblastoma (Rb), p53, p15(INK4B), and p16(INK4A). Aberrant expression occurred in 33 (85%) patients in the following frequencies: Rb, 51%; p16(INK4A), 41%; p53, 26%. Thirteen patients (33%) had abnormalities in 2 or more genes. Outcomes were compared in patients with 0 to 1 abnormality versus patients with multiple abnormalities. The 2 groups did not differ in a large number of clinical and laboratory characteristics. The CR rates for patients with 0 to 1 and multiple abnormalities were similar (69% and 54%, respectively). Patients with 0 to 1 abnormality had a median survival time of 25 months (n = 26; 95% CI, 13-46 months) versus 8 months (n = 13; 95% CI, 4-12 months) for those with multiple abnormalities (P <.01). Stem cells (CD34+lin-) were isolated from adult ALL bone marrows and tested for p16(INK4A) expression by immunocytochemistry. In 3 of 5 patients lymphoblasts and sorted stem cells lacked p16(INK4A) expression. In 2 other patients only 50% of sorted stem cells expressed p16(INK4A). By contrast, p16 expression was present in the CD34+ lin- compartment in 95% (median) of 9 patients whose lymphoblasts expressed p16(INK4A). Therefore, cell cycle regulatory gene abnormalities are frequently present in adult ALL lymphoblasts, and they may be important determinants of disease outcome. The presence of these abnormalities in the stem compartment suggests that they contribute to leukemogenesis. Eradication of the stem cell subset harboring these abnormalities may be important to achieve cure.

Brain size and neuropsychological functioning in long-term survivors of pediatric acute lymphoblastic leukemia.

PubMed

Mulcahy Levy, Jean M; Hunger, Stephen P

2013-10-01

With the increased survival of pediatric cancer patients the interest in the late effects of treatments is rapidly increasing. Long-term survival rates for children with acute lymphoblastic leukemia (ALL) now approach 90%. Treatment for ALL includes intensified central nervous system (CNS)-directed therapy, which is associated with risks for long-term neurocognitive effects. It is becoming clear that current therapies can have not only a detrimental effect on IQ, processing speed, and memory, but also on structural changes that lead to permanent alterations of the organization of the CNS. Understanding how the CNS is affected by the treatments is a critical step in evaluating current therapies and developing interventions to decrease the incidence and severity of long-term changes in brain anatomy and function.

Brain size and neuropsychological functioning in long-term survivors of pediatric acute lymphoblastic leukemia

PubMed Central

Mulcahy Levy, Jean M

2013-01-01

With the increased survival of pediatric cancer patients the interest in the late effects of treatments is rapidly increasing. Long-term survival rates for children with acute lymphoblastic leukemia (ALL) now approach 90%. Treatment for ALL includes intensified central nervous system (CNS)-directed therapy, which is associated with risks for long-term neurocognitive effects. It is becoming clear that current therapies can have not only a detrimental effect on IQ, processing speed, and memory, but also on structural changes that lead to permanent alterations of the organization of the CNS. Understanding how the CNS is affected by the treatments is a critical step in evaluating current therapies and developing interventions to decrease the incidence and severity of long-term changes in brain anatomy and function. PMID:26835308

Methylenetetrahydrofolate reductase and glutathione S-tranferase gene polymorphisms in secondary mixed phenotype acute leukemia: a case report.

PubMed

Skoric, Dejan; Ivana, Joksic; Tanja, Radic; Jovana, Jakovljevic; Petar, Ivanovski; Tatjana, Simic

2014-04-01

Therapy-induced leukemia is a well-known clinical syndrome occurring as a late complication in patients treated with cytotoxic therapy. We herein present results of analysis of common gene polymorphisms in methylenetetrahydrofolate reductase (MTHFR) and glutathione S-transferase (GST) genes in a 10-year-old boy who developed very rare type of cancer, mixed phenotype acute leukemia, 6 years after treatment of acute lymphoblastic leukemia. Impairment in function of GST and MTHFR enzymes found in our patient may have contributed to the development of secondary mixed phenotype acute leukemia, although precise mechanism remains elusive.

Unrelated umbilical cord blood transplant for adult acute lymphoblastic leukemia in first and second complete remission: a comparison with allografts from adult unrelated donors

PubMed Central

Marks, David I.; Woo, Kwang Ahn; Zhong, Xiaobo; Appelbaum, Frederick R.; Bachanova, Veronika; Barker, Juliet N.; Brunstein, Claudio G.; Gibson, John; Kebriaei, Partow; Lazarus, Hillard M.; Olsson, Richard; Perales, Miguel-Angel; Pidala, Joseph; Savani, Bipin; Rocha, Vanderson; Eapen, Mary

2014-01-01

Allogeneic hematopoietic cell transplantation has an established role in the treatment of adults with acute lymphoblastic leukemia whose survival when recipients of grafts from adult unrelated donors approaches that of recipients of grafts from sibling donors. Our aim was to determine the role of mismatched unrelated cord blood grafts in transplantation for 802 adults with acute lymphoblastic leukemia in first or second complete remission. Using Cox regression we compared outcomes after 116 mismatched single or double cord blood transplants, 546 peripheral blood progenitor cell transplants and 140 bone marrow transplants. The characteristics of the recipients and their diseases were similar except cord blood recipients were younger, more likely to be non-Caucasians and more likely to have a low white blood cell count at diagnosis. There were differences in donor-recipient human leukocyte antigen-match depending on the source of the graft. Most adult donor transplants were matched at the allele-level considering human leukocyte antigens-A, -B, -C and –DRB1. In contrast, most cord blood transplants were mismatched and considered antigen-level matching; 57% were mismatched at two loci and 29% at one locus whereas only 29% of adult donor transplants were mismatched at one locus and none at two loci. There were no differences in the 3-year probabilities of survival between recipients of cord blood (44%), matched adult donor (44%) and mismatched adult donor (43%) transplants. Cord blood transplants engrafted slower and were associated with less grade 2–4 acute but similar chronic graft-versus-host disease, relapse, and transplant-related mortality. The survival of cord blood graft recipients was similar to that of recipients of matched or mismatched unrelated adult donor grafts and so cord blood should be considered a valid alternative source of stem cells for adults with acute lymphoblastic leukemia in the absence of a matched unrelated adult donor. PMID:24056817

A novel 2,6-diisopropylphenyl-docosahexaenoamide conjugate induces apoptosis in T cell acute lymphoblastic leukemia cell lines

DOE Office of Scientific and Technical Information (OSTI.GOV)

Altenburg, Jeffrey D.; Harvey, Kevin A.; McCray, Sharon

2011-07-29

Highlights: {yields} 2,6-Diisopropylphenyl-docosahexaenoamide conjugates (DIP-DHA) inhibits the proliferation of T-cell leukemic cell lines. {yields} DIP-DHA resulted in increased activation of caspase-3, and caspase-7. {yields} DIP-DHA significantly downregulated CXCR4 surface expression. -- Abstract: We have previously characterized the effects of 2,6-diisopropylphenyl-docosahexaenoamide (DIP-DHA) conjugates and their analogs on the proliferation and progression of breast cancer cell lines. For this study, we investigated the effects of the DIP-DHA conjugate on 2 representative T cell acute lymphoblastic leukemia (T-ALL) cell lines: CEM and Jurkat. Treatment of both cell lines with DIP-DHA resulted in significantly greater inhibition of proliferation and induction of apoptosis than thatmore » of parent compounds, 2,6-diisopropylphenol (DIP) or docosahexaenoate (DHA). Treatment of the cells with DIP-DHA resulted in increased activation of caspase-3, and caspase-7. Furthermore, induction of apoptosis in both cell lines was reversed in the presence of a caspase family inhibitor. Treatment with DIP-DHA reduced mitochondrial membrane potential. These observations suggest that the effects are driven by intrinsic apoptotic pathways. DIP-DHA treatment also downregulated surface CXCR4 expression, an important chemokine receptor involved in cancer metastasis that is highly expressed in both CEM and Jurkat cells. In conclusion, our data suggest that the DIP-DHA conjugate exhibits significantly more potent effects on CEM and Jurkat cells than that of DIP or DHA alone. These conjugates have potential use for treatment of patients with T cell acute lymphoblastic leukemia.« less

Systematic chemical and molecular profiling of MLL-rearranged infant acute lymphoblastic leukemia reveals efficacy of romidepsin

PubMed Central

Cruickshank, M N; Ford, J; Cheung, L C; Heng, J; Singh, S; Wells, J; Failes, T W; Arndt, G M; Smithers, N; Prinjha, R K; Anderson, D; Carter, K W; Gout, A M; Lassmann, T; O'Reilly, J; Cole, C H; Kotecha, R S; Kees, U R

2017-01-01

To address the poor prognosis of mixed lineage leukemia (MLL)-rearranged infant acute lymphoblastic leukemia (iALL), we generated a panel of cell lines from primary patient samples and investigated cytotoxic responses to contemporary and novel Food and Drug Administration-approved chemotherapeutics. To characterize representation of primary disease within cell lines, molecular features were compared using RNA-sequencing and cytogenetics. High-throughput screening revealed variable efficacy of currently used drugs, however identified consistent efficacy of three novel drug classes: proteasome inhibitors, histone deacetylase inhibitors and cyclin-dependent kinase inhibitors. Gene expression of drug targets was highly reproducible comparing iALL cell lines to matched primary specimens. Histone deacetylase inhibitors, including romidepsin (ROM), enhanced the activity of a key component of iALL therapy, cytarabine (ARAC) in vitro and combined administration of ROM and ARAC to xenografted mice further reduced leukemia burden. Molecular studies showed that ROM reduces expression of cytidine deaminase, an enzyme involved in ARAC deactivation, and enhances the DNA damage–response to ARAC. In conclusion, we present a valuable resource for drug discovery, including the first systematic analysis of transcriptome reproducibility in vitro, and have identified ROM as a promising therapeutic for MLL-rearranged iALL. PMID:27443263

The evolution of clinical trials for infant acute lymphoblastic leukemia

PubMed Central

Kotecha, R S; Gottardo, N G; Kees, U R; Cole, C H

2014-01-01

Acute lymphoblastic leukemia (ALL) in infants has a significantly inferior outcome in comparison with older children. Despite initial improvements in survival of infants with ALL since establishment of the first pediatric cooperative group ALL trials, the poor outcome has plateaued in recent years. Historically, infants were treated on risk-adapted childhood ALL protocols. These studies were pivotal in identifying the need for infant-specific protocols, delineating prognostic categories and the requirement for a more unified approach between study groups to overcome limitations in accrual because of low incidence. This subsequently led to the development of collaborative infant-specific studies. Landmark outcomes have included the elimination of cranial radiotherapy following the discovery of intrathecal and high-dose systemic therapy as a superior and effective treatment strategy for central nervous system disease prophylaxis, with improved neurodevelopmental outcome. Universal prospective identification of independent adverse prognostic factors, including presence of a mixed lineage leukemia rearrangement and young age, has established the basis for risk stratification within current trials. The infant-specific trials have defined limits to which conventional chemotherapeutic agents can be intensified to optimize the balance between treatment efficacy and toxicity. Despite variations in therapeutic intensity, there has been no recent improvement in survival due to the equilibrium between relapse and toxicity. Ultimately, to improve the outcome for infants with ALL, key areas still to be addressed include identification and adaptation of novel prognostic markers and innovative therapies, establishing the role of hematopoietic stem cell transplantation in first complete remission, treatment strategies for relapsed/refractory disease and monitoring and timely intervention of late effects in survivors. This would be best achieved through a single unified

Zerumbone-loaded nanostructured lipid carrier induces G2/M cell cycle arrest and apoptosis via mitochondrial pathway in a human lymphoblastic leukemia cell line

PubMed Central

Rahman, Heshu Sulaiman; Rasedee, Abdullah; Abdul, Ahmad Bustamam; Zeenathul, Nazariah Allaudin; Othman, Hemn Hassan; Yeap, Swee Keong; How, Chee Wun; Hafiza, Wan Abd Ghani Wan Nor

2014-01-01

This investigation evaluated the antileukemia properties of a zerumbone (ZER)-loaded nanostructured lipid carrier (NLC) prepared by hot high-pressure homogenization techniques in an acute human lymphoblastic leukemia (Jurkat) cell line in vitro. The apoptogenic effect of the ZER-NLC on Jurkat cells was determined by fluorescent and electron microscopy, Annexin V-fluorescein isothiocyanate, Tdt-mediated dUTP nick-end labeling assay, cell cycle analysis, and caspase activity. An MTT (3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide) assay showed that ZER-NLC did not have adverse effects on normal human peripheral blood mononuclear cells. ZER-NLC arrested the Jurkat cells at G2/M phase with inactivation of cyclin B1 protein. The study also showed that the antiproliferative effect of ZER-NLC on Jurkat cells is through the intrinsic apoptotic pathway via activation of caspase-3 and caspase-9, release of cytochrome c from the mitochondria into the cytosol, and subsequent cleavage of poly (adenosine diphosphate-ribose) polymerase (PARP). These findings show that the ZER-NLC is a potentially useful treatment for acute lymphoblastic leukemia in humans. PMID:24549090

Familial history of cancer and childhood acute leukemia: a French population-based case-control study.

PubMed

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

2007-10-01

A case-control study was conducted to investigate the role of a familial history of cancer in the etiology of childhood acute leukemia. The history of cancer in the relatives of 472 cases was compared with that of 567 population-based controls. Recruitment was frequency matched on age, sex 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. A familial history of solid tumor in first or second-degree relatives was associated with an increased risk of acute lymphoblastic leukemia (odds ratio (OR)=1.6 [95% confidence interval, 1.2-2.1]), while a familial history of hematopoietic malignancies in first or second-degree relatives was associated with an increased risk of acute myeloid leukemia (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 acute leukemia and familial history of genital cancers and brain tumor were also observed (OR=2.7 [1.2-5.8] and OR=10.7 [1.3-86], respectively). 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.

Ethnic differences in the frequency of subtypes of childhood acute lymphoblastic leukemia: results of the Malaysia-Singapore Leukemia Study Group.

PubMed

Ariffin, Hany; Chen, Siew-Peng; Kwok, Cecilia S; Quah, Thuan-Chong; Lin, Hai-Peng; Yeoh, Allen E J

2007-01-01

Childhood acute lymphoblastic leukemia (ALL) is clinically heterogeneous with prognostically and biologically distinct subtypes. Although racial differences in frequency of different types of childhood ALL have been reported, many are confounded by selected or limited population samples. The Malaysia-Singapore (MA-SPORE) Leukemia Study Group provided a unique platform for the study of the frequency of major subgroups of childhood ALL in a large cohort of unselected multiethnic Asian children. Screening for the prognostically important chromosome abnormalities (TEL-AML1, BCR-ABL, E2A-PBX1, and MLL) using multiplex reverse-transcription polymerase chain reaction was performed on 299 consecutive patients with ALL at 3 study centers (236 de novo, 63 at relapse), with the ethnic composition predominantly Chinese (51.8%) and Malay (34.8%). Reverse-transcription polymerase chain reaction was successful in 278 (93%) of cases screened. The commonest fusion transcript was TEL-AML1 (19.1%) followed by BCR-ABL (7.8%), MLL rearrangements (4.2%), and E2A-PBX1 (3.1%). Chinese have a significantly lower frequency of TEL-AML1 (13.3% in de novo patients) compared with Malays (22.2%) and Indians (21.7%) (P=0.04). Malays have a lower frequency of T-ALL (6.2%) compared with the Chinese and Indians (9.8%). Both Malays (7.4%) and Chinese (5.0%) have significantly higher frequency of BCR-ABL compared with the Indian population (P<0.05) despite a similar median age at presentation. Our study suggests that there are indeed significant and important racial differences in the frequency of subtypes of childhood ALL. Comprehensive subgrouping of childhood ALL may reveal interesting population frequency differences of the various subtypes, their risk factors and hopefully, its etiology.

CD20 positivity and white blood cell count predict treatment outcomes in Philadelphia chromosome-negative acute lymphoblastic leukemia patients ineligible for pediatric-inspired chemotherapy.

PubMed

Isshiki, Yusuke; Ohwada, Chikako; Sakaida, Emiko; Onoda, Masahiro; Aotsuka, Nobuyuki; Tanaka, Hiroaki; Fukazawa, Motoharu; Cho, Ryuko; Sugawara, Takeaki; Kawaguchi, Takeharu; Hara, Satoru; Yokota, Akira

2017-11-01

The efficacy of conventional chemotherapy and allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been controversial as post-remission therapies for adult Philadelphia chromosome-negative acute lymphoblastic leukemia patients. We retrospectively analyzed 96 adolescent and adult cases of Philadelphia chromosome-negative acute lymphoblastic leukemia to evaluate whether allo-HSCT should be performed after first complete remission (1CR). In total, 34 patients received chemotherapy followed by allo-HSCT (HSCT group) and 62 received chemotherapy alone (chemotherapy group). No significant differences in the event-free survival (EFS) or overall survival were observed between the two groups. In the chemotherapy group, use of pediatric regimens was significantly associated with favorable EFS, while high white blood cell (WBC) count and CD20 positivity were associated with poor outcome. In patients who received pediatric regimens, subsequent allo-HSCT did not influence EFS. In patients who received conventional chemotherapy (adult regimen), subsequent allo-HSCT did not improve EFS. High WBC count and CD20 positivity were also significantly associated with poor EFS in patients who received adult regimens. Patients with low WBC count and absence of CD20 who received adult regimens did not benefit from allo-HSCT. Allo-HSCT may not be required in the pediatric regimen-eligible patients; however, pediatric regimen-ineligible patients with either CD20 positivity or high WBC count should receive allo-HSCT after achieving 1CR. This study was registered at http://www.umin.ac.jp/ctr/ as #C000016287. © The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

Quantitation of human thymus/leukemia-associated antigen by radioimmunoassay in different forms of leukemia.

PubMed

Chechik, B E; Jason, J; Shore, A; Baker, M; Dosch, H M; Gelfand, E W

1979-12-01

Using a radioimmunoassay, increased levels of a human thymus/leukemia-associated antigen (HThy-L) have been detected in leukemic cells and plasma from most patients with E-rosette-positive acute lymphoblastic leukemia (ALL) and a number of patients with E-rosette-negative ALL, acute myeloblastic leukemia (AML), acute monomyelocytic leukemia (AMML), and acute undifferentiated leukemia (AVL). Low levels of HThy-L have been demonstrated in white cells from patients with chronic myelocytic leukemia (stable phase) and in mononuclear cells from patients with chronic lymphatic leukemia. The relationship between HThy-L and differentiation of hematopoietic cells is discussed.

[Late sequelae of central nervous system prophylaxis in children with acute lymphoblastic leukemia: high doses of intravenous methotrexate versus radiotherapy of the central nervous system--review of literature].

PubMed

Zając-Spychała, Olga; Wachowiak, Jacek

2012-01-01

Acute lymphoblastic leukemia is the most common malignancy in children. All current therapy regimens used in the treatment of childhood acute lymphoblastic leukemia include prophylaxis of the central nervous system. Initially it was thought that the best way of central nervous system prophylaxis is radiotherapy. But despite its effectiveness this method, may cause late sequelae and complications. In the programme currently used in Poland to treat acute lymphoblastic leukemia, prophylactic radiotherapy has been reduced by 50% (12 Gy) and is used only in patients stratified into the high risk group and in patients diagnosed as T-cell ALL (T-ALL). Complementary to radiotherapy, intrathecal methotrexate is given alone or in combination with cytarabine and hydrocortisone is given, as well as systemic chemotherapy with intravenous methotrexate is administered in high or medium doses (depending on risk groups and leukemia immunophenotype). Recent studies have shown that high dose irradiation of the central nervous system impairs cognitive development causing memory loss, visuomotor coordination impairment, attention disorders and reduction in the intelligence quotient. It has been proved that the degree of cognitive impairment depends on the radiation dose directed to the medial temporal lobe structures, particularly in the hippocampus and the surrounding cortex. Also, methotrexate used intravenously in high doses, interferes with the metabolism of folic acid which is necessary for normal development and the optimal functioning of neurons in the central nervous system. It has been proved that patients who have been treated with high doses of methotrexate are characterized by reduced memory skills and a lower intelligence quotient. The literature data concerning long term neuroanatomical abnormalities and neuropsychological deficits are ambiguous, and there is still no data concerning current methods of central nervous system prophylaxis with low doses of irradiation in

Acute leukemias of ambiguous lineage.

PubMed

Béné, Marie C; Porwit, Anna

2012-02-01

The 2008 edition of the WHO Classification of Tumors of Haematopoietic and Lymphoid Tissues recognizes a special category called "leukemias of ambiguous lineage." The vast majority of these rare leukemias are classified as mixed phenotype acute leukemia (MPAL), although acute undifferentiated leukemias and natural killer lymphoblastic leukemias are also included. The major immunophenotypic markers used by the WHO 2008 to determine the lineage for these proliferations are myeloperoxidase, CD19, and cytoplasmic CD3. However, extensive immunophenotyping is necessary to confirm that the cells indeed belong to 2 different lineages or coexpress differentiation antigens of more than 1 lineage. Specific subsets of MPAL are defined by chromosomal anomalies such as the t(9;22) Philadelphia chromosome BCR-ABL1 or involvement of the MLL gene on chromosome 11q23. Other MPAL are divided into B/myeloid NOS, T/myeloid NOS, B/T NOS, and B/T/myeloid NOS. MPAL are usually of dire prognosis, respond variably to chemotherapy of acute lymphoblastic or acute myeloblastic type, and benefit most from rapid allogeneic hematopoietic stem cell transplantation.

The evolving role of chemotherapy and hematopoietic cell transplants in Ph-positive acute lymphoblastic leukemia in adults.

PubMed

Litzow, M R; Fielding, A K; Luger, S M; Paietta, E; Ofran, Y; Rowe, J M; Goldstone, A H; Tallman, M S; Lazarus, H M

2017-12-01

The introduction of the tyrosine kinase inhibitors (TKI) into the treatment of patients with Ph or BCR-ABL1-positive acute lymphoblastic leukemia has revolutionized the treatment of this poor prognosis acute leukemia. The combination of TKI with chemotherapy has improved response rates and allowed more patients to proceed to allogeneic hematopoietic cell transplant (alloHCT). Older patients have excellent responses to TKI and corticosteroids or in combination with minimal chemotherapy. This raises the question as to whether patients require full-intensity chemotherapy with TKI to achieve molecular remissions. The pediatricians have proposed that cure is achievable without alloHCT in children. These results have suggested that many patients may not require traditional chemotherapy in addition to TKI to achieve remission, and that patients who achieve a negative minimal residual disease state may not require alloHCT. The data in support of these questions is presented here and a suggested future clinical trial design based on these data is proposed.

Lack of association between polymorphisms in genes MTHFR and MDR1 with risk of childhood acute lymphoblastic leukemia.

PubMed

Kreile, Madara; Rots, Dmitrijs; Piekuse, Linda; Cebura, Elizabete; Grutupa, Marika; Kovalova, Zhanna; Lace, Baiba

2014-01-01

Acute lymphoblastic leukemia (ALL) is a complex disease caused by interactions between hazardous exogenous or/and endogenous agents and many mild effect inherited susceptibility mutations. Some of them are known, but their functional roles still requireinvestigation. Age is a recognized risk factor; children with disease onset after the age of ten have worse prognosis, presumably also triggered by inherited factors. The MDR1 gene polymorphisms rs1045642, rs2032582 and MTHFR gene polymorphisms rs1801131 and rs1801133 were genotyped in 68 ALL patients in remission and 102 age and gender matched controls; parental DNA samples were also available for 42 probands. No case control association was found between analyzed polymorphisms and a risk of childhood ALL development. Linkage disequilibrium was not observed in a family-based association study either. Only marginal association was observed between genetic marker rs2032582A and later disease onset (p=0.04). Our data suggest that late age of ALL onset could be triggered by mild effect common alleles.

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

PubMed Central

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

2017-01-01

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

Cellular kinetics of CTL019 in relapsed/refractory B-cell acute lymphoblastic leukemia and chronic lymphocytic leukemia

PubMed Central

Maude, Shannon L.; Porter, David L.; Frey, Noelle; Wood, Patricia; Han, Xia; Waldron, Edward; Chakraborty, Abhijit; Awasthi, Rakesh; Levine, Bruce L.; Melenhorst, J. Joseph; Grupp, Stephan A.; June, Carl H.; Lacey, Simon F.

2017-01-01

Tisagenlecleucel (CTL019) is an investigational immunotherapy that involves reprogramming a patient’s own T cells with a transgene encoding a chimeric antigen receptor to identify and eliminate CD19-expressing cells. We previously reported that CTL019 achieved impressive clinical efficacy in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL), including the expansion and persistence of CTL019 cells, which correlates with response to therapy. Here, we performed formal cellular kinetic analyses of CTL019 in a larger cohort of 103 patients treated with CTL019 in 2 different diseases (ALL and CLL). CTL019 was measured in peripheral blood and bone marrow, using quantitative polymerase chain reaction and flow cytometry. CTL019 levels in peripheral blood typically peaked at 10 to 14 days postinfusion and then declined slowly over time. Patients with complete response (CR)/CR with incomplete count recovery had higher levels of CTL019 in peripheral blood, with greater maximal concentration and area under the curve values compared with nonresponding patients (P < .0001 for each). CTL019 transgene levels were measurable up to 780 days in peripheral blood. CTL019 trafficking and persistence were observed in bone marrow and cerebrospinal fluid. CTL019 expansion correlated with severity of cytokine release syndrome (CRS) and preinfusion tumor burden in pediatric ALL. The results described here are the first detailed formal presentation of cellular kinetics across 2 diseases and highlight the importance of the application of in vivo cellular kinetic analyses to characterize clinical efficacy and CRS severity associated with CTL019 therapy. PMID:28935694

Evaluation of the miRNA profiling and effectiveness of the propolis on B-cell acute lymphoblastic leukemia cell line.

PubMed

Yilmaz, Ugur Cem; Bagca, Bakiye Goker; Karaca, Emin; Durmaz, Asude; Durmaz, Burak; Aykut, Ayca; Kayalar, Husniye; Avci, Cigir Biray; Susluer, Sunde Yilmaz; Gunduz, Cumhur; Cogulu, Ozgur

2016-12-01

Acute lymphoblastic leukemia (ALL) is one of the most frequent causes of death from cancer. Since the discovery of chemotherapeutic agents, ALL has become a model for improvement of survival. In parallel to this, serious side effects were observed and new natural therapeutic options has been discussed. One of these substances is called propolis which is a resinous substance gathered by honeybees. In the molecular era, miRNAs have been shown to play crucial roles in the development of many clinical conditions. The aim of this study is to evaluate the effect of Aydın propolis on 81 human miRNA activity in CCRF-SB leukemia cell line. Apoptotic effects of propolis on cell lines were also evaluated and apoptosis were found to be induced 1.5 fold in B-cell leukemia cells. The expression of 63 miRNAs (46 miRNAs were downregulated, 19 miRNAs were upregulated) in propolis treated leukemia cells have changed significantly (p<0.05). In conclusion propolis has changed expression of miRNAs which have epigenetic effects on leukemic cells. It is thought that it can be a promising agent for ALL treatment for future studies. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Emerging biological therapies to treat acute lymphoblastic leukemia.

PubMed

Huguet, Françoise; Tavitian, Suzanne

2017-03-01

Various settings of acute lymphoblastic leukemia (ALL) represent unmet medical needs: first remission at high risk of relapse, such as persistent minimal residual disease (MRD); relapse/refractoriness (R/R); elderly patients. Biological therapies targeting widely-shared antigens of blast cells have entered the clinic in B-cell precursor (BCP)-ALL. Area covered: Results of phase II/III trials of monoclonal antibodies (MoAbs) and phase I/II trials of adoptive cell therapy by chimeric antigen receptor-engineered T cells (CAR-T cells) are presented. Rituximab, a naked anti-CD20 MoAb, improves the results of chemotherapy in Philadelphia chromosome-negative BCP-ALL. Inotuzumab ozogamicin, an anti-CD22 immunotoxin, yields complete remission (CR) rates of 80% in R/R patients and in elderly newly diagnosed patients. Blinatumomab, a bispecific anti-CD19 and anti-CD3 agent redirects effector T cells towards B leukemic cells, is approved in R/R patients (40% CR, duration 6 months) and under investigation in MRD+ CR patients (80% negativation). Autologous anti-CD19 CAR-T cells undergo proliferation and persistence in the recipient. In limited series, they salvage more than 80% of advanced patients. Cytokine-release syndrome, encephalopathy and B-cell aplasia are shared, to varying extents, by blinatumomab and CAR-T cells. Expert opinion: Despite technological, ethical and clinical issues, biological therapies are currently changing the paradigm of treatment in BCP-ALL, and seem promised to dramatic developments.

Heterogeneity in acute undifferentiated leukemia.

PubMed

LeMaistre, A; Childs, C C; Hirsch-Ginsberg, C; Reuben, J; Cork, A; Trujillo, J M; Andersson, B; McCredie, K B; Freireich, E; Stass, S A

1988-01-01

From January 1985 to May 1987, we studied 256 adults with newly diagnosed acute leukemia. Acute undifferentiated leukemia (AUL) was diagnosed in 12 of the 256 (4.6%) cases when lineage could not be delineated by light microscopy and light cytochemistry. To further characterize the blasts, immunophenotyping, ultrastructural myeloperoxidase (UMPO), and ultrastructural platelet peroxidase parameters were examined in 10, 11, and 6 of the 12 cases, respectively. Five cases demonstrated UMPO and were reclassified as acute myeloblastic leukemia (AML). Of the six UMPO-negative cases, three had a myeloid and one had a mixed immunophenotype. One UMPO-negative patient with a myeloid immunophenotype was probed for the immunoglobulin heavy chain gene (JH) and the beta chain of the T-cell receptor gene (Tcr beta) with no evidence of rearrangement. Six cases were treated with standard acute lymphoblastic leukemia (ALL) chemotherapy and failed to achieve complete remission (CR). Various AML chemotherapeutic regimens produced CR in only 3 of the 12 cases. One case was treated with gamma interferon and the other 2 with high-dose Ara-C. Our findings indicate a myeloid lineage can be detected by UMPO (5/12) in some cases of AUL. A germline configuration with JH and Tcr beta in one case as well as a myeloid immunophenotype in 3 UMPO-negative cases raises the possibility that myeloid lineage commitment may occur in the absence of myeloid peroxidase (MPO) cytochemical positivity.

The Association Between Motor Skills and Academic Achievement Among Pediatric Survivors of Acute Lymphoblastic Leukemia.

PubMed

Balsamo, Lyn M; Sint, Kyaw J; Neglia, Joseph P; Brouwers, Pim; Kadan-Lottick, Nina S

2016-04-01

Assess the association between fine motor (FM) and visual-motor integration (VMI) skills and academic achievement in pediatric acute lymphoblastic leukemia (ALL) survivors. In this 28-site cross-sectional study of 256 children in first remission, a mean of 8.9 ± 2.2 years after treatment for standard-risk precursor-B ALL, validated measures of FM, VMI, reading, math, and intelligence were administered at mean follow-up age of 12.8 ± 2.5 years.   VMI was significantly associated with written math calculation ability (p < .0069) after adjusting for intelligence (p < .0001). VMI was more strongly associated with math in those with lower intelligence (p = .0141). Word decoding was also significantly associated with VMI but with no effect modification by intelligence. FM skills were not associated with either reading or math achievement. These findings suggest that VMI is associated with aspects of math and reading achievement in leukemia survivors. These skills may be amenable to intervention. © The Author 2015. Published by Oxford University Press on behalf of the Society of Pediatric Psychology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

[Leading causes of death during the induction therapy in pediatric patients with acute lymphoblastic leukemia].

PubMed

Aguilar-Hernández, Máximo; Fernández-Castillo, Gabriela; Núñez-Villegas, Nora Nancy; Pérez-Casillas, Ruy Xavier; Núñez-Enríquez, Juan Carlos

2017-01-01

Leukemias are the leading cause of childhood cancer. In most developed countries 1-2% of patients die during remission induction; however, in developing countries, this figure is higher and the causes of death apparently vary among the populations studied. The aim was to determine the cause of death during remission induction in pediatric patients with acute lymphoblastic leukemia (ALL) in the hospital "Dr. Gaudencio González Garza" of Centro Médico Nacional La Raza from January 1, 2009, to December 31, 2014. A retrospective cohort study was carried out and a descriptive statistical analysis was performed. During the study period, a total of 463 patients with ALL were diagnosed, out of which 5.4% died (n = 25). Among the patients who died, 64% (n = 16) were female and 60% had high-risk clinical features at diagnosis. The main causes of death were septic shock and bleeding. Early mortality was five times higher than the one reported for developed countries, while the causes of death did not differ. Close monitoring is necessary to detect and promptly treat complications secondary to chemotherapy toxicity in Mexican pediatric patients with ALL.

Tyrosine kinase fusion genes in pediatric BCR-ABL1-like acute lymphoblastic leukemia

PubMed Central

Boer, Judith M.; Steeghs, Elisabeth M.P.; Marchante, João R.M.; Boeree, Aurélie; Beaudoin, James J.; Berna Beverloo, H.; Kuiper, Roland P.; Escherich, Gabriele; van der Velden, Vincent H.J.; van der Schoot, C. Ellen; de Groot-Kruseman, Hester A.; Pieters, Rob; den Boer, Monique L.

2017-01-01

Approximately 15% of pediatric B cell precursor acute lymphoblastic leukemia (BCP-ALL) is characterized by gene expression similar to that of BCR-ABL1-positive disease and unfavorable prognosis. This BCR-ABL1-like subtype shows a high frequency of B-cell development gene aberrations and tyrosine kinase-activating lesions. To evaluate the clinical significance of tyrosine kinase gene fusions in children with BCP-ALL, we studied the frequency of recently identified tyrosine kinase fusions, associated genetic features, and prognosis in a representative Dutch/German cohort. We identified 14 tyrosine kinase fusions among 77 BCR-ABL1-like cases (18%) and none among 76 non-BCR-ABL1-like B-other cases. Novel exon fusions were identified for RCSD1-ABL2 and TERF2-JAK2. JAK2 mutation was mutually exclusive with tyrosine kinase fusions and only occurred in cases with high CRLF2 expression. The non/late response rate and levels of minimal residual disease in the fusion-positive BCR-ABL1-like group were higher than in the non-BCR-ABL1-like B-others (p<0.01), and also higher, albeit not statistically significant, compared with the fusion-negative BCR-ABL1-like group. The 8-year cumulative incidence of relapse in the fusion-positive BCR-ABL1-like group (35%) was comparable with that in the fusion-negative BCR-ABL1-like group (35%), and worse than in the non-BCR-ABL1-like B-other group (17%, p=0.07). IKZF1 deletions, predominantly other than the dominant-negative isoform and full deletion, co-occurred with tyrosine kinase fusions. This study shows that tyrosine kinase fusion-positive cases are a high-risk subtype of BCP-ALL, which warrants further studies with specific kinase inhibitors to improve outcome. PMID:27894077

Polycyclic Aromatic Hydrocarbons in Residential Dust and Risk of Childhood Acute Lymphoblastic Leukemia

PubMed Central

Deziel, NC; Rull, RP; Colt, JS; Reynolds, P; Whitehead, TP; Gunier, RB; Month, SR; Taggart, DR; Buffler, P; Ward, MH; Metayer, C

2014-01-01

Several polycyclic aromatic hydrocarbons (PAHs) are known or probable human carcinogens. We evaluated the relationship between PAH exposure and risk of childhood acute lymphoblastic leukemia (ALL) using concentrations in residential dust as an exposure indicator. We conducted a population-based case-control study (251 ALL cases, 306 birth-certificate controls) in Northern and Central California from 2001–2007. We collected residential dust using a high volume small surface sampler (HVS3) (n=185 cases, 212 controls) or by sampling from participants’ household vacuum cleaners (n=66 cases, 94 controls). We evaluated log-transformed concentrations of 9 individual PAHs, the summed PAHs, and the summed PAHs weighted by their carcinogenic potency (the toxic equivalence). We calculated odds ratios (ORs) and 95% confidence intervals (CI) using logistic regression adjusting for demographic characteristics and duration between diagnosis/reference date and dust collection. Among participants with HVS3 dust, risk of ALL was not associated with increasing concentration of any PAHs (based on OR per ln(ng/g). Among participants with vacuum dust, we observed positive associations between ALL risk and increasing concentrations of benzo[a]pyrene (OR per ln[ng/g]=1.42, 95% CI=0.95, 2.12), dibenzo[a,h]anthracene (OR=1.98, 95% CI=1.11, 3.55), benzo[k]fluoranthene (OR=1.71, 95% CI= 0.91, 3.22), indeno[1,2,3-cd]pyrene (OR=1.81, 95% CI=1.04, 3.16), and the toxic equivalence (OR=2.35, 95% CI=1.18, 4.69). The increased ALL risk among participants with vacuum dust suggests that PAH exposure may increase the risk of childhood ALL; however, reasons for the different results based on HVS3 dust samples deserve further study. PMID:24948546

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

PubMed

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

2017-06-01

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

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

PubMed Central

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

2017-01-01

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

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

PubMed Central

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

2015-01-01

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

Do polymorphisms of 5,10-methylenetetrahydrofolate reductase (MTHFR) gene affect the risk of childhood acute lymphoblastic leukemia?

PubMed

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

2006-01-01

Meta-analysis has become an important statistical tool in genetic association studies, since it may provide more powerful and precise estimates. However, meta-analytic studies are prone to several potential biases not only because the preferential publication of "positive'' studies but also due to difficulties in obtaining all relevant information during the study selection process. In this letter, we point out major problems in meta-analysis that may lead to biased conclusions, illustrating an empirical example of two recent meta-analyses on the relation between MTHFR polymorphisms and risk of acute lymphoblastic leukemia that, despite the similarity in statistical methods and period of study selection, provided partially conflicting results.

The association between methylenetetrahydrofolate reductase C677 > T polymorphisms and risk of pediatric acute lymphoblastic leukemia in Asia.

PubMed

Lin, Shiguang; Liu, Qin; Zeng, Xiaoming

2014-11-01

The association between methylenetetrahydrofolate reductase (MTHFR) C677 > T polymorphisms and pediatric acute lymphoblastic leukemia (ALL) risk in Asia is controversial. The aim of this meta-analysis was to further assess the relationship between MTHFR C677 > T polymorphisms and pediatric ALL for Chinese children. Studies about the MTHFR C677 > T polymorphisms and pediatric ALL risk were searched in the Medline, PubMed, EMBASE, Wanfang and CNIK databases. The genotype of the case and control group were extracted and pooled by meta-analysis. The association between ALL risk and C677 > T polymorphisms was demonstrated by odds ratio (OR) and its 95% confidence interval (CI). Twelve articles were included in this study with 1803 ALL cases and 4146 controls. In recessive genetic model (TT vs. CC + CT), the OR was 0.37 (95%CI: 0.31-0.43); in dominant genetic model (TT + CT vs. CC) the OR was 0.94 (95%CI: 0.82-1.06); and in the homozygous model the OR was 0.84 (95%CI: 0.69-1.03). The results indicated that Asian children with TT genotype of MTHFR gene may have less risk of developing ALL.

The effect of race on the CYP3A-mediated metabolism of vincristine in pediatric patients with acute lymphoblastic leukemia.

PubMed

Sims, Rosalyn P

2016-02-01

The purpose of this preliminary study was to compare racial background and CYP3A distribution in pediatric acute lymphoblastic leukemia patients as it relates to vincristine-related neurotoxicity. Patients with B-precursor acute lymphoblastic leukemia treated at Children's Hospital of Michigan were eligible to participate in this study. Determination of the CYP3A variant for each patient was done using Qiagen DNA Blood Mini Kit and polymerase chain reaction amplification. Patients were monitored during their leukemia treatment course for vincristine-related neurotoxicity. Fifty-four patients were enrolled. Twenty-nine Caucasian patients (81%) and 13 African-American patients (77%) experienced neurotoxicity. CYP3A genotyping was done for 52 patients. Two African-American and two Caucasian patients were homozygous A/A for the CYP3A5*3 polymorphism. Three of these patients (75%) experienced grade 2 neuropathy. Two Caucasian patients and one African-American patient were heterozygous A/G. Two of these patients (66.7%) experienced grade 2 or 3 neuropathy. Thirty-five patients (67.3%) were homozygous for the mutant inactive G/G allele for CYP3A5*3, eight African-American and 27 Caucasian patients. Of these, six of the African-American patients (75%) and 22 of the Caucasian patients (81.5%) experienced neuropathy. The CYP3A5*3 genotype causes very low expression of the CYP3A5 protein and hence decreased vincristine metabolism. In this study, patients who expressed CYP3A5*3 had an increased incidence of vincristine-related neurotoxicity. Overall, a greater percentage of Caucasian patients had documented incidences of neurotoxicity. A larger sample size and more detailed gene analysis are needed for future studies. © The Author(s) 2014.

Hyperthyroidism secondary to disseminated mucormycosis in a child with acute lymphoblastic leukemia: case report and a review of published reports.

PubMed

Irga, Ninela; Kosiak, Wojciech; Jaworski, Radoslaw; Komarnicka, Jolanta; Birkholz, Dorota

2013-02-01

Thyroiditis due to fungal infection is an extremely rare cause of hyperthyroidism. The most common etiological factor of thyroiditis is Aspergillus. Infections due to members of the Mucorales have been an increasing clinical problem in recent years, and the prognosis in generalized infections due to those fungi is usually very poor. No hyperthyroidism in a child with thyroiditis due to mucormycosis has been reported in the literature so far. We describe a clinical course of generalized mucormycosis with thyroid involvement in a 12-year-old girl treated for acute lymphoblastic leukemia. The child underwent a hyperthyroidism connected with thyroid involvement due to a fungal process. The diagnosis was based on the clinical signs, laboratory findings and typical ultrasound scan; however, later attempt to amplify the fungi DNA from the tissue block has failed. The child died because of multiorgan failure due to general fungal infection 49 days after the invasive fungal infection was diagnosed. The generalized mucormycosis is always connected with poor prognosis and the mortality is high.

Subacute methotrexate neurotoxicity and cerebral venous sinus thrombosis in a 12-year-old with acute lymphoblastic leukemia and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism: homocysteine-mediated methotrexate neurotoxicity via direct endothelial injury.

PubMed

Mahadeo, Kris M; Dhall, Girish; Panigrahy, Ashok; Lastra, Carlos; Ettinger, Lawrence J

2010-02-01

From as early as the 1970s methotrexate has been associated with disseminated necrotizing leukoencephalopathy and other neurotoxic sequelae. Yet, a clear mechanism for methotrexate-induced neurotoxicity has not been established. The authors describe the case of a 12-year-old male with acute lymphoblastic leukemia and a homozygous methylenetetrahydrofolate reductase C677T mutation, who developed subacute methotrexate-induced toxicity and cerebral venous thrombosis after receiving intrathecal methotrexate. The role of homocysteine as a possible mediator in methotrexate-induced neurotoxicity via direct endothelial injury is discussed.

Acute lymphoblastic leukemia in very young children. Diagnostic and therapeutic aspects of 43 cases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Leverger, G.; Bancillon, A.; Schaison, G.

Between 1974 and 1982, 43 children less than 2 years of age were treated in the hematology department of Hospital Saint-Louis for acute lymphoblastic leukemia (ALL). Of the patients who presented before 18 months of age, 80% had a WBC greater than 100,000 microliter and/or a great tumor bulk. As a result of our experience, treatment regimens have been changed here from conventional chemotherapy to a very intensive program with a heavy induction (vincristine, daunorubicin, cyclophosphamide, prednisone, and L-asparaginase) and monthly reinductions with the same drugs plus ArA-C, without maintenance. Prophylaxis included CNS irradiation (16-24 Gy) after 12 months ofmore » age, plus intrathecal methotrexate. Complete remission (CR) occurred in 78% before 18 months and in 100% between 18 and 24 months of age at diagnosis. In this report the probability of a prolonged CR (33% at 2 years) was the same before and after 12 months of age. However, younger patients were more intensively treated. The prognosis for children less than 1 year of age who received very intensive chemotherapy has greatly improved, with a significantly higher probability of long CR (p less than 0.02). Presently, 10 of 43 children are in CR 27 months to 8 years after diagnosis. Of 18 patients aged less than 1 year at diagnosis, four are in CR. No relapse occurred after 23 months. None of these patients presented with important sequellae, with the exception of one child who suffered from severe bacterial meningitis. An aggressive chemotherapy program is indicated in patients less than 2 years of age. The feasibility of this mode of treatment in young patients is possible only with the help of specific supportive care.« less

An inherited genetic variant in CEP72 promoter predisposes to vincristine-induced peripheral neuropathy in adults with acute lymphoblastic leukemia

PubMed Central

Stock, Wendy; Diouf, Barthelemy; Crews, Kristine R.; Pei, Deqing; Cheng, Cheng; Laumann, Kristina; Mandrekar, Sumithra J.; Luger, Selina; Advani, Anjali; Stone, Richard M.; Larson, Richard A.; Evans, William E.

2016-01-01

Peripheral neuropathy is a major toxicity of vincristine, yet no strategies exist for identifying at-risk adult patients. We used a case-control design of 48 adults receiving protocol therapy for acute lymphoblastic leukemia (ALL) who developed vincristine-induced neuropathy (NCI Grade 2-4) during treatment, and 48 matched controls who did not develop grade 2-4 neuropathy. Peripheral neuropathy was prospectively graded by NCI criteria. CEP72 promoter genotype (rs924607) was determined using PCR based SNP genotyping. Frequency of the CEP72 T/T genotype was higher in cases (31% vs 10%, p=0.0221) and the incidence of vincristine-induced neuropathy (grades 2-4) was significantly higher in patients homozygous for the CEP72 T/T genotype. 75% of the 20 patients homozygous for the CEP72 T allele developed grade 2-4 neuropathy, compared to 44% of patients with CEP72 CC or CT genotype (p=0.0221). The CEP72 polymorphism can identify adults at increased risk of vincristine-induced peripheral neuropathy. PMID:27618250

Oral or parenteral administration of curcumin does not prevent the growth of high-risk t(4;11) acute lymphoblastic leukemia cells engrafted into a NOD/SCID mouse model

USDA-ARS?s Scientific Manuscript database

The efficacy of orally and parenterally administered curcumin was evaluated in NOD.CB17-Prkdcscid/J mice engrafted with the human t(4;11) acute lymphoblastic leukemia line SEM. SEM cells were injected into the tail vein and engraftment was monitored by flow cytometry. Once engraftment was observed...

Unilateral optic disk edema with central retinal artery and vein occlusions as the presenting signs of relapse in acute lymphoblastic leukemia.

PubMed

Salazar Méndez, R; Fonollá Gil, M

2014-11-01

A 39-year-old man with Philadelphia chromosome-positive acute lymphoblastic leukemia (LAL Ph+) developed progressive vision loss to no light perception in his right eye. He had optic disk edema and later developed central artery and vein occlusions. Pan-photocoagulation, as well as radiotherapy of the whole brain were performed in several fractions. Unfortunately the patient died of hematological relapse 4 months later. Optic nerve infiltration may appear as an isolated sign of a leukemia relapse, even before a hematological relapse occurs. Leukemic optic neuropathy is a critical sign, not only for vision, but also for life, and radiotherapy should be immediately performed before irreversible optic nerve damage occurs. Copyright © 2013 Sociedad Española de Oftalmología. Published by Elsevier Espana. All rights reserved.

Ex vivo drug response profiling detects recurrent sensitivity patterns in drug-resistant acute lymphoblastic leukemia.

PubMed

Frismantas, Viktoras; Dobay, Maria Pamela; Rinaldi, Anna; Tchinda, Joelle; Dunn, Samuel H; Kunz, Joachim; Richter-Pechanska, Paulina; Marovca, Blerim; Pail, Orrin; Jenni, Silvia; Diaz-Flores, Ernesto; Chang, Bill H; Brown, Timothy J; Collins, Robert H; Uhrig, Sebastian; Balasubramanian, Gnana P; Bandapalli, Obul R; Higi, Salome; Eugster, Sabrina; Voegeli, Pamela; Delorenzi, Mauro; Cario, Gunnar; Loh, Mignon L; Schrappe, Martin; Stanulla, Martin; Kulozik, Andreas E; Muckenthaler, Martina U; Saha, Vaskar; Irving, Julie A; Meisel, Roland; Radimerski, Thomas; Von Stackelberg, Arend; Eckert, Cornelia; Tyner, Jeffrey W; Horvath, Peter; Bornhauser, Beat C; Bourquin, Jean-Pierre

2017-03-16

Drug sensitivity and resistance testing on diagnostic leukemia samples should provide important functional information to guide actionable target and biomarker discovery. We provide proof of concept data by profiling 60 drugs on 68 acute lymphoblastic leukemia (ALL) samples mostly from resistant disease in cocultures of bone marrow stromal cells. Patient-derived xenografts retained the original pattern of mutations found in the matched patient material. Stromal coculture did not prevent leukemia cell cycle activity, but a specific sensitivity profile to cell cycle-related drugs identified samples with higher cell proliferation both in vitro and in vivo as leukemia xenografts. In patients with refractory relapses, individual patterns of marked drug resistance and exceptional responses to new agents of immediate clinical relevance were detected. The BCL2-inhibitor venetoclax was highly active below 10 nM in B-cell precursor ALL (BCP-ALL) subsets, including MLL -AF4 and TCF3-HLF ALL, and in some T-cell ALLs (T-ALLs), predicting in vivo activity as a single agent and in combination with dexamethasone and vincristine. Unexpected sensitivity to dasatinib with half maximal inhibitory concentration values below 20 nM was detected in 2 independent T-ALL cohorts, which correlated with similar cytotoxic activity of the SRC inhibitor KX2-391 and inhibition of SRC phosphorylation. A patient with refractory T-ALL was treated with dasatinib on the basis of drug profiling information and achieved a 5-month remission. Thus, drug profiling captures disease-relevant features and unexpected sensitivity to relevant drugs, which warrants further exploration of this functional assay in the context of clinical trials to develop drug repurposing strategies for patients with urgent medical needs. © 2017 by The American Society of Hematology.

[Copy number alterations in adult patients with mature B acute lymphoblastic leukemia treated with specific immunochemotherapy].

PubMed

Ribera, Jordi; Zamora, Lurdes; García, Olga; Hernández-Rivas, Jesús-María; Genescà, Eulàlia; Ribera, Josep-Maria

2016-12-02

Unlike Burkitt lymphoma, molecular abnormalities other than C-MYC rearrangements have scarcely been studied in patients with mature B acute lymphoblastic leukemia (B-ALL). The aim of this study was to analyze the frequency and prognostic significance of copy number alterations (CNA) in genes involved in lymphoid differentiation, cell cycle and tumor suppression in adult patients with B-ALL. We have analyzed by multiplex ligation-dependent probe amplification the genetic material from bone marrow at diagnosis from 25 adult B-ALL patients treated with rituximab and specific chemotherapy. The most frequent CNA were alterations in the 14q32.33 region (11 cases, 44%) followed by alterations in the cell cycle regulator genes CDKN2A/B and RB1 (16%). No correlation between the presence of specific CNA and the clinical-biologic features or the response to therapy was found. The high frequency of CNA in the 14q32.33 region, CDKN2A/B and RB1 found in our study could contribute to the aggressiveness and invasiveness of mature B-ALL. Copyright © 2016 Elsevier España, S.L.U. All rights reserved.

Microdeletions are a general feature of adult and adolescent acute lymphoblastic leukemia: Unexpected similarities with pediatric disease

PubMed Central

Paulsson, Kajsa; Cazier, Jean-Baptiste; MacDougall, Finlay; Stevens, Jane; Stasevich, Irina; Vrcelj, Nikoletta; Chaplin, Tracy; Lillington, Debra M.; Lister, T. Andrew; Young, Bryan D.

2008-01-01

We present here a genome-wide map of abnormalities found in diagnostic samples from 45 adults and adolescents with acute lymphoblastic leukemia (ALL). A 500K SNP array analysis uncovered frequent genetic abnormalities, with cryptic deletions constituting half of the detected changes, implying that microdeletions are a characteristic feature of this malignancy. Importantly, the pattern of deletions resembled that recently reported in pediatric ALL, suggesting that adult, adolescent, and childhood cases may be more similar on the genetic level than previously thought. Thus, 70% of the cases displayed deletion of one or more of the CDKN2A, PAX5, IKZF1, ETV6, RB1, and EBF1 genes. Furthermore, several genes not previously implicated in the pathogenesis of ALL were identified as possible recurrent targets of deletion. In total, the SNP array analysis identified 367 genetic abnormalities not corresponding to known copy number polymorphisms, with all but two cases (96%) displaying at least one cryptic change. The resolution level of this SNP array study is the highest used to date to investigate a malignant hematologic disorder. Our findings provide insights into the leukemogenic process and may be clinically important in adult and adolescent ALL. Most importantly, we report that microdeletions of key genes appear to be a common, characteristic feature of ALL that is shared among different clinical, morphological, and cytogenetic subgroups. PMID:18458336

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

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

Repression of BIM mediates survival signaling by MYC and AKT in high-risk T-cell acute lymphoblastic leukemia.

PubMed

Reynolds, C; Roderick, J E; LaBelle, J L; Bird, G; Mathieu, R; Bodaar, K; Colon, D; Pyati, U; Stevenson, K E; Qi, J; Harris, M; Silverman, L B; Sallan, S E; Bradner, J E; Neuberg, D S; Look, A T; Walensky, L D; Kelliher, M A; Gutierrez, A

2014-09-01

Treatment resistance in T-cell acute lymphoblastic leukemia (T-ALL) is associated with phosphatase and tensin homolog (PTEN) deletions and resultant phosphatidylinositol 3'-kinase (PI3K)-AKT pathway activation, as well as MYC overexpression, and these pathways repress mitochondrial apoptosis in established T-lymphoblasts through poorly defined mechanisms. Normal T-cell progenitors are hypersensitive to mitochondrial apoptosis, a phenotype that is dependent on the expression of proapoptotic BIM. In a conditional zebrafish model, MYC downregulation induced BIM expression in T-lymphoblasts, an effect that was blunted by expression of constitutively active AKT. In human T-ALL cell lines and treatment-resistant patient samples, treatment with MYC or PI3K-AKT pathway inhibitors each induced BIM upregulation and apoptosis, indicating that BIM is repressed downstream of MYC and PI3K-AKT in high-risk T-ALL. Restoring BIM function in human T-ALL cells using a stapled peptide mimetic of the BIM BH3 domain had therapeutic activity, indicating that BIM repression is required for T-ALL viability. In the zebrafish model, where MYC downregulation induces T-ALL regression via mitochondrial apoptosis, T-ALL persisted despite MYC downregulation in 10% of bim wild-type zebrafish, 18% of bim heterozygotes and in 33% of bim homozygous mutants (P=0.017). We conclude that downregulation of BIM represents a key survival signal downstream of oncogenic MYC and PI3K-AKT signaling in treatment-resistant T-ALL.

Establishment of a new human pre-B acute lymphoblastic leukemia cell line (KMO-90) with 1;19 translocation carrying p53 gene alterations.

PubMed

Sotomatsu, M; Hayashi, Y; Kawamura, M; Yugami, S; Shitara, T

1993-10-01

A new human pre-B acute lymphoblastic leukemia cell line (KMO-90) was established from the bone marrow sample of a 12-year-old girl with acute lymphoblastic leukemia (ALL) carrying 1;19 chromosome translocation. KMO-90 cells expressed HLA-DR, CD10, CD19, and CD22 antigens. These cells had also cytoplasmic immunoglobulin lacking surface immunoglobulin, indicating that these had a pre-B phenotype. Chromosome analysis of this cell line showed 48, XX, +8, +19, t(1;19)(q23;p13). Southern blot analysis showed the same sized rearrangements of the E2A gene in KMO-90 cells as those in the original leukemic cells. By means of reverse transcriptase-polymerase chain reaction analysis, we detected E2A/PBX1 fusion transcripts in KMO-90 cells. KMO-90 is useful when studying the role of the 1;19 translocation in the etiology of pre-B ALL. Furthermore, we studied alterations of the p53 gene in this cell line by polymerase chain reaction, single-strand conformation polymorphism analysis. KMO-90 cells were identified to have a point mutation at codon 177 (CCC-->TCC) of the p53 gene, suggesting that alterations of the p53 gene may have an important role in the establishment of this cell line.

Clinical Utility of Ammonia Concentration as a Diagnostic Test in Monitoring of the Treatment with L-Asparaginase in Children with Acute Lymphoblastic Leukemia

PubMed Central

Czogała, Małgorzata; Balwierz, Walentyna; Sztefko, Krystyna; Rogatko, Iwona

2014-01-01

L-asparaginase (ASP) is an enzyme used as one of the basic regimens in the acute lymphoblastic leukemia (ALL) therapy. Because of the possibility of the enzyme inactivation by antibodies, monitoring of ASP activity is essential. The aim of the study was to examine if plasma concentration of ammonia, a direct product of the reaction catalyzed by ASP, can be used in the assessment of ASP activity. A group of 87 patients with acute lymphoblastic leukemia treated in the Department of Pediatric Oncology and Hematology in Krakow was enrolled to the study. ASP activity and ammonia concentration were measured after ASP administrations during induction. A positive correlation was found between the ammonia concentration and ASP activity (R = 0.44; P < 0.0001) and between the medium values of ammonia concentration and ASP activity (R = 0.56; P < 0.0001). The analysis of ROC curves revealed the moderate accuracy of the ammonia concentration values in the ASP activity assessment. It was also found that the medium value of ammonia concentrations can be useful in identification of the patients with low (<100 IU/L) and undetectable (<30 IU/L) ASP activity. The plasma ammonia concentration may reflect ASP activity and can be useful when a direct measurement of the activity is unavailable. PMID:25157375

Genetic evaluation of childhood acute lymphoblastic leukemia in Iraq using FTA cards.

PubMed

Al-Kzayer, Lika'a Fasih Y; Sakashita, Kazuo; Matsuda, Kazuyuki; Al-Hadad, Salma Abbas; Al-Jadiry, Mazin Faisal; Abed, Wisam Majeed; Abdulkadhim, Jaafar M H; Al-Shujairi, Tariq Abadi; Hasan, Janan Ghalib; Al-Abdullah, Hussam M Salih; Al-Ani, Mouroge H; Saber, Paiman Ali I; Inoshita, Toshi; Kamata, Minoru; Koike, Kenichi

2012-09-01

Genetic examination of childhood leukemia has not been available in Iraq. We here report the frequency of TEL-AML1, E2A-PBX1, MLL-AF4, and BCR-ABL chimeric transcripts in 264 Iraqi children newly diagnosed with acute lymphoblastic leukemia (ALL), using FTA cards impregnated with bone marrow aspirate or whole blood. The diagnosis of ALL was made according to standard French-American-British morphologic criteria. Based on the results of storage temperature and duration, most of the FTA samples were preserved at 4°C for up to 6 weeks in five Iraqi hospitals and then transferred to Japan for molecular analysis. Nested reverse transcription-polymerase chain reaction was adopted for the analysis. TEL-AML1 chimeric transcript product was found in 32 (12.1%) of 264 ALL patients. Eleven (4.2%) patients, 4 (1.5%) patients, and 11 (4.2%) patients had E2A-PBX1 mRNA, MLL-AF4 mRNA, and BCR-ABL mRNA, respectively. One patient had both TEL-AML1 and E2A-PBX1 fusion genes. The incidence of TEL-AML1 in Iraqi ALL children appears to be similar to or slightly higher than those of Jordan (12%) and Kuwait (7%). The prevalence and clinical findings of ALL patients with either E2A-PBX1 or BCR-ABL were comparable to the data reported elsewhere. International collaboration via FTA cards may be helpful to improve diagnosis and management of patients with hematological malignancies in low-income and underdeveloped countries. Copyright © 2012 Wiley Periodicals, Inc.

Recent Advances in the Biology and Treatment of T Cell Acute Lymphoblastic Leukemia.

PubMed

Hefazi, Mehrdad; Litzow, Mark R

2018-06-15

This article provides an overview of the current knowledge regarding the biology and treatment of T cell acute lymphoblastic leukemia (T-ALL) and highlights the most recent findings in this field over the past 5 years. Remarkable progress has been made in the genomic landscape of T-ALL over the past few years. The discovery of activating mutations of NOTCH1 and FBXW7 in a majority of patients has been a seminal observation, with several early phase clinical trials currently exploring these as potential therapeutic targets. Characterization of early T cell precursor ALL, incorporation of minimal residual disease assessment into therapeutic protocols, and use of pediatric-intensive regimens along with judicious use of allogeneic HCT have significantly improved risk stratification and treatment outcomes. Improved risk stratification and the use of novel targeted therapies based on recent genomic discoveries are expected to change the therapeutic landscape of T-ALL and hopefully improve the outcomes of this historically poor prognosis disease.

Leydig-cell function in children after direct testicular irradiation for acute lymphoblastic leukemia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Brauner, R.; Czernichow, P.; Cramer, P.

To assess the effect of testicular irradiation on testicular endocrine function, we studied 12 boys with acute lymphoblastic leukemia who had been treated with direct testicular irradiation 10 months to 8 1/2 years earlier. Insufficient Leydig-cell function, manifested by a low response of plasma testosterone to chorionic gonadotropin or an increased basal level of plasma luteinizing hormone (or both), was observed in 10 patients, 7 of whom were pubertal. Two of these patients had a compensated testicular endocrine insufficiency with only high plasma concentrations of luteinizing hormone. Testosterone secretion was severely impaired in three pubertal boys studied more than fourmore » years after testicular irradiation. A diminished testicular volume indicating tubular atrophy was found in all pubertal patients, including three who had not received cyclophosphamide or cytarabine. These data indicate that testosterone insufficiency is a frequent complication of testicular irradiation, although some patients continue to have Leydig-cell activity for several years after therapy.« less

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

ClinicalTrials.gov

2018-03-15

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

Infusion of Expanded Cord Blood Cells in Addition to Single Cord Blood Transplant in Treating Patients With Acute Leukemia, Chronic Myeloid Leukemia, or Myelodysplastic Syndromes

ClinicalTrials.gov

2018-03-26

Acute Biphenotypic Leukemia; Acute Lymphoblastic Leukemia in Remission; Acute Myeloid Leukemia in Remission; Blasts Under 10 Percent of Bone Marrow Nucleated Cells; Blasts Under 5 Percent of Bone Marrow Nucleated Cells; Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Cytogenetic Abnormality; High Risk Myelodysplastic Syndrome; Myelodysplastic Syndrome With Excess Blasts; Pancytopenia; Refractory Anemia

A genome-wide association study of susceptibility to acute lymphoblastic leukemia in adolescents and young adults.

PubMed

Perez-Andreu, Virginia; Roberts, Kathryn G; Xu, Heng; Smith, Colton; Zhang, Hui; Yang, Wenjian; Harvey, Richard C; Payne-Turner, Debbie; Devidas, Meenakshi; Cheng, I-Ming; Carroll, William L; Heerema, Nyla A; Carroll, Andrew J; Raetz, Elizabeth A; Gastier-Foster, Julie M; Marcucci, Guido; Bloomfield, Clara D; Mrózek, Krzysztof; Kohlschmidt, Jessica; Stock, Wendy; Kornblau, Steven M; Konopleva, Marina; Paietta, Elisabeth; Rowe, Jacob M; Luger, Selina M; Tallman, Martin S; Dean, Michael; Burchard, Esteban G; Torgerson, Dara G; Yue, Feng; Wang, Yanli; Pui, Ching-Hon; Jeha, Sima; Relling, Mary V; Evans, William E; Gerhard, Daniela S; Loh, Mignon L; Willman, Cheryl L; Hunger, Stephen P; Mullighan, Charles G; Yang, Jun J

2015-01-22

Acute lymphoblastic leukemia (ALL) in adolescents and young adults (AYA) is characterized by distinct presenting features and inferior prognosis compared with pediatric ALL. We performed a genome-wide association study (GWAS) to comprehensively identify inherited genetic variants associated with susceptibility to AYA ALL. In the discovery GWAS, we compared genotype frequency at 635 297 single nucleotide polymorphisms (SNPs) in 308 AYA ALL cases and 6,661 non-ALL controls by using a logistic regression model with genetic ancestry as a covariate. SNPs that reached P ≤ 5 × 10(-8) in GWAS were tested in an independent cohort of 162 AYA ALL cases and 5,755 non-ALL controls. We identified a single genome-wide significant susceptibility locus in GATA3: rs3824662, odds ratio (OR), 1.77 (P = 2.8 × 10(-10)) and rs3781093, OR, 1.73 (P = 3.2 × 10(-9)). These findings were validated in the replication cohort. The risk allele at rs3824662 was most frequent in Philadelphia chromosome (Ph)-like ALL but also conferred susceptibility to non-Ph-like ALL in AYAs. In 1,827 non-selected ALL cases, the risk allele frequency at this SNP was positively correlated with age at diagnosis (P = 6.29 × 10(-11)). Our results from this first GWAS of AYA ALL susceptibility point to unique biology underlying leukemogenesis and potentially distinct disease etiology by age group.

Pharmacogenetic Predictors of Treatment-Related Toxicity Among Children With Acute Lymphoblastic Leukemia.

PubMed

Maxwell, Rochelle R; Cole, Peter D

2017-06-01

The aim of this review is to summarize the most recent and most robust pharmacogenetic predictors of treatment-related toxicity (TRT) in childhood acute lymphoblastic leukemia (ALL). Multiple studies have examined the toxicities of the primary chemotherapeutic agents used to treat childhood ALL in relation to host genetic factors. However, few results have been replicated independently, largely due to cohort differences in ancestry, chemotherapy treatment protocols, and definitions of toxicities. To date, there is only one widely accepted clinical guideline for dose modification based on gene status: thiopurine dosing based on TPMT genotype. Based on recent data, it is likely that this guideline will be modified to incorporate other gene variants, such as NUDT15. We highlight genetic variants that have been consistently associated with TRT across treatment groups, as well as those that best illustrate the underlying pathophysiology of TRT. In the coming decade, we expect that survivorship care will routinely specify screening recommendations based on genetics. Furthermore, clinical trials testing protective interventions may modify inclusion criteria based on genetically determined risk of specific TRTs.

Minimal Residual Disease Assessment and Risk-based Therapy in Acute Lymphoblastic Leukemia.

PubMed

Bassan, Renato; Intermesoli, Tamara; Scattolin, Annamaria; Viero, Piera; Maino, Elena; Sancetta, Rosaria; Carobolante, Francesca; Gianni, Francesca; Stefanoni, Paola; Tosi, Manuela; Spinelli, Orietta; Rambaldi, Alessandro

2017-07-01

The study of minimal residual disease (MRD) in adult patients with acute lymphoblastic leukemia (ALL) allows a greater refinement of the individual risk classification and is the best support for risk-specific therapy with or without allogeneic hematopoietic cell transplantation (HCT). Using case-specific sensitive molecular probes or multiparametric flow cytometry on marrow samples obtained from the end of induction until midconsolidation, MRD assays can detect up to 1 leukemic cell of 10,000 total mononuclear cells (sensitivity, 0.01%; ie, ≥10 4 ). This cutoff, presently bound to technical limitations and subject to improvement, reflects the individual chemosensitivity and is strongly correlated with treatment outcome. The chance for cure is approximately 70% in the MRD-negative subset but only 20% to 30% in MRD-positive patients, in any diagnostic and risk subset. As shown by prospective trials from Germany, Italy, Spain, and France-Switzerland-Belgium, approximately 50% to 70% of unselected adult patients with Philadelphia-negative ALL achieve and maintain an early MRD response, whereas the remainder do not, including a substantial proportion of clinically standard-risk patients, and require an HCT to avert at least partially the risk of relapse. Along with the diffusion of more effective "pediatric-inspired" chemotherapy programs, the MRD analysis is an integral part of a modern management strategy, guiding the decision process to transplant or not, in which case nonrelapse mortality using HCT in first remission-still 10% to 20%-is totally abolished. The use of new agents such as monoclonal antibodies, small inhibitors, and chimeric antigen receptor T cells is opening a new era of MRD-directed therapies, that will further increase survival rates. Copyright © 2017 Elsevier Inc. All rights reserved.

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

PubMed

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

2016-03-01

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

Gain-of-function mutations in interleukin-7 receptor-α (IL7R) in childhood acute lymphoblastic leukemias