42 results on '"Hunger, Stephen P"'
Search Results
2. The genomic landscape of pediatric acute lymphoblastic leukemia and precision medicine opportunities.
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Tran, Thai Hoa and Hunger, Stephen P.
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LYMPHOBLASTIC leukemia , *INDIVIDUALIZED medicine , *ACUTE leukemia , *PROGNOSIS , *CHILDHOOD cancer - Abstract
Acute lymphoblastic leukemia (ALL) is the most common childhood cancer and constitutes approximately 25 % of cancer diagnoses among children under the age of 15 (Howlader et al., 2013) [ 1 ]. Overall, about half of ALL cases occur in children and adolescents and it is the most common acute leukemia until the early 20s, after which acute myeloid leukemia predominates. ALL is the most successful treatment paradigm in pediatric cancer medicine as illustrated by the significant survival rate improvement from ∼10 % in the 1960s to >90 % today (Hunger et al., 2015) [ 2 ]. This remarkable success stems from the progressive improvement in the efficacy of risk-adapted multiagent chemotherapy regimens with effective central nervous system (CNS) prophylaxis via well-designed randomized clinical trials conducted by international collaborative consortia, enhanced supportive care measures to decrease treatment-related mortality, in-depth understanding of the genetic basis of ALL, and refinement in treatment response assessment through serial minimal residual disease (MRD) monitoring (Pui et al., 2015) [ 3 ]. These advances collectively contribute to a decline in mortality rate of 23.5% for children diagnosed with ALL in the US from 2000 to 2010 (Smith et al., 2014) [ 4 ]. Nevertheless, outcomes of older adolescents and young adults with ALL still lag behind those of their younger counterparts despite pediatric-inspired chemotherapy regimens (Stock et al., 2019) [ 5 ], relapsed/refractory childhood ALL is associated with poor outcomes (Rheingold et al., 2019) [ 6 ], and ALL still represents the leading causes of cancer-related deaths (Smith et al., 2010) [ 7 ]. The last two decades have witnessed important genomic discoveries in ALL, enabled by advances in next-generation sequencing (NGS) technologies to characterize the landscape of germline and somatic alterations in ALL, some of which have important diagnostic, prognostic and therapeutic implications. Comprehensive genomic analysis of large cohorts of children and adults with ALL has revised the taxonomy of ALL in the molecular era by identifying novel clonal, subtype-defined chromosomal alterations associated with distinct gene expression signatures, thus reducing the proportion of patients previously labelled as "Others" from 25 % to approximately 5 % (Mullighan et al., 2019) [ 8 ]. Insights into the genomics of ALL further provide compelling biologic rationale to expand the scope of precision medicine therapies for childhood ALL. Herein, we summarize a decade of genomic discoveries to highlight three different facets of precision medicine in pediatric ALL: 1) inherited predispositions of ALL; 2) relevant molecularly targeted therapies in genomically-defined ALL subtypes; and 3) treatment response monitoring via pharmacogenomics and novel MRD biomarkers. [ABSTRACT FROM AUTHOR]
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- 2022
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3. Molecular Mechanisms of ARID5B-Mediated Genetic Susceptibility to Acute Lymphoblastic Leukemia.
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Zhao, Xujie, Qian, Maoxiang, Goodings, Charnise, Zhang, Yang, Yang, Wenjian, Wang, Ping, Xu, Beisi, Tian, Cheng, Pui, Ching-Hon, Hunger, Stephen P, Raetz, Elizabeth A, Devidas, Meenakshi, Relling, Mary V, Loh, Mignon L, Savic, Daniel, Li, Chunliang, and Yang, Jun J
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SEQUENCE analysis ,LYMPHOBLASTIC leukemia ,GENETIC polymorphisms ,DISEASE susceptibility ,DNA-binding proteins ,RESEARCH funding ,TRANSCRIPTION factors - Abstract
Background: There is growing evidence for the inherited basis of susceptibility to childhood acute lymphoblastic leukemia (ALL). Genome-wide association studies have identified non-coding ALL risk variants at the ARID5B gene locus, but their exact functional effects and the molecular mechanism linking ARID5B to B-cell ALL leukemogenesis remain largely unknown.Methods: We performed targeted sequencing of ARID5B in germline DNA of 5008 children with ALL. Variants were evaluated for association with ALL susceptibility using 3644 patients from the UK10K cohort as non-ALL controls, under an additive model. Cis-regulatory elements in ARID5B were systematically identified using dCas9-KRAB-mediated enhancer interference system enhancer screen in ALL cells. Disruption of transcription factor binding by ARID5B variant was predicted informatically and then confirmed using chromatin immunoprecipitation and coimmunoprecipitation. ARID5B variant association with hematological traits was examined using UK Biobank dataset. All statistical tests were 2-sided.Results: We identified 54 common variants in ARID5B statistically significantly associated with leukemia risk, all of which were noncoding. Six cis-regulatory elements at the ARID5B locus were discovered using CRISPR-based high-throughput enhancer screening. Strikingly, the top ALL risk variant (rs7090445, P = 5.57 × 10-45) is located precisely within the strongest enhancer element, which is also distally tethered to the ARID5B promoter. The variant allele disrupts the MEF2C binding motif sequence, resulting in reduced MEF2C affinity and decreased local chromosome accessibility. MEF2C influences ARID5B expression in ALL, likely via a transcription factor complex with RUNX1. Using the UK Biobank dataset (n = 349 861), we showed that rs7090445 was also associated with lymphocyte percentage and count in the general population (P = 8.6 × 10-22 and 2.1 × 10-18, respectively).Conclusions: Our results indicate that ALL risk variants in ARID5B function by modulating cis-regulatory elements at this locus. [ABSTRACT FROM AUTHOR]- Published
- 2022
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4. Genome-Wide Association Study of Susceptibility Loci for TCF3-PBX1 Acute Lymphoblastic Leukemia in Children.
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Lee, Shawn H. R, Qian, Maoxiang, Yang, Wentao, Diedrich, Jonathan D, Raetz, Elizabeth, Yang, Wenjian, Dong, Qian, Devidas, Meenakshi, Pei, Deqing, Yeoh, Allen, Cheng, Cheng, Pui, Ching-Hon, Evans, William E, Mullighan, Charles G, Hunger, Stephen P, Savic, Daniel, Relling, Mary V, Loh, Mignon L, Yang, Jun J, and Lee, Shawn H R
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GENOME-wide association studies ,LYMPHOBLASTIC leukemia ,ACUTE leukemia ,CHILDHOOD cancer ,CELL fusion ,SOMATIC mutation ,PROTEINS ,RESEARCH ,SEQUENCE analysis ,RESEARCH methodology ,EVALUATION research ,COMPARATIVE studies ,DISEASE susceptibility ,RESEARCH funding ,ACUTE diseases - Abstract
Acute lymphoblastic leukemia (ALL) is the most common cancer in children. TCF3-PBX1 fusion defines a common molecular subtype of ALL with unique clinical features, but the molecular basis of its inherited susceptibility is unknown. In a genome-wide association study of 1494 ALL cases and 2057 non-ALL controls, we identified a germline risk locus located in an intergenic region between BCL11A and PAPOLG: rs2665658, P = 1.88 × 10-8 for TCF3-PBX1 ALL vs non-ALL, and P = 1.70 × 10-8 for TCF3-PBX1 ALL vs other-ALL. The lead variant was validated in a replication cohort, and conditional analyses pointed to a single causal variant with subtype-specific effect. The risk variant is located in a regulatory DNA element uniquely activated in ALL cells with the TCF3-PBX1 fusion and may distally modulate the transcription of the adjacent gene REL. Our results expand the understanding of subtype-specific ALL susceptibility and highlight plausible interplay between germline variants and somatic genomic abnormalities in ALL pathogenesis. [ABSTRACT FROM AUTHOR]
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- 2021
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5. Effect of Postreinduction Therapy Consolidation With Blinatumomab vs Chemotherapy on Disease-Free Survival in Children, Adolescents, and Young Adults With First Relapse of B-Cell Acute Lymphoblastic Leukemia: A Randomized Clinical Trial.
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Brown, Patrick A., Ji, Lingyun, Xu, Xinxin, Devidas, Meenakshi, Hogan, Laura E., Borowitz, Michael J., Raetz, Elizabeth A., Zugmaier, Gerhard, Sharon, Elad, Bernhardt, Melanie B., Terezakis, Stephanie A., Gore, Lia, Whitlock, James A., Pulsipher, Michael A., Hunger, Stephen P., and Loh, Mignon L.
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LYMPHOBLASTIC leukemia treatment ,LYMPHOBLASTIC leukemia in children ,IMMUNOTHERAPY ,CANCER chemotherapy ,STEM cell transplantation ,CANCER relapse ,THERAPEUTIC use of immunoglobulins ,THERAPEUTIC use of antineoplastic agents ,RESEARCH ,IMMUNOGLOBULINS ,LYMPHOBLASTIC leukemia ,RESEARCH methodology ,ANTINEOPLASTIC agents ,PROGNOSIS ,MEDICAL cooperation ,EVALUATION research ,DISEASE relapse ,COMPARATIVE studies ,RANDOMIZED controlled trials ,LYMPHOCYTIC leukemia ,DRUG therapy ,RESEARCH funding ,HEMATOPOIETIC stem cell transplantation ,COMBINED modality therapy - Abstract
Importance: Standard chemotherapy for first relapse of B-cell acute lymphoblastic leukemia (B-ALL) in children, adolescents, and young adults is associated with high rates of severe toxicities, subsequent relapse, and death, especially for patients with early relapse (high risk) or late relapse with residual disease after reinduction chemotherapy (intermediate risk). Blinatumomab, a bispecific CD3 to CD19 T cell-engaging antibody construct, is efficacious in relapsed/refractory B-ALL and has a favorable toxicity profile.Objective: To determine whether substituting blinatumomab for intensive chemotherapy in consolidation therapy would improve survival in children, adolescents, and young adults with high- and intermediate-risk first relapse of B-ALL.Design, Setting, and Participants: This trial was a randomized phase 3 clinical trial conducted by the Children's Oncology Group at 155 hospitals in the US, Canada, Australia, and New Zealand with enrollment from December 2014 to September 2019 and follow-up until September 30, 2020. Eligible patients included those aged 1 to 30 years with B-ALL first relapse, excluding those with Down syndrome, Philadelphia chromosome-positive ALL, prior hematopoietic stem cell transplant, or prior blinatumomab treatment (n = 669).Interventions: All patients received a 4-week reinduction chemotherapy course, followed by randomized assignment to receive 2 cycles of blinatumomab (n = 105) or 2 cycles of multiagent chemotherapy (n = 103), each followed by transplant.Main Outcome and Measures: The primary end point was disease-free survival and the secondary end point was overall survival, both from the time of randomization. The threshold for statistical significance was set at a 1-sided P <.025.Results: Among 208 randomized patients (median age, 9 years; 97 [47%] females), 118 (57%) completed the randomized therapy. Randomization was terminated at the recommendation of the data and safety monitoring committee without meeting stopping rules for efficacy or futility; at that point, 80 of 131 planned events occurred. With 2.9 years of median follow-up, 2-year disease-free survival was 54.4% for the blinatumomab group vs 39.0% for the chemotherapy group (hazard ratio for disease progression or mortality, 0.70 [95% CI, 0.47-1.03]); 1-sided P = .03). Two-year overall survival was 71.3% for the blinatumomab group vs 58.4% for the chemotherapy group (hazard ratio for mortality, 0.62 [95% CI, 0.39-0.98]; 1-sided P = .02). Rates of notable serious adverse events included infection (15%), febrile neutropenia (5%), sepsis (2%), and mucositis (1%) for the blinatumomab group and infection (65%), febrile neutropenia (58%), sepsis (27%), and mucositis (28%) for the chemotherapy group.Conclusions and Relevance: Among children, adolescents, and young adults with high- and intermediate-risk first relapse of B-ALL, postreinduction treatment with blinatumomab compared with chemotherapy, followed by transplant, did not result in a statistically significant difference in disease-free survival. However, study interpretation is limited by early termination with possible underpowering for the primary end point.Trial Registration: ClinicalTrials.gov Identifier: NCT02101853. [ABSTRACT FROM AUTHOR]- Published
- 2021
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6. Mixed-phenotype acute leukemia: A cohort and consensus research strategy from the Children's Oncology Group Acute Leukemia of Ambiguous Lineage Task Force.
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Orgel, Etan, Alexander, Thomas B., Wood, Brent L., Kahwash, Samir B., Devidas, Meenakshi, Dai, Yunfeng, Alonzo, Todd A., Mullighan, Charles G., Inaba, Hiroto, Hunger, Stephen P., Raetz, Elizabeth A., Gamis, Alan S., Rabin, Karen R., Carroll, Andrew J., Heerema, Nyla A., Berman, Jason N., Woods, William G., Loh, Mignon L., Zweidler‐McKay, Patrick A., and Horan, John T.
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ACUTE leukemia ,HEMATOPOIETIC stem cell transplantation ,TASK forces ,LYMPHOBLASTIC leukemia ,ACUTE myeloid leukemia ,RESEARCH ,CLINICAL trials ,RESEARCH methodology ,PROGNOSIS ,PEDIATRICS ,EVALUATION research ,MEDICAL cooperation ,COMPARATIVE studies ,LYMPHOCYTIC leukemia ,IMMUNOPHENOTYPING ,RESEARCH funding - Abstract
Background: Optimal chemotherapy for treating mixed-phenotype acute leukemia (MPAL) and the role of hematopoietic stem cell transplantation (HSCT) remain uncertain. Major limitations in interpreting available data are MPAL's rarity and the use of definitions other than the currently widely accepted criteria: the World Health Organization 2016 (WHO2016) classification.Methods: To assess the relative efficacy of chemotherapy types for treating pediatric MPAL, the Children's Oncology Group (COG) Acute Leukemia of Ambiguous Lineage Task Force assembled a retrospective cohort of centrally reviewed WHO2016 MPAL cases selected from banking studies for acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Patients were not treated in COG trials; treatment and outcome data were captured separately. The findings were then integrated with the available, mixed literature to develop a prospective trial in pediatric MPAL.Results: The central review confirmed that 54 of 70 cases fulfilled WHO2016 criteria for MPAL. ALL induction regimens achieved remission in 72% of the cases (28 of 39), whereas AML regimens achieved remission in 69% (9 of 13). The 5-year event-free survival (EFS) and overall survival (OS) rates for the entire cohort were 72% ± 8% and 77% ± 7%, respectively. EFS and OS were 75% ± 13% and 84% ± 11%, respectively, for those receiving ALL chemotherapy alone without HSCT (n = 21).Conclusions: The results of the COG MPAL cohort and a literature review suggest that ALL chemotherapy without HSCT may be the preferred initial therapy. A prospective trial within the COG is proposed to investigate this approach; AML chemotherapy and/or HSCT will be reserved for those with treatment failure as assessed by minimal residual disease. Embedded biology studies will provide further insight into MPAL genomics. [ABSTRACT FROM AUTHOR]- Published
- 2020
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7. Fanconi-BRCA pathway mutations in childhood T-cell acute lymphoblastic leukemia.
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Pouliot, Gayle P., Degar, James, Hinze, Laura, Kochupurakkal, Bose, Vo, Chau D., Burns, Melissa A., Moreau, Lisa, Ganesa, Chirag, Roderick, Justine, Peirs, Sofie, Menten, Bjorn, Loh, Mignon L., Hunger, Stephen P., Silverman, Lewis B., Harris, Marian H., Stevenson, Kristen E., Weinstock, David M., Weng, Andrew P., Van Vlierberghe, Pieter, and D'Andrea, Alan D.
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LYMPHOBLASTIC leukemia ,ACUTE leukemia ,PATHOLOGY ,BONE marrow ,CHROMOSOMES ,ALLELES - Abstract
BRCA2 (also known as FANCD1) is a core component of the Fanconi pathway and suppresses transformation of immature T-cells in mice. However, the contribution of Fanconi-BRCA pathway deficiency to human T-cell acute lymphoblastic leukemia (T-ALL) remains undefined. We identified point mutations in 9 (23%) of 40 human T-ALL cases analyzed, with variant allele fractions consistent with heterozygous mutations early in tumor evolution. Two of these mutations were present in remission bone marrow specimens, suggesting germline alterations. BRCA2 was the most commonly mutated gene. The identified Fanconi-BRCA mutations encode hypomorphic or null alleles, as evidenced by their inability to fully rescue Fanconi-deficient cells from chromosome breakage, cytotoxicity and/or G2/M arrest upon treatment with DNA cross-linking agents. Disabling the tumor suppressor activity of the Fanconi-BRCA pathway is generally thought to require biallelic gene mutations. However, all mutations identified were monoallelic, and most cases appeared to retain expression of the wild-type allele. Using isogenic T-ALL cells, we found that BRCA2 haploinsufficiency induces selective hypersensitivity to ATR inhibition, in vitro and in vivo. These findings implicate Fanconi-BRCA pathway haploinsufficiency in the molecular pathogenesis of T-ALL, and provide a therapeutic rationale for inhibition of ATR or other druggable effectors of homologous recombination. [ABSTRACT FROM AUTHOR]
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- 2019
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8. Plasma asparaginase activity and asparagine depletion in acute lymphoblastic leukemia patients treated with pegaspargase on Children's Oncology Group AALL07P4.
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Schore, Reuven J., Devidas, Meenakshi, Bleyer, Archie, Reaman, Gregory H., Winick, Naomi, Loh, Mignon L., Raetz, Elizabeth A., Carroll, William L., Hunger, Stephen P., and Angiolillo, Anne L.
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LYMPHOBLASTIC leukemia ,ACUTE leukemia ,CLINICAL trial registries ,ESSENTIAL amino acids ,ASPARAGINASE - Abstract
The efficacy of asparaginase in acute lymphoblastic leukemia (ALL) is dependent on depletion of asparagine, an essential amino acid for ALL cells. The target level of plasma asparaginase activity to achieve asparagine depletion has been between 0.05 and 0.4 IU/mL. COG AALL07P4 examined the asparaginase activity and plasma and CSF asparagine concentration of pegaspargase when given intravenously in the treatment of NCI high risk ALL. Matched plasma asparaginase/asparagine levels of the clearance of 54 doses of pegaspargase given in induction or consolidation demonstrated that all patients who had a plasma asparaginase level >0.02 IU/mL had undetectable plasma asparagine. No difference was observed in CSF asparagine levels associated with matched plasma asparaginase levels of 0.02–0.049 versus 0.05–0.22 IU/mL (p =.25). Our data suggest that a plasma asparaginase activity level of 0.02 IU/mL can effectively deplete plasma asparagine. The data also indicate that the 95% CI for plasma asparagine depletion after a pegaspargase dose is 22–29 days. Clinical trial registration: identifier NCT00671034. [ABSTRACT FROM AUTHOR]
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- 2019
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9. Toxicity associated with intensive postinduction therapy incorporating clofarabine in the very high‐risk stratum of patients with newly diagnosed high‐risk B‐lymphoblastic leukemia: A report from the Children's Oncology Group study AALL1131
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Salzer, Wanda L., Burke, Michael J., Devidas, Meenakshi, Chen, Si, Gore, Lia, Larsen, Eric C., Borowitz, Michael, Wood, Brent, Heerema, Nyla A., Carroll, Andrew J., Hilden, Joanne M., Loh, Mignon L., Raetz, Elizabeth A., Winick, Naomi J., Carroll, William L., and Hunger, Stephen P.
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LYMPHOBLASTIC leukemia ,TOXICITY testing ,EXPERIMENTAL toxicology ,CYCLOPHOSPHAMIDE ,PATIENTS ,CANCER risk factors - Abstract
Background: Children, adolescents, and young adults with very high-risk (VHR) B acute lymphoblastic leukemia (B-ALL) have poor outcomes, and novel therapies are needed for this subgroup. The AALL1131 study evaluated postinduction therapy using cyclophosphamide (CPM), etoposide (ETOP), and clofarabine (CLOF) for patients with VHR B-ALL.Methods: Patients who were 1 to 30 years old and had VHR B-ALL received modified Berlin-Frankfurt-Münster therapy after induction and were randomized to 1) CPM, cytarabine, mercaptopurine, vincristine (VCR), and pegaspargase (control arm), 2) CPM, ETOP, VCR, and pegaspargase (experimental arm 1), or 3) CPM, ETOP, CLOF (30 mg/m2 /d × 5), VCR, and pegaspargase (experimental arm 2) during the second half of consolidation and delayed intensification.Results: The rates of grade 4/5 infections and grade 3/4 pancreatitis were significantly increased in experimental arm 2. The dose of CLOF was, therefore, reduced to 20 mg/m2 /d × 5, and myeloid growth factor was required after CLOF administration. Despite these changes, 4 of 39 patients (10.3%) developed grade 4 infections, with 1 of these patients developing a grade 5 acute kidney injury attributed to CLOF, whereas only 1 of 46 patients (2.2%) in experimental arm 1 developed grade 4 infections, and there were no grade 4/5 infections in the control arm (n = 20). Four patients in experimental arm 2 had prolonged cytopenias for >60 days, whereas none did in the control arm or experimental arm 1. Counts failed to recover for 2 of these patients, one having a grade 5 acute kidney injury and the other removed from protocol therapy; both events occurred 92 days after the start of consolidation part 2.Conclusions: In AALL1131, CLOF, administered with CPM and ETOP, was associated with unacceptable toxicity. Cancer 2018;124:1150-9. © 2017 American Cancer Society. [ABSTRACT FROM AUTHOR]- Published
- 2018
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10. Longitudinal analysis of quality-of-life outcomes in children during treatment for acute lymphoblastic leukemia: A report from the Children's Oncology Group AALL0932 trial.
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Zheng, Daniel J., Lu, Xiaomin, Schore, Reuven J., Balsamo, Lyn, Devidas, Meenakshi, Winick, Naomi J., Raetz, Elizabeth A., Loh, Mignon L., Carroll, William L., Sung, Lillian, Hunger, Stephen P., Angiolillo, Anne L., Kadan‐Lottick, Nina S., and Kadan-Lottick, Nina S
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QUALITY of life ,LYMPHOBLASTIC leukemia ,LYMPHOBLASTIC leukemia treatment ,LEUKEMIA in children ,ONCOLOGY ,HEALTH outcome assessment ,DIAGNOSIS ,GENETICS ,ALEXITHYMIA ,COMPARATIVE studies ,HUMAN reproduction ,LONGITUDINAL method ,RESEARCH methodology ,MEDICAL cooperation ,RESEARCH ,RESEARCH funding ,EVALUATION research - Abstract
Background: Children with average-risk acute lymphoblastic leukemia (AR-ALL) face many challenges that can adversely affect their quality of life (QOL). However, to the authors' knowledge, patterns and predictors of QOL impairment during therapy have not been well characterized to date.Methods: Patients with AR-ALL who were enrolled on the Children's Oncology Group AALL0932 trial were offered participation in this prospective cohort study if they were aged ≥4 years at the time of diagnosis and had an English-speaking parent. At approximately 2 months, 8 months, 17 months, 26 months, and 38 months (boys only) after diagnosis, parents completed the Pediatric Quality of Life Inventory Generic Core Scales Version 4.0 (PedsQL4.0) and McMaster Family Assessment Device instruments for QOL (physical, emotional, and social functioning) and family functioning, respectively. The proportions of individuals scoring in the impaired range (2 standard deviations below the population mean) were calculated at each time point. Longitudinal impairment patterns and predictors were examined.Results: A total of 594 participants with AR-ALL were diagnosed at a mean age of 6.0 years (standard deviation, 1.6 years). At 2 months, a substantial proportion of participants had impaired scores for physical (36.5%; 95% confidence interval [95% CI], 32.3%-40.8%) and emotional (26.2%; 95% CI, 22.5%-30.2%) functioning compared with population norms of 2.3%. These elevations persisted at 26 months. Emotional impairment at 2 months (odds ratio, 3.4; 95% CI, 1.5-7.7) was found to significantly predict emotional impairment at 26 months. In repeated measures analysis with multivariate modeling, unhealthy family functioning (odds ratio, 1.5; 95% CI, 1.1-2.1) significantly predicted emotional impairment controlling for age and sex. QOL outcomes were similar between sexes at the end of therapy (26 months for girls and 38 months for boys).Conclusions: Many children with AR-ALL experience physical and emotional functioning impairment that begins early in treatment and persists. Early screening may identify high-risk patients who might benefit from family-based interventions. Cancer 2018;124:571-9. © 2017 American Cancer Society. [ABSTRACT FROM AUTHOR]- Published
- 2018
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11. Genomic characterization of paediatric acute lymphoblastic leukaemia: an opportunity for precision medicine therapeutics.
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Tasian, Sarah K. and Hunger, Stephen P.
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LYMPHOBLASTIC leukemia , *INDIVIDUALIZED medicine , *GENOMICS , *EPIGENETICS , *CANCER chemotherapy - Abstract
Major advances in genetic and epigenetic profiling of acute lymphoblastic leukaemia ( ALL) have enhanced the understanding of key biological subsets of de novo and relapsed ALL, which has led to improved risk stratification of patients. These achievements have further defined critical leukaemia-associated pathways and somatic alterations that may be preferentially sensitive to treatment with kinase inhibitors, epigenetic therapy or other novel agents. Therapeutic success in childhood ALL currently relies upon refined risk stratification of patients based on (i) underlying biological and clinical characteristics, and (ii) depth of initial treatment response with appropriate modulation of chemotherapy intensity. This review describes the current mutational landscape of childhood ALL and discusses opportunities for substantial improvements in survival with implementation of molecularly targeted therapies. [ABSTRACT FROM AUTHOR]
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- 2017
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12. Prevalence and predictors of anxiety and depression after completion of chemotherapy for childhood acute lymphoblastic leukemia: A prospective longitudinal study.
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Kunin‐Batson, Alicia S., Lu, Xiaomin, Balsamo, Lyn, Graber, Kelsey, Devidas, Meenakshi, Hunger, Stephen P., Carroll, William L., Winick, Naomi J., Mattano, Leonard A., Maloney, Kelly W., and Kadan‐Lottick, Nina S.
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CANCER chemotherapy ,LYMPHOBLASTIC leukemia ,PSYCHOSOCIAL factors ,CONFIDENCE intervals ,ADRENOCORTICAL hormones ,ANTINEOPLASTIC agents ,ANXIETY ,CLINICAL trials ,MENTAL depression ,LONGITUDINAL method ,RESEARCH funding ,FAMILY relations ,DISEASE prevalence ,PSYCHOLOGY - Abstract
Background: The months immediately after the completion of treatment for childhood acute lymphoblastic leukemia (ALL) are often regarded as a stressful time for children and families. In this prospective, longitudinal study, the prevalence and predictors of anxiety and depressive symptoms after the completion of treatment were examined.Methods: Participants included 160 children aged 2 to 9 years with standard-risk ALL who were enrolled on Children's Oncology Group protocol AALL0331. Parents completed standardized rating scales of their children's emotional-behavioral functioning and measures of coping and family functioning at approximately 1 month, 6 months, and 12 months after diagnosis and again 3 months after the completion of chemotherapy.Results: At 3 months off therapy, approximately 24% of survivors had at-risk/clinically elevated anxiety scores and 28% had elevated depression scores, which are significantly higher than the expected 15% in the general population (P = .028 and .001, respectively). Patients with elevated anxiety 1 month after diagnosis were at greater risk of off-therapy anxiety (odds ratio, 4.1; 95% confidence interval, 1.31-12.73 [P = .022]) and those with elevated depressive symptoms 6 months after diagnosis were at greater risk of off-therapy depression (odds ratio, 7.88; 95% confidence interval, 2.61-23.81 [P = .0002]). In adjusted longitudinal analyses, unhealthy family functioning (P = .008) and less reliance on social support coping (P = .009) were found to be associated with risk of emotional distress. Children from Spanish-speaking families (P = .05) also were found to be at a greater risk of distress.Conclusions: A significant percentage of children experience emotional distress during and after therapy for ALL. These data provide a compelling rationale for targeted early screening and psychosocial interventions to support family functioning and coping skills. Cancer 2016;122:1608-17. © 2015 American Cancer Society. [ABSTRACT FROM AUTHOR]- Published
- 2016
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13. Anxiety, pain, and nausea during the treatment of standard-risk childhood acute lymphoblastic leukemia: A prospective, longitudinal study from the Children's Oncology Group.
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Dupuis, L. Lee, Lu, Xiaomin, Mitchell, Hannah‐Rose, Sung, Lillian, Devidas, Meenakshi, Mattano, Leonard A., Carroll, William L., Winick, Naomi, Hunger, Stephen P., Maloney, Kelly W., and Kadan‐Lottick, Nina S.
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ANXIETY ,LYMPHOBLASTIC leukemia ,NAUSEA ,PAIN ,ANTIMETABOLITES ,ANTINEOPLASTIC agents ,ASPARAGINASE ,DRUG therapy ,COMPARATIVE studies ,LONGITUDINAL method ,RESEARCH methodology ,MEDICAL cooperation ,METHOTREXATE ,PARENTS ,POLYETHYLENE glycol ,RESEARCH ,VINCRISTINE ,EVALUATION research ,RANDOMIZED controlled trials ,DEXAMETHASONE ,CYCLOPHOSPHAMIDE ,CYTARABINE ,PSYCHOLOGY - Abstract
Background: This prospective study describes the procedure-related anxiety, treatment-related anxiety, pain, and nausea experienced by children with standard-risk acute lymphoblastic leukemia (ALL) during the first year of treatment.Methods: This study was undertaken at 31 Children's Oncology Group (COG) sites. Eligible children who were 2 to 9.99 years old were enrolled in a COG trial for patients with newly diagnosed standard-risk ALL from 2005 to 2009. Parents completed a demographic survey at the baseline and the Pediatric Quality of Life Inventory 3.0 Cancer Module (proxy version) and the General Functioning Scale of the Family Assessment Device 1, 6, and 12 months after the diagnosis. The association between patient-related (age, sex, ethnicity, and treatment), parent-related (marital status and education), and family-related factors (functioning, income, and size) and symptom scores was evaluated.Results: The mean scores for procedure-related anxiety, treatment-related anxiety, and pain improved during the first year of treatment (P < .0389). The mean nausea score was poorer 6 months after the diagnosis in comparison with the other assessments (P = .0085). A younger age at diagnosis was associated with significantly worse procedure-related anxiety (P = .004). An older age (P = .0002) and assignment to the intensified consolidation study arm (P = .02) were associated with significantly worse nausea.Conclusions: Children with ALL experienced decreasing treatment-related anxiety, procedure-related anxiety, and pain during the first year of treatment. In comparison with scores at 1 and 12 months, nausea was worse 6 months after the diagnosis. Minimization of procedure-related anxiety in younger children and improved nausea control in older children and those receiving more intensified treatment should be prioritized. [ABSTRACT FROM AUTHOR]- Published
- 2016
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14. Biologic and clinical characteristics of adolescent and young adult cancers: Acute lymphoblastic leukemia, colorectal cancer, breast cancer, melanoma, and sarcoma.
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Tricoli, James V., Blair, Donald G., Anders, Carey K., Bleyer, W. Archie, Boardman, Lisa A., Khan, Javed, Kummar, Shivaani, Hayes‐Lattin, Brandon, Hunger, Stephen P., Merchant, Melinda, Seibel, Nita L., Thurin, Magdalena, Willman, Cheryl L., and Hayes-Lattin, Brandon
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CANCER patients ,LYMPHOBLASTIC leukemia ,BREAST cancer ,COLON cancer ,BREAST tumors ,COLON tumors ,MELANOMA ,RECTUM tumors ,RESEARCH funding ,SARCOMA - Abstract
Adolescent and young adult (AYA) patients with cancer have not attained the same improvements in overall survival as either younger children or older adults. One possible reason for this disparity may be that the AYA cancers exhibit unique biologic characteristics, resulting in differences in clinical and treatment resistance behaviors. This report from the biologic component of the jointly sponsored National Cancer Institute and LiveStrong Foundation workshop entitled "Next Steps in Adolescent and Young Adult Oncology" summarizes the current status of biologic and translational research progress for 5 AYA cancers; colorectal cancer breast cancer, acute lymphoblastic leukemia, melanoma, and sarcoma. Conclusions from this meeting included the need for basic biologic, genomic, and model development for AYA cancers as well as translational research studies to elucidate any fundamental differences between pediatric, AYA, and adult cancers. The biologic questions for future research are whether there are mutational or signaling pathway differences (for example, between adult and AYA colorectal cancer) that can be clinically exploited to develop novel therapies for treating AYA cancers and to develop companion diagnostics. [ABSTRACT FROM AUTHOR]
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- 2016
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15. Redefining ALL classification: toward detecting high-risk ALL and implementing precision medicine.
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Hunger, Stephen P. and Mullighan, Charles G.
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LYMPHOBLASTIC leukemia in children , *LYMPHOBLASTIC leukemia , *CHROMATIN , *HUMAN cell cycle , *PROGENITOR cells , *DIAGNOSIS , *CANCER risk factors - Abstract
Acute lymphoblastic leukemia (ALL) is the commonest childhood tumor and remains a leading cause of cancer death in the young. In the last decade, microarray and sequencing analysis of large ALL cohorts has revolutionized our understanding of the genetic basis of this disease. These studies have identified new ALL subtypes, each characterized by constellations of structural and sequence alterations that perturb key cellular pathways, including lymphoid development, cell-cycle regulation, and tumor suppression; cytokine receptor, kinase, and Ras signaling; and chromatin modifications. Several of these pathways, particularly kinase-activating lesions and epigenetic alterations, are logical targets for new precision medicine therapies. Genomic profiling has also identified important interactions between inherited genetic variants that influence the risk of leukemia development and the somatic genetic alterations that are required to establish the leukemic clone. Moreover, sequential sequencing studies at diagnosis, remission, and relapse have provided important insights into the relationship among genetic variants, clonal heterogeneity, and the risk of relapse. Ongoing studies are extending our understanding of coding and noncoding genetic alterations in B-progenitor and T-lineage ALL and using these insights to inform the development of faithful experimental models to test the efficacy of new treatment approaches. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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16. Signalling thresholds and negative B-cell selection in acute lymphoblastic leukaemia.
- Author
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Chen, Zhengshan, Shojaee, Seyedmehdi, Buchner, Maike, Geng, Huimin, Lee, Jae Woong, Klemm, Lars, Titz, Björn, Graeber, Thomas G., Park, Eugene, Tan, Ying Xim, Satterthwaite, Anne, Paietta, Elisabeth, Hunger, Stephen P., Willman, Cheryl L., Melnick, Ari, Loh, Mignon L., Jung, Jae U., Coligan, John E., Bolland, Silvia, and Mak, Tak W.
- Subjects
B cell receptors ,LYMPHOBLASTIC leukemia ,PROTEIN-tyrosine kinases ,LYMPHOCYTIC leukemia ,PROTEIN kinases - Abstract
B cells are selected for an intermediate level of B-cell antigen receptor (BCR) signalling strength: attenuation below minimum (for example, non-functional BCR) or hyperactivation above maximum (for example, self-reactive BCR) thresholds of signalling strength causes negative selection. In ∼25% of cases, acute lymphoblastic leukaemia (ALL) cells carry the oncogenic BCR-ABL1 tyrosine kinase (Philadelphia chromosome positive), which mimics constitutively active pre-BCR signalling. Current therapeutic approaches are largely focused on the development of more potent tyrosine kinase inhibitors to suppress oncogenic signalling below a minimum threshold for survival. We tested the hypothesis that targeted hyperactivation-above a maximum threshold-will engage a deletional checkpoint for removal of self-reactive B cells and selectively kill ALL cells. Here we find, by testing various components of proximal pre-BCR signalling in mouse BCR-ABL1 cells, that an incremental increase of Syk tyrosine kinase activity was required and sufficient to induce cell death. Hyperactive Syk was functionally equivalent to acute activation of a self-reactive BCR on ALL cells. Despite oncogenic transformation, this basic mechanism of negative selection was still functional in ALL cells. Unlike normal pre-B cells, patient-derived ALL cells express the inhibitory receptors PECAM1, CD300A and LAIR1 at high levels. Genetic studies revealed that Pecam1, Cd300a and Lair1 are critical to calibrate oncogenic signalling strength through recruitment of the inhibitory phosphatases Ptpn6 (ref. 7) and Inpp5d (ref. 8). Using a novel small-molecule inhibitor of INPP5D (also known as SHIP1), we demonstrated that pharmacological hyperactivation of SYK and engagement of negative B-cell selection represents a promising new strategy to overcome drug resistance in human ALL. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
17. Wnt inhibition leads to improved chemosensitivity in paediatric acute lymphoblastic leukaemia.
- Author
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Dandekar, Smita, Romanos‐Sirakis, Eleny, Pais, Faye, Bhatla, Teena, Jones, Courtney, Bourgeois, Wallace, Hunger, Stephen P., Raetz, Elizabeth A., Hermiston, Michelle L., Dasgupta, Ramanuj, Morrison, Debra J., and Carroll, William L.
- Subjects
LYMPHOBLASTIC leukemia diagnosis ,LYMPHOBLASTIC leukemia ,LYMPHOBLASTIC leukemia prognosis ,LYMPHOBLASTIC leukemia treatment ,CANCER chemotherapy ,WNT proteins ,APOPTOSIS ,PATIENTS - Abstract
While childhood acute lymphoblastic leukaemia ( ALL) is now highly curable, the dismal prognosis for children who relapse warrants novel therapeutic approaches. Previously, using an integrated genomic analysis of matched diagnosis-relapse paired samples, we identified overactivation of the Wnt pathway as a possible mechanism of recurrence. To validate these findings and document whether Wnt inhibition may sensitize cells to chemotherapy, we analysed the expression of activated β-catenin (and its downstream target BIRC5) using multiparameter phosphoflow cytometry and tested the efficacy of a recently developed Wnt inhibitor, iCRT14, in ALL cell lines and patient samples. We observed increased activation of β-catenin at relapse in 6/10 patients. Furthermore, treatment of leukaemic cell lines with iCRT14 led to significant downregulation of Wnt target genes and combination with traditional chemotherapeutic drugs resulted in a synergistic decrease in viability as well as a significant increase in apoptotic cell death. Finally, pre-treatment of purified blasts from patients with relapsed leukaemia with the Wnt inhibitor followed by exposure to prednisolone, restored chemosensitivity in these cells. Our results demonstrate that overactivation of the Wnt pathway may contribute to chemoresistance in relapsed childhood ALL and that Wnt-inhibition may be a promising therapeutic approach. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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18. A prospective study of anxiety, depression, and behavioral changes in the first year after a diagnosis of childhood acute lymphoblastic leukemia: a report from the Children's Oncology Group.
- Author
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Myers, Regina M, Balsamo, Lyn, Lu, Xiaomin, Devidas, Meenakshi, Hunger, Stephen P, Carroll, William L, Winick, Naomi J, Maloney, Kelly W, and Kadan-Lottick, Nina S
- Subjects
ANTINEOPLASTIC agents ,LYMPHOBLASTIC leukemia diagnosis ,PSYCHOLOGICAL adaptation ,AGGRESSION (Psychology) ,ANXIETY ,ASPARAGINASE ,BEHAVIOR ,MENTAL depression ,EMOTIONS ,LONGITUDINAL method ,LYMPHOBLASTIC leukemia ,POLYETHYLENE glycol ,PSYCHOLOGICAL tests ,PSYCHOMOTOR disorders ,QUESTIONNAIRES ,RESEARCH funding ,VINCRISTINE ,DEXAMETHASONE ,CYCLOPHOSPHAMIDE ,PSYCHOLOGICAL factors ,PSYCHOLOGY - Abstract
Background: The authors prospectively assessed anxiety, depression, and behavior in children with standard-risk acute lymphoblastic leukemia (SR-ALL) during the first year of therapy and identified associated risk factors.Methods: A cohort study was performed of 159 children (aged 2 years-9.99 years) with SR-ALL who were enrolled on Children's Oncology Group protocol AALL0331 at 31 sites. Parents completed the Behavior Assessment System for Children, the General Functioning Scale of the Family Assessment Device, and the Coping Health Inventory for Parents at approximately 1, 6, and 12 months after diagnosis.Results: Overall, mean scores for anxiety, depression, aggression, and hyperactivity were similar to population norms. However, more children scored in the at-risk/clinical range for depression than the expected 15% at 1 month (21.7%; P= .022), 6 months (28.6%; P< .001), and 12 months (21.1%; P= .032). For anxiety, more children scored in the at-risk/clinical range at 1 month (25.2% vs 15%; P= .001), but then reverted to expected levels. On adjusted analysis, unhealthy family functioning was found to be predictive of anxiety (odds ratio [OR], 2.24; P= .033) and depression (OR, 2.40; P= .008). Hispanic ethnicity was associated with anxiety (OR, 3.35; P= .009). Worse physical functioning (P= .049), unmarried parents (P= .017), and less reliance on social support (P= .004) were found to be associated with depression. Emotional distress at 1 month predicted anxiety (OR, 7.11; P= .002) and depression (OR, 3.31; P= .023) at 12 months.Conclusions: Anxiety is a significant problem in a subpopulation of patients with SR-ALL immediately after diagnosis, whereas depression remains a significant problem for at least 1 year. Children of Hispanic ethnicity or those with unhealthy family functioning may be particularly vulnerable. These data suggest that clinicians should screen for anxiety and depression throughout the first year of therapy. [ABSTRACT FROM AUTHOR]- Published
- 2014
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- View/download PDF
19. Predicting relapse risk in childhood acute lymphoblastic leukaemia.
- Author
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Teachey, David T. and Hunger, Stephen P.
- Subjects
- *
LYMPHOBLASTIC leukemia in children , *CANCER relapse , *CANCER chemotherapy , *ANTINEOPLASTIC agents , *LYMPHOBLASTIC leukemia , *LEUKOCYTE count , *HEMATOLOGIC malignancies , *CANCER risk factors - Abstract
Intensive multi-agent chemotherapy regimens and the introduction of risk-stratified therapy have substantially improved cure rates for children with acute lymphoblastic leukaemia ( ALL). Current risk allocation schemas are imperfect, as some children are classified as lower-risk and treated with less intensive therapy relapse, while others deemed higher-risk are probably over-treated. Most cooperative groups previously used morphological clearance of blasts in blood and marrow during the initial phases of chemotherapy as a primary factor for risk group allocation; however, this has largely been replaced by the detection of minimal residual disease ( MRD). Other than age and white blood cell count ( WBC) at presentation, many clinical variables previously used for risk group allocation are no longer prognostic, as MRD and the presence of sentinel genetic lesions are more reliable at predicting outcome. Currently, a number of sentinel genetic lesions are used by most cooperative groups for risk stratification; however, in the near future patients will probably be risk-stratified using genomic signatures and clustering algorithms, rather than individual genetic alterations. This review will describe the clinical, biological, and response-based features known to predict relapse risk in childhood ALL, including those currently used and those likely to be used in the near future to risk-stratify therapy. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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- View/download PDF
20. Relapse-specific mutations in NT5C2 in childhood acute lymphoblastic leukemia.
- Author
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Meyer, Julia A, Wang, Jinhua, Hogan, Laura E, Yang, Jun J, Dandekar, Smita, Patel, Jay P, Tang, Zuojian, Zumbo, Paul, Li, Sheng, Zavadil, Jiri, Levine, Ross L, Cardozo, Timothy, Hunger, Stephen P, Raetz, Elizabeth A, Evans, William E, Morrison, Debra J, Mason, Christopher E, and Carroll, William L
- Subjects
LYMPHOBLASTIC leukemia ,LEUKEMIA treatment ,DRUG resistance ,BONE marrow diseases ,GENETIC mutation - Abstract
Relapsed childhood acute lymphoblastic leukemia (ALL) carries a poor prognosis, despite intensive retreatment, owing to intrinsic drug resistance. The biological pathways that mediate resistance are unknown. Here, we report the transcriptome profiles of matched diagnosis and relapse bone marrow specimens from ten individuals with pediatric B-lymphoblastic leukemia using RNA sequencing. Transcriptome sequencing identified 20 newly acquired, novel nonsynonymous mutations not present at initial diagnosis, with 2 individuals harboring relapse-specific mutations in the same gene, NT5C2, encoding a 5′-nucleotidase. Full-exon sequencing of NT5C2 was completed in 61 further relapse specimens, identifying additional mutations in 5 cases. Enzymatic analysis of mutant proteins showed that base substitutions conferred increased enzymatic activity and resistance to treatment with nucleoside analog therapies. Clinically, all individuals who harbored NT5C2 mutations relapsed early, within 36 months of initial diagnosis (P = 0.03). These results suggest that mutations in NT5C2 are associated with the outgrowth of drug-resistant clones in ALL. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
21. Outcomes after Induction Failure in Childhood Acute Lymphoblastic Leukemia.
- Author
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Schrappe, Martin, Hunger, Stephen P., Pui, Ching-Hon, Saha, Vaskar, Gaynon, Paul S., Baruchel, André, Conter, Valentino, Otten, Jacques, Ohara, Akira, Versluys, Anne Birgitta, Escherich, Gabriele, Heyman, Mats, Silverman, Lewis B., Horibe, Keizo, Mann, Georg, Camitta, Bruce M., Harbott, Jochen, Riehm, Hansjörg, Richards, Sue, and Devidas, Meenakshi
- Subjects
- *
LYMPHOBLASTIC leukemia , *CANCER chemotherapy , *LEUKEMIA , *BONE marrow , *HTLV , *DRUG therapy - Abstract
Background: Failure of remission-induction therapy is a rare but highly adverse event in children and adolescents with acute lymphoblastic leukemia (ALL). Methods: We identified induction failure, defined by the persistence of leukemic blasts in blood, bone marrow, or any extramedullary site after 4 to 6 weeks of remission-induction therapy, in 1041 of 44,017 patients (2.4%) 0 to 18 years of age with newly diagnosed ALL who were treated by a total of 14 cooperative study groups between 1985 and 2000. We analyzed the relationships among disease characteristics, treatments administered, and outcomes in these patients. Results: Patients with induction failure frequently presented with high-risk features, including older age, high leukocyte count, leukemia with a T-cell phenotype, the Philadelphia chromosome, and 11q23 rearrangement. With a median follow-up period of 8.3 years (range, 1.5 to 22.1), the 10-year survival rate (±SE) was estimated at only 32±1%. An age of 10 years or older, T-cell leukemia, the presence of an 11q23 rearrangement, and 25% or more blasts in the bone marrow at the end of induction therapy were associated with a particularly poor outcome. High hyperdiploidy (a modal chromosome number >50) and an age of 1 to 5 years were associated with a favorable outcome in patients with precursor B-cell leukemia. Allogeneic stem-cell transplantation from matched, related donors was associated with improved outcomes in T-cell leukemia. Children younger than 6 years of age with precursor B-cell leukemia and no adverse genetic features had a 10-year survival rate of 72±5% when treated with chemotherapy only. Conclusions: Pediatric ALL with induction failure is highly heterogeneous. Patients who have T-cell leukemia appear to have a better outcome with allogeneic stem-cell transplantation than with chemotherapy, whereas patients who have precursor B-cell leukemia without other adverse features appear to have a better outcome with chemotherapy. (Funded by Deutsche Krebshilfe and others.) [ABSTRACT FROM PUBLISHER]
- Published
- 2012
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- View/download PDF
22. L-Asparaginase Treatment in Acute Lymphoblastic Leukemia.
- Author
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Pieters, Rob, Hunger, Stephen P., Boos, Joachim, Rizzari, Carmelo, Silverman, Lewis, Baruchel, Andre, Goekbuget, Nicola, Schrappe, Martin, and Ching-Hon Pui
- Subjects
- *
ASPARAGINASE , *LYMPHOBLASTIC leukemia , *ESCHERICHIA coli , *ENZYMES - Abstract
Asparaginases are a cornerstone of treatment protocols for acute lymphoblastic leukemia (ALL) and are used for remission induction and intensification treatment in all pediatric regimens and in the majority of adult treatment protocols. Extensive clinical data have shown that intensive asparaginase treatment improves clinical outcomes in childhood ALL. Three asparaginase preparations are available: the native asparaginase derived from Escherichia coli (E. coli asparaginase), a pegylated form of this enzyme (PEG-asparaginase), and a product isolated from Erwinia chrysanthemi, ie, Erwinia asparaginase. Clinical hypersensitivity reactions and silent inactivation due to antibodies against E. coli asparaginase, lead to inactivation of E coli asparaginase in up to 60% of cases. Current treatment protocols include E. coli asparaginase or PEG-asparaginase for first-line treatment of ALL. Typically, patients exhibiting sensitivity to one formulation of asparaginase are switched to another to ensure they receive the most efficacious treatment regimen possible. Erwinia asparaginase is used as a second- or third-line treatment in European and US protocols. Despite the universal inclusion of asparaginase in such treatment protocols, debate on the optimal formulation and dosage of these agents continues. This article provides an overview of available evidence for optimal use of Erwinia asparaginase in the treatment of ALL. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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- View/download PDF
23. Glucocorticoid selection for pediatric ALL.
- Author
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Hunger, Stephen P.
- Subjects
- *
LYMPHOBLASTIC leukemia , *GLUCOCORTICOIDS , *CLINICAL trials , *DEXAMETHASONE , *PREDNISONE , *CANCER chemotherapy , *PROGRESSION-free survival - Abstract
In this issue of Blood, Möricke et al report findings from the Associazione Italiana di Ematologia e Oncologia Pediatrica-Berlin-Frankfurt-Münster (AIEOP-BFM) acute lymphoblastic leukemia (ALL) 2000 clinical trial that substituting dexamethasone for prednisone during induction chemotherapy for children and adolescents with ALL improved event-free survival (EFS), but had no impact on overall survival (OS).1 [ABSTRACT FROM AUTHOR]
- Published
- 2016
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- View/download PDF
24. JAK mutations in high-risk childhood acute lymphoblastic leukemia.
- Author
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Mullighan, Charles G., Jinghui Zhang, Harvey, Richard C., Collins-Underwood, J. Racquel, Schulman, Brenda A., Phillips, Letha A., Tasian, Sarah K., Loh, Mignon L., Xiaoping Su, Wei Liu, Devidas, Meenakshi, Atlas, Susan R., I.-Ming Chen, Clifford, Robert J., Gerhard, Daniela S., Carroll, William L., Reaman, Gregory H., Smith, Malcolm, Downing, James R., and Hunger, Stephen P.
- Subjects
LYMPHOBLASTIC leukemia ,GENETIC mutation ,PROTEIN-tyrosine kinases ,GENE expression ,GROWTH factors ,PEDIATRICS - Abstract
Pediatric acute lymphoblastic leukemia (ALL) is a heterogeneous disease consisting of distinct clinical and biological subtypes that are characterized by specific chromosomal abnormalities or gene mutations. Mutation of genes encoding tyrosine kinases is uncommon in ALL, with theexception of Philadelphia chromosome-positive ALL, where the t(9,22)(q34;q11) translocation encodes the constitutively active BCR-ABL1 tyrosine kinase. We recently identified a poor prognostic subgroup of pediatric BCR-ABL 1-negative ALL patients characterized by deletion of IKZF1 (encoding the lymphoid transcription factor IKAROS) and a gene expression signature similar to BCR-ABL1-positive ALL, raising the possibility of activated tyrosine kinase signaling within this leukemia sub- type. Here, we report activating mutations in the Janus kinases JAK1 (n = 3), JAK2 (n = 16), and JAK3 (n = 1) in 20(10.7%) of 187 BCR-ABL1-negative, high-risk pediatric ALL cases. The JAK1 and JAK2 mutations involved highly conserved residues in the kinase and pseudokinase domains and resulted in constitutive JAK-STAT activation and growth factor independence of Ba/F3-EpoR cells. The presence of JAK mutations was significantly associated with alteration of IKZF1 (70% of all JAK-mutated cases and 87.5% of cases with JAK2 mutations; P = 0.001) and deletion of CDKN2A/B (70% of all JAK-mutated cases and 68.9% of JAK2-mutated cases). The JAK-mutated cases had a gene expression signature similar to BCR-ABL1 pediatric ALL, and they had a poor outcome. These results suggest that inhibition of JAK signaling is a logical target for therapeutic intervention in JAK mutated ALL. [ABSTRACT FROM AUTHOR]
- Published
- 2009
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- View/download PDF
25. Controversies of and Unique Issues in Hematopoietic Cell Transplantation for Infant Leukemia
- Author
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Hunger, Stephen P., Loh, K. Mignon, Baker, K. Scott, and Schultz, Kirk R.
- Subjects
- *
LEUKEMIA , *CELL transplantation , *LYMPHOBLASTIC leukemia , *STEM cells - Abstract
Infants with leukemia who require hematopoietic cell transplantation (HCT) remain 1 of the most significant challenges in pediatric stem cell transplant. Infant leukemia is characterized by a unique biology including a predominance mixed lineage leukemia(MLL) gene rearrangement and juvenile myelomonocytic leukemia. Moreover, the long-term effects of transplantation are particularly prominent in infants who have active endocrine, cardiovascular, pulmonary, neurologic, musculoskeletal, hearing, and vision development, with the added risk of second malignant neoplasms. Currently, there is no solid basis to support allogeneic HCT as first-line therapy for infant acute lymphoblastic leukemia-first remission (ALL-CR1), although indicated for other infant leukemias, including juvenile myelomonocytic leukemia (JMML). The relative long-term toxicity of total body irridiation (TBI) versus non-TBI containing preparative regimens for HCT in infants remains controversial, with the differences, especially on neurocognitive function, unknown. [Copyright &y& Elsevier]
- Published
- 2009
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- View/download PDF
26. Resolution of ambiguous low-level positive quantitative polymerase chain reaction results in TEL-AML1 positive ALL using a post-PCR fluorescent oligoligation method.
- Author
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I.-Ming Chen, Chakerian, Artemis, Devidas, Meenakshi, Borowitz, Michael J., Hunger, Stephen P., Willman, Cheryl L., and Viswanatha, David S.
- Subjects
POLYMERASE chain reaction ,LEUKEMIA ,LYMPHOBLASTIC leukemia ,THERAPEUTICS ,ANEMIA ,CANCER - Abstract
The interpretation of low-level or non-reproducible amplification results in clinical quantitative polymerase chain reaction (Q-PCR) assays can be difficult to definitively resolve. Concerning minimal residual disease detection in leukaemia, indeterminate low-level results might create prognostic or therapeutic dilemmas. We evaluated low-level, ambiguous Q-PCR results in a study of paired diagnostic and end-induction (day 29) TEL-AML1 positive acute lymphoblastic leukaemia samples utilising a novel fluorescent primer ligation detection assay. The data presented here indicate that a significant number of low-level apparent Q-PCR positive results may be spurious or non-specific in nature, requiring additional technical manoeuvres for confirmation of true positive cases. [ABSTRACT FROM AUTHOR]
- Published
- 2006
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27. E2A–PBX1 fusion in adult acute lymphoblastic leukaemia: biological and clinical features.
- Author
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Foa, Robin, Vitale, Antonella, Mancini, Marco, Cuneo, Antonio, Mecucci, Cristina, Elia, Loredana, Lombardo, Romina, Saglio, Giuseppe, Torelli, Giuseppe, Annino, Luciana, Specchia, Giorgina, Damasio, Eugenio, Recchia, Anna, Di Raimondo, Francesco, Morra, Enrica, Volpe, Ettore, Tafuri, Agostino, Fazi, Paola, Hunger, Stephen P., and Mandelli, Franco
- Subjects
LYMPHOBLASTIC leukemia ,HEMATOLOGY - Abstract
Summary. Molecular and cytogenetic studies performed in 305 adult acute lymphoblastic leukaemia (ALL) patients enrolled in the gimema (Gruppo Italiano Malattie EMatologiche dell'Adulto) multicentric protocols identified an E2A–PBX1 fusion and/or t(1;19) in 10 patients (3·3%). All had common ALL, were mostly CyIg
+ and were CD34/CD13/CD33– . Nine patients achieved a complete remission (CR); five patients showed a haematological relapse after 7 months (median). Four patients are alive in first CR with a median follow-up of 29 months; three patients are molecularly negative. This abnormality is frequently associated with early treatment failure. E2A–PBX1+ adult ALL should be considered for intensified treatment strategies and monitoring of minimal residual disease. [ABSTRACT FROM AUTHOR]- Published
- 2003
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- View/download PDF
28. Site-specific translocation and evidence of postnatal origin of the t(1;19) E2A-PBX1 fusion in childhood acute lymphoblastic leukemia.
- Author
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Wiemels, Joseph L., Leonard, Brian C., Yunxia Wang, Segal, Mark R., Hunger, Stephen P., Smith, Martyn T., Crouse, Vonda, Xiaomei Ma, Buffler, Patricia A., and Pine, Sharon R.
- Subjects
CHROMOSOMAL translocation ,LYMPHOBLASTIC leukemia - Abstract
The t(1;19) translocation yields a fusion between E2A and PBX1 genes and occurs in 5% of acute lymphoblastic leukemia in children and adults. We used chromosomal translocations and Ig heavy chain (IGH)/T cell antigen receptor (TCR) rearrangements to develop an understanding of the etiology and natural history of this subtype of leukemia. We sequenced the genomic fusion between E2A and PBX1 in 22 preB acute lymphoblastic leukemias and two cell lines. The prenatal origin of the leukemia was assessed in 15 pediatric patients by screening for the clonotypic E2A-PBX1 translocation in neonatal blood spots, or Guthrie cards, obtained from the children at the time of birth. Two patients were determined to be weakly positive for the fusion at the time of birth, in contrast to previously studied childhood leukemia fusions, t(12;21), t(8;21), and t(4;11), which were predominantly prenatal. The presence of extensive N-nucleotides at the point of fusion in the E2A-PBX1 translocation as well as specific characteristics of the IGH/TCR rearrangements provided additional evidence for a postnatal, preB cell origin. Intriguingly, 16 of 24 breakpoints on the 3.2-kb E2A intron 14 were located within 5 bp, providing evidence for a site-specific recombination mechanism. Breakpoints on the 232-kb PBX1 intron 1 were more dispersed but highly clustered proximal to exon 2. In sum, the translocation breakpoints displayed evidence of unique temporal, ontological, and mechanistic formation than the previously analyzed pediatric leukemia translocation breakpoints and emphasize the need to differentiate cytogenetic and molecular subgroups for studies of leukemia causality. [ABSTRACT FROM AUTHOR]
- Published
- 2002
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- View/download PDF
29. Imatinib resistant BCR- ABL1 mutations at relapse in children with Ph+ ALL: a Children's Oncology Group ( COG) study.
- Author
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Chang, Bill H., Willis, Stephanie G., Stork, Linda, Hunger, Stephen P., Carroll, William L., Camitta, Bruce M., Winick, Naomi J., Druker, Brian J., and Schultz, Kirk R.
- Subjects
IMATINIB ,LYMPHOBLASTIC leukemia ,GENETIC mutation ,PROTEIN-tyrosine kinases ,JUVENILE diseases - Abstract
The article discusses the impact of imatinib resistant BCR-ABL1 on children with Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph
+ ALL). It is mentioned that, relapsed adults on imatinib monotherapy have a resistant mutation within the kinase domain of BCR-ABL1. It is also mentioned that, tyrosine kinases are essential for Ph+ ALL transformation.- Published
- 2012
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- View/download PDF
30. Identification of four novel associations for B-cell acute lymphoblastic leukaemia risk.
- Author
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Vijayakrishnan, Jayaram, Qian, Maoxiang, Studd, James B., Yang, Wenjian, Kinnersley, Ben, Law, Philip J., Broderick, Peter, Raetz, Elizabeth A., Allan, James, Pui, Ching-Hon, Vora, Ajay, Evans, William E., Moorman, Anthony, Yeoh, Allen, Yang, Wentao, Li, Chunliang, Bartram, Claus R., Mullighan, Charles G., Zimmerman, Martin, and Hunger, Stephen P.
- Subjects
B cells ,LYMPHOBLASTIC leukemia ,DISEASE susceptibility ,META-analysis ,GENOMICS - Abstract
There is increasing evidence for a strong inherited genetic basis of susceptibility to acute lymphoblastic leukaemia (ALL) in children. To identify new risk variants for B-cell ALL (B-ALL) we conducted a meta-analysis with four GWAS (genome-wide association studies), totalling 5321 cases and 16,666 controls of European descent. We herein describe novel risk loci for B-ALL at 9q21.31 (rs76925697, P = 2.11 × 10
−8 ), for high-hyperdiploid ALL at 5q31.1 (rs886285, P = 1.56 × 10−8 ) and 6p21.31 (rs210143 in BAK1, P = 2.21 × 10−8 ), and ETV6-RUNX1 ALL at 17q21.32 (rs10853104 in IGF2BP1, P = 1.82 × 10−8 ). Particularly notable are the pleiotropic effects of the BAK1 variant on multiple haematological malignancies and specific effects of IGF2BP1 on ETV6-RUNX1 ALL evidenced by both germline and somatic genomic analyses. Integration of GWAS signals with transcriptomic/epigenomic profiling and 3D chromatin interaction data for these leukaemia risk loci suggests deregulation of B-cell development and the cell cycle as central mechanisms governing genetic susceptibility to ALL. B-cell acute lymphoblastic leukaemia (B-ALL) is a common childhood cancer. Here, the authors conducted a meta-analysis with four genome-wide association studies, totalling 5,321 cases and 16,666 controls of European descent, identifying B-ALL risk loci, whose integration with epigenomic profiling indicates cell-cycle and B-cell development deregulation as central mechanisms in B-ALL susceptibility, often in a subtype-specific fashion. [ABSTRACT FROM AUTHOR]- Published
- 2019
- Full Text
- View/download PDF
31. Philadelphia chromosome-like acute lymphoblastic leukemia.
- Author
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Tasian, Sarah K., Loh, Mignon L., and Hunger, Stephen P.
- Subjects
- *
LYMPHOBLASTIC leukemia , *CHROMOSOME abnormalities , *GENE expression , *RAS oncogenes , *CYTOKINE receptors , *PROTEIN-tyrosine kinases , *STAT proteins - Abstract
Philadelphia chromosome (Ph)-like acute lymphoblastic leukemia (ALL), also referred to as BCR-ABL1-like ALL, is a high-risk subset with a gene expression profile that shares significant overlap with that of Ph-positive (Ph+) ALL and is suggestive of activated kinase signaling. Although Ph+ ALL is defined by BCRABL1 fusion, Ph-like ALL cases contain a variety of genomic alterations that activate kinase and cytokine receptor signaling. These alterations can be grouped into major subclasses that include ABL-class fusions involving ABL1, ABL2, CSF1R, and PDGFRB that phenocopy BCR-ABL1 and alterations of CRLF2, JAK2, and EPOR that activate JAK/STAT signaling. Additional genomic alterations in Ph-like ALL activate other kinases, including BLNK, DGKH, FGFR1, IL2RB, LYN, NTRK3, PDGFRA, PTK2B, TYK2, and the RAS signaling pathway. Recent studies have helped to define the genomic landscape of Ph-like ALL and how it varies across the age spectrum, associated clinical features and outcomes, and genetic risk factors. Preclinical studies and anecdotal reports show that targeted inhibitors of relevant signaling pathways are active in specific Ph-like ALL subsets, and precision medicine trials have been initiated for this high-risk ALL subset. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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- View/download PDF
32. Higher Reported Lung Dose Received During Total Body Irradiation for Allogeneic Hematopoietic Stem Cell Transplantation in Children With Acute Lymphoblastic Leukemia Is Associated With Inferior Survival: A Report from the Children's Oncology Group.
- Author
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Esiashvili, Natia, Lu, Xiaomin, Ulin, Ken, Laurie, Fran, Kessel, Sandy, Kalapurakal, John A., Merchant, Thomas E., Followill, David S., Sathiaseelan, Vythialinga, Schmitter, Mary K., Devidas, Meenakshi, Chen, Yichen, Wall, Donna A., Brown, Patrick A., Hunger, Stephen P., Grupp, Stephan A., and Pulsipher, Michael A.
- Subjects
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HEMATOPOIETIC stem cell transplantation , *TOTAL body irradiation , *LYMPHOBLASTIC leukemia , *ACUTE leukemia , *PROPORTIONAL hazards models - Abstract
Purpose: To examine the relationship between lung radiation dose and survival outcomes in children undergoing total body irradiation (TBI)-based hematopoietic stem cell transplantation (HSCT) for acute lymphoblastic leukemia on the Children's Oncology Group trial.Methods and Materials: TBI (1200 or 1320 cGy given twice daily in 6 or 8 fractions) was used as part of 3 HSCT preparative regimens, allowing institutional flexibility regarding TBI techniques, including lung shielding. Lung doses as reported by each participating institution were calculated for different patient setups, with and without shielding, with a variety of dose calculation techniques. The association between lung dose and transplant-related mortality, relapse-free survival, and overall survival (OS) was examined using the Cox proportional hazards regression model controlling for the following variables: TBI dose rate, TBI fields, patient position during TBI, donor type, and pre-HSCT minimal residual disease level.Results: Of a total of 143 eligible patients, 127 had lung doses available for this analysis. The TBI techniques were heterogeneous. The mean lung dose was reported as 904.5 cGy (standard deviation, ±232.3). Patients treated with lateral fields were more likely to receive lung doses ≥800 cGy (P < .001). The influence of lung dose ≥800 cGy on transplant-related mortality was not significant (hazard ratio [HR], 1.78; P = .21). On univariate analysis, lung dose ≥800 cGy was associated with inferior relapse-free survival (HR, 1.76; P = .04) and OS (HR, 1.85; P = .03). In the multivariate analysis, OS maintained statistical significance (HR, 1.85; P = .04).Conclusions: The variability in TBI techniques resulted in uncertainty with reported lung doses. Lateral fields were associated with higher lung dose, and thus they should be avoided. Patients treated with lung dose <800 cGy in this study had better outcomes. This approach is currently being investigated in the Children's Oncology Group AALL1331 study. Additionally, the Imaging and Radiation Oncology Core Group is evaluating effects of TBI techniques on lung doses using a phantom. [ABSTRACT FROM AUTHOR]- Published
- 2019
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- View/download PDF
33. ETV6-NTRK3 induces aggressive acute lymphoblastic leukemia highly sensitive to selective TRK inhibition.
- Author
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Roberts, Kathryn G., Janke, Laura J., Yaqi Zhao, Seth, Aman, Jing Ma, Finkelstein, David, Smith, Steve, Ebata, Kevin, Tuch, Brian B., Hunger, Stephen P., and Mullighan, Charles G.
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LYMPHOBLASTIC leukemia , *PROTEIN-tyrosine kinases - Published
- 2018
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34. Preclinical efficacy of daratumumab in T-cell acute lymphoblastic leukemia.
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Bride, Karen L., Vincent, Tiffaney L., Soo-Yeon Im, Aplenc, Richard, Barrett, David M., Carroll, William L., Carson, Robin, Yunfeng Dai, Devidas, Meenakshi, Dunsmore, Kimberly P., Fuller, Tori, Glisovic-Aplenc, Tina, Horton, Terzah M., Hunger, Stephen P., Loh, Mignon L., Maude, Shannon L., Raetz, Elizabeth A., Winter, Stuart S., Grupp, Stephan A., and Hermiston, Michelle L.
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LYMPHOBLASTIC leukemia , *T cells , *CANCER treatment , *IMMUNOTHERAPY , *B cells - Abstract
As a consequence of acquired or intrinsic disease resistance, the prognosis for patients with relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL) is dismal. Novel, less toxic drugs are clearly needed. One of the most promising emerging therapeutic strategies for cancer treatment is targeted immunotherapy. Immune therapies have improved outcomes for patients with other hematologic malignancies including B-cell ALL; however no immune therapy has been successfully developed for T-ALL. We hypothesize targeting CD38 will be effective against T-ALL. We demonstrate that blasts from patients with T-ALL have robust surface CD38 surface expression and that this expression remains stable after exposure to multiagent chemotherapy. CD38 is expressed at very low levels on normal lymphoid and myeloid cells and on a few tissues of nonhematopoietic origin. suggesting that CD38 may be an ideal target. Daratumumab is a human immunoglobulin G1 K monoclonal antibody that binds CD38, and has been demonstrated to be safe and effective in patients with refractory multiple myeloma. We tested daratumumab in a large panel of T-ALL patient-derived xenografts (PDX) and found striking efficacy in 14 of 15 different PDX. These data suggest that daratumumab is a promising novel therapy for pediatric T-ALL patients. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
35. Genetic risk factors for the development of osteonecrosis in children under age 10 treated for acute lymphoblastic leukemia.
- Author
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Karol, Seth E., Mattano Jr., Leonard A., Wenjian Yang, Maloney, Kelly W., Smith, Colton, ChengCheng Liu, Ramsey, Laura B., Fernandez, Christian A., Chang, Tamara Y., Neale, Geoffrey, Cheng Cheng, Mardis, Elaine, Fulton, Robert, Scheet, Paul, San Lucas, F. Anthony, Larsen, Eric C., Loh, Mignon L., Raetz, Elizabeth A., Hunger, Stephen P., and Devidas, Meenakshi
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OSTEONECROSIS , *LYMPHOBLASTIC leukemia , *GENETICS , *COHORT analysis , *HEMATOLOGIC malignancies - Abstract
Osteonecrosis is a dose-limiting toxicity in the treatment of pediatric acute lymphoblastic leukemia (ALL). Prior studies on the genetics of osteonecrosis have focused on patients ≥10 years of age, leaving the genetic risk factors for the larger group of children <10 years incompletely understood. Here, we perform the first evaluation of genetic risk factors for osteonecrosis in children <10 years. The discovery cohort comprised 82 cases of osteonecrosis and 287 controls treated on Children's Oncology Group (COG) standard-risk ALL protocol AALL0331 (NCT00103285, https://clinicaltrials.gov/ct2/show/NCT00103285), with results tested for replication in 817 children <10 years treated on COG protocol AALL0232 (NCT00075725, https://clinicaltrials.gov/ct2/show/NCT00075725). The top replicated single nucleotide polymorphisms (SNPs) were near bone morphogenic protein 7 [BMP7: rs75161997, P = 5.34 × 10–8 (odds ratio [OR] 15.0) and P = .0498 (OR 8.44) in the discovery and replication cohorts, respectively] and PROX1-antisense RNA1 (PROX1-AS1: rs1891059, P=2.28×10–7 [OR 6.48] and P=.0077 [OR 3.78] for the discovery and replication cohorts, respectively). The top replicated nonsynonymous SNP, rs34144324, was in a glutamate receptor gene (GRID2, P 5 8.65 3 1026 [OR 3.46] and P = .0136 [OR 10.8] in the discovery and replication cohorts, respectively). In a meta-analysis, the BMP7 and PROX1-AS1 variants (rs75161997 and rs1891059, respectively) met the significance threshold of <5 × 10–8. Top replicated SNPs were enriched in enhancers active in mesenchymal stem cells, and analysis of annotated genes demonstrated enrichment inglutamate receptor and adipogenesis pathways. These data may provide new insights into the pathophysiology of osteonecrosis. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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36. Erk Negative Feedback Control Enables Pre-B Cell Transformation and Represents a Therapeutic Target in Acute Lymphoblastic Leukemia.
- Author
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Shojaee, Seyedmehdi, Caeser, Rebecca, Buchner, Maike, Park, Eugene, Swaminathan, Srividya, Hurtz, Christian, Geng, Huimin, Chan, Lai N., Klemm, Lars, Hofmann, Wolf-Karsten, Qiu, Yi Hua, Zhang, Nianxiang, Coombes, Kevin R., Paietta, Elisabeth, Molkentin, Jeffery, Koeffler, H. Phillip, Willman, Cheryl L., Hunger, Stephen P., Melnick, Ari, and Kornblau, Steven M.
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PHYSIOLOGICAL control systems , *LYMPHOBLASTIC leukemia , *B cells , *ONCOGENES , *CELL death , *DRUG resistance - Abstract
Summary Studying mechanisms of malignant transformation of human pre-B cells, we found that acute activation of oncogenes induced immediate cell death in the vast majority of cells. Few surviving pre-B cell clones had acquired permissiveness to oncogenic signaling by strong activation of negative feedback regulation of Erk signaling. Studying negative feedback regulation of Erk in genetic experiments at three different levels, we found that Spry2 , Dusp6 , and Etv5 were essential for oncogenic transformation in mouse models for pre-B acute lymphoblastic leukemia (ALL). Interestingly, a small molecule inhibitor of DUSP6 selectively induced cell death in patient-derived pre-B ALL cells and overcame conventional mechanisms of drug-resistance. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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37. Genome-wide analysis links NFATC2 with asparaginase hypersensitivity.
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Fernandez, Christian A., Smith, Colton, Wenjian Yang, Mullighan, Charles G., Chunxu Qu, Larsen, Eric, Bowman, W. Paul, Chengcheng Liu, Ramsey, Laura B., Chang, Tamara, Karol, Seth E., Loh, Mignon L., Raetz, Elizabeth A., Winick, Naomi J., Hunger, Stephen P., Carroll, William L., Jeha, Sima, Ching-Hon Pui, Evans, William E., and Devidas, Meenakshi
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LYMPHOBLASTIC leukemia , *ALLERGIES , *ASPARAGINASE , *AMIDASES , *GENOMES - Abstract
Asparaginase is used to treat acute lymphoblastic leukemia (ALL); however, hypersensitivity reactions can lead to suboptimal asparaginase exposure. Our objective was to use a g enome-wide approach to identify loci associated with asparaginase hypersensitivity in children with ALL enrolled on St. Jude Children's Research Hospital (SJCRH) protocols Total XIIIA (n = 154), Total XV (n = 498), and Total XVI (n = 271), or Children's Oncology Group protocols POG 9906 (n = 222) and AALL0232 (n = 2163). Germline DNA was genotyped using the Affymetrix 500K, Affymetrix 6.0, or the lllumina Exome BeadChip array. In multivariate logistic regression, the intronic rs6021191 variant in nuclear factor of activated T cells 2 (NFATC2) had the strongest association with hypersensitivity (P = 4.1 x 10-8; odds ratio [OR] = 3.11). RNA-seq data available from 65 SJCRH A LL tumor samples and 52 Yoruba HapMap samples showed that samples carrying the rs6021191 variant had higher NFATC2 expression compared with noncarriers (P = 1.1 x 10-3 and 0.03, respectively). The top ranked nonsynonymous polymorphism was rs17885382 in HLA-DRB1 (P = 3.2 x 10-6; OR = 1.63), which is in near complete linkage disequilibrium with the HLA-DRB1*07:01 allele we previously observed in a candidate gene study. The strongest risk factors for asparaginase allergy are variants within genes regulating the immune response. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
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38. Efficacy of JAK/STAT pathway inhibition in murine xenograft models of early T-cell precursor (ETP) acute lymphoblastic leukemia.
- Author
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Maude, Shannon L., Dolai, Sibasish, Delgado-Martin, Cristina, Vincent, Tiffaney, Robbins, Alissa, Selvanathan, Arthavan, Ryan, Theresa, Hall, Junior, Wood, Andrew C., Tasian, Sarah K., Hunger, Stephen P., Loh, Mignon L., Mullighan, Charles G., Wood, Brent L., Hermiston, Michelle L., Grupp, Stephan A., Lock, Richard B., and Teachey, David T.
- Subjects
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LYMPHOBLASTIC leukemia , *LYMPHOCYTIC leukemia , *CYTOKINES , *INTERLEUKIN-7 , *INTERLEUKINS - Abstract
Early T-cell precursor (ETP) acute lymphoblastic leukemia (ALL) is a recently described subtype of T-ALL characterized by a unique immunophenotype and genomic profile, as well as a high rate of induction failure. Frequent mutations in cytokine receptor and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathways led us to hypothesize that ETP-ALL is dependent on JAK/STAT signaling. Here we demonstrate aberrant activation of the JAK/STAT pathway in ETP-ALL blasts relative to non-ETP T-ALL. Moreover, ETP-ALL showed hyperactivation of STAT5 in response to interleukin-7, an effect that was abrogated by the JAK1/2 inhibitor ruxolitinib. In vivo, ruxolitinib displayed activity in 6 of 6 patient-derived murine xenograft models of ETP-ALL, with profound single-agent efficacy in 5 models. Ruxolitinib treatment decreased peripheral blast counts relative to pretreatment levels and compared with control (P< .01) in 5 of 6 ETP-ALL xenografts, with marked reduction in mean splenic blast counts (P< .01) in 6 of 6 samples. Surprisingly, both JAK/STAT pathway activation and ruxolitinib efficacy were independent of the presence of JAK/STAT pathway mutations, raising the possibility that the therapeutic potential of ruxolitinib in ETP-ALL extends beyond those cases with JAK mutations. These findings establish the preclinical in vivo efficacy of ruxolitinib in ETP-ALL, a biologically distinct subtype for which novel therapies are needed. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
39. An oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element.
- Author
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Mansour, Marc R., Abraham, Brian J., Anders, Lars, Berezovskaya, Alla, Gutierrez, Alejandro, Durbin, Adam D., Etchin, Julia, Lawton, Lee, Sallan, Stephen E., Silverman, Lewis B., Loh, Mignon L., Hunger, Stephen P., Sanda, Takaomi, Young, Richard A., and Look, A. Thomas
- Subjects
- *
CANCER genetics , *ONCOGENES , *GENE expression , *SOMATIC mutation , *HISTONE acetylation , *LYSINE , *LYMPHOBLASTIC leukemia , *T cells , *GENETICS - Abstract
In certain human cancers, the expression of critical oncogenes is driven from large regulatory elements, called super-enhancers, that recruit much of the cell's transcriptional apparatus and are defined by extensive acetylation of histone H3 lysine 27 (H3K27ac). In a subset of T-cell acute lymphoblastic leukemia (T-ALL) cases, we found that heterozygous somatic mutations are acquired that introduce binding motifs for the MYB transcription factor in a precise noncoding site, which creates a super-enhancer upstream of the TAL1 oncogene. MYB binds to this new site and recruits its H3K27 acetylase-binding partner CBP, as well as core components of a major leukemogenic transcriptional complex that contains RUNX1, GATA-3, and TAL1 itself. Additionally, most endogenous super-enhancers found in T-ALL cells are occupied by MYB and CBP, which suggests a general role for MYB in super-enhancer initiation. Thus, this study identifies a genetic mechanism responsible for the generation of oncogenic super-enhancers in malignant cells. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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40. Erwinia asparaginase achieves therapeutic activity after pegaspargase allergy: a report from the Children's Oncology Group.
- Author
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Salzer, Wanda L., Asselin, Barbara, Supko, Jeffrey G., Devidas, Meenakshi, Kaiser, Nicole A., Plourde, Paul, Winick, Naomi J., Reaman, Gregory H., Raetz, Elizabeth, Carroll, William L., and Hunger, Stephen P.
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ERWINIA , *ASPARAGINASE , *LYMPHOBLASTIC leukemia , *DRUG dosage , *HYPERGLYCEMIA , *PATIENTS - Abstract
AALL07P2 evaluated whether substitution of Erwinia asparaginase 25000 IU/m² for 6 doses given intramuscularly Monday/Wednesday/Friday (M/W/F) to children and young adults with acute lymphoblastic leukemia and clinical allergy to pegaspargase would provide a 48-hour nadir serum asparaginase activity (NSAA) ⩾0.10 IU/mL. AALL07P2 enrolled 55 eligible/evaluable patients. NSAA ⩾0.1 IU/mL was achieved in 38 of 41 patients (92.7%) with acceptable samples 48 hours and in 38 of 43 patients (88.4%) 72 hours after dosing during course 1. Among samples obtained during all courses, 95.8% (252 of 263) of 48-hour samples and 84.5% (125 of 148) of 72-hour samples had NSAA ⩾0.10-IU/mL. Pharmacokinetic parameters were estimated by fitting the serum asparaginase activity-time course for all 6 doses given during course 1 to a 1-compartment open model with first order absorption. Erwinia asparaginase administered with this schedule achieved therapeutic NSAA at both 48 and 72 hours and was well tolerated with no reports of hemorrhage, thrombosis, or death, and few cases of grade 2 to 3 allergic reaction (n = 6), grade 1 to 3 hyperglycemia (n = 6), or grade 1 pancreatitis (n = 1). Following allergy to pegaspargase, Erwinia asparaginase 25000 IU/m2 × 6 intramuscularly M/W/F can be substituted for a single dose of pegaspargase. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
41. Targeting JAK1/2 and mTOR in murine xenograft models of Ph-like acute lymphoblastic leukemia.
- Author
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Maude, Shannon L., Tasian, Sarah K., Vincent, Tiffaney, Hall, Junior W., Sheen, Cecilia, Roberts, Kathryn G., Seif, Alix E., Barrett, David M., Chen, I-Ming, Collins, J. Racquel, Mullighan, Charles G., Hunger, Stephen P., Harvey, Richard C., Willman, Cheryl L., Fridman, Jordan S., Loh, Mignon L., Grupp, Stephan A., and Teachey, David T.
- Subjects
- *
MTOR protein , *XENOGRAFTS , *LYMPHOBLASTIC leukemia , *GENE rearrangement , *POINT mutation (Biology) , *CHROMOSOME abnormalities , *GENE expression , *LABORATORY mice - Abstract
CRLF2 rearrangements, JAK1/2 point mutations, and JAK2 fusion genes have been identified in Philadelphia chromosome (Ph)-like acute lymphoblastic leukemia (ALL), a recently described subtype of pediatric high-risk B-precursor ALL (B-ALL) which exhibits a gene expression profile similar to Ph-positive ALL and has a poor prognosis. Hyperactive JAK/STAT and PI3K/mammalian target of rapamycin (mTOR) signaling is common in this highrisk subset. We, therefore, investigated the efficacy of the JAK inhibitor ruxolitlnib and the mTOR Inhibitor rapamycin in xenograft models of 8 pediatric B-ALL cases with and without CRLF2 and JAK genomic lesions. Ruxolitinib treatment yielded significantly lower peripheral blast counts compared with vehicle (P < .05) In 6 of 8 human leukemia xenografts and lower splenic blast counts (P < .05) in 8 of 8 samples. Enhanced responses to ruxolitinib were observed in samples harboring JAK-activating lesions and higher levels of STAT5 phosphorylation. Rapamycin controlled leukemia burden in all 8 B-ALL samples. Survival analysis of 2 representative B-ALL xenografts demonstrated prolonged survival with rapamycin treatment compared with vehicle (P < .01). These data demonstrate preclinical in vivo efficacy of ruxolitinib and rapamycin in this high-risk B-ALL subtype, for which novel treatments are urgently needed, and high-light the therapeutic potential of targeted kinase inhibition in Ph-like ALL. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
42. The BCL11B tumor suppressor is mutated across the major molecular subtypes of T-cell acute lymphoblastic leukemia.
- Author
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Gutierrez, Alejandro, Kentsis, Alex, Sanda, Takaomi, Holmfeldt, Linda, Shann-Ching Chen, Jianhua Zhang, Protopopov, Alexei, Chin, Lynda, Dahlberg, Suzanne E., Neuberg, Donna S., Silverman, Lewis B., Winter, Stuart S., Hunger, Stephen P., Sallan, Stephen E., Shan Zha, Alt, Frederick W., Downing, James R., Mullighan, Charles G., and Look, A. Thomas
- Subjects
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TUMOR suppressor genes , *TUMOR suppressor proteins , *LYMPHOBLASTIC leukemia , *LEUKEMIA , *T cells , *CARCINOGENESIS - Abstract
The BCL11B transcription factor is required for normal T-cell development, and has recently been implicated in the pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL) induced by TLX overexpression or Atm deficiency. To comprehensively assess the contribution of BCL11B inactivation to human T-ALL, we performed DNA copy number and sequencing analyses of T-ALL diagnostic specimens, revealing monoallelic BCL11B deletions or missense mutations in 9% (n = 10 of 117) of cases. Structural homology modeling revealed that several of the BCL11B mutations disrupted the structure of zinc finger domains required for this transcription factor to bind DNA. BCL11B haploinsufficiency occurred across each of the major molecular subtypes of T-ALL, including early T-cell precursor, HOXA-positive, LEF1-inactivated, and TAL1-positive subtypes, which have differentiation arrest at diverse stages of thymocyte development. Our findings provide compelling evidence that BCL11B is a haploinsufficient tumor suppressor that collaborates with all major T-ALL oncogenic lesions in human thymocyte transformation. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF
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