Publications by authors named "Lewis B Silverman"

132 Publications

Matched Targeted Therapy for Pediatric Patients with Relapsed, Refractory or High-risk Leukemias: A Report from the LEAP Consortium.

Cancer Discov 2021 Feb 9. Epub 2021 Feb 9.

Department of Pediatrics and The Center for Childhood Cancer Research, Children's Hospital of Philadelphia.

Despite a remarkable increase in the genomic profiling of cancer, integration of genomic discoveries into clinical care has lagged behind. We report the feasibility of rapid identification of targetable mutations in 153 pediatric patients with relapsed/refractory or high-risk leukemias enrolled on a prospective clinical trial conducted by the LEAP Consortium. Eighteen percent of patients had a high confidence, Tier 1 or 2, recommendation. We describe clinical responses in the 14% of patients with relapsed/refractory leukemia who received the matched targeted therapy. Further, in order to inform future targeted therapy for patients, we validated variants of uncertain significance (VUS), performed ex vivo drug sensitivity testing in patient leukemia samples, and identified new combinations of targeted therapies in cell lines and patient-derived xenograft models. These data and our collaborative approach should inform the design of future precision medicine trials.
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http://dx.doi.org/10.1158/2159-8290.CD-20-0564DOI Listing
February 2021

Genetic ancestry and skeletal toxicities among childhood acute lymphoblastic leukemia patients in the DFCI 05-001 cohort.

Blood Adv 2021 01;5(2):451-458

Jacob School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY.

Hispanic children have a higher incidence of acute lymphoblastic leukemia (ALL) and inferior treatment outcomes relative to non-Hispanic White children. We previously reported that Hispanic children with ALL had lower risk of fracture and osteonecrosis. To unravel the genetic root of such ethnic differences, we genotyped 449 patients from the DFCI 05-001 cohort and analyzed their ancestry. Patients with discordant clinical and genetic ancestral groups were reclassified, and those with unknown ancestry were reassigned on the basis of genetic estimates. Both clinical and genetic ancestries were analyzed in relation to risk of bone toxicities and survival outcomes. Consistent with clinically reported race/ethnicity, genetically defined Hispanic and Black patients had significantly lower risk of fracture (Hispanic: subdistribution hazard ratio [SHR], 0.42; 95% confidence interval [CI], 0.22-0.81; P = .01; Black: SHR, 0.28; 95% CI, 0.10-0.75; P = .01), and osteonecrosis (Hispanic: SHR, 0.12; 95% CI, 0.02-0.93; P = .04; Black: SHR, 0.24; 95% CI, 0.08-0.78; P = .02). The lower risk was driven by African but not Native American or Asian ancestry. In addition, patients with a higher percentage of Native American ancestry had significantly poorer overall survival and event-free survival. Our study revealed that the lower risk of bone toxicities among Black and Hispanic children treated for ALL was attributed, in part, to the percentage of African ancestry in their genetic admixture. The findings provide suggestive evidence for the protective effects of genetic factors associated with African decent against bone damage caused by ALL treatment and clues for future studies to identify underlying biological mechanisms.
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http://dx.doi.org/10.1182/bloodadvances.2020003060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839368PMC
January 2021

Single-cell RNA-seq reveals developmental plasticity with coexisting oncogenic states and immune evasion programs in ETP-ALL.

Blood 2021 May;137(18):2463-2480

Broad Institute of MIT and Harvard, Cambridge, MA.

Lineage plasticity and stemness have been invoked as causes of therapy resistance in cancer, because these flexible states allow cancer cells to dedifferentiate and alter their dependencies. We investigated such resistance mechanisms in relapsed/refractory early T-cell progenitor acute lymphoblastic leukemia (ETP-ALL) carrying activating NOTCH1 mutations via full-length single-cell RNA sequencing (scRNA-seq) of malignant and microenvironmental cells. We identified 2 highly distinct stem-like states that critically differed with regard to cell cycle and oncogenic signaling. Fast-cycling stem-like leukemia cells demonstrated Notch activation and were effectively eliminated in patients by Notch inhibition, whereas slow-cycling stem-like cells were Notch independent and rather relied on PI3K signaling, likely explaining the poor efficacy of Notch inhibition in this disease. Remarkably, we found that both stem-like states could differentiate into a more mature leukemia state with prominent immunomodulatory functions, including high expression of the LGALS9 checkpoint molecule. These cells promoted an immunosuppressive leukemia ecosystem with clonal accumulation of dysfunctional CD8+ T cells that expressed HAVCR2, the cognate receptor for LGALS9. Our study identified complex interactions between signaling programs, cellular plasticity, and immune programs that characterize ETP-ALL, illustrating the multidimensionality of tumor heterogeneity. In this scenario, combination therapies targeting diverse oncogenic states and the immune ecosystem seem most promising to successfully eliminate tumor cells that escape treatment through coexisting transcriptional programs.
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http://dx.doi.org/10.1182/blood.2019004547DOI Listing
May 2021

Identification of prognostic factors in childhood T-cell acute lymphoblastic leukemia: Results from DFCI ALL Consortium Protocols 05-001 and 11-001.

Pediatr Blood Cancer 2021 01 7;68(1):e28719. Epub 2020 Oct 7.

Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.

Background/objectives: While outcomes for pediatric T-cell acute lymphoblastic leukemia (T-ALL) are favorable, there are few widely accepted prognostic factors, limiting the ability to risk stratify therapy.

Design/methods: Dana-Farber Cancer Institute (DFCI) Protocols 05-001 and 11-001 enrolled pediatric patients with newly diagnosed B- or T-ALL from 2005 to 2011 and from 2012 to 2015, respectively. Protocol therapy was nearly identical for patients with T-ALL (N = 123), who were all initially assigned to the high-risk arm. End-induction minimal residual disease (MRD) was assessed by reverse transcription polymerase chain reaction (RT-PCR) or next-generation sequencing (NGS), but was not used to modify postinduction therapy. Early T-cell precursor (ETP) status was determined by flow cytometry. Cases with sufficient diagnostic DNA were retrospectively evaluated by targeted NGS of known genetic drivers of T-ALL, including Notch, PI3K, and Ras pathway genes.

Results: The 5-year event-free survival (EFS) and overall survival (OS) for patients with T-ALL was 81% (95% CI, 73-87%) and 90% (95% CI, 83-94%), respectively. ETP phenotype was associated with failure to achieve complete remission, but not with inferior OS. Low end-induction MRD (<10 ) was associated with superior disease-free survival (DFS). Pathogenic mutations of the PI3K pathway were mutually exclusive of ETP phenotype and were associated with inferior 5-year DFS and OS.

Conclusions: Together, our findings demonstrate that ETP phenotype, end-induction MRD, and PI3K pathway mutation status are prognostically relevant in pediatric T-ALL and should be considered for risk classification in future trials. DFCI Protocols 05-001 and 11-001 are registered at www.clinicaltrials.gov as NCT00165087 and NCT01574274, respectively.
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http://dx.doi.org/10.1002/pbc.28719DOI Listing
January 2021

Fatal capillary leak syndrome in a child with acute lymphoblastic leukemia treated with moxetumomab pasudotox for pre-transplant minimal residual disease reduction.

Pediatr Blood Cancer 2021 01 22;68(1):e28574. Epub 2020 Sep 22.

Pediatric Hematology-Oncology, Children's Hospital Los Angeles, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.

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http://dx.doi.org/10.1002/pbc.28574DOI Listing
January 2021

How we approach Philadelphia chromosome-positive acute lymphoblastic leukemia in children and young adults.

Pediatr Blood Cancer 2020 10 11;67(10):e28543. Epub 2020 Aug 11.

Division of Pediatric Hematology/Oncology, Department of Pediatrics and Center for Childhood Cancer Research, The Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.

Treatment for children with Philadelphia chromosome-positive acute lymphoblastic leukemia has changed radically over the past 20 years. This type of leukemia used to have dismal prognosis, but today cure rates have improved with combination of cytotoxic chemotherapy and a tyrosine kinase inhibitor such as imatinib or dasatinib, with hematopoietic stem cell transplant reserved for patients who are at high risk based on slow response to therapy or who relapse. Treating these patients can be challenging particularly if they are not enrolled on a clinical trial. Here, we describe our approach to these patients.
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http://dx.doi.org/10.1002/pbc.28543DOI Listing
October 2020

Reduced Morbidity and Mortality in Survivors of Childhood Acute Lymphoblastic Leukemia: A Report From the Childhood Cancer Survivor Study.

J Clin Oncol 2020 10 24;38(29):3418-3429. Epub 2020 Jul 24.

Division of Hematology/Oncology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.

Purpose: Risk-stratified therapy, which modifies treatment on the basis of clinical and biologic features, has improved 5-year overall survival of childhood acute lymphoblastic leukemia (ALL) to 90%, but its impact on long-term toxicity remains unknown.

Methods: We assessed all-cause and health-related late mortality (including late effects of cancer therapy), subsequent malignant neoplasms (SMNs), chronic health conditions, and neurocognitive outcomes among 6,148 survivors of childhood ALL (median age, 27.9 years; range, 5.9-61.9 years) diagnosed between 1970 and 1999. Therapy combinations and treatment intensity defined 6 groups: 1970s-like (70s), standard- or high-risk 1980s-like (80sSR, 80sHR) and 1990s-like (90sSR, 90sHR), and relapse/transplantation (R/BMT). Cumulative incidence, standardized mortality ratios, and standardized incidence ratios were compared between treatment groups and with the US population.

Results: Overall, 20-year all-cause late mortality was 6.6% (95% CI, 6.0 to 7.1). Compared with 70s, 90sSR and 90sHR experienced lower health-related late mortality (rate ratio [95% CI]: 90sSR, 0.2 [0.1 to 0.4]; 90sHR, 0.3 [0.1 to 0.7]), comparable to the US population (standardized mortality ratio [95% CI]: 90sSR, 1.3 [0.8 to 2.0]; 90sHR, 1.7 [0.7 to 3.5]). Compared with 70s, 90sSR had a lower rate of SMN (rate ratio [95% CI], 0.3 [0.1 to 0.6]) that was not different from that of the US population (standardized incidence ratio [95% CI], 1.0 [0.6 to 1.6]). The 90sSR group had fewer severe chronic health conditions than the 70s (20-year cumulative incidence [95% CI], 11.0% [9.7% to 12.3%] 22.5% [19.4% to 25.5%]) and a lower prevalence of impaired memory (prevalence ratio [95% CI], 0.7 [0.6 to 0.9]) and task efficiency (0.5 [0.4 to 0.7]).

Conclusion: Risk-stratified therapy has reduced late morbidity and mortality among contemporary survivors of standard-risk ALL, represented by 90sSR. Health-related late mortality and SMN risks among 5-year survivors of contemporary, standard-risk childhood ALL are comparable to the general population.
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http://dx.doi.org/10.1200/JCO.20.00493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527155PMC
October 2020

HLA alleles associated with asparaginase hypersensitivity in childhood ALL: a report from the DFCI Consortium.

Pharmacogenomics 2020 06 6;21(8):541-547. Epub 2020 May 6.

Charles-Bruneau Cancer Center, CHU Sainte-Justine Research Center, University of Montreal, Montreal, Quebec, H3T 1C5, Canada.

To evaluate the association between human leukocyte antigen (HLA) alleles and native asparaginase hypersensitivity (AH) in children with acute lymphoblastic leukemia (ALL) who received Dana-Farber Cancer Institute treatment protocols. , and alleles were retrieved from available whole exome sequencing data of a subset of childhood ALL patients from Quebec ALL cohort and analyzed for an association with AH. PCR assay was developed to analyze associated alleles in the entire discovery and replication cohorts. Two alleles in linkage disequilibrium ( and ) were associated with AH. Additional analyses, performed to distinguish between haplotypes with and without allele, showed that the association was dependent on the presence of . This study confirms the implication of , and alleles in developing AH in childhood ALL.
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http://dx.doi.org/10.2217/pgs-2019-0195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299187PMC
June 2020

Protective Effects of Dietary Intake of Antioxidants and Treatment-Related Toxicity in Childhood Leukemia: A Report From the DALLT Cohort.

J Clin Oncol 2020 07 24;38(19):2151-2159. Epub 2020 Apr 24.

Department of Pediatrics, Roswell Park Comprehensive Cancer Center and University at Buffalo Jacobs School of Medicine and Biomedical Sciences, Buffalo, NY.

Purpose: The benefits and risks of supplementation with antioxidants during cancer therapy have been a controversial area. Few studies have systematically evaluated dietary intake of antioxidants with toxicity and survival in childhood cancer. We sought to determine the role of dietary intake of antioxidants on rates of infections, mucositis, relapse, and disease-free survival during induction and postinduction phases of therapy among children and adolescents with acute lymphoblastic leukemia (ALL).

Patients And Methods: We enrolled 794 children in a prospective clinical trial for treatment of ALL. Dietary intake was prospectively evaluated by a food frequency questionnaire. The association between dietary intake of antioxidants and treatment-related toxicities and survival were evaluated with the Benjamini-Hochberg false discovery rate (q) and logistic regression and the Kaplan-Meier method, respectively.

Results: Dietary surveys were available for analysis from 614 (77%), and 561 (71%) participants at diagnosis and at end of induction, respectively. Of 513 participants who completed the dietary surveys at both time points, 120 (23%) and 87 (16%) experienced a bacterial infection and 22 (4%) and 55 (10%) experienced mucositis during the induction or postinduction phases of treatment, respectively. Increased intake of dietary antioxidants was associated with significantly lower rates of infection and mucositis. No association with relapse or disease-free survival was observed. Supplementation was not associated with toxicity, relapse, or survival.

Conclusion: Consumption of antioxidants through dietary intake was associated with reduced rates of infection or mucositis, with no increased risk of relapse or reduced survival. Dietary counseling on a well-balanced diet that includes an array of antioxidants from food sources alone may confer a benefit from infections and mucositis during treatment of childhood ALL.
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http://dx.doi.org/10.1200/JCO.19.02555DOI Listing
July 2020

Fanconi-BRCA pathway mutations in childhood T-cell acute lymphoblastic leukemia.

PLoS One 2019 13;14(11):e0221288. Epub 2019 Nov 13.

Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts, United States of America.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0221288PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6853288PMC
March 2020

Genes identified through genome-wide association studies of osteonecrosis in childhood acute lymphoblastic leukemia patients.

Pharmacogenomics 2019 11 5;20(17):1189-1197. Epub 2019 Nov 5.

Charles-Bruneau Cancer Center, CHU Sainte-Justine Research Center, University of Montreal, Montreal, QC H3T 1C5, Canada.

To evaluate top-ranking genes identified through genome-wide association studies for an association with corticosteroid-related osteonecrosis in children with acute lymphoblastic leukemia (ALL) who received Dana-Farber Cancer Institute treatment protocols. Lead SNPs from these studies, as well as other variants in the same genes, pooled from whole exome sequencing data, were analyzed for an association with osteonecrosis in childhood ALL patients from Quebec cohort. Top-ranking variants were verified in the replication patient group. The analyses of variants in the locus derived from whole exome sequencing data showed an association of several correlated SNPs (rs11553746, rs2290911, rs7595075, rs2306060 and rs79716074). The rs79716074 defines *B haplotype of the gene, which is well known for its functional role. This study confirms implication of the gene in the treatment-related osteonecrosis in childhood ALL and identifies novel, potentially causal variant of this complication.
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http://dx.doi.org/10.2217/pgs-2019-0087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7026765PMC
November 2019

Toxicity and response after CD19-specific CAR T-cell therapy in pediatric/young adult relapsed/refractory B-ALL.

Blood 2019 12;134(26):2361-2368

Center For Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY.

Chimeric antigen receptor (CAR) T cells have demonstrated clinical benefit in patients with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). We undertook a multicenter clinical trial to determine toxicity, feasibility, and response for this therapy. A total of 25 pediatric/young adult patients (age, 1-22.5 years) with R/R B-ALL were treated with 19-28z CAR T cells. Conditioning chemotherapy included high-dose (3 g/m2) cyclophosphamide (HD-Cy) for 17 patients and low-dose (≤1.5 g/m2) cyclophosphamide (LD-Cy) for 8 patients. Fifteen patients had pretreatment minimal residual disease (MRD; <5% blasts in bone marrow), and 10 patients had pretreatment morphologic evidence of disease (≥5% blasts in bone marrow). All toxicities were reversible, including severe cytokine release syndrome in 16% (4 of 25) and severe neurotoxicity in 28% (7 of 25) of patients. Treated patients were assessed for response, and, among the evaluable patients (n = 24), response and peak CAR T-cell expansion were superior in the HD-Cy/MRD cohorts, as compared with the LD-Cy/morphologic cohorts without an increase in toxicity. Our data support the safety of CD19-specific CAR T-cell therapy for R/R B-ALL. Our data also suggest that dose intensity of conditioning chemotherapy and minimal pretreatment disease burden have a positive impact on response without a negative effect on toxicity. This trial was registered at www.clinicaltrials.gov as #NCT01860937.
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http://dx.doi.org/10.1182/blood.2019001641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6933289PMC
December 2019

Outcome of Infants Younger Than 1 Year With Acute Lymphoblastic Leukemia Treated With the Interfant-06 Protocol: Results From an International Phase III Randomized Study.

J Clin Oncol 2019 09 8;37(25):2246-2256. Epub 2019 Jul 8.

University of Milano-Bicocca, Monza, Italy.

Purpose: Infant acute lymphoblastic leukemia (ALL) is characterized by () gene rearrangements and coexpression of myeloid markers. The Interfant-06 study, comprising 18 national and international study groups, tested whether myeloid-style consolidation chemotherapy is superior to lymphoid style, the role of stem-cell transplantation (SCT), and which factors had independent prognostic value.

Materials And Methods: Three risk groups were defined: low risk (LR): germline; high risk (HR): -rearranged and older than 6 months with WBC count 300 × 10/L or more or a poor prednisone response; and medium risk (MR): all other -rearranged cases. Patients in the MR and HR groups were randomly assigned to receive the lymphoid course low-dose cytosine arabinoside [araC], 6-mercaptopurine, cyclophosphamide (IB) or experimental myeloid courses, namely araC, daunorubicin, etoposide (ADE) and mitoxantrone, araC, etoposide (MAE).

Results: A total of 651 infants were included, with 6-year event-free survival (EFS) and overall survival of 46.1% (SE, 2.1) and 58.2% (SE, 2.0). In West European/North American groups, 6-year EFS and overall survival were 49.4% (SE, 2.5) and 62.1% (SE, 2.4), which were 10% to 12% higher than in other countries. The 6-year probability of disease-free survival was comparable for the randomized arms (ADE+MAE 39.3% [SE 4.0; n = 169] IB 36.8% [SE, 3.9; n = 161]; log-rank = .47). The 6-year EFS rate of patients in the HR group was 20.9% (SE, 3.4) with the intention to undergo SCT; only 46% of them received SCT, because many had early events. rearrangement was the strongest prognostic factor for EFS, followed by age, WBC count, and prednisone response.

Conclusion: Early intensification with postinduction myeloid-type chemotherapy courses did not significantly improve outcome for infant ALL compared with the lymphoid-type course IB. Outcome for infant ALL in Interfant-06 did not improve compared with that in Interfant-99.
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http://dx.doi.org/10.1200/JCO.19.00261DOI Listing
September 2019

Divide and conquer: Evaluation of a redesign of a pediatric teaching service.

Pediatr Blood Cancer 2019 07 29;66(7):e27738. Epub 2019 Mar 29.

Harvard Medical School, Boston, Massachusetts.

Background: Increasing census and work compression on the pediatric inpatient hematologic malignancy (IHM) service yielded resident dissatisfaction, impaired learning, and decreased perceived quality of patient care. This study aimed to evaluate the impact of a service redesign on resident perceptions of (a) the educational value of the rotation and (b) the safety of patient care. As a secondary objective, we evaluated the impact on the time of day of patient discharge.

Procedure: A bundled intervention on the IHM service was instituted, including decreased patient volumes, intentional patient assignment, intentional faculty selection, and increased weekend staffing. We distributed an annual survey to end-of-the-year junior residents. We compared responses from residents who experienced the redesign (2017) with residents whose experience predated the redesign (2016). We compared the time of day of patient discharge before and after the redesign.

Results: Survey completion rates were 70% (28/40) in 2016 and 57% (29/51) in 2017. Redesign residents rated their educational experience and perceived ability to care for patients on the nights and weekends significantly higher than previous residents. Redesign residents reported that their clinical education was compromised by excessive service less frequently than previous residents (24% vs 82%, P < 0.001). The time of day of patient discharge after the redesign was 35 minutes earlier than before the redesign (4:06 pm vs 4:41 pm, P = 0.01, 95% CI = -63, -6).

Conclusions: A redesign initiative of an oncology service led to improved resident perceptions of the educational value of the rotation and ability to provide safe care to patients, along with earlier discharge times.
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http://dx.doi.org/10.1002/pbc.27738DOI Listing
July 2019

Outcome of Children With Hypodiploid Acute Lymphoblastic Leukemia: A Retrospective Multinational Study.

J Clin Oncol 2019 04 18;37(10):770-779. Epub 2019 Jan 18.

2 University of Milano-Bicocca, Monza, Italy.

Purpose: We determined the prognostic factors and utility of allogeneic hematopoietic cell transplantation among children with newly diagnosed hypodiploid acute lymphoblastic leukemia (ALL) treated in contemporary clinical trials.

Patients And Methods: This retrospective study collected data on 306 patients with hypodiploid ALL who were enrolled in the protocols of 16 cooperative study groups or institutions between 1997 and 2013. The clinical and biologic characteristics, early therapeutic responses as determined by minimal residual disease (MRD) assessment, treatment with or without MRD-stratified protocols, and allogeneic transplantation were analyzed for their impact on outcome.

Results: With a median follow-up of 6.6 years, the 5-year event-free survival rate was 55.1% (95% CI, 49.3% to 61.5%), and the 5-year overall survival rate was 61.2% (95% CI, 55.5% to 67.4%) for the 272 evaluable patients. Negative MRD at the end of remission induction, high hypodiploidy with 44 chromosomes, and treatment in MRD-stratified protocols were associated with a favorable prognosis, with a 5-year event-free survival rate of 75% (95% CI, 66.0% to 85.0%), 74% (95% CI, 61.0% to 89.0%), and 62% (95% CI, 55.0% to 69.0%), respectively. After exclusion of patients with high hypodiploidy with 44 chromosomes and adjustment for waiting time to transplantation and for covariables in a Poisson model, disease-free survival did not differ significantly ( P = .16) between the 42 patients who underwent transplantation and the 186 patients who received chemotherapy only, with an estimated 5-year survival rate of 59% (95% CI, 46.5% to 75.0%) versus 51.5% (95% CI, 44.7% to 59.4%), respectively. Transplantation produced no significant impact on outcome compared with chemotherapy alone, especially among the subgroup of patients who achieved a negative MRD status upon completion of remission induction.

Conclusion: MRD-stratified treatments improved the outcome for children with hypodiploid ALL. Allogeneic transplantation did not significantly improve outcome overall and, in particular, for patients who achieved MRD-negative status after induction.
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http://dx.doi.org/10.1200/JCO.18.00822DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7051863PMC
April 2019

Fluctuations in dietary intake during treatment for childhood leukemia: A report from the DALLT cohort.

Clin Nutr 2019 12 3;38(6):2866-2874. Epub 2019 Jan 3.

Department of Pediatrics, Roswell Park Cancer Institute and University at Buffalo School of Medicine and Biomedical Sciences, Buffalo, NY, United States.

Background: Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. Nutritional morbidities are a persistent problem facing pediatric patients during and after treatment and age-gender groups that are at risk for nutritional conditions have not been clearly identified. Therapy is a contributing factor; however, the role of dietary intake remains largely unknown. Prior to conduct of interventional trials, an understanding of the effects of treatment on fluctuations in dietary intake is necessary.

Methods: We enrolled 794 children with ALL in a prospective clinical trial. Dietary intake was collected with a food frequency questionnaire at diagnosis and throughout the course of treatment for pediatric ALL. Reported values were compared to the Dietary Recommended Intake (DRI), and normative values (NHANES). Hierarchical linear models and multilevel mixed-effects ordered logistic regression models were used to evaluate longitudinal changes in dietary intake; independent samples t-test with Bonferroni correction was performed to compare to NHANES.

Results: Of the evaluable participants at each timepoint, dietary intake was obtained on 81% (n = 640), 74% (n = 580) and 74% (n = 558) at diagnosis, end of induction phase of treatment, and continuation, respectively. Despite exposure to corticosteroids, caloric intake decreased over therapy for most age-gender groups. Predictive models of excess intake found reduced odds of over-consuming calories (OR 0.738, P < 0.05); however, increased odds of over-consuming fat (OR 6.971, P < 0.001). When compared to NHANES, we consistently found that ≥1/3 of children were consuming calories in excess of normative values. For select micronutrients, a small proportion of participants were above or below the DRI at each time evaluated.

Conclusions: Our study suggests that dietary intake fluctuates during treatment for ALL as compared to age-gender recommended and normative values. Improving our understanding of nutrient fluctuations and dietary quality will facilitate subsequent analyses addressing relationships of dietary intake, toxicity, and survival.
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http://dx.doi.org/10.1016/j.clnu.2018.12.021DOI Listing
December 2019

A single institutional review of pediatric Bacillus spp. bloodstream infections demonstrates increased incidence among children with cancer.

Pediatr Blood Cancer 2019 04 11;66(4):e27568. Epub 2018 Dec 11.

Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts.

Background: Bacillus species are known to cause severe infection in immunocompromised hosts. The incidence of Bacillus bloodstream infections and characteristics of infection among children with cancer or indication for hematopoietic cell transplant (HCT) is unknown.

Methods: We performed a retrospective medical record review of all cases of Bacillus bacteremia between January 1, 2005, and December 31, 2014, at Boston Children's Hospital. We report average incidences from 2012 to 2014. We performed a detailed review of infections among children with cancer or undergoing HCT and a case-control study to evaluate whether neutropenia at diagnosis caries higher risk of Bacillus infection for children with acute lymphoblastic leukemia (ALL).

Results: One hundred fourteen children developed Bacillus bacteremia during the study period, with an estimated incidence of 0.27/1,000 patients. Among children treated for cancer or undergoing HCT, there were 37 bloodstream infections (2.0/1,000 patients). Of the 37 oncology/HCT patients, oncologic diagnoses included ALL (18), acute myeloid leukemia (3), myelodysplastic syndrome (1), solid tumors (8), and 7 children were undergoing HCT. The incidence of infection among children with ALL was 34/1,000 patients and all central nervous system (CNS) infections (6) and deaths (3) occurred in this population. Neutropenia at time of diagnosis in children with ALL was not associated with risk of infection (P = 0.17).

Discussion: We report the first hospital-wide analysis of Bacillus infection and found that immunocompromised children experience a significant proportion of Bacillus infections. Children with ALL have a high incidence of infection and are at higher risk of CNS involvement and death.
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http://dx.doi.org/10.1002/pbc.27568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6664817PMC
April 2019

Trypsin-encoding variations influence the risk of asparaginase-associated pancreatitis in children with acute lymphoblastic leukemia: a Ponte di Legno toxicity working group report.

Haematologica 2019 03 22;104(3):556-563. Epub 2018 Nov 22.

Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark

Asparaginase-associated pancreatitis is a life-threatening toxicity to childhood acute lymphoblastic leukemia treatment. To elucidate genetic predisposition and asparaginase-associated pancreatitis pathogenesis, ten trial groups contributed remission samples from patients aged 1.0-17.9 years treated for acute lymphoblastic leukemia between 2000 and 2016. Cases (n=244) were defined by the presence of at least two of the following criteria: (i) abdominal pain; (ii) levels of pancreatic enzymes ≥3 × upper normal limit; and (iii) imaging compatible with pancreatitis. Controls (n=1320) completed intended asparaginase therapy, with 78% receiving ≥8 injections of pegylated-asparaginase, without developing asparaginase-associated pancreatitis. rs62228256 on 20q13.2 showed the strongest association with the development of asparaginase-associated pancreatitis (odds ratio=3.75; =5.2×10). Moreover, rs13228878 (OR=0.61; =7.1×10) and rs10273639 (OR=0.62; =1.1×10) on 7q34 showed significant association with the risk of asparaginase-associated pancreatitis. A Dana Farber Cancer Institute ALL Consortium cohort consisting of patients treated on protocols between 1987 and 2004 (controls=285, cases=33), and the Children's Oncology Group AALL0232 cohort (controls=2653, cases=76) were available as replication cohorts for the 20q13.2 and 7q34 variants, respectively. While rs62228256 was not validated as a risk factor (=0.77), both rs13228878 (=0.03) and rs10273639 (=0.04) were. rs13228878 and rs10273639 are in high linkage disequilibrium (r=0.94) and associated with elevated expression of the gene, which encodes for trypsinogen, and are known risk variants for alcohol-associated and sporadic pancreatitis in adults. Intra-pancreatic trypsinogen cleavage to proteolytic trypsin induces autodigestion and pancreatitis. In conclusion, this study finds a shared genetic predisposition between asparaginase-associated pancreatitis and non-asparaginase-associated pancreatitis, and targeting the trypsinogen activation pathway may enable identification of effective interventions for asparaginase-associated pancreatitis.
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http://dx.doi.org/10.3324/haematol.2018.199356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6395330PMC
March 2019

PRC2 loss induces chemoresistance by repressing apoptosis in T cell acute lymphoblastic leukemia.

J Exp Med 2018 12 7;215(12):3094-3114. Epub 2018 Nov 7.

Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA

The tendency of mitochondria to undergo or resist BCL2-controlled apoptosis (so-called mitochondrial priming) is a powerful predictor of response to cytotoxic chemotherapy. Fully exploiting this finding will require unraveling the molecular genetics underlying phenotypic variability in mitochondrial priming. Here, we report that mitochondrial apoptosis resistance in T cell acute lymphoblastic leukemia (T-ALL) is mediated by inactivation of polycomb repressive complex 2 (PRC2). In T-ALL clinical specimens, loss-of-function mutations of PRC2 core components (, , or ) were associated with mitochondrial apoptosis resistance. In T-ALL cells, PRC2 depletion induced resistance to apoptosis induction by multiple chemotherapeutics with distinct mechanisms of action. PRC2 loss induced apoptosis resistance via transcriptional up-regulation of the LIM domain transcription factor and downstream up-regulation of the mitochondrial chaperone These findings demonstrate the importance of mitochondrial apoptotic priming as a prognostic factor in T-ALL and implicate mitochondrial chaperone function as a molecular determinant of chemotherapy response.
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http://dx.doi.org/10.1084/jem.20180570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279404PMC
December 2018

Genomic and clinical characterization of B/T mixed phenotype acute leukemia reveals recurrent features and T-ALL like mutations.

Am J Hematol 2018 11 26;93(11):1358-1367. Epub 2018 Sep 26.

Department of Pathology, Boston Children's Hospital, Boston, Massachusetts.

The B/T subtype of mixed phenotype acute leukemia (B/T MPAL) is defined by co-expression of antigens of both B- and T-cell lineages on leukemic blasts. Although it has been suggested that multilineage antigen expression portends poor response to chemotherapy, the clinical characteristics and driver mutations that underlie the pathogenesis of this rare subtype of acute leukemia are scarcely known. We identified nine cases of B/T MPAL from multiple institutions and correlated clinical and immunophenotypic findings with next-generation sequencing data. We report that B/T MPAL commonly presents with lymphadenopathy in adolescence and young adulthood. While the tumors have diverse cytogenetic and genomic perturbations, recurrent acquired aberrations include mutations in the putative transcriptional regulator PHF6 and the JAK-STAT and Ras signaling pathways. Alterations were also identified in genes encoding hematopoietic transcription factors, cell cycle regulators/tumor suppressors, and chromatin modifying enzymes. The genomic landscape of B/T MPAL strongly resembles that of T-ALL subgroups associated with early developmental arrest, while genetic alterations that are common in B-ALL were rarely seen. Two-thirds of the patients responded to ALL-based chemotherapy with or without stem cell transplantation. Our observations lay the groundwork for further study of the unique biology and clinical trajectory of B/T MPAL.
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http://dx.doi.org/10.1002/ajh.25256DOI Listing
November 2018

Refining risk classification in childhood B acute lymphoblastic leukemia: results of DFCI ALL Consortium Protocol 05-001.

Blood Adv 2018 06;2(12):1449-1458

Department of Pediatric Oncology, Dana-Farber Cancer Institute.

Dana-Farber Cancer Institute (DFCI) ALL Consortium Protocol 05-001 tested a new risk stratification system in children and adolescents with newly diagnosed acute lymphoblastic leukemia (ALL). At study entry, B-ALL patients were classified as standard risk (SR) or high risk (HR) based on age, white blood cell (WBC) count, and central nervous system status. After achieving complete remission (CR), patients with high end-induction minimal residual disease (MRD) (≥10 by polymerase chain reaction analysis of patient-specific antigen receptor rearrangements) and/or adverse cytogenetics ( rearrangement or hypodiploidy) were reclassified as very high risk (VHR) and received intensified therapy. deletion status was retrospectively evaluated by multiplex ligation-dependent probe amplification. Between 2005 and 2011, 678 Philadelphia chromosome-negative B-ALL patients aged 1 to 18 years enrolled; 651 achieved CR and 648 received a final risk group. Among all 678 patients, 5-year event-free survival (EFS) was 87% (95% confidence interval [CI], 84-89) and overall survival 93% (95% CI, 90-94). Five-year disease-free survival of SR patients (N = 407) was 94% (95% CI, 91-96), HR (N = 176) was 84% (95% CI, 77-88), and VHR (N = 65) was 79% (95% CI, 67-87). deletion was present in 62 of 385 (16%) assessed patients and was associated with inferior 5-year EFS (63%; 95% CI, 49%-74% vs 88%; 95% CI, 84%-91%; < .001), and higher 5-year cumulative incidence of relapse, including among those with low MRD (24% vs 8%, = .001). In multivariable analysis, age ≥15 years, WBC ≥50 × 10/L, deletion, and MRD ≥10 was each associated with inferior outcome. In conclusion, risk-stratified therapy on DFCI 05-001 resulted in favorable outcomes for B-ALL patients, including those with VHR features. deletion was an independent predictor of inferior outcome. This trial was registered at www.clinicaltrials.gov as #NCT00400946.
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http://dx.doi.org/10.1182/bloodadvances.2018016584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6020806PMC
June 2018

Outcome of children and adolescents with Down syndrome treated on Dana-Farber Cancer Institute Acute Lymphoblastic Leukemia Consortium protocols 00-001 and 05-001.

Pediatr Blood Cancer 2018 10 7;65(10):e27256. Epub 2018 Jun 7.

Department of Pediatric Oncology, Dana-Farber Cancer Institute and Division of Pediatric Hematology-Oncology, Boston Children's Hospital, Boston, MA, USA.

Background: Children and adolescents with Down syndrome (DS) and acute lymphoblastic leukemia (ALL) are reported to have increased relapse rates and therapy-related mortality (TRM). Treatment regimens for DS-ALL patients often include therapy modifications. Dana-Farber Cancer Institute (DFCI) ALL Consortium protocols have used same risk-stratified treatment for patients with and without DS.

Procedures: We compared clinical and outcome data of DS (n = 38) and non-DS (n = 1,248) patients enrolled on two consecutive DFCI ALL trials 00-001 (2000-2004) and 05-001 (2005-2011) with similar risk adapted therapy regardless of DS status.

Results: There was no difference in demographic or presenting clinical features between two groups except absence of T-cell phenotype and lower frequency of hyperdiploidy in DS-ALL group. All DS-ALL patients achieved complete remission; four relapsed and one subsequently died. There was no TRM in DS-ALL patients. DS-ALL patients had significantly higher rates of mucositis (52% vs. 12%, p < 0.001), non-CNS thrombosis (18% vs. 8%; p = 0.036), and seizure (16% vs. 5%, p = 0.010). Compared to non-DS-ALL patients, DS-ALL patients had a higher incidence of infections during all therapy phases. The 5-year event-free and overall survival rates of DS-ALL patients were similar to non-DS-ALL patients (91% [95% confidence interval (CI), 81-100] vs. 84% [95% CI, 82-86]; 97% [95% CI, 92-100] vs. 91% [95% CI, 90-93]).

Conclusion: The low rates of relapse and TRM indicate that uniform risk-stratified therapy for DS-ALL and non-DS-ALL patients on DFCI ALL Consortium protocols was safe and effective, although the increased rate of toxicity in the DS-ALL patients highlights the importance of supportive care during therapy.
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http://dx.doi.org/10.1002/pbc.27256DOI Listing
October 2018

Dasatinib Plus Intensive Chemotherapy in Children, Adolescents, and Young Adults With Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: Results of Children's Oncology Group Trial AALL0622.

J Clin Oncol 2018 08 29;36(22):2306-2314. Epub 2018 May 29.

William B. Slayton, John A. Kairalla, Meenakshi Devidas, Xinlei Mi, and Sherri L. Mizrahy, University of Florida, Gainesville, FL; Kirk R. Schultz, BC Children's Research Institute, University of British Columbia, Vancouver, British Columbia, Canada; Michael A. Pulsipher, Children's Hospital of Los Angeles, Los Angeles; Lance Sieger, University of California Los Angles-Harbor, Torrance; Mignon L. Loh, University of California San Francisco, San Francisco, CA; Bill H. Chang, Oregon Health and Science University, Portland, OR; Charles Mullighan, Ilaria Iacobucci, and Thomas Merchant, St Jude's Research Hospital, Memphis, TN; Lewis B. Silverman, Dana-Farber Cancer Institute, Boston, MA; Michael J. Borowitz, Johns Hopkins University, Baltimore, MD; Andrew J. Carroll, University of Alabama at Birmingham, Birmingham, AL; Nyla A. Heerema, Ohio State University; Julie M. Gastier-Foster, Nationwide Children's Hospital, Columbus, OH; Brent L. Wood, University of Washington Seattle, Seattle, WA; Valerie I. Brown, Penn State Health Children's Hospital, Hershey; Stephen P. Hunger, Children's Hospital of Philadelphia, Philadelphia, PA; Marilyn J. Siegel, Washington University School of Medicine, St Louis, MO; Elizabeth A. Raetz, University of Utah, Salt Lake City, UT; Naomi J. Winick, University of Texas Southwestern Medical Center, Dallas, TX; and William L. Carroll, New York University Langone Health Center, New York, NY.

Purpose Addition of imatinib to intensive chemotherapy improved survival for children and young adults with Philadelphia chromosome-positive acute lymphoblastic leukemia. Compared with imatinib, dasatinib has increased potency, CNS penetration, and activity against imatinib-resistant clones. Patients and Methods Children's Oncology Group (COG) trial AALL0622 (Bristol Myers Squibb trial CA180-204) tested safety and feasibility of adding dasatinib to intensive chemotherapy starting at induction day 15 in patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia age 1 to 30 years. Allogeneic hematopoietic stem-cell transplantation (HSCT) was recommended for patients at high risk based on slow response and for those with a matched family donor regardless of response after at least 11 weeks of therapy. Patients at standard risk based on rapid response received chemotherapy plus dasatinib for an additional 120 weeks. Patients with overt CNS leukemia received cranial irradiation. Results Sixty eligible patients were enrolled. Five-year overall (OS) and event-free survival rates (± standard deviations [SD]) were 86% ± 5% and 60% ± 7% overall, 87% ± 5% and 61% ± 7% for standard-risk patients (n = 48; 19% underwent HSCT), and 89% ± 13% and 67% ± 19% for high-risk patients (n = 9; 89% underwent HSCT), respectively. Five-year cumulative incidence (± SD) of CNS relapse was 15% ± 6%. Outcomes (± SDs) were similar to those in COG AALL0031, which used the same chemotherapy with continuous imatinib: 5-year OS of 81% ± 6% versus 86% ± 5% ( P = .63) and 5-year disease-free survival of 68% ± 7% versus 60% ± 7% ( P = 0.31) for AALL0031 versus AALL0622, respectively. IKZF1 deletions, present in 56% of tested patients, were associated with significantly inferior OS and event-free survival overall and in standard-risk patients. Conclusion Dasatinib was well tolerated with chemotherapy and provided outcomes similar to those with imatinib in COG AALL0031, where all patients received cranial irradiation. Our results support limiting HSCT to slow responders and suggest a potential role for transplantation in rapid responders with IKZF1 deletions.
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http://dx.doi.org/10.1200/JCO.2017.76.7228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6067800PMC
August 2018

Hedgehog pathway mutations drive oncogenic transformation in high-risk T-cell acute lymphoblastic leukemia.

Leukemia 2018 10 20;32(10):2126-2137. Epub 2018 Mar 20.

Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, 02115, USA.

The role of Hedgehog signaling in normal and malignant T-cell development is controversial. Recently, Hedgehog pathway mutations have been described in T-ALL, but whether mutational activation of Hedgehog signaling drives T-cell transformation is unknown, hindering the rationale for therapeutic intervention. Here, we show that Hedgehog pathway mutations predict chemotherapy resistance in human T-ALL, and drive oncogenic transformation in a zebrafish model of the disease. We found Hedgehog pathway mutations in 16% of 109 childhood T-ALL cases, most commonly affecting its negative regulator PTCH1. Hedgehog mutations were associated with resistance to induction chemotherapy (P = 0.009). Transduction of wild-type PTCH1 into PTCH1-mutant T-ALL cells induced apoptosis (P = 0.005), a phenotype that was reversed by downstream Hedgehog pathway activation (P = 0.007). Transduction of most mutant PTCH1, SUFU, and GLI alleles into mammalian cells induced aberrant regulation of Hedgehog signaling, indicating that these mutations are pathogenic. Using a CRISPR/Cas9 system for lineage-restricted gene disruption in transgenic zebrafish, we found that ptch1 mutations accelerated the onset of notch1-induced T-ALL (P = 0.0001), and pharmacologic Hedgehog pathway inhibition had therapeutic activity. Thus, Hedgehog-activating mutations are driver oncogenic alterations in high-risk T-ALL, providing a molecular rationale for targeted therapy in this disease.
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http://dx.doi.org/10.1038/s41375-018-0097-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6148437PMC
October 2018

Phase I trial of the mTOR inhibitor everolimus in combination with multi-agent chemotherapy in relapsed childhood acute lymphoblastic leukemia.

Pediatr Blood Cancer 2018 07 30;65(7):e27062. Epub 2018 Mar 30.

Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, Massachusetts.

Background: We sought to determine the feasibility of co-administering everolimus with a four-drug reinduction in children and adolescents with acute lymphoblastic leukemia (ALL) experiencing a first marrow relapse.

Procedure: This phase I study tested everolimus with vincristine, prednisone, pegaspargase and doxorubicin in patients with marrow relapse occurring >18 months after first complete remission (CR). The primary aim was to identify the maximum tolerated dose of everolimus. Three dose levels (DLs) were tested during dose escalation (2, 3, and 5 mg/m /day). Additional patients were enrolled at the 3- and 5 mg/m /day DLs to further evaluate toxicity (dose expansion).

Results: Thirteen patients enrolled during dose escalation and nine during dose expansion. During dose escalation, one dose-limiting toxicity occurred (grade 4 hyperbilirubinemia) in six evaluable patients at DL3 (5 mg/m /day). The most common grade ≥3 adverse events were febrile neutropenia, infections, transaminitis, hyperbilirubinemia, and hypophosphatemia. Two of the 12 patients treated at DL3 developed Rothia mucilaginosa meningitis. Nineteen patients (86%) achieved a second CR (CR2). Of those, 13 (68%) had a low end-reinduction minimal residual disease (MRD) level (≤10 by polymerase chain reaction-based assay). The CR2 rate for patients with B-cell ALL treated at DL3 (n = 12) was 92%; 82% of these patients had low MRD.

Conclusions: Everolimus combined with four-drug reinduction chemotherapy was generally well tolerated and associated with favorable rates of CR2 and low end-reinduction MRD. The recommended phase 2 dose of everolimus given in combination with a four-drug reinduction is 5 mg/m /day. This promising combination should be further evaluated in a larger patient cohort.
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http://dx.doi.org/10.1002/pbc.27062DOI Listing
July 2018

Prognostic impact of kinase-activating fusions and IKZF1 deletions in pediatric high-risk B-lineage acute lymphoblastic leukemia.

Blood Adv 2018 03;2(5):529-533

Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, MA.

Recurrent chromosomal rearrangements carry prognostic significance in pediatric B-lineage acute lymphoblastic leukemia (B-ALL). Recent genome-wide analyses identified a high-risk B-ALL subtype characterized by a diverse spectrum of genetic alterations activating kinases and cytokine receptor genes. This subtype is associated with a poor prognosis when treated with conventional chemotherapy but has demonstrated sensitivity to the relevant tyrosine kinase inhibitors. We sought to determine the frequency of kinase-activating fusions among National Cancer Institute (NCI) high-risk, Ph-negative, B-ALL patients enrolled on Dana-Farber Cancer Institute ALL Consortium Protocol 05-001 and to describe their associated clinical characteristics and outcomes. Among the 105 patients screened, 16 (15%) harbored an ABL-class fusion (: n = 1; : n = 1; : n = 1; : n = 1) or a fusion activating the JAK-STAT pathway (: n = 8; : n = 4). Sixty-nine percent of patients with an identified fusion had a concomitant deletion (n = 11). In univariate analysis, fusion-positivity and deletion were each associated with inferior event-free survival; deletion retained statistical significance in multivariable analysis (hazard ratio, 2.64; = .019). Our findings support therapy intensification for -altered patients, irrespective of the presence of a kinase-activating fusion.
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http://dx.doi.org/10.1182/bloodadvances.2017014704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5851421PMC
March 2018

Influence of BCL2L11 polymorphism on osteonecrosis during treatment of childhood acute lymphoblastic leukemia.

Pharmacogenomics J 2019 02 27;19(1):33-41. Epub 2017 Dec 27.

Charles-Bruneau Cancer Center, CHU Sainte-Justine Research Center, Montreal, QC, Canada.

Osteonecrosis (ON) is corticosteroid-related complication, reported in children with acute lymphoblastic leukemia (ALL). We have previously found that polymorphisms in BCL2L11 gene coding for pro-apoptotic Bim protein influence reduction of overall survival (OS) in a corticosteroid (CS) dose-dependent manner in childhood ALL patients. The same set of SNPs was here investigated for an association with CS-related ON assessed retrospectively in 304 children with ALL from Quebec (QcALL cohort) who received Dana-Farber Cancer Institute (DFCI) ALL treatment protocols. Two-year cumulative incidence of symptomatic ON was 10.6%. Two BCL2L11 polymorphisms, the 891T>G (rs2241843) in all QcALL patients and 29201C>T (rs724710) in high-risk group were significantly associated with ON, P = 0.009 and P = 0.003, respectively. The association remained significant in multivariate model (HR = 2.4, 95% CI 1.2-4.8, P = 0.01 and HR = 5.7, 95% CI 1.6-20.9, P = 0.008). Both polymorphisms influenced viability of dexamethasone treated lymphoblastoid cell lines (P ≤ 0.03). The 891T>G influenced Bim gamma isoform levels (0.03) and its association with ON was also confirmed in replication DFCI cohort (N = 168, P = 0.03). QcALL children had a high incidence of ON during therapy, which was highly associated with BCL2L11 polymorphisms.
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http://dx.doi.org/10.1038/s41397-017-0002-4DOI Listing
February 2019