Faculty Bibliography
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292
Targetable kinase gene fusions in high risk B-ALL: a study from the Children's Oncology Group
Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk subtype characterized by genomic alterations that activate cytokine receptor and kinase signaling. We examined the frequency and spectrum of targetable genetic lesions in a retrospective cohort of 1389 consecutively diagnosed childhood B-ALL patients with high-risk clinical features and/or elevated minimal residual disease at the end of remission induction therapy. The Ph-like gene expression profile was identified in 341 of 1389 patients, 57 of which were excluded from additional analysis because of the presence of BCR-ABL1 (n=46) or ETV6-RUNX1 (n=11). Among the remaining 284 (20.4%) patients, overexpression and rearrangement of CRLF2 (IGH-CRLF2 or P2RY8-CRLF2) were identified in 124 (43.7%), with concomitant genomic alterations activating the JAK-STAT pathway (JAK1, JAK2, IL7R) identified in 63 patients (50.8% of CRLF2-rearranged cases). Of the remaining patients, using RT-PCR or transcriptome sequencing, we identified targetable ABL-class fusions (ABL1, ABL2, CSF1R and PDGFRB) in 14.1% of Ph-like ALL cases, EPOR rearrangements or JAK2 fusions (8.8%), alterations activating other JAK-STAT signaling genes (IL7R, SH2B3, JAK1; 6.3%) and other kinases (FLT3, NTRK3, LYN; 4.6%), and mutations involving the Ras pathway (KRAS, NRAS, NF1, PTPN11; 6%). We identified eight new rearrangement partners for four kinase genes previously reported to be rearranged in Ph-like ALL. The current findings provide support for the precision-medicine testing and treatment approach for Ph-like ALL that has been implemented in Children's Oncology Group ALL trials.
PMCID:5482101
PMID: 28408464
ISSN: 1528-0020
CID: 2528372
Genetics of ancestry-specific risk for relapse in acute lymphoblastic leukemia
The causes of individual relapses in children with acute lymphoblastic leukemia (ALL) remain incompletely understood. We evaluated the contribution of germline genetic factors to relapse in 2225 children treated on Children's Oncology Group trial AALL0232. We identified 302 germline single nucleotide polymorphisms (SNPs) associated with relapse after adjusting for treatment and ancestry and 715 additional SNPs associated with relapse in an ancestry-specific manner. We tested for replication of these relapse-associated SNPs in external data sets of antileukemic drug pharmacokinetics and pharmacodynamics and an independent clinical cohort. 224 SNPs were associated with rapid drug clearance or drug resistance, and 32 were replicated in the independent cohort. The adverse risk associated with black and Hispanic ancestries was attenuated by addition of the 4 SNPs most strongly associated with relapse in these populations [for blacks: model without SNPs hazard ratio (HR)=2.32, P=2.27 x 10-4, model with SNPs HR=1.07, P=0.79; for Hispanics: model without SNPs HR=1.7, P=8.23 x 10-5, model with SNPs HR=1.31, P=0.065]. Relapse SNPs associated with asparaginase resistance or allergy were overrepresented among SNPs associated with relapse in the more asparaginase intensive treatment arm (20/54 in Capizzi-methorexate arm vs 8/54 in high-dose methotrexate arm, P=0.015). Inherited genetic variation contributes to race-specific and treatment-specific relapse risk.Leukemia accepted article preview online, 18 January 2017. doi:10.1038/leu.2017.24.
PMCID:5462853
PMID: 28096535
ISSN: 1476-5551
CID: 2413872
Beating the Clock in T-Cell Acute Lymphoblastic Leukemia
CDK4/6 inhibition was synergistic with dexmethasome and everolimus but antagonistic with conventional chemotherapy in T-cell acute lymphoblastic leukemia (T-ALL) pre-clinical models. Cyclin dependent kinase inhibition in combination with glucocorticoids and mTOR inhibition offers a unique therapeutic opportunity in T-ALL.
PMID: 28007775
ISSN: 1078-0432
CID: 2374552
Advances in pediatric hematology/oncology
PMID: 27870690
ISSN: 1531-698x
CID: 2927232
Hematology (American Society of Hematology. Education Program). 2016:2016(1):580-588.DOI: 10.1182/asheducation-2016.1.580
T-cell acute lymphoblastic leukemia
T-cell acute lymphoblastic leukemia (T-ALL) is biologically distinct from its B lymphoblastic (B-ALL) counterpart and shows different kinetic patterns of disease response. Although very similar regimens are used to treat T-ALL and B-ALL, distinctions in response to different elements of therapy have been observed. Similar to B-ALL, the key prognostic determinant in T-ALL is minimal residual disease (MRD) response. Unlike B-ALL, other factors including age, white blood cell count at diagnosis, and genetics of the ALL blasts are not independently prognostic when MRD response is included. Recent insights into T-ALL biology, using modern genomic techniques, have identified a number of recurrent lesions that can be grouped into several targetable pathways, including Notch, Jak/Stat, PI3K/Akt/mTOR, and MAPK. With contemporary chemotherapy, outcomes for de novo T-ALL have steadily improved and now approach those observed in B-ALL, with approximately 85% 5-year event-free survival. Unfortunately, salvage has remained poor, with less than 25% event-free and overall survival rates for relapsed disease. Thus, current efforts are focused on preventing relapse by augmenting therapy for high-risk patients, sparing toxicity in favorable subsets and developing new approaches for the treatment of recurrent disease.
PMID: 27913532
ISSN: 1520-4383
CID: 2927222
The Genomic Landscape of T-Lineage Acute Lymphoblastic Leukemia [Meeting Abstract]
ISI:000384818800370
ISSN: 1545-5017
CID: 2385902
MLL rearrangements impact outcome in HOXA-deregulated T-lineage acute lymphoblastic leukemia: a Children's Oncology Group Study
PMCID:5014577
PMID: 26952838
ISSN: 1476-5551
CID: 2237792
Seven great achievements in pediatric research in the past 40 y
PMID: 27556199
ISSN: 1530-0447
CID: 2927242
A Pilot Study of Intensified PEG-Asparaginase in High-risk Acute Lymphoblastic Leukemia: Children's Oncology Group Study AALL08P1
AALL08P1 was designed to determine whether biweekly intensified pegaspargase (I-PEG) was feasible and safe in pediatric patients with newly diagnosed high-risk B-precursor lymphoblastic leukemia when given with Children's Oncology Group hemiaugmented BFM therapy. High-risk average (HR-Avg) patients received standard pegaspargase dosing (6 doses), whereas high-risk high (HR-High) patients received I-PEG biweekly from the start of Consolidation until day 1 of Maintenance. Feasibility and safety were defined in advance as >/=65% of patients tolerating at least 8 doses of I-PEG and 90% requiring /=8 total doses of I-PEG and 50% (15/30) took
PMCID:4955695
PMID: 27299599
ISSN: 1536-3678
CID: 2184802
Dexamethasone and High-Dose Methotrexate Improve Outcome for Children and Young Adults With High-Risk B-Acute Lymphoblastic Leukemia: A Report From Children's Oncology Group Study AALL0232
PURPOSE: Survival for children and young adults with high-risk B-acute lymphoblastic leukemia has improved significantly, but 20% to 25% of patients are not cured. Children's Oncology Group study AALL0232 tested two interventions to improve survival. PATIENTS AND METHODS: Between January 2004 and January 2011, AALL0232 enrolled 3,154 participants 1 to 30 years old with newly diagnosed high-risk B-acute lymphoblastic leukemia. By using a 2 x 2 factorial design, 2,914 participants were randomly assigned to receive dexamethasone (14 days) versus prednisone (28 days) during induction and high-dose methotrexate versus Capizzi escalating-dose methotrexate plus pegaspargase during interim maintenance 1. RESULTS: Planned interim monitoring showed the superiority of the high-dose methotrexate regimens, which exceeded the predefined boundary and led to cessation of enrollment in January 2011. At that time, participants randomly assigned to high-dose methotrexate during interim maintenance 1 versus those randomly assigned to Capizzi methotrexate had a 5-year event-free survival (EFS) of 82% versus 75.4% (P = .006). Mature final data showed 5-year EFS rates of 79.6% for high-dose methotrexate and 75.2% for Capizzi methotrexate (P = .008). High-dose methotrexate decreased both marrow and CNS recurrences. Patients 1 to 9 years old who received dexamethasone and high-dose methotrexate had a superior outcome compared with those who received the other three regimens (5-year EFS, 91.2% v 83.2%, 80.8%, and 82.1%; P = .015). Older participants derived no benefit from dexamethasone during induction and experienced excess rates of osteonecrosis. CONCLUSION: High-dose methotrexate is superior to Capizzi methotrexate for the treatment of high-risk B-acute lymphoblastic leukemia, with no increase in acute toxicity. Dexamethasone given during induction benefited younger children but provided no benefit and was associated with a higher risk of osteonecrosis among participants 10 years and older.
PMCID:4981974
PMID: 27114587
ISSN: 1527-7755
CID: 2092442
