Grant Details
Grant Number: |
1R03CA256550-01 Interpret this number |
Primary Investigator: |
Teachey, David |
Organization: |
Children'S Hosp Of Philadelphia |
Project Title: |
Genomic Profiling of T-Cell Acute Lymphoblastic Leukemia in Children |
Fiscal Year: |
2021 |
Abstract
PROJECT SUMMARY/ABSTRACT
The outcome for patients with relapsed T-ALL is dismal with 3-year event free survival of <15%. Thus, the primary
goal in the treatment of T-ALL is to prevent relapse, which requires accurate risk stratification. Unfortunately, no
genetic alterations have been identified to date that are reproducibly prognostic independent of minimal residual
disease (MRD), making it difficult at diagnosis to identify which patients are more likely to relapse. AALL0434
was a Children's Oncology Group-initiated phase 3 randomized clinical trial comparing Capizzi-style escalating
methotrexate plus pegaspargase (CMTX) vs. high dose methotrexate (HDMTX), with/without six 5-day courses
of nelarabine. Survival on this study was superior to any prior trial for de novo T-ALL, changing the standard of
care. Yet, a substantial minority (~15%) of patients had relapsed or refractory (r/r) disease. Our group recently
received an X01/Gabriella Miller Kids First award to perform comprehensive genomic profiling on 1262 cases of
T-ALL treated on the AALL0434 clinical trial (1X01HD100702-01). This includes whole genome sequencing
(WGS), whole exome sequencing (WES), and transcriptome profiling (RNAseq) of tumor and WGS of germline.
We have separately performed copy number analysis (SNP) on germline samples that will be integrated with
this work. We hypothesize that comprehensive genomic profiling of the entire AALL0434 cohort will identify
recurrent genetic alterations that can be segregated into biologically relevant deregulated pathways that can be
combined with MRD to identify patients at risk for poor outcomes before they relapse and provide rationale for
treatment with alternative therapies. In addition, a number of small recent studies demonstrated that many of the
biologically relevant alterations in T-ALL occur in non-coding regions of the genome, but no large studies have
performed whole genome sequencing in T-ALL. We further hypothesize that whole genome sequencing of a
large cohort of patients with T-ALL will identify novel lesions in coding and non-coding regions that will be highly
impactful in the understanding of T-ALL pathogenesis. We will test our hypotheses with the following specific
aims: (1) identify recurrent genetic alterations that predict poor outcome in T-ALL; (2) identify novel alterations,
including non-coding alterations in T-ALL; and (3) identify germline genetic variants that predispose to T-ALL.
The goal of the Kids First Program is improve understanding of genetic mechanisms of disease, leading to
improved diagnostic capabilities and ultimately more targeted therapies or interventions. This proposal will meet
that important goal through identification of germline and somatic alterations in T-ALL that can be used to identify
patients that are likely to relapse before they relapse and can be treated with new therapies.
Publications
Identification and targeting of treatment resistant progenitor populations in T-cell Acute Lymphoblastic Leukemia.
Authors: Tan K.
, Xu J.
, Chen C.
, Vincent T.
, Pölönen P.
, Hu J.
, Yoshimura S.
, Yu W.
, Sussman J.
, Chen C.H.
, et al.
.
Source: Research square, 2023-10-30; , .
EPub date: 2023-10-30.
PMID: 37961674
Related Citations
Central nervous system status is prognostic in T-cell acute lymphoblastic leukemia: a Children's Oncology Group report.
Authors: Gossai N.P.
, Devidas M.
, Chen Z.
, Wood B.L.
, Zweidler-McKay P.A.
, Rabin K.R.
, Loh M.L.
, Raetz E.A.
, Winick N.J.
, Burke M.J.
, et al.
.
Source: Blood, 2023-04-13; 141(15), p. 1802-1811.
PMID: 36603187
Related Citations
SOHO State of the Art Updates and Next Questions | Novel Approaches to Pediatric T-cell ALL and T-Lymphoblastic Lymphoma.
Authors: Summers R.J.
, Teachey D.T.
.
Source: Clinical lymphoma, myeloma & leukemia, 2022 Oct; 22(10), p. 718-725.
EPub date: 2022-07-20.
PMID: 35941070
Related Citations
Comprehensive Serum Proteome Profiling of Cytokine Release Syndrome and Immune Effector Cell-Associated Neurotoxicity Syndrome Patients with B-Cell ALL Receiving CAR T19.
Authors: Diorio C.
, Shraim R.
, Myers R.
, Behrens E.M.
, Canna S.
, Bassiri H.
, Aplenc R.
, Burudpakdee C.
, Chen F.
, DiNofia A.M.
, et al.
.
Source: Clinical cancer research : an official journal of the American Association for Cancer Research, 2022-09-01; 28(17), p. 3804-3813.
PMID: 35705524
Related Citations
Rational drug combinations with CDK4/6 inhibitors in acute lymphoblastic leukemia.
Authors: Bride K.L.
, Hu H.
, Tikhonova A.
, Fuller T.J.
, Vincent T.L.
, Shraim R.
, Li M.M.
, Carroll W.L.
, Raetz E.A.
, Aifantis I.
, et al.
.
Source: Haematologica, 2022-08-01; 107(8), p. 1746-1757.
EPub date: 2022-08-01.
PMID: 34937317
Related Citations
Children's Oncology Group Trial AALL1231: A Phase III Clinical Trial Testing Bortezomib in Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia and Lymphoma.
Authors: Teachey D.T.
, Devidas M.
, Wood B.L.
, Chen Z.
, Hayashi R.J.
, Hermiston M.L.
, Annett R.D.
, Archer J.H.
, Asselin B.L.
, August K.J.
, et al.
.
Source: Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2022-07-01; 40(19), p. 2106-2118.
EPub date: 2022-03-10.
PMID: 35271306
Related Citations
Potential Role of IFNγ Inhibition in Refractory Cytokine Release Syndrome Associated with CAR T-cell Therapy.
Authors: McNerney K.O.
, DiNofia A.M.
, Teachey D.T.
, Grupp S.A.
, Maude S.L.
.
Source: Blood cancer discovery, 2022-03-01; 3(2), p. 90-94.
PMID: 35015687
Related Citations