Gabriella Miller Kids First Pediatric Research Program in Pediatric T-Cell Acute Lymphoblastic Leukemia

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. Through the TARGET initiative, RNA sequencing (RNA-Seq), DNA copy number analysis, and whole-exome sequencing (WES) were performed on 264 T-ALL patients treated on AALL0434, demonstrating recurrent alterations could be grouped into 10 different potentially targetable functional pathways. This analysis was not powered to examine associations between genetic lesions with outcome, because too few patients with r/r disease were included. This project is dedicated to testing the hypothesis 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 (WGS) in T-ALL. This project also tests the hypothesis that WGS 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.These hypotheses are tested by performing comprehensive genomic profiling (WGS, WES, RNA-Seq, and copy number analysis) of the entire AALL0434 cohort with available samples 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 and to increased toxicity to chemotherapy.]]>
Approximately 1350 were selected for WGS, WES, and transcriptome profiling (RNA-Seq) of tumor DNA/RNA and WGS of germline DNA as part of the Gabriella Miller Kids First T-ALL project. 1545 eligible and evaluable patients with T-ALL were treated on the Children's Oncology Group (COG) phase 3 clinical trial AALL0434. Of the 1545, 1430 patients had available diagnostic and remission samples, and signed consent for future research. Of those, approximately 1350 samples had DNA and approximately 1040 samples had RNA that passed quality control for sequencing.]]>
The outcome for children with relapsed T-cell acute lymphoblastic leukemia (T-ALL) is dismal. Thus, the primary goal of T-ALL treatment is to prevent relapse, which requires accurate risk stratification. There are no known genetic alterations in childhood T-ALL that are reproducibly prognostic independent of minimal residual disease (MRD), making it difficult to ascertain at diagnosis which patients are more likely to relapse. AALL0434 was a Children's Oncology Group-initiated phase 3 randomized clinical trial for children and young adults with T-ALL. Survival on this study was superior to any prior trial for de novo T-ALL, and has changed the standard of care. Yet, a substantial minority (~15%) of patients had relapsed or refractory (r/r) disease. The long-term goal of this project is to enhance understanding of T-ALL disease biology in order to improve risk stratification, allowing integration of novel agents into front-line therapy and prevent relapse. In order to improve understanding of T-ALL biology, comprehensive genomic profiling of the entire AALL0434 cohort with available samples will be performed to 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. Approximately 1350 cases of T-ALL from children and young adults treated on AALL0434 were selected for WGS, WES, and transcriptome profiling (RNA-Seq) of tumor DNA/RNA and WGS of germline DNA as part of the Gabriella Miller Kids First T-ALL project. These patients were all treated at a COG institution. The COG is a National Cancer Institute supported clinical trials group. It is the world's largest organization devoted exclusively to childhood and adolescent cancer research. The COG unites more than 9,000 experts in childhood cancer at more than 200 leading children's hospitals, universities, and cancer centers across North America, Australia, New Zealand, and Europe in the fight against childhood cancer. 88.4% of patients enrolled on AALL0434 were treated in the US. The other children were treated in Canada (6.7%), Australia (3.7%), Switzerland (0.1%), and New Zealand (1.1%). ]]>