Meeting
2023 ASCO Annual Meeting
Genomic determinants of outcome in acute lymphoblastic leukemia: A Children’s Oncology Group study.
Authors
Ti-Cheng Chang
St. Jude Children’s Research Hospital, Memphis, TN
Ti-Cheng Chang , Wenan Chen , Abdelrahman Elsayed , Stanley B. Pounds , Mary Shago , Karen R. Rabin , Elizabeth A. Raetz , Meenakshi Devidas , Cheng Cheng , Anne L. Angiolillo , Andrew J. Carroll , Nyla A Heerema , Ilaria Iacobucci , Kelly W. Maloney , Ching-Hon Pui , Nilsa C. Ramirez , Stephen Hunger , Gang Wu , Charles Grenfell Mullighan , Mignon L. Loh
Organizations
St. Jude Children’s Research Hospital, Memphis, TN, St. Jude Children's Research Hospital, Memphis, TN, The Hospital for Sick Children, Toronto, ON, Canada, Texas Children's Cancer Center, Houston, TX, Perlmutter Cancer Center and NYU Langone, New York, NY, Children's National Medical Center, Washington, DC, Children's Hospital of Alabama, Birmingham, AL, Ohio State University in Columbus, Columbus, OH, Children's Hospital Colorado, Aurora, CO, Gynecologic Oncology Group Tissue Bank, Biopathology Center, Research Institute at Nationwide Children's Hospital, Columbus, OH, Children's Hospital of Philadelphia, Philadelphia, PA, Seattle Children's Hospital, Seattle, WA
Research Funding
U.S. National Institutes of Health
U.S. National Institutes of Health, St Baldrick’s Foundation, American Lebanese Syrian Associated Charities of St. Jude Children’s Research Hospital
Background: While cure rates for childhoodacute lymphoblastic leukemia (ALL) exceed 90%, half of relapses arise in those originally classified with standard risk (SR) disease. Methods: We performed genome/transcriptome sequencing of diagnostic and germline samples of children with SR (n=1381) B-ALL or high-risk (HR) B-ALL with favorable cytogenetics (ETV6:RUNX1 or double trisomy (DT) of chromosomes (chr) 4+10; n=115) to identify predictors of relapse. We used a case-control study to analyze 439 patients who relapsed and 1057 who remained in complete remission for > 5 years. Results: Genomic subtype was associated with relapse. Unbalanced ETV6:RUNX1 translocations were more common than balanced in relapse patients (OR=2.01, CI=1.25-3.20, P=0.002). Conversely, balanced TCF3:PBX1 translocations were more often associated with relapse than unbalanced in TCF3:PBX1 ALL (OR=0.11, CI=0.01-0.50, P=0.003). A striking finding was the high relapse rate in PAX5 altered ALL (57 of 116 cases (49%); OR=3.29, CI=2.16-5.01, P=3.49x10-8). The nature of the heterogeneous PAX5 driver alterations of this subtype influenced relapse risk, with internal PAX5 amplifications and biallelic PAX5 alterations associated with the highest risk. Specific chr gains influenced outcome in hyperdiploid ALL, with gain of chr 10 and disomy of chr 7 associated with favorable outcome (OR=0.27, CI=0.17-0.42, P=8.02x10-10, St Jude Children’s Research Hospital (SJCRH) validation cohort: OR=0.22, CI=0.05-0.80, P=0.009), while disomy of chr 10 and 17 and gain of chr 6 were enriched in patients that relapsed (OR=7.16, CI=2.63-21.51, P=2.19x10-5; SJCRH cohort: OR=21.32, CI=3.62-119.30, P=0.0004). Genomic alterations were also associated with relapse in a subtype-dependent manner, including alterations of INO80 in ETV6:RUNX1, IKZF1 and CREBBP in hyperdiploid, and FHIT in Ph-like ALL. Conclusions: Genetic subtype, aneuploidy patterns, and secondary genomic alterations influence risk of relapse in children otherwise classified with SR ALL, or HR ALL with favorable genetics. Comprehensive genomic analysis is required for optimal risk stratification and treatment allocation, and particularly to study reduction of therapy in the lowest risk patients.
| Genetic Driver | Odds Ratio | Confidence Interval | N (remission) | N (relapse) | p-value |
|---|---|---|---|---|---|
| ETV6:RUNX1 (557) | 1.00 | N/A | 428 | 129 | N/A |
| Hyperdiploid with DT (319) | 0.65 | 0.45-0.93 | 264 | 55 | 1.66×10⁻² |
| Hyperdiploid, no DT (195) | 1.75 | 1.21-2.51 | 129 | 66 | 2.79×10⁻³ |
| PAX5alt (116) | 3.29 | 2.16-5.01 | 59 | 57 | 3.49×10⁻⁸ |
| DUX4 (54) | 1.16 | 0.60-2.15 | 39 | 15 | 6.56×10⁻¹ |
| TCF3-PBX1 (54) | 1.39 | 0.73-2.53 | 37 | 17 | 3.04×10⁻¹ |
| B-Other (44) | 4.39 | 2.34-8.34 | 19 | 25 | 4.88×10⁻⁶ |
| ETV6:RUNX1-like (36) | 3.99 | 2.01-7.96 | 17 | 19 | 9.52×10⁻⁵ |
| Ph-like (36) | 2.14 | 1.04-4.28 | 22 | 14 | 3.82×10⁻² |
*Only subsets with > 35 cases are included; all compared to ETV6:RUNX1.
Disclaimer
This material on this page is ©2024 American Society of Clinical Oncology, all rights reserved. Licensing available upon request. For more information, please contact licensing@asco.org
Abstract Details
Session Type
Oral Abstract Session
Session Title
Pediatric Oncology II
Track
Pediatric Oncology
Sub Track
Leukemia/Lymphoma
Citation
J Clin Oncol 41, 2023 (suppl 16; abstr 10015)
DOI
10.1200/JCO.2023.41.16_suppl.10015
Abstract #
10015
Abstract Disclosures
Similar Abstracts
Abstract
2023 ASCO Annual Meeting
Mini-hyper-CVD with venetoclax (Ven) for patients with relapsed/refractory (R/R) Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL): A phase II study.
First Author: Marianne Zoghbi
Abstract
2023 ASCO Annual Meeting
Subgroup analysis from a phase II trial of ponatinib and blinatumomab in relapsed/refractory (R/R) Philadelphia chromosome-positive acute lymphoblastic leukemia or chronic myeloid leukemia in lymphoid blast phase.
First Author: Marianne Zoghbi
Abstract
2020 ASCO Virtual Scientific Program
Temsirolimus combined with etoposide and cyclophosphamide for relapsed/refractory acute lymphoblastic leukemia: Therapeutic advances in Childhood Leukemia Consortium (TACL 2014-001) trial.
First Author: Susan R. Rheingold
Abstract
2023 ASCO Annual Meeting
Low-intensity chemotherapy (mini-HCVD) and ponatinib followed by blinatumomab (blina) and ponatinib for the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL): A phase II study.
First Author: Lewis Fady Nasr