PMID- 37098241 OWN - NLM STAT- MEDLINE DCOM- 20230630 LR - 20240320 IS - 1527-7755 (Electronic) IS - 0732-183X (Print) IS - 0732-183X (Linking) VI - 41 IP - 19 DP - 2023 Jul 1 TI - The Clinicogenomic Landscape of Induction Failure in Childhood and Young Adult T-Cell Acute Lymphoblastic Leukemia. PG - 3545-3556 LID - 10.1200/JCO.22.02734 [doi] AB - PURPOSE: Failure to respond to induction chemotherapy portends a poor outcome in childhood acute lymphoblastic leukemia (ALL) and is more frequent in T-cell ALL (T-ALL) than B-cell ALL. We aimed to address the limited understanding of clinical and genetic factors that influence outcome in a cohort of patients with T-ALL induction failure (IF). METHODS: We studied all cases of T-ALL IF on two consecutive multinational randomized trials, UKALL2003 and UKALL2011, to define risk factors, treatment, and outcomes. We performed multiomic profiling to characterize the genomic landscape. RESULTS: IF occurred in 10.3% of cases and was significantly associated with increasing age, occurring in 20% of patients age 16 years and older. Five-year overall survival (OS) rates were 52.1% in IF and 90.2% in responsive patients (P < .001). Despite increased use of nelarabine-based chemotherapy consolidated by hematopoietic stem-cell transplant in UKALL2011, there was no improvement in outcome. Persistent end-of-consolidation molecular residual disease resulted in a significantly worse outcome (5-year OS, 14.3% v 68.5%; HR, 4.10; 95% CI, 1.35 to 12.45; P = .0071). Genomic profiling revealed a heterogeneous picture with 25 different initiating lesions converging on 10 subtype-defining genes. There was a remarkable abundance of TAL1 noncoding lesions, associated with a dismal outcome (5-year OS, 12.5%). Combining TAL1 lesions with mutations in the MYC and RAS pathways produces a genetic stratifier that identifies patients highly likely to fail conventional therapy (5-year OS, 23.1% v 86.4%; HR, 6.84; 95% CI, 2.78 to 16.78; P < .0001) and who should therefore be considered for experimental agents. CONCLUSION: The outcome of IF in T-ALL remains poor with current therapy. The lack of a unifying genetic driver suggests alternative approaches, particularly using immunotherapy, are urgently needed. FAU - O'Connor, David AU - O'Connor D AUID- ORCID: 0000-0003-3542-5976 AD - UCL Cancer Institute, University College London, London, United Kingdom. AD - Department of Haematology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom. FAU - Demeulemeester, Jonas AU - Demeulemeester J AUID- ORCID: 0000-0002-2660-2478 AD - The Francis Crick Institute, London, United Kingdom. AD - VIB-KU Leuven Center for Cancer Biology, Leuven, Belgium. AD - Department of Oncology, Laboratory for Integrative Cancer Genomics, KU Leuven, Leuven, Belgium. FAU - Conde, Lucia AU - Conde L AUID- ORCID: 0000-0001-5180-543X AD - UCL Cancer Institute, University College London, London, United Kingdom. FAU - Kirkwood, Amy AU - Kirkwood A AD - CR UK & UCL Cancer Trials Centre, UCL Cancer Institute, UCL, London, United Kingdom. FAU - Fung, Kent AU - Fung K AUID- ORCID: 0000-0002-5797-1268 AD - UCL Cancer Institute, University College London, London, United Kingdom. FAU - Papaleonidopoulou, Foteini AU - Papaleonidopoulou F AUID- ORCID: 0000-0001-9955-9477 AD - UCL Cancer Institute, University College London, London, United Kingdom. AD - The Francis Crick Institute, London, United Kingdom. FAU - Bloye, Gianna AU - Bloye G AUID- ORCID: 0009-0006-3478-9937 AD - UCL Cancer Institute, University College London, London, United Kingdom. FAU - Farah, Nadine AU - Farah N AUID- ORCID: 0000-0002-3945-9981 AD - UCL Cancer Institute, University College London, London, United Kingdom. FAU - Rahman, Sunniyat AU - Rahman S AUID- ORCID: 0000-0001-5374-7376 AD - UCL Cancer Institute, University College London, London, United Kingdom. AD - Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. AD - Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia. FAU - Hancock, Jeremy AU - Hancock J AD - South West Genomic Laboratory Hub, North Bristol NHS Trust, Bristol, United Kingdom. FAU - Bateman, Caroline AU - Bateman C AUID- ORCID: 0000-0003-2759-8279 AD - The Children's Hospital at Westmead, Sydney, NSW, Australia. FAU - Inglott, Sarah AU - Inglott S AD - Department of Haematology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom. FAU - Mee, Jon AU - Mee J AD - Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham, United Kingdom. FAU - Herrero, Javier AU - Herrero J AUID- ORCID: 0000-0001-7313-717X AD - UCL Cancer Institute, University College London, London, United Kingdom. FAU - Van Loo, Peter AU - Van Loo P AD - The Francis Crick Institute, London, United Kingdom. AD - Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX. AD - Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX. FAU - Moorman, Anthony V AU - Moorman AV AUID- ORCID: 0000-0002-9781-6107 AD - Wolfson Childhood Cancer Centre, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom. FAU - Vora, Ajay AU - Vora A AUID- ORCID: 0000-0002-2167-4368 AD - Department of Haematology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom. FAU - Mansour, Marc R AU - Mansour MR AD - UCL Cancer Institute, University College London, London, United Kingdom. AD - Department of Developmental Biology and Cancer, UCL Great Ormond Street Institute of Child Health, London, United Kingdom. LA - eng GR - 15014/LLR_/Blood Cancer UK/United Kingdom GR - 27177/CRUK_/Cancer Research UK/United Kingdom GR - C416/A25145/CRUK_/Cancer Research UK/United Kingdom GR - 12026/LLR_/Blood Cancer UK/United Kingdom GR - FC001202/ARC_/Arthritis Research UK/United Kingdom GR - MRC_/Medical Research Council/United Kingdom GR - A27177/CRUK_/Cancer Research UK/United Kingdom GR - WT_/Wellcome Trust/United Kingdom GR - 25354/CRUK_/Cancer Research UK/United Kingdom GR - 10060/LLR_/Blood Cancer UK/United Kingdom PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230425 PL - United States TA - J Clin Oncol JT - Journal of clinical oncology : official journal of the American Society of Clinical Oncology JID - 8309333 SB - IM MH - Humans MH - Young Adult MH - Adolescent MH - *Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy MH - Treatment Outcome MH - *Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy/genetics MH - *Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy MH - *Hematopoietic Stem Cell Transplantation MH - T-Lymphocytes MH - Prognosis PMC - PMC10306434 COIS- The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). EDAT- 2023/04/25 18:42 MHDA- 2023/06/30 06:43 PMCR- 2023/04/25 CRDT- 2023/04/25 16:12 PHST- 2023/06/30 06:43 [medline] PHST- 2023/04/25 18:42 [pubmed] PHST- 2023/04/25 16:12 [entrez] PHST- 2023/04/25 00:00 [pmc-release] AID - JCO.22.02734 [pii] AID - 10.1200/JCO.22.02734 [doi] PST - ppublish SO - J Clin Oncol. 2023 Jul 1;41(19):3545-3556. doi: 10.1200/JCO.22.02734. Epub 2023 Apr 25.