{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T12:59:03Z","timestamp":1791896343283,"version":"4.3.4"},"reference-count":41,"publisher":"American Society of Clinical Oncology (ASCO)","issue":"19","content-domain":{"domain":["ascopubs.org"],"crossmark-restriction":true},"short-container-title":["JCO"],"published-print":{"date-parts":[[2023,7,1]]},"abstract":"<jats:sec><jats:title>PURPOSE<\/jats:title><jats:p> 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). <\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p> 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. <\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p> 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 &lt; .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 &lt; .0001) and who should therefore be considered for experimental agents. <\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSION<\/jats:title><jats:p> 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. <\/jats:p><\/jats:sec>","DOI":"10.1200\/jco.22.02734","type":"journal-article","created":{"date-parts":[[2023,4,25]],"date-time":"2023-04-25T20:05:17Z","timestamp":1682453117000},"page":"3545-3556","update-policy":"https:\/\/doi.org\/10.1200\/crossmark","source":"Crossref","is-referenced-by-count":26,"title":["The Clinicogenomic Landscape of Induction Failure in Childhood and Young Adult T-Cell Acute Lymphoblastic Leukemia"],"prefix":"10.1200","volume":"41","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3542-5976","authenticated-orcid":false,"given":"David","family":"O'Connor","sequence":"first","affiliation":[{"name":"UCL Cancer Institute, University College London, London, United Kingdom"},{"name":"Department of Haematology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United 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