The Clinicogenomic Landscape of Induction Failure in Childhood and Young Adult T-Cell Acute Lymphoblastic Leukemia

O&#39;Connor, D; Demeulemeester, J; Conde, L; Kirkwood, A; Fung, K; Papaleonidopoulou, F; Bloye, G; Farah, N; Rahman, S; Hancock, J; Bateman, C; Inglott, S; Mee, J; Herrero, J; Van Loo, P; Moorman, AV; Vora, A; Mansour, MR

Author(s): O'Connor, D; Demeulemeester, J; Conde, L; Kirkwood, A; Fung, K; Papaleonidopoulou, F; Bloye, G; Farah, N; Rahman, S; Hancock, J; Bateman, C; Inglott, S; Mee, J; Herrero, J; Van Loo, P; Moorman, AV; Vora, A; Mansour, MR;
Details: Publication Year 2023-07-01,Volume 41,Issue #19,Page 3545-3556
Journal Title: Journal of Clinical Oncology
Publication Type: Research article
Abstract: 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.
Publisher: American Society of Clinical Oncology
Keywords: Humans; Young Adult; Adolescent; *Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy; Treatment Outcome; *Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy/genetics; *Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy; *Hematopoietic Stem Cell Transplantation; T-Lymphocytes; Prognosis
Department(s): Laboratory Research
PubMed ID: 37098241
Publisher's Version: https://doi.org/10.1200/JCO.22.02734
Open Access at Publisher's Site: https://doi.org/10.1200/jco.22.02734
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2023-10-12 05:13:33

Last Modified: 2023-10-12 05:16:23