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

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.

FIG 1.

T-ALL IF cohorts and outcome. (A) Seventy-one patients of the 711 patients with T-ALL on the UKALL2003 and UKALL2011 trials suffered IF. One patient withdrew consent and was excluded from further analyses, leaving 70 cases in the trial cohort. Thirty-five of these patients were included in the genomics cohort with an additional 13 nontrial IF cases. (B) Kaplan-Meier curve showing event-free survival for patients with IF versus those who achieved remission on the UKALL2003 and UKALL2011 trials. (C) Kaplan-Meier curve showing overall survival for patients with IF versus those who achieved remission on the UKALL2003 and UKALL2011 trials. ^aIncludes 16 UKALL 2003 patients in CR but with no details and one UKALL 2011 patient with no data postregistration submitted. ^bAny MRD. ^cRising WCC, switched treatment before D28. ^dAny MRD. BM, bone marrow; CR, complete remission; IF, induction failure; MRD, minimal residual disease; T-ALL, T-cell acute lymphoblastic leukemia; WCC, white cell count.

FIG 2.

Treatment of T-ALL IF. (A) Swimmer plot displaying postinduction treatment of patients with IF split by trial. Standard chemotherapy indicates standard trial treatment. Nelarabine indicates nelarabine given either alone or in combination with other agents. High-dose chemotherapy indicates other non–nelarabine-containing regimens, most commonly FLA-IDA. (B) Kaplan-Meier plot showing OS of patients treated with nelarabine versus those not treated with nelarabine. (C) Kaplan-Meier plot showing OS of patients who received SCT versus those who did not. The SCT group included 33 patients (one excluded as underwent SCT when not in remission). The no SCT group included all 31 patients who remitted and were alive and in remission on day 91 (the date of the earliest SCT). (D) Kaplan-Meier plot showing OS of patients with end-of-consolidation MRD more than 1% versus MRD < 1%. CR, complete remission; FLA-IDA, fludarabine, cytarabine, idarubicin chemotherapy; HSCT, hematopoietic stem-cell transplantation; IF, induction failure; MRD, minimal residual disease; OS, overall survival; SCT, stem-cell transplant; T-ALL, T-cell acute lymphoblastic leukemia.

FIG 3.

Phenotypic and genetic classification of T-ALL IF. (A) Proportion of flow cytometry–defined ETP phenotype in IF versus responsive cases. (B) Relationship between ETP status, genetic subgroup, and initiating genomic driver lesion. Note that all TAL1 cases co-occurred with either a LMO1 or LMO2 lesion, which is not shown in the figure. (C) Proportion of genetic subtypes in IF versus responsive cases of T-ALL. (D) Landscape of TAL1 driver lesion types in IF versus responsive cases of T-ALL. *P < .05, ***P < .001. ETP, early thymic progenitor; IF, induction failure; T-ALL, T-cell acute lymphoblastic leukemia.

FIG 4.

Mutational landscape of IF T-ALL. (A) Oncoplot showing somatic variants, ETP status, ABD status, outcome, and genetic subtype in IF T-ALL. (B) Frequency of mutations in IF versus responsive T-ALL. Names of genes showing a significant difference (P < .05) are in red. ABD, absence of biallelic deletion; ETP, early thymic progenitor; IF, induction failure; T-ALL, T-cell acute lymphoblastic leukemia.

FIG 5.

Genomic biomarkers of outcome in IF T-ALL. (A) Kaplan-Meier plot showing OS by genetic subtype. (B) Kaplan-Meier plot showing OS on the basis of the presence or absence of a mutation in the TAL1 gene or MYC or RAS pathways. IF, induction failure; OS, overall survival; T-ALL, T-cell acute lymphoblastic leukemia; TMR, TAL1/MYC/RAS.