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.

Decoding the genetic symphony: Profiling protein-coding and long noncoding RNA expression in T-acute lymphoblastic leukemia for clinical insights

“…It is more prevalent in males than in females ( 1 ). Although the prognosis of T-ALL has improved considerably over the years, the outcomes remain inferior to those of B-lineage ALL, particularly in relapsed and refractory settings ( 4 ).…”

Focal Deletions of a Promoter Tether Activate theIRX3Oncogene in T Cell Acute Lymphoblastic Leukemia

“…T-ALL exhibits archetypal cancer phenotypes including arrested cellular differentiation and replicative immortality of T cell progenitors following acquisition of somatic mutations (25)(26)(27). Additionally patients with refractory disease or those that relapse after induction chemotherapy have poor prognosis (28,29). Although most T-ALL oncogenes TAL1, LMO2, TLX1, TLX3, NKX2-1 and MYB are ectopically expressed by well characterized mechanisms of oncogene activation, some oncogenes are aberrantly expressed with no known genetic lesion, and thus provide an opportunity for the discovery of novel mechanisms of oncogene activation (30,31).…”