In an analysis reported in the Journal of Clinical Oncology, O’Connor et al found that pediatric and young adult patients with T-cell acute lymphoblastic leukemia (T-ALL) who did not respond to induction therapy had poorer outcomes vs those with induction response. The investigators also attempted to identify factors associated with induction failure.
The study included data on patients with T-ALL from two consecutive UK/Irish trials (UKALL2003 and UKALL2011). Among 5,876 patients with ALL in the two studies, 711 (12.1%) had T-ALL; of these, 688 were assessed at end of induction.
Among 688 patients assessed at end of induction, induction failure occurred in 71 (10.3%). Event-free survival at 5 years was 84.0% in induction responders vs 47.9% in patients with induction failure (hazard ratio [HR] = 4.14, 95% confidence interval [CI] = 2.82–6.07, P < .001). Overall survival at 5 years was 90.2% vs 52.1% (HR = 6.38, 95% CI = 4.17–9.76, P < .001).
Increased use of nelarabine-based chemotherapy consolidated by hematopoietic stem cell transplantation (HSCT) in UKALL2011 was not associated with improved outcomes. In an analysis of treatment received, 5-year overall survival for patients who did vs did not receive nelarabine was 39.1% vs 59.2% (HR = 1.72, P =.11) and 5-year overall survival for those who did vs did not undergo HSCT was 52.8% vs 61.3% (HR = 1.23, P = .59).
Risk of induction failure increased with increasing age, occurring in 5.6% of patients aged < 10 years, 12.9% of those aged 10 to 16 years, and 20% of those aged > 16 years (overall P < .001).
On multivariate analysis among all patients, being on the higher end of the consolidation measurable residual disease (MRD) level was associated with poorer event-free survival (HR per 1 log increase = 1.30, P = .011). Patients with ≥ 1% end of consolidation had an increased risk of death (5-year overall survival = 14.3% vs 68.5%; HR = 4.10, P = .0071).
Genomic profiling showed heterogeneity of the genetic landscape in patients with induction failure, with 25 different initiating lesions converging on 10 subtype-defining genes. The relative proportion of genetic subtypes differed significantly between responsive and induction failure cases; induction failure was restricted to HOXA, TAL1, TLX3, and LMO2/LYL1 subtypes, with almost half of cases being of the HOXA subtype.
An abundance of TAL1 noncoding lesions were seen, with presence of these lesions being associated with a 5-year overall survival rate of 12.5%. Combination of TAL1 lesions with mutations in the MYC and RAS pathways yielded a genetic stratifier identifying patients likely to fail conventional therapy (5-year overall survival = 23.1% vs 86.4%; HR = 6.84, P < .0001); as noted by the investigators, such patients should be considered for experimental agents.
The investigators concluded, “The outcome of induction failure in T-ALL remains poor with current therapy. The lack of a unifying genetic driver suggests alternative approaches, particularly using immunotherapy, are urgently needed.”
David O’Connor, PhD, MBChB, of the Department of Haematology, UCL Cancer Institute, London, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by Blood Cancer UK, Cancer Research UK, and others. For full disclosures of the study authors, visit ascopubs.org.The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.