A clinicogenomic analysis of childhood and young adult T-cell acute lymphoblastic leukemia (T-ALL) confirmed poor outcomes despite treatment with chemotherapy and hematopoietic stem cell transplant (HSCT).

In addition, several alterations of noncoding areas and genes were associated with treatment failure and shorter survival, according to a study reported in the Journal of Clinical Oncology.

The cohort study analyzed data from 70 patients with T-ALL from the UKALL2003 and UKALL2011 trials whose disease failed induction therapy to characterize factors associated with outcomes. The overall rate of induction failure (IF) in these trials was 10.3%. A responsive cohort comprised 264 patients with T-ALL from the COG AALL0434 trial.

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IF was significantly associated with shorter overall survival (OS), with a 5-year rate of 52.1% compared with 90.2% among patients who responded in the trials (hazard ratio [HR], 6.38; 95% CI, 4.17-9.76; P <.001). Survival outcomes were not improved with nelarabine-based chemotherapy (HR, 1.72; 95% CI, 0.88-3.42; P =.11) or HSCT (HR, 1.23; 95% CI, 0.58-2.58; P =.59).

The genomic profile of the IF group was heterogenous. However, although the overall frequency of TAL1 alterations was lower in the IF group, the authors noted an abundance of noncoding alterations, which was significantly associated with a low 5-year OS of 12.5%. Patients with noncoding TAL1 mutations did not survive, and 2 did not achieve remission.

The combination of TAL1 alterations with MYC or RAS pathway mutations was significantly associated with shorter OS as well, with 5-year rates of 23.1% compared with 86.4% among patients without these genomic characteristics (HR, 6.84; 95% CI, 2.78-16.78; P <.0001).

Recurrent mutations were found in CHD4 and NuRD, both of which were not previously identified in T-ALL. “The lack of unifying genetic driver suggests alternate approaches, particularly using immunotherapy, are urgently needed,” the authors concluded.

Disclosures: Some study authors declared affiliations with biotech, pharmaceutical, or device companies. Please see the original reference for a full list of disclosures.

O’Connor D, Demeulemeester J, Conde L, et al. The Clinicogenomic landscape of induction failure in childhood and young adult T-cell acute lymphoblastic leukemia. J Clin Oncol. Published online April 25, 2023. doi: 10.1200/JCO.22.02734