ATM germ line pathogenic variants affect outcomes in children with ataxia-telangiectasia and hematological malignancies

Abstract

AbstractAtaxia telangiectasia (AT) is an autosomal-recessive disorder caused by pathogenic variants (PVs) of the ATM gene. Children with AT are predisposed to hematological malignancies. We aimed to investigate their characteristics and outcomes in order to generate data-based treatment recommendations. In this multinational, observational study we report 202 patients aged ≤25 years with AT and hematological malignancies from 25 countries. Ninety-one patients (45%) presented with mature B-cell lymphomas, 82 (41%) with acute lymphoblastic leukemia/lymphoma, 21 (10%) with Hodgkin lymphoma, and 8 (4%) with other hematological malignancies. Four-year overall survival and event-free survival (EFS) were 50.8% (95% confidence interval [CI], 43.6-59.1) and 47.9% (95% CI, 40.8-56.2), respectively. Cure rates have not significantly improved over the last 4 decades (P = .76). The major cause of treatment failure was treatment-related mortality (TRM) with a 4-year cumulative incidence of 25.9% (95% CI, 19.5-32.4). Germ line ATM PVs were categorized as null or hypomorphic, and patients with available genetic data (n = 110) were classified as having absent (n = 81) or residual (n = 29) ATM kinase activity. Four-year EFS was 39.4% (95% CI, 29-53.3) vs 78.7% (95% CI, 63.7-97.2; P < .001), and TRM rates were 37.6% (95% CI, 26.4-48.7) vs 4.0% (95% CI, 0-11.8; P = .017) for those with absent and residual ATM kinase activity, respectively. Absence of ATM kinase activity was independently associated with decreased EFS (hazard ratio [HR], 0.362; 95% CI, 0.16-0.82; P = .009) and increased TRM (HR, 14.11; 95% CI, 1.36-146.31; P = .029). Patients with AT and leukemia/lymphoma may benefit from deescalated therapy for patients with absent ATM kinase activity and near-standard therapy regimens for those with residual kinase activity.