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Author Spotlight: Deciphering the Role of ATM in Ataxia-Telangiectasia and the Associated Cerebellar Degeneration
Published on: December 27, 2024
ATM germ line pathogenic variants affect outcomes in children with ataxia-telangiectasia and hematological
Sarah Elitzur1, Ruth Shiloh1,2, Jan L C Loeffen3
1Department of Pediatric Hematology and Oncology, Schneider Children's Medical Center and Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Insights
Children with Ataxia-Telangiectasia (A-T) and hematological malignancies have poor survival. ATM kinase activity levels significantly impact outcomes, suggesting tailored treatment strategies based on genetic profiles are crucial for improving event-free survival and reducing treatment-related mortality.
Area of Science:
- Oncology
- Genetics
- Pediatrics
Background:
- Ataxia-Telangiectasia (A-T) is an inherited disorder caused by pathogenic variants (PVs) in the ATM gene.
- A-T predisposes children to hematological malignancies, including lymphomas and acute lymphoblastic leukemia/lymphoma.
- Current treatment strategies and outcomes for pediatric A-T patients with hematological malignancies require further investigation.
Purpose of the Study:
- To investigate the characteristics and outcomes of pediatric patients with Ataxia-Telangiectasia and hematological malignancies.
- To generate data-based treatment recommendations tailored to the genetic profiles of these patients.
- To assess the impact of ATM kinase activity on survival and treatment-related mortality.
Main Methods:
- A multinational, observational study involving 202 patients aged ≤25 years with A-T and hematological malignancies from 25 countries.
- Classification of hematological malignancies, including mature B-cell lymphomas, acute lymphoblastic leukemia/lymphoma, and Hodgkin lymphoma.
- Categorization of germline ATM PVs into null or hypomorphic, and classification of patients based on absent or residual ATM kinase activity.
Main Results:
- Four-year overall survival was 50.8% and event-free survival (EFS) was 47.9%.
- Treatment-related mortality (TRM) was a major cause of treatment failure, with a four-year cumulative incidence of 25.9%.
- Patients with absent ATM kinase activity had significantly worse EFS (39.4%) and higher TRM (37.6%) compared to those with residual activity (EFS 78.7%, TRM 4.0%).
Conclusions:
- Survival rates for pediatric patients with A-T and hematological malignancies have not improved significantly over four decades.
- Absence of ATM kinase activity is independently associated with decreased EFS and increased TRM.
- De-escalated therapy for patients with absent ATM kinase activity and near-standard regimens for those with residual ATM kinase activity may improve outcomes.
Abstract:
Ataxia-telangiectasia (A-T) is an autosomal-recessive disorder caused by pathogenic variants (PVs) of the ATM gene, predisposing children to hematological malignancies. We investigated their characteristics and outcomes to generate data-based treatment recommendations. In this multinational, observational study we report 202 patients aged ≤25 years with A-T 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 four decades (P = .76). The major cause of treatment failure was treatment-related mortality (TRM) with a four-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 (HR = 0.362, 95% CI, 0.16-0.82; P = .009) and increased TRM (hazard ratio [HR] = 14.11, 95% CI, 1.36-146.31; P = .029). Patients with A-T 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.
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