Document Type

Article

Publication Date

11-1-2016

Identifier

PMCID: PMC5446304 DOI: 10.1200/JCO.2016.66.9622

Abstract

Purpose Suboptimal outcomes for children with acute myeloid leukemia (AML) necessitate maximally intensive therapy. Consequently, serious adverse events, such as prolonged periods of profound myelosuppression, contribute to AML treatment-related mortality. Telomeres, the repetitive DNA-protein structures at chromosome ends, influence cellular replicative capacity in that critically short telomeres can induce cell senescence or apoptosis. Our objective was to evaluate the impact of telomere length on duration of post-therapy neutropenia in a pediatric AML cohort. Patients and Methods Patients were diagnosed with de novo AML, enrolled in Children's Oncology Group study AAML0531, and included those with (n = 53) and without (n = 62) significantly delayed neutrophil recovery after chemotherapy. We used quantitative polymerase chain reaction to measure telomere content (TC), a validated proxy for telomere length, from remission bone marrow samples obtained after the second induction chemotherapy course. Results Less TC was significantly associated with prolonged neutropenia after the fourth ( P < .001) and fifth chemotherapy courses ( P = .002). Cox regression adjusting for age at diagnosis confirmed that TC remained independently predictive of time to recovery of absolute neutrophil count for both the fourth and fifth courses ( P = .002 and .009, respectively). DNA from patients was analyzed for germline mutations in four telomere maintenance genes associated with telomere biology disorders. Sequence analysis revealed no enrichment of rare or novel variants in the delayed recovery group. Conclusion Our results suggest that TC at end of AML induction is associated with hematopoietic reconstitution capacity independently of age and may identify those at highest risk for markedly delayed bone marrow recovery after AML therapy.

Journal Title

Journal of clinical oncology : official journal of the American Society of Clinical Oncology

Volume

34

Issue

31

First Page

3766

Last Page

3772

MeSH Keywords

Acute Disease; Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cohort Studies; Female; Humans; Infant; Kaplan-Meier Estimate; Leukemia, Myeloid; Male; Neutrophils; Outcome Assessment (Health Care); Prognosis; Proportional Hazards Models; Remission Induction; Telomere

Keywords

AML

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