Shorter Remission Telomere Length Predicts Delayed Neutrophil Recovery After Acute Myeloid Leukemia Therapy: A Report From the Children’s Oncology Group

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.

Bone marrow mononuclear cell telomere length in acute myeloid leukaemia and high‐risk myelodysplastic syndrome

“…However, this difference did not explain the association between telomere length and age at diagnosis. In contrast, after achieving remission, the association between telomere length and age at remission was not different from the association between telomere length and age in the general population, as has been shown previously . At relapse, there was no association between telomere length and age.…”

“…In another study (n = 187), long telomere length at diagnosis was associated with low‐risk disease and a high extent of the increase in telomere length from diagnosis to remission was associated with improved overall survival in acute promyelocytic leukaemia (APL) patients . In a study of 97 children and young adults with AML, shorter telomere length after chemotherapy induction was associated with a delay in neutrophil recovery in later chemotherapy courses . Two studies did not detect any prognostic information in telomere length, one examining AML patients at diagnosis (n = 137) and one examining AML patients at remission (n = 396) …”

Relative Telomere Length before Hematopoietic Cell Transplantation and Outcome after Unrelated Donor Hematopoietic Cell Transplantation for Acute Leukemia

“…For example, in a study of 97 pediatric and young adults with AML, shorter telomere length after chemotherapy induction was associated with a delay in neutrophil recovery in later chemotherapy courses(11). In a single center study of 178 patients who underwent myeloablative matched sibling HCT, mainly for hematological malignancy, longer recipient pre-HCT telomere length was associated with a lower risk of treatment related mortality (TRM) (HR=0.4, 95% CI = 0.2–0.8), but no other outcome (12).…”

Severe therapy‐related toxicities after treatment for Hodgkin lymphoma due to a pathogenic TERT variant and shortened telomeres

“…We propose that much of the excessive toxicity our patient experienced may have been attributed to her shortened telomeres and telomerase deficiency. She demonstrated slow marrow reconstitution following chemotherapy, likely due to ineffective hematopoiesis, comparable to children with AML with shortened TL after intensive chemotherapy . Her progressive BM changes 33 months following completion of therapy may be a prelude of BM failure or MDS as frequently observed in patients with a TBD .…”