title: 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.
authors.affiliation: Robert B. Gerbing and Todd A. Alonzo, Children's Oncology Group, Monrovia; Todd A. Alonzo, University of Southern California, Los Angeles, CA; Lillian Sung, Hospital for Sick Children, Toronto, Ontario, Canada; Alan S. Gamis, Children's Mercy Hospitals and Clinics, Kansas City, MO; Soheil Meshinchi, University of Washington School of Medicine, Seattle, WA; and Sharon E. Plon, Alison A. Bertuch, and Maria M. Gramatges, Baylor College of Medicine, Houston, TX.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Gerbing
authors.affiliation: Robert B. Gerbing and Todd A. Alonzo, Children's Oncology Group, Monrovia; Todd A. Alonzo, University of Southern California, Los Angeles, CA; Lillian Sung, Hospital for Sick Children, Toronto, Ontario, Canada; Alan S. Gamis, Children's Mercy Hospitals and Clinics, Kansas City, MO; Soheil Meshinchi, University of Washington School of Medicine, Seattle, WA; and Sharon E. Plon, Alison A. Bertuch, and Maria M. Gramatges, Baylor College of Medicine, Houston, TX.
authors.forename: Todd A
authors.initials: TA
authors.lastname: Alonzo
authors.affiliation: Robert B. Gerbing and Todd A. Alonzo, Children's Oncology Group, Monrovia; Todd A. Alonzo, University of Southern California, Los Angeles, CA; Lillian Sung, Hospital for Sick Children, Toronto, Ontario, Canada; Alan S. Gamis, Children's Mercy Hospitals and Clinics, Kansas City, MO; Soheil Meshinchi, University of Washington School of Medicine, Seattle, WA; and Sharon E. Plon, Alison A. Bertuch, and Maria M. Gramatges, Baylor College of Medicine, Houston, TX.
authors.forename: Lillian
authors.initials: L
authors.lastname: Sung
authors.affiliation: Robert B. Gerbing and Todd A. Alonzo, Children's Oncology Group, Monrovia; Todd A. Alonzo, University of Southern California, Los Angeles, CA; Lillian Sung, Hospital for Sick Children, Toronto, Ontario, Canada; Alan S. Gamis, Children's Mercy Hospitals and Clinics, Kansas City, MO; Soheil Meshinchi, University of Washington School of Medicine, Seattle, WA; and Sharon E. Plon, Alison A. Bertuch, and Maria M. Gramatges, Baylor College of Medicine, Houston, TX.
authors.forename: Alan S
authors.initials: AS
authors.lastname: Gamis
authors.affiliation: Robert B. Gerbing and Todd A. Alonzo, Children's Oncology Group, Monrovia; Todd A. Alonzo, University of Southern California, Los Angeles, CA; Lillian Sung, Hospital for Sick Children, Toronto, Ontario, Canada; Alan S. Gamis, Children's Mercy Hospitals and Clinics, Kansas City, MO; Soheil Meshinchi, University of Washington School of Medicine, Seattle, WA; and Sharon E. Plon, Alison A. Bertuch, and Maria M. Gramatges, Baylor College of Medicine, Houston, TX.
authors.forename: Soheil
authors.initials: S
authors.lastname: Meshinchi
authors.affiliation: Robert B. Gerbing and Todd A. Alonzo, Children's Oncology Group, Monrovia; Todd A. Alonzo, University of Southern California, Los Angeles, CA; Lillian Sung, Hospital for Sick Children, Toronto, Ontario, Canada; Alan S. Gamis, Children's Mercy Hospitals and Clinics, Kansas City, MO; Soheil Meshinchi, University of Washington School of Medicine, Seattle, WA; and Sharon E. Plon, Alison A. Bertuch, and Maria M. Gramatges, Baylor College of Medicine, Houston, TX.
authors.forename: Sharon E
authors.initials: SE
authors.lastname: Plon
authors.affiliation: Robert B. Gerbing and Todd A. Alonzo, Children's Oncology Group, Monrovia; Todd A. Alonzo, University of Southern California, Los Angeles, CA; Lillian Sung, Hospital for Sick Children, Toronto, Ontario, Canada; Alan S. Gamis, Children's Mercy Hospitals and Clinics, Kansas City, MO; Soheil Meshinchi, University of Washington School of Medicine, Seattle, WA; and Sharon E. Plon, Alison A. Bertuch, and Maria M. Gramatges, Baylor College of Medicine, Houston, TX.
authors.forename: Alison A
authors.initials: AA
authors.lastname: Bertuch
authors.affiliation: Robert B. Gerbing and Todd A. Alonzo, Children's Oncology Group, Monrovia; Todd A. Alonzo, University of Southern California, Los Angeles, CA; Lillian Sung, Hospital for Sick Children, Toronto, Ontario, Canada; Alan S. Gamis, Children's Mercy Hospitals and Clinics, Kansas City, MO; Soheil Meshinchi, University of Washington School of Medicine, Seattle, WA; and Sharon E. Plon, Alison A. Bertuch, and Maria M. Gramatges, Baylor College of Medicine, Houston, TX.
authors.forename: Maria M
authors.initials: MM
authors.lastname: Gramatges
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007223:Infant; D053208:Kaplan-Meier Estimate; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D017063:Outcome Assessment, Health Care / Q000379:methods / Q000706:statistics & numerical data; D011379:Prognosis; D016016:Proportional Hazards Models; D012074:Remission Induction; D016615:Telomere / Q000187:drug effects* / Q000235:genetics