title: Effect of Recipient Age and Stem Cell Source on the Association between Donor Telomere Length and Survival after Allogeneic Unrelated Hematopoietic Cell Transplantation for Severe Aplastic Anemia.
abstract: We previously showed an association between donor leukocyte relative telomere length (RTL) and post-hematopoietic cell transplantation (HCT) survival in patients with severe aplastic anemia (SAA) who received bone marrow grafts at ages <40 years. Here, we tested the generalizability of the prior findings in an independent validation cohort and by recipient age and stem cell source in the combined discovery and validation cohorts. We used monoplex quantitative real-time PCR to measure RTL in: (1) a new SAA validation cohort of 428 patients (age range, .2 to 77 years) with available pretransplantation donor blood samples in the Center for International Blood and Marrow Transplant Research repository, and (2) 278 patients from the original cohort who had sufficient DNA to repeat RTL testing. We used Cox proportional hazard models to calculate hazard ratios (HRs), and 95% confidence intervals (CIs) across categories of donor RTL. Data from the validation cohort showed no association between donor RTL and patient survival, but further analysis identified differences by recipient age and stem cell source as the likely explanation. In patients <40 years, the HR comparing longest with shortest and middle RTL tertiles = .75; 95% CI,  .44 to 1.30 versus HR = 1.05; 95% CI, .59 to 1.89 for patients ≥40 years, P interaction = .37. In bone marrow recipients, the HR = .68; 95% CI, .72 to 1.10 versus HR = 1.29; 95% CI, .64 to 2.62 for peripheral blood stem cell grafts; P interaction = .88. Analyses using data from the 2 cohorts showed a statistically significant survival benefit only in <40-year-old patients receiving bone marrow graft (HR comparing longest and middle RTL tertiles with shortest = .69; 95% CI, .50 to .95, P = .02). The study suggested that the association between donor RTL and post-HCT outcomes in recipients with SAA may vary by recipient age and stem cell source. A larger study is needed to account for multiple comparisons and to further test the generalizability of our findings.
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland. Electronic address: gadallas@mail.nih.gov.
authors.forename: Shahinaz M
authors.initials: SM
authors.lastname: Gadalla
authors.affiliation: Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, Wisconsin; Division of Biostatistics, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland; Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland.
authors.forename: Casey
authors.initials: C
authors.lastname: Dagnall
authors.affiliation: Center for International Blood and Marrow Transplant Research, Minneapolis, Minnesota.
authors.forename: Michael
authors.initials: M
authors.lastname: Haagenson
authors.affiliation: Center for International Blood and Marrow Transplant Research, Minneapolis, Minnesota.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Spellman
authors.affiliation: Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland; Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland.
authors.forename: Belynda
authors.initials: B
authors.lastname: Hicks
authors.affiliation: Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland; Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland.
authors.forename: Kristine
authors.initials: K
authors.lastname: Jones
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.
authors.forename: Hormuzd A
authors.initials: HA
authors.lastname: Katki
authors.affiliation: Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, Wisconsin; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Savage
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000741:Anemia, Aplastic / Q000175:diagnosis / Q000401:mortality / Q000628:therapy*; D016026:Bone Marrow Transplantation / Q000379:methods / Q000401:mortality; D002648:Child; D002675:Child, Preschool; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods* / Q000401:mortality; D006801:Humans; D007223:Infant; D008875:Middle Aged; D011379:Prognosis; D060888:Real-Time Polymerase Chain Reaction; D013234:Stem Cells / Q000276:immunology*; D013534:Survival; D016615:Telomere / Q000648:ultrastructure*; D066027:Transplant Recipients; D061349:Unrelated Donors; D055815:Young Adult
keywords: Aplastic anemia; Donor selection; Hematopoietic cell transplantation; Survival; Telomere length