Donor Telomere Length Predicts Recipient Survival after Allogeneic Hematopoietic Cell Transplantation in Patients with Bone Marrow Failure Syndromes

Background. Telomeres are long nucleotide repeats and an associated protein complex at chromosome ends essential for chromosomal stability. They shorten with every cell division and thus are a marker of cellular replicative capacity. We hypothesized that telomere length may be a predictive marker for outcomes after hematopoietic cell transplantation (HCT).

Method. We used quantitative PCR (qPCR) to measure pre-transplant relative telomere length (RTL) in blood DNA of 342 young recipients (median age=14 yr; range=0.5–39) and their matched unrelated donors (median age=36 yr; range=19-61). HCTs were performed for marrow failure syndromes between 1989 and 2007 and reported to the Center for International Blood and Marrow Transplant Research (CIBMTR), and the National Marrow Donor Program (NMDP). The log-rank test was used to compare survival across RTL categories. For multivariable models, we used Cox proportional hazard models and calculated hazard ratios (HR) and 95% confidence intervals (CI) comparing outcome across RTL categories.

Results. Patients were followed for up to 20 years (median=6.3 years; range=0.5–20.7), with an overall survival (OS) probability at 3 years of 49% (44-55).  There were 243 (71%) with severe aplastic anemia, 87 (25%) with Fanconi anemia, and 12 (4%) with Diamond Blackfan anemia. Pre-transplant RTL in the recipients was not associated with post-transplant outcomes, including OS (3-year survival probability=51% and 46%, in RTL ≥25% percentile and <25^th percentile-for age, respectively; p=0.76); acute (p=0.53 at 100 days) or chronic GVHD (p=0.99 at 1 year) and neutrophil engraftment (p=0.48). Pre-transplant donor RTL was a significant predictor for OS after HCT, with longer donor telomere length associated with improved survival (3 year OS 59%, 49%, and 38%, in the longest, intermediate, and shortest tertiles, respectively; p=0.006). No association between donor RTL and either acute or chronic GVHD or engraftment was observed. Donor RTL was correlated with age (R²=0.12, p<0.0001), but after adjusting for donor age and factors known to influence patient survival after HCT (such as prior treatment and time between diagnosis and transplant), donor RTL remained a statistically significant predictor for recipient survival (HR=0.63, 95% CI=0.45-0.87, p=0.006 for longest tertile compared to the intermediate and shortest tertiles)(fig). There was no significant interaction between donor RTL and the patient's underlying disease. Results were similar when the analysis was limited to the severe aplastic anemia group.

Conclusions. Our data suggest that longer donor telomere lengths are significantly associated with improved OS after HCT for marrow failure syndromes, independent of donor age. Additional studies of post-HCT donor telomere dynamics are required to further explain this observation.