Association between donor leukocyte telomere length and survival after unrelated allogeneic hematopoietic cell transplantation for severe aplastic anemia

Abstract

Importance: Telomeres protect chromosome ends and are markers of cellular aging and replicative capacity.

Objective: To evaluate the association between recipient and donor pretransplant leukocyte telomere length with outcomes after unrelated donor allogeneic hematopoietic cell transplantation (HCT) for patients with severe aplastic anemia.

Design, participants, and setting: The study included 330 patients (235 acquired, 85 Fanconi anemia, and 10 Diamond-Blackfan anemia) and their unrelated donors who had pre-HCT blood samples and clinical and outcome data available at the Center for International Blood and Marrow Transplant Research. Patients underwent HCT between 1989 and 2007 in 84 centers and were followed-up to March 2013.

Exposures: Recipient and donor pre-HCT leukocyte telomere length classified into long (third tertile) and short (first and second tertiles combined) based on donor telomere length distribution.

Main outcomes and measures: Overall survival, neutrophil recovery, and acute and chronic graft-vs-host disease, as ascertained by transplant centers through regular patient follow-up.

Results: Longer donor leukocyte telomere length was associated with higher survival probability (5-year overall survival, 56%; number at risk, 57; cumulative deaths, 50) than shorter donor leukocyte telomere length (5-year overall survival, 40%; number at risk, 71; cumulative deaths, 128; P = .009). The association remained statistically significant after adjusting for donor age, disease subtype, Karnofsky performance score, graft type, HLA matching, prior aplastic anemia therapy, race/ethnicity, and calendar year of transplant (hazard ratio [HR], 0.61; 95% CI, 0.44-0.86). Similar results were noted in analyses stratified on severe aplastic anemia subtype, recipient age, HLA matching, calendar year of transplant, and conditioning regimen. There was no association between donor telomere length and neutrophil engraftment at 28 days (cumulative incidence, 86% vs 85%; HR, 0.94; 95% CI, 0.73-1.22), acute graft-vs-host disease grades III-IV at 100 days (cumulative incidence, 22% vs 28%; HR, 0.77; 95% CI, 0.48-1.23), or chronic graft-vs-host disease at 1-year (cumulative incidence, 28% vs 30%; HR, 0.81; 95% CI, 0.53-1.24) for long vs short, respectively. Pretransplant leukocyte telomere length in the recipients was not associated with posttransplant survival (HR, 0.91; 95% CI, 0.64-1.30).

Conclusions and relevance: Longer donor leukocyte telomere length was associated with increased 5-year survival in patients who received HCT for severe aplastic anemia. Patient leukocyte telomere length was not associated with survival. The results of this observational study suggest that donor leukocyte telomere length may have a role in long-term posttransplant survival.

Figure 1

The probability of overall survival after hematopoietic cell transplant for patients with severe aplastic anemia by donor leukocyte telomere length

Figure 2. Hematopoietic cell transplant outcomes for patients with severe aplastic anemia by donor leukocyte telomere length

A) Cumulative incidence of neutrophil recovery; B) Cumulative incidence of platelet recovery; C) Cumulative incidence of acute graft-versus-host disease grade III/IV; D) Cumulative incidence of chronic graft-versus-host disease

Figure 2. Hematopoietic cell transplant outcomes for patients with severe aplastic anemia by donor leukocyte telomere length

A) Cumulative incidence of neutrophil recovery; B) Cumulative incidence of platelet recovery; C) Cumulative incidence of acute graft-versus-host disease grade III/IV; D) Cumulative incidence of chronic graft-versus-host disease

Figure 2. Hematopoietic cell transplant outcomes for patients with severe aplastic anemia by donor leukocyte telomere length

A) Cumulative incidence of neutrophil recovery; B) Cumulative incidence of platelet recovery; C) Cumulative incidence of acute graft-versus-host disease grade III/IV; D) Cumulative incidence of chronic graft-versus-host disease

Figure 2. Hematopoietic cell transplant outcomes for patients with severe aplastic anemia by donor leukocyte telomere length

A) Cumulative incidence of neutrophil recovery; B) Cumulative incidence of platelet recovery; C) Cumulative incidence of acute graft-versus-host disease grade III/IV; D) Cumulative incidence of chronic graft-versus-host disease