Donor Telomere Length Influences Engraftment and Outcome in Aplastic Anemia Patients Undergoing Matched Related Stem Cell Transplantation

Introduction

Haematopoietic stem cell transplant (HSCT) is the treatment of choice in young patients (age < 50 years) with aplastic anaemia [AA]. Several factors play a role in determining the outcome of HSCT. Gadalla et al [JAMA 2015] suggested a correlation between donor telomere length and overall survival in patients undergoing unrelated donor transplantation for severe aplastic anaemia. We analysed the influence of telomere length (TL) in modulating the outcome of AA patients who undergo either a matched sibling (MRD), matched unrelated (MUD) or a haploidentical donor HSCT.

Methods

Patients undergoing HSCT for AA at our centre between 2001 and 2017 who had DNA samples available for analysis were included in this study. Clinical parameters were documented in a standard format. DNA was extracted from recipient (pre-HSCT) and their donors and telomere length was measured using quantitative real-time PCR (qPCR) using relative quantitation method. The association between telomere length (TL) and clinical parameters were analysed using SPSS Software.

Results

Of the 290 patients who underwent HSCT for AA between 2001 and 2017, at the Christian Medical College, Vellore, India, good quality DNA samples were available for 170 pairs. The median age of AA patients was 21.5 (2-57) years and the donors were 28 (1-60) years respectively. Twenty patients fulfilled criteria for non-severe aplastic anemia [NSAA] (12%) while 120 had severe aplastic anaemia [SAA] (70%) and 30 had very severe aplastic anaemia [VSAA] (18%). Out of the 170 patients, 137 underwent MRD transplant; 9 MUD and 24 had haplo-identical donors. Majority (94%) had conditioning with fludarabine and cyclophosphamide and the predominant graft source was PBSC (n=162, 95%). The mean time to achieve an ANC of >500/mm³ was 15 ± 3 days. The incidence of graft failure, aGVHD and chGVHD were 13% (n=22), 25% (n=43) and 23% (n=39) respectively. Out of the 170 patients, 114 patients are alive and 56 had expired at the time of analysis.

Patients had lower relative TL as compared to donors [Median pTL - 0.79 (range: 0.07 - 4.08) vs dTL - 0.87 (range: 0.04 - 5.76) p=0.032]. TL of donor was categorized into long and short based on the median TL in donors (long >0.87 and short <0.87). There was no significant correlation between patients' TL and age (r=-0.12, p=0.114). In donors, TL negatively correlated with age (r=-0.177; p=0.021). The median time to engraftment was shorter in donors with higher TL (long - 14 days (range: 10 - 22) vs short - 15 days (range: 9 - 28), p=0.031). There was no significant association between donor TL and aGVHD (Long- 41.9% vs short- 58.1%; p=0.2). The incidence of graft failure was 11.2% among patients having a MRD donor; it was significantly higher in patients whose donor had short TL [19.2% vs 4.5%; p=0.018]. Logistic regression analysis showed that long donor TL was significantly associated with faster engraftment (p=0.041) and better outcomes (p=0.031; multivariate: p=0.035).

Conclusion

Telomere length in the donor plays an important role in engraftment, graft failure and overall survival in patients undergoing matched related donor transplant for aplastic anaemia. Newer strategies may need to be worked out to reduce graft failure in donors who have short telomere length.