Increased age-associated mortality risk in HLA-mismatched hematopoietic stem cell transplantation

We investigated a possible interaction between age-associated risk and HLA-mismatch associated risk on prognosis in different age categories of recipients of unrelated hematopoietic stem cell transplants (HSCT) (n=3019). Patients over 55 years of age transplanted with 8/10 donors showed a mortality risk of 2.27 (CI 1.70-3.03, P<0.001) and 3.48 (CI 2.49-4.86, P<0.001) when compared to 10/10 matched patients in the same age group and to 10/10 matched patients aged 18-35 years, respectively. Compared to 10/10 matched transplantations within each age category, the Hazards Ratio for 8/10 matched transplantation was 1.14, 1.40 and 2.27 in patients aged 18-35 years, 36-55 and above 55 years. Modeling age as continuous variable showed different levels of risk attributed to age at the time of transplantation [OS: 10/10: Hazards Ratio 1.015 (per life year); 9/10: Hazards Ratio: 1.019; 8/10: Hazards Ratio 1.026]. The interaction term was significant for 8/10 transplantations (P=0.009). Findings for disease-free survival and transplant-related mortality were similar. Statistical models were stratified for diagnosis and included clinically relevant predictors except cytomegalovirus status and Karnofsky performance status. The risk conferred by age at the time of transplantation varies according to the number of HLA-mismatches and leads to a disproportional increase in risk for elderly patients, particularly with double mismatched donors. Our findings highlight the importance of HLA-matching, especially in patients over 55 years of age, as HLA-mismatches are less well tolerated in these patients. The interaction between age-associated risk and HLA-mismatches should be considered in donor selection and in the risk assessment of elderly HSCT recipients.