Landmark stem cell trial: Genetic mismatch no longer a barrier to survival
A multicentre trial has demonstrated that patients receiving stem cell transplants from unrelated donors with multiple genetic mismatches can achieve survival rates comparable to those with better-matched donors when using post-transplant cyclophosphamide prophylaxis.
The findings, presented at the American Society of Hematology annual meeting, could substantially expand donor availability for patients with blood cancers, particularly those from non-European backgrounds.
Expanding donor compatibility criteria
The ACCESS trial, sponsored by the US-based National Marrow Donor Program, enrolled 268 adults with blood cancers who received peripheral blood stem cell grafts from unrelated donors aged 35 or younger. Participants were divided into two groups: 85 patients with four to six HLA markers matched and 183 patients with seven of eight markers matched. The research team, including Dr Antonio Jimenez Jimenez from Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, found that one-year overall survival reached 86% in the more mismatched group compared with 79% in the less mismatched group.
The significance of these results extends beyond survival figures. Currently, only approximately 29% of Black patients can identify a fully matched donor in the registry, compared with 89% of non-Hispanic white patients. By demonstrating acceptable outcomes with four to six of eight HLA matches, the study suggests that nearly 99% of patients could potentially access suitable donors through international registries.
GVHD rates remain manageable
Graft-versus-host disease represents a major concern in allogeneic transplantation, occurring when donor immune cells attack recipient tissues. The ACCESS trial monitored both acute and chronic GVHD rates across both cohorts. At six months post-transplant, grade II-IV acute GVHD occurred in 34% of patients with four to six matched markers and 39% of those with seven matched markers. Grade III-IV acute GVHD rates were 7% and 8% respectively. Moderate to severe chronic GVHD at one year affected 8% of the more mismatched group and 11% of the less mismatched group.
These comparable GVHD rates between groups suggest that post-transplant cyclophosphamide effectively controls alloreactive responses despite increased HLA disparity. The drug targets proliferating alloreactive T cells whilst sparing quiescent stem cells, thereby establishing tolerance whilst maintaining graft function.
Post-transplant cyclophosphamide enables broader matching
The protective regimen using post-transplant cyclophosphamide has transformed donor selection criteria. Dr Jimenez Jimenez noted: “Cyclophosphamide has changed the landscape of transplantation and donor utilization trends. It allows us to safely use donors who would have been considered unsuitable just a few years ago.”
One-year relapse incidence was 23% in the more mismatched group compared with 17% in patients receiving seven of eight matched grafts. Non-relapse mortality remained low at 8% and 14% respectively. Graft-versus-host disease-free, relapse-free survival was 55% for patients with four to six matches and 51% for those with seven matches.
Implications for clinical practice
The study’s findings permit clinicians to prioritise additional donor characteristics beyond HLA matching. Younger donor age, for instance, correlates with improved transplant outcomes. With expanded matching criteria, transplant centres can select optimal donors based on multiple factors rather than being constrained by stringent HLA requirements.
Notably, 61% of patients in the more mismatched group identified as other than non-Hispanic white, reflecting the trial’s success in addressing disparities in donor availability for diverse patient populations. The research builds upon previous work by Dr Jimenez Jimenez and colleagues, who demonstrated the feasibility of this strategy using bone marrow grafts in earlier multicentre trials.
Future directions
The ACCESS trial was not randomised, and the investigators acknowledge that further research is needed to optimise dosing strategies and extend these approaches to paediatric patients. Ongoing studies continue to refine post-transplant cyclophosphamide protocols across different conditioning regimens and graft sources.
The research is to be presented on 8 December 2025 at the American Society of Hematology annual meeting in Orlando and was highlighted in a special press briefing on 6 December 2025.
Reference
Jimenez Jimenez, A., et al. (2025). Mismatching of unrelated donors beyond a single HLA-locus does not adversely impact outcomes at one year following transplantation: Results from the NMDP sponsored ACCESS study. To be presented at the American Society of Hematology Annual Meeting, Orlando, FL, 8 December 2025.
