Blood cancer patients who cannot find a closely matched stem cell donor may soon have a broader path to transplantation. New findings from the multicenter ACCESS clinical trial suggest that carefully selected younger donors with substantial genetic mismatches can still produce encouraging outcomes when transplantation is paired with post-transplant cyclophosphamide, a treatment strategy designed to control dangerous immune reactions. The results challenge a long-standing assumption in hematopoietic cell transplantation: that the closest possible donor match must always be the best option. Instead, the research points toward a more flexible approach in which donor age, immune biology and the transplant platform are considered together.
The study, published in Blood Advances, evaluated outcomes in adults with blood cancers who underwent allogeneic hematopoietic cell transplantation using peripheral blood stem cells from unrelated donors. The analysis included 268 patients enrolled in the ACCESS trial, a phase 2 study sponsored by the National Marrow Donor Program and conducted through the Center for International Blood and Marrow Transplant Research. Patients had diseases including leukemia, lymphoma, myelodysplastic syndromes and related disorders for which transplantation can offer the possibility of long-term remission. All donors were between 18 and 35 years old, allowing investigators to examine the impact of HLA mismatch within a uniformly young donor population.
For decades, donor selection has centered on human leukocyte antigen, or HLA, matching. HLA proteins sit on the surface of cells and help the immune system distinguish the body’s own tissues from foreign material. When a patient receives stem cells from another person, differences in these markers can cause donor-derived immune cells to attack healthy tissues, producing graft-versus-host disease, or GVHD. Severe GVHD can damage the skin, liver, intestines and other organs, and historically the risk was considered high enough that physicians often avoided donors with major HLA differences whenever a closer match was available. Patients unable to identify a suitable donor could face prolonged searches or lose access to transplantation altogether.
Post-transplant cyclophosphamide, commonly known as PTCy, has changed the balance between donor availability and immune risk. The drug is administered shortly after transplantation and targets highly reactive donor T cells, which are among the principal drivers of acute GVHD. Because these activated cells are especially vulnerable during a brief window after infusion, PTCy can suppress harmful immune responses while allowing enough donor immune cells to survive and establish a new blood-forming system. This approach does not eliminate all complications, but it has enabled transplant specialists to use donor sources that once would have been considered too mismatched.
The new ACCESS analysis focused on patients receiving grafts with either 7 of 8 HLA markers matched or fewer than 7 of 8 matched. The more mismatched group most commonly involved donors matched at six of eight key HLA markers. One year after transplantation, overall survival was 85.6% among recipients of the more mismatched grafts, compared with 78.6% among those receiving 7/8 matched grafts. Rates of severe acute and chronic GVHD remained relatively low in both groups, while relapse and non-relapse mortality were also described as favorable. Although the numerical results may appear surprising, the investigators emphasize that the study was exploratory and was not designed to prove that the two donor groups were equivalent.
The findings are important because donor mismatch is only one factor influencing transplant success. Younger donors may provide advantages related to immune-cell function, cellular fitness and the ability of the graft to reconstitute blood production after treatment. Previous research has associated younger donor age with improved transplantation outcomes, although the precise biological mechanisms remain under investigation. By limiting the ACCESS trial to donors between 18 and 35, researchers reduced the potential influence of donor age and were able to explore whether a younger donor with a greater HLA mismatch could be a reasonable option when a closer match was unavailable or impractical.
Antonio Martin Jimenez Jimenez, M.D., associate professor of clinical medicine in the Division of Transplantation and Cellular Therapy at Sylvester Comprehensive Cancer Center, part of the University of Miami Miller School of Medicine, was among the investigators involved in the work. He said the results suggest that the limits traditionally placed on donor mismatch may not be absolute when an appropriate transplant platform is used. The implications extend beyond a single trial: transplant programs may be able to search more efficiently, reduce delays and offer potentially curative therapy to patients who lack an ideal donor. At Sylvester, mismatched unrelated donors now represent the primary donor source for allogeneic hematopoietic cell transplantation, reflecting how developments in GVHD prevention have moved from clinical research into routine care.
The study also reflects a broader transformation in the way transplant physicians evaluate donors. A donor is no longer judged solely by the number of matching HLA markers. Clinicians increasingly consider age, the specific location and direction of HLA mismatches, the source of stem cells, the patient’s disease status, conditioning regimen and the method used to prevent GVHD. These variables can interact in complex ways. A younger donor with a greater mismatch may, under some circumstances, be preferable to an older donor with a closer match, particularly if PTCy and other supportive strategies can reduce immune toxicity. The challenge is determining which combinations are safest for individual patients rather than applying one universal hierarchy.
The researchers caution that the ACCESS results should not be interpreted as evidence that any mismatched donor is suitable for every patient. Donor assignments were not randomized, and the exploratory analysis cannot exclude the possibility that differences between groups were influenced by patient characteristics, disease risk or treatment decisions. Longer follow-up will be needed to assess overall survival, relapse, chronic GVHD, infections, immune recovery and quality of life. Even so, the findings add momentum to a field increasingly focused on expanding donor access without sacrificing safety. For patients facing aggressive blood cancers, a larger and more intelligently evaluated donor pool could shorten the path to transplantation and create opportunities that were previously closed.
The central message from ACCESS is that donor selection is becoming a multidimensional science. Rather than treating genetic matching as a rigid pass-or-fail test, physicians are working toward individualized assessments that integrate immunology, donor age and transplant technology. “The field is moving beyond evaluating a donor based on a single characteristic,” Jimenez Jimenez said. “Our goal is to identify the best possible donor for each patient.” As post-transplant cyclophosphamide continues to reshape the risk calculus, carefully selected mismatched donors may become an increasingly important part of modern blood cancer care.
Subject of Research: Stem cell transplantation for patients with blood cancers, with a focus on mismatched unrelated donors, HLA matching, donor age and post-transplant cyclophosphamide.
Article Title: Outcomes after 7/8 and <7/8 mismatched unrelated donor PBSC transplantation with PTCy: results from the ACCESS trial
News Publication Date: 20-Aug-2026
Web References: https://ashpublications.org/bloodadvances/article/doi/10.1182/bloodadvances.2026021081/570271/Outcomes-after-7-8-and-lt-7-8-mismatched-unrelated
References: https://doi.org/10.1182/bloodadvances.2026021081
Image Credits: Sylvester Comprehensive Cancer Center
Keywords: Blood cancer, leukemia, lymphoma, stem cell transplantation, hematopoietic cell transplantation, HLA matching, mismatched unrelated donors, post-transplant cyclophosphamide, graft-versus-host disease, ACCESS trial, donor age, Blood Advances
