Post-transplant cyclophosphamide makes mismatched unrelated donor stem cell transplants as effective as matched ones

At the 67th ASH Annual Meeting in Orlando, held December 6 to 9, 2025, a team from the University of Miami presented results that bear on a hard question in blood cancer care: who can be a donor. The work was also published in the journal Blood. Its finding is that a chemotherapy drug, cyclophosphamide, given after a stem cell transplant can make transplants from unrelated donors with extensive genetic mismatches about as safe and effective as those from well-matched donors.

Allogeneic hematopoietic cell transplantation is a curative treatment for common types of blood cancer. Donors have long been chosen by counting how many human leukocyte antigen (HLA) markers they share with the patient. These markers encode proteins that act as immune receptors on cell surfaces. A match on eight markers has historically given the best results, while fewer matches have been linked to lower survival and more graft-versus-host disease (GVHD), a complication in which donor cells attack the recipient's own cells.

That standard has left some patients far worse off in the search. A Black patient has only a 29% chance of finding a fully matched donor, compared with 89% for non-Hispanic white patients. Earlier research showed that post-transplant cyclophosphamide improved outcomes when donors were related but mismatched, and the same investigators had reported encouraging results with bone marrow grafts from mismatched unrelated donors.

The new study is the largest to test the approach in unrelated donors matching only four to seven of eight HLA markers, and it used peripheral blood grafts. These are the most common graft source and are collected in an outpatient process akin to donating blood. It enrolled 268 adults: 183 had seven matched markers, and 85 had four to six.

The primary endpoint was survival at one year. In the seven-match group, 79% were alive; in the four-to-six group, 86% were. Other measures were also similar between the groups. GVHD-free, relapse-free survival was 51% and 55%. Relapse occurred in 17% and 23%. Non-relapse mortality was 14% and 8%.

GVHD rates were comparable and relatively low. Acute grade 2-4 GVHD at six months occurred in 39% of the seven-match patients and 34% of the four-to-six group. Moderate-to-severe chronic GVHD at one year was 11% and 8%.

One difference appeared. Primary graft failure, in which transplanted cells do not begin producing healthy blood cells, occurred in 3% of the seven-match recipients and 7% of those with four to six matches. It was limited to older adults who received reduced intensity conditioning, and the researchers plan further analyses to understand and prevent it in that subgroup.

"With a post-transplant cyclophosphamide-based GVHD prevention strategy, outcomes following mismatched unrelated donor transplant are similar to those achieved with matched donors," said senior author Antonio Jimenez-Jimenez, MD, associate professor of medicine at Sylvester Comprehensive Cancer Center, part of the University of Miami Miller School of Medicine. He said roughly 99% of patients could now have access to a suitable donor on international registries. Doctors might also weigh other donor traits, such as younger age, more heavily. The results matched his group's earlier bone marrow study, suggesting peripheral blood grafts work in this setting, which he said makes transplantation easier for patients and safer for donors.

He cautioned that the study was not randomized and that larger studies are needed to confirm the findings. Related work is underway, including a companion study of pediatric bone marrow transplant recipients and a trial refining the cyclophosphamide dosing to cut toxicity while keeping its benefits.