Phase 2 Trial Shows Promising Survival Rates for Stem Cell Transplants from Mismatched Unrelated Donors

A multicenter phase 2 trial has demonstrated that stem cell transplants from HLA-mismatched unrelated donors can achieve excellent survival outcomes when combined with post-transplant cyclophosphamide (PTCy) prophylaxis, potentially expanding access to curative treatment for patients with advanced hematologic malignancies.

The ACCESS trial, published in the Journal of Clinical Oncology, enrolled 145 adult patients between September 2021 and August 2023 across 21 centers in the United States. Results showed one-year overall survival rates of 83.8% in the myeloablative conditioning group and 78.6% in the reduced-intensity conditioning group, with notably low rates of severe graft-versus-host disease (GVHD).

Study Design and Patient Population

The trial stratified patients into two cohorts based on conditioning regimen intensity: 75 patients received myeloablative conditioning (MAC) and 70 received reduced-intensity or nonmyeloablative conditioning (RIC/NMA). All patients received peripheral blood stem cells from mismatched unrelated donors and the same GVHD prophylactic regimen of cyclophosphamide, tacrolimus, and mycophenolate mofetil.

Significantly, 59% of enrolled patients self-identified within underrepresented racial or ethnic groups, with 71% in the MAC cohort and 46% in the RIC/NMA cohort. This population typically faces greater challenges in identifying HLA-matched donors due to more complex HLA haplotypes and underrepresentation in global donor registries.

GVHD Control and Safety Outcomes

The study achieved remarkably low rates of severe GVHD despite using peripheral blood stem cells, which historically carry higher GVHD risk compared to bone marrow grafts. Grades 3-4 acute GVHD at six months occurred in 8% of MAC patients and 10% of RIC/NMA patients. Moderate-to-severe chronic GVHD at one year affected 10.3% of MAC patients and 8.6% of RIC/NMA patients.

"Their results provide evidence that post-transplant cyclophosphamide effectively controls GVHD despite the use of peripheral blood stem cells, which will simplify stem cell transplants, rendering it easier and safer for donors," wrote lead author Monzr M. Al Malki, M.D., and colleagues.

The safety profile was generally consistent with known HSCT risks, though high rates of bacterial and viral infections were observed, likely due to prolonged immunosuppression associated with PTCy-based prophylaxis.

HLA Matching Flexibility

An exploratory analysis revealed that overall survival did not differ significantly based on the degree of HLA mismatch. Among patients whose donors matched at fewer than 7 of 8 HLA alleles (32% of the cohort), one-year survival was similar to those with 7 of 8 matches: 90.9% versus 80.6% in the MAC group and 82.6% versus 76.6% in the RIC/NMA group.

The researchers noted that loosening HLA matching criteria could increase the likelihood of identifying potential unrelated donors to virtually 100% of patients, regardless of ancestry, while allowing prioritization of other donor characteristics such as young age.

Clinical Implications

The findings address a critical health equity issue in stem cell transplantation. Patients from marginalized racial and ethnic groups are far less likely than non-Hispanic whites to have HLA-matched donors in worldwide registries, limiting their access to potentially curative treatment.

Al Malki and colleagues stated that one of their main reasons for conducting this study was to provide sufficient evidence in favor of mismatched unrelated donors to justify a phase 3 trial comparing them to more closely matched donors.

The study results lay groundwork for future randomized trials comparing mismatched unrelated donor transplants with haploidentical donor transplantation, ultimately aiming to optimize access and outcomes for all patients requiring stem cell transplants regardless of ancestry or socioeconomic status.