TOPLINE

In adults requiring reduced-intensity or non-myeloablative conditioning, posttransplant cyclophosphamide (PTCy)-based graft-vs-host disease (GVHD) prophylaxis was associated with encouraging outcomes after human leukocyte antigen (HLA)-mismatched unrelated donor allogeneic hematopoietic cell transplantation (allo-HCT). The 1-year overall survival reached nearly 80%, while non-relapse mortality remained low at 12.5%; severe infections affected nearly 40% of participants within the first year.

METHODOLOGY

• Patients without a fully HLA-matched donor have limited transplant options. Prior research has shown that PTCy reduces GVHD after haploidentical transplants. This study examined whether the same approach could be used with reduced-intensity or non-myeloablative conditioning in patients receiving mismatched unrelated donor transplants.
• This multicenter phase 2 clinical trial enrolled 193 adult participants (median age, 65.0 years; 52.3% women) from an initial cohort and a planned expansion cohort. All participants had hematologic malignancies requiring allo-HCT with reduced-intensity or non-myeloablative conditioning and lacked an available matched sibling donor or an HLA-8/8 matched unrelated donor. 
• Participants received peripheral blood stem cell allografts from HLA 4-7/8 matched unrelated donors aged ≤ 35 years; donor HLA matching was 7/8 in 131 (67.9%), 6/8 in 51 (26.4%), and 4-5/8 in 11 (5.7%) participants.
• Conditioning regimens included fludarabine plus melphalan in 120 (62.2%), fludarabine plus busulfan in 38 (19.7%), and fludarabine plus cyclophosphamide and 200 cGy total body irradiation in 32 (16.6%) participants. GVHD prophylaxis consisted of cyclophosphamide 50 mg/kg on days 3 and 4 post-HCT, mycophenolate mofetil from days 5 to 35, and tacrolimus from days 5 to 100, followed by tapering to discontinuation by day 180 in the absence of GVHD.  
• The primary outcome was 1-year overall survival; secondary outcomes included relapse, non-relapse mortality, acute and chronic GVHD incidence, as well as infections and adverse events.

TAKEAWAY

• The 1-year overall survival was 79.6% for the entire cohort, with similar estimates for recipients of HLA 7/8-matched (77.8%) and HLA < 7/8-matched (83.7%) donors. The 1-year cumulative incidence was 12.5% for non-relapse mortality and 17.3% for relapse, while 1-year GVHD-free, relapse-free survival was 53.5%.
• Acute GVHD was common, with a 6-month cumulative incidence of 40.5% for grade 2-4 disease and 7.8% for grade 3-4 disease; the 1-year cumulative incidence of moderate-to-severe chronic GVHD was 10.1%.
• Severe infections (grade 3-5) occurred in 39.0% of patients by 1 year, with bacterial and viral infections being most common; the cumulative incidence of cytomegalovirus infection was 28.4% at 1 year. 
• Grade 1-4 cytokine release syndrome occurred in 28.0% of patients by day 7, six patients experienced unexpected grade 3-5 cardiac adverse events, and infectious complications or sepsis accounted for 11 of 19 total deaths.

IN PRACTICE

"Given that many patients lack an HLA-matched donor, application of these results expands access to HCT," the study authors wrote, concluding that ″MMUDs [mismatched unrelated donors] are appropriate alternative donors for patients that require reduced intensity conditioning regimens, and therefore extend access to this life-saving procedure to people of diverse ancestry.″

SOURCE

The study, led by Brian C. Shaffer, MD, Memorial Sloan Kettering Cancer Center in New York, was published online in the American Journal of Hematology.

LIMITATIONS

The study used standard-dose cyclophosphamide, whereas recent trials suggest reduced doses may reduce toxicity, particularly in high-risk populations. The study did not include anti-thymocyte globulin, and its role in combination with posttransplant cyclophosphamide remains under investigation.

DISCLOSURES

The study was supported by grants from the National Cancer Institute, National Heart, Lung and Blood Institute, National Institute of Allergy and Infectious Diseases, and Health Resources and Services Administration. Shaffer reported consulting for Gamida Cell and receiving research funding from Genentech. Multiple authors reported receiving consulting fees, research support, or honoraria from various pharmaceutical and biotechnology companies, including Sanofi, Incyte, and Gilead Sciences. Additional  disclosures are reported in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.