Mixed Results With Cyclophosphamide in Mismatched Unrelated Stem Cell Transplants

Analyses of two large stem-cell transplant registries yielded conflicting results about the effect of post-transplant cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis on the risks of human leukocyte antigen (HLA) mismatch in unrelated donor transplants.

One study showed similar OS and GVHD relapse-free survival (GRFS) with matched or mismatched unrelated donor (MUD, MMUD) transplants. In contrast, the second study showed lower overall survival (OS) after HLA-mismatched transplants, driven by class I HLA mismatches, which were unaffected by PTCy.

Both analyses were published in the Journal of Clinical Oncology.

Although the studies provided additional support for PTCy in MUD, the lack of agreement for MMUD suggests cautious consideration before recommending changes to the current approach to donor selection, concluded Ronjon Chakraverty, PhD, MBChB, of the University of Oxford in England, in an accompanying editorial.

“Although PTCy represents an important innovation, it should only be considered a step on a journey for better GVHD prevention, not its final destination,” he wrote. “Cardiotoxicity, relative delays in engraftment, and potential increases in infection are all potential risks of PTCy. A current snapshot of GVHD prophylaxis trials in clinicaltrials.gov reveals multiple studies that seek to further refine the PTCy approach.”

“Future trials should also be extended to patients receiving HLA-mismatched unrelated donor transplants and compared with other promising GVHD prevention strategies,” Chakraverty added. “Such trials should also seek to incorporate better clinical endpoints that more reliably account for the dynamic variability of GVHD, for example, where it resolves over time.”

Access to allogeneic stem-cell transplant remains limited for patients of non-European ancestry if HLA matching is required. PTCy for GVHD prophylaxis “represents a truly disruptive technology,” as its low cost and efficacy after haploidentical bone marrow transplants have had a major clinical effect in the field and improved access for patients who do not have an HLA-matched donor, Chakraverty stated.

Whether PTCy can reduce the risks associated with HLA disparity after MMUD remained unclear and was the primary issue addressed by both registry-based studies.

An analysis of the Center for International Blood and Marrow Transplant Research database involved 10,025 adults who underwent MUD or single HLA locus MMUD transplants from 2017 to 2021 with either PTCy- or calcineurin inhibitor (CNI)-based GVHD prophylaxis. The study population comprised 7,272 recipients of MUD with CNI and 1,681 with PTCy, 613 recipients of MMUD with CNI and 459 with PTCy, reported Steven Devine, MD, of the National Marrow Donor Program in Minneapolis, and co-authors.

The primary outcomes were 3-year OS and GRFS after MUD or single-locus MMUD. Most (70.9%) of the transplants were for acute leukemia and the remainder for myelodysplastic syndromes (MDS). The patients had a median age of 60.7 years and a median follow-up of 36.6 months.

The results showed no significant difference in 3-year OS (HR 0.96, 95% CI 0.82-1.11) or 3-year GRFS (HR 0.90, 95% CI 0.79-1.02) between patients who underwent MMUD or MUD with PTCy. As compared with MUD transplants with CNI, OS was improved after MUD with PTCy (HR 0.88, 95% CI 0.80-0.96, P=0.004) and GRFS was improved with PTCy after either MUD (HR 0.61, 95% CI 0.57-0.66, P<0.0001) or MMUD (HR 0.68, 95% CI 0.60-0.76, P<0.0001).

“Benefit from PTCy was independent of patient ancestry,” the authors concluded. “Global registry-level analysis demonstrated that inclusion of MMUD increased donor availability regardless of recipient ancestry.”

The second analysis involved 17,292 adult unrelated-donor transplants from the European Society for Blood and Marrow Transplantation registry. The transplants occurred from 2005 to 2020 and had six-locus, high-resolution typing for donors and recipients, reported Katharina Fleischhauer, MD, of University Hospital Essen in Germany, and co-authors. Most transplants were for acute leukemia or MDS, and the primary endpoint was OS.

HLA mismatched transplants had worse survival as compared with fully matched transplants (HR 1.23, 95% CI 1.14-1.33, P<0.001). The overall disparity owed to class I HLA mismatches (HLA-A, -B, and -C, HR 1.29, 95% CI 1.19-1.41, P<0.001), whereas class II HLA mismatches (HLA-DRB1 and -DQB1) did not significantly affect OS (HR 1.07, 95% CI 0.93-1.23).

Use of PTCy prophylaxis improved GRFS versus conventional prophylaxis in HLA-matched transplants (HR 0.77, 95% CI 0.66-0.90, P<0.001). However, HLA mismatching was associated with increased mortality in PTCy transplants (HR 1.32, 95% CI 1.04-1.68, P=0.003), similar to non-PTCy transplants.

“Taken together, our findings suggest that HLA class I, in particular at the antigen and PBM [peptide-binding motif] level, should be prioritized over class II matching in contemporary unrelated donor selection and that these recommendations still hold also for transplants performed under PTCy-based GVHD prophylaxis,” Fleischhauer and colleagues concluded. “However, compiling larger, preferentially multiregistry data and evidence from prospective clinical trials is highly needed to better understand the role of HLA in the era of PTCy.”

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