Post-HCT Cyclophosphamide Boosts Transplant Success

Increased access to allogeneic hematopoietic cell transplant (HCT) is feasible for patients who lack an HLA-matched donor with the use of post-transplant cyclophosphamide (PTCy), according to a prospective phase II study.

Use of PTCy resulted in an overall survival rate of 76% at 1 year, as well as a low incidence of severe acute graft-versus-host-disease (GVHD), in patients — almost half of whom were ethnic minorities — who did not have a well-matched donor in the family or in donor registries, reported Bronwen Shaw, MD, PhD, of the Center for International Blood and Marrow Transplantation Research, Medical College of Wisconsin in Milwaukee, and colleagues.

While allogeneic HCT is a curative procedure for a number of hematologic and immunologic disorders, the best outcomes have historically been seen in the setting of a well-matched related (such as a sibling) or unrelated donor, they noted in the Journal of Clinical Oncology.

“But the problem is that certain patients — and particularly patients from ethnic minorities — may not have a sibling or a matched unrelated donor,” Shaw told MedPage Today. Ethnic minorities tend to be underrepresented in the large donor registries, she added. “And even registries in Brazil, India, and Africa don’t account for the genetic mixing that is occurring, which means that finding a donor even in a large registry can be like finding a needle in a haystack.”

A previous analysis published in the New England Journal of Medicine illustrated the barriers faced by minority populations, showing that the likelihood of finding a matched unrelated donor was 75% for Caucasian patients compared with just 16% for African-American patients.

“So, in a way we are faced with an issue of inequitable access based on genetic factors,” said Shaw. “And although we can do transplants with mismatched unrelated donors, the outcomes have not been as good.”

Survival for these patients has been historically inferior, with increased incidence of GVHD and graft failure when standard calcineurin inhibitor-based GVHD prophylaxis is used. Thus, in this study, Shaw and colleagues wanted to evaluate the feasibility and effectiveness of HCT in mismatched unrelated donors with the use of PTCy.

“The idea was that this would reduce the side effects they would get with the transplant, and improve outcomes so that we can remove that equity barrier, as well as the assumption that these patients will do worse, even with a transplant,” Shaw explained.

The concept of using PTCy built on previous studies performed in the mismatched related (haploidentical) donor setting. The rationale behind it is that recently activated, alloreactive effector T cells responsible for GVHD are selectively sensitive to the toxic effects of PTCy, while regulator T-cell function is preserved, thus avoiding more widespread immunosuppressive effects.

“The approach of using post-transplant cyclophosphamide targets immune cells that cause negative complications, but preserve the cells that maintain disease control and keeps infection control,” Shaw explained. This addresses the problems associated with multiple HLA-mismatches in the haploidentical donor setting, and has resulted in acceptable rates of engraftment, GVHD, and survival in single-center and multicenter trials.

This phase II study, sponsored by the National Marrow Donor Program (NMDP), included 80 patients enrolled at 11 transplant centers from December 2016 to March 2019; 48% were ethnic minorities. Eligible patients were 15 to 71 years of age; had a diagnosis of acute or chronic leukemia, myelodysplastic syndrome, or lymphoma; and were eligible for a standard-of-care first allogeneic HCT using bone marrow as the stem cell source.

Following myeloablative or reduced-intensity conditioning-based HCT, patients received PTCy on days 3 and 4, with sirolimus and mycophenolate mofetil for GVHD prophylaxis starting on day 5.

The primary endpoint was 1-year OS, hypothesized to be 65% or better, which was met with a 1-year rate of 76% for the entire cohort, and 72% and 79% in the myeloablative and reduced-intensity conditioning arms. Secondary endpoints of engraftment >90% and incidence of grade 3/4 acute GVHD <15% at 100 days were also met.

“The outcomes were excellent at 1 year, with over 70% survival,” Shaw noted, adding that results were similar to those of mismatched related HCT. “This suggests that if you use this cyclophosphamide platform you can mitigate the donor mismatch in a way that previous strategies we had for preventing some immunological complications just didn’t do.”

While the results of this study are restricted by the exclusive use of harvested bone marrow rather than peripheral blood stem cells, it shows that performing allogeneic HCT from a mismatched unrelated donor “is feasible, safe, and effective, provided a PTCy platform is used for GVHD prophylaxis,” wrote Mohamad Mohty, MD, PhD, of Sorbonne University in Paris, and Florent Malard, MD, PhD, of Saint Antoine Hospital in Paris, in an accompanying editorial.

Shaw noted that there are plans to launch the phase II ACCESS trial, also sponsored by NMDP, which is designed to expand the reach of the PTCy approach by incorporating peripheral blood stem cells as a graft source.