PTCy Offers New Hope for Mismatched Stem Cell Transplants in Leukemia, MDS


Jeff Auletta, MD, discussed how PTCy-based graft-vs-host disease prophylaxis offers a promising approach for expanding access to successful cell transplantation regardless of donor match or patient ethnicity.

Blood cancer cells under the microscope: © stock_acc -

Blood cancer cells under the microscope: © stock_acc -

Traditionally, hematopoietic cell transplants (HCTs) relied on perfectly matched 8/8 HLA matched donors to minimize complications like graft-vs-host disease (GVHD). However, finding such donors can be difficult, especially for certain ethnicities.

Investigators, including Jeff Auletta, MD, investigated the impact of a posttransplant cyclophosphamide (PTCy) regimen on survival outcomes in HCT. The study, presented at the 2024 Transplantation and Cellular Therapy Tandem Meetings, compared outcomes in patients receiving HCT with either fully matched (8/8) or partially mismatched (7/8) unrelated donors (URD). They analyzed results for patients receiving either PTCy or a calcineurin inhibitor (CNI) like tacrolimus or cyclosporine to prevent GVHD.

PTCy appears to eliminate the previously observed survival disadvantages for patients receiving a 7/8 compared to an 8/8 donor using CNI-based GVHD prophylaxis. Both 8/8 and 7/8 URD transplants using PTCy had better survival rates than those receiving CNIs.

These findings suggest that PTCy allows for successful transplants with partially mismatched donors, increasing access to HCT for a wider group of patients. While a fully matched donor remains ideal, 7/8 URD HCT with PTCy appears to be a viable alternative, particularly for patients with ethnically diverse backgrounds.

In an interview with Targeted OncologyTM, Auletta, senior vice president of health equity at the National Marrow Donor Program and chief scientific officer at the Center for International Blood and Marrow Transplant Research (CIBMTR), discussed how PTCy-based GVHD prophylaxis offers a promising approach for expanding access to successful HCT regardless of donor match or patient ethnicity.

Targeted Oncology: What was the rationale behind this study?

Auletta: We [were] presenting work that basically shows that using a mismatched, unrelated donor has similar outcomes as using a match unrelated donor in the context of using posttransplant cyclophosphamide as graft-vs-host disease prophylaxis.

What are matched and mismatched donors?

Typically, for allogeneic stem cell transplant, when we are using someone else's stem cells, we need to match proteins on the cells of the donor and the recipient. Historically, we have been using the best match for that, [and that is] called a matched unrelated donor. Now, there are newer alternative donor transplant platforms that enable us to use more mismatched, unrelated donors, which means disparity in HLA typing between donor and recipient. This is crucial because, typically, when we look at the ability to find a match, unrelated donor for a patient who has an ethnically diverse background, we are limited based upon the genetic profile of the registry. For example, the likelihood of finding an 8/8 matched unrelated donor varies from 80% in non-Hispanic White patients to 29% in Black/African American patients. Therefore, the more ethnically diverse patients do not have the ability to receive a matched unrelated donor transplant. However, by using the mismatched unrelated donor transplant, we can increase the likelihood of finding a donor to nearly 100% for all race and ethnic groups.

What were the goals of the study?

The goals of this study were to compare overall survival and graft-vs-host disease-free, relapse-free survival between 2 graft-vs-host disease regimens. One is calcineurin inhibitor-based GVHD prophylaxis, and the other is posttransplant cyclophosphamide-based GVHD prophylaxis. What we wanted to do was to compare outcomes between mismatched unrelated and matched unrelated donor transplant recipients using these GvHD prophylaxes because we knew historically that mismatched unrelated donor transplant outcomes were inferior with respect to overall survival to matched unrelated donor transplants. That goes back to a seminal study performed by Stephanie Lee [MD] and colleagues in the CIBMTR [that] showed that for every 1 level of HLA mismatch, there was an associated 10% decrement in 5-year overall survival. That was in the context of calcineurin inhibitor-based GVHD prophylaxis. But now, in the mismatched unrelated donor setting, whether that is related or unrelated, posttransplant cyclophosphamide is the predominant graft-vs-host disease prophylaxis. That is why we wanted to compare those outcomes between posttransplant cyclophosphamide and calcineurin inhibitor-based GVHD prophylaxis in the mismatched unrelated donor setting.

Could you summarize your findings?

We found that with using calcineurin inhibitor-based GVHD prophylaxis, there was an outcome disparity in overall survival between 8/ 8 and 7/ 8 unrelated donor transplants. However, using posttransplant cyclophosphamide, we found that the overall survival was similar between 8/ 8 and 7/ 8 unrelated donor transplants. In addition, we found that graft-vs-host disease-free, relapse-free survival was similar between 8/8 and 7/8 unrelated donor transplants when using calcineurin inhibitor-based GVHD prophylaxis. However, when using posttransplant cyclophosphamide-based GVHD prophylaxis, graft-vs-host disease-free/relapse-free survival was the same between 8/8 and 7/8 unrelated donor transplants and higher than unrelated donor transplants receiving calcineurin inhibitor-based GVHD prophylaxis.

What are some of the takeaways from these findings?

There are 3 takeaways of the study. The first is always to refer a patient with a transplantable disease indication sooner than later to a transplant center. This study looked at acute leukemia and myelodysplasia. Typically, community physicians do not often see these diagnoses as often as solid tumor cancers in their patients. For hematologic malignancies, transplant centers are the way to go in terms of early referral. The second takeaway is ethnically diverse patients deserve equal outcomes. This study enables ethnically diverse patients to receive life-saving therapy like stem cell transplants. The last is the use of posttransplant cyclophosphamide has clearly been a major advantage the field and has taken the field in another direction in terms of using alternative donor transplants, specifically enabling more ethnically diverse patients to receive stem cell transplant.

Auletta J, Al Malki M, Shaffer B, et al. Post transplant cyclophosphamide eliminates disparity in GvHD-free, relapse-free survival and overall survival between 8/8 matched and 7/8 mismatched unrelated donor hematopoietic cell transplantation in adults with acute leukemia or MDS. Presented at the 2024 Transplantation and Cellular Therapy Tandem Meetings. February 21-24, 2024. San Antonio, TX. Abstract 30.
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