Importance of donor HLA matching confirmed, but research highlights health disparity
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For years, hematopoietic stem cell transplantation physicians have viewed a matched unrelated donor as the gold standard when a matched related donor is unavailable.
But with seemingly similar outcomes using a haploidentical graft source with posttransplant cyclophosphamide as a graft-versus-host disease prophylaxis, does that gold standard still hold true?
Research published in Blood confirmed a matched unrelated donor should continue to be the preferred graft source when one is available, especially for patients with hematologic malignancies who receive reduced-intensity conditioning regimens.
However, that is only part of the story.
The research also highlighted a known health disparity that makes haploidentical HSCT and other alternative donor sources necessary: Non-white patients are much less likely than white patients to have available matched unrelated donors. This limits their access to HSCT.
In this commentary, I will summarize recent research and discuss efforts in the transplant and cell therapy community to make HSCT more accessible to patients who are ethnically diverse.
Preferred donor source
The CIBMTR (Center for International Blood and Marrow Transplant Research) observational study led by Mahasweta Gooptu, MD, assistant professor of medicine at Dana-Farber Cancer Institute, differed from past research that compared matched unrelated donor and haploidentical HSCT for patients with acute lymphoblastic leukemia, acute myeloid leukemia or myelodysplastic syndrome.
Historically, when comparing haploidentical to matched unrelated donor HSCT, previous researchers found similar transplant outcomes between the two donor types. However, both graft sources (bone marrow from haploidentical donors and peripheral blood from matched unrelated donors) and GVHD prophylaxis (posttransplant cyclophosphamide for haploidentical transplant, and calcineurin inhibitor and methotrexate for matched unrelated donor transplant) differed among donor types.
Gooptu and colleagues compared transplant outcomes between haploidentical and matched unrelated donor transplants using posttransplant cyclophosphamide as GVHD prophylaxis — a more apples-to-apples comparison.
Specifically, they analyzed data on adults with ALL, AML or myelodysplastic syndrome reported to the CIBMTR by 111 transplant centers from 2011 to 2018. Data from patients who received reduced-intensity conditioning were reviewed separately from those who received myeloablative conditioning.
The results from the reduced-intensity conditioning group were particularly striking.
Patients who received a matched unrelated donor transplant had higher 2-year DFS (55% vs. 41%) and 2-year OS (67% vs. 54%) than those who received a haploidentical transplant.
In addition, 2-year rates of graft failure, acute grade 2 to grade 4 GVHD, acute grade 3/grade 4 GVHD, and nonrelapse mortality were lower for recipients of matched unrelated donor transplant.
Researchers reported no differences in OS, DFS, graft failure or relapse in the myeloablative conditioning group. However, the matched unrelated donor recipients experienced lower incidence of grade 3/grade 4 acute GVHD and chronic GVHD than haploidentical recipients.
Subset analyses limited to the last few years of the study period (2016 to 2018), white patients and peripheral blood grafts further demonstrated the disparity in outcomes favoring matched unrelated donor over haploidentical donor types.
What does this mean for clinical practice? The results of this study support that physicians should prioritize using an available matched unrelated donor when considering the use of reduced-intensity conditioning for patients with hematologic malignancies whenever one is available.
A gap remains
Even armed with this information, physicians face a barrier.
We know a matched unrelated donor is not always available, particularly for non-white patients.
Although Be The Match Registry is the most diverse listing of potential unrelated donors in the world — providing access to more than 39 million potential donors — chances of having a matched donor range greatly depending on a patient’s ethnic background.
For example, Black and African American patients have a 29% chance of finding a matched donor. Asian patients have a 47% chance, and white patients have a 79% chance.
This was evident in the research from Gooptu and colleagues.
Patients who received a haploidentical transplant were less likely to be white regardless of the conditioning regimen they received.
People of color represented 28% of study participants in the haploidentical reduced-intensity conditioning group and 31% in the haploidentical myeloablative conditioning group. That compares with 5% in the matched unrelated donor reduced-intensity conditioning group and 12% in the matched unrelated donor myeloablative conditioning group.
At the National Marrow Donor Program (NMDP)/Be The Match, we have intensified our efforts to expand the ethnic diversity of the Be The Match Registry through education and community outreach.
Closing the access gap
This work takes time — time that patients with hematologic malignancies often do not have.
That is why we have research underway to assess the safety and efficacy of using a mismatched unrelated donor with posttransplant cyclophosphamide prophylaxis, an approach that could significantly increase access to HSCT for ethnically diverse patients and decrease time to transplant in the context of aggressive malignant disease.
To this end, NMDP-sponsored phase 2 trial assessed human leukocyte antigen (HLA)-mismatched unrelated donor bone marrow transplantation with posttransplant cyclophosphamide. Nearly 50% of study participants were ethnically diverse.
The researchers aimed to achieve 65% or higher 1-year survival after mismatched unrelated donor (4/8 to 7/8) using bone marrow as a graft source.
Results — published earlier this year in Journal of Clinical Oncology — were encouraging, with a 76% 1-year OS rate.
Researchers concluded that using mismatched unrelated donor types was safe and effective and could significantly expand access and potentially expedite time to HSCT for ethnically diverse populations.
As a follow-up study, NMDP/Be The Match is partnering with pediatric and adult transplant centers to conduct the ACCESS clinical trial.
Researchers intend to assess efficacy and safety of mismatched unrelated donor peripheral blood stem cells for adults or bone marrow for children in combination with posttransplant cyclophosphamide.
Enrollment is expected to begin later this year.
Although a matched unrelated donor likely will remain the preferred option for HSCT outside a matched related donor, use of haploidentical donors and mismatched unrelated donors can expand this potentially life-saving option to many more patients in need.
References:
Ciurea S, et al. Blood. 2015;doi:10.1182/blood-2015-04-639831.
Gooptu M, et al. Blood. 2021;doi:10.1182/blood.2021011281.
Gragert L, et al. N Engl J Med. 2014;doi:10.1056/NEJMsa1311707.
National Marrow Donor Program/Be The Match. IT-Ideation Department. February 2021.
Shaw B, et al. J Clin Oncol. 2021;doi:10.1200/JCO.20.03502.
For more information:
Jeffery Auletta, MD, can be reached at jaulett3@nmdp.org.
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