Novel approach may eliminate survival disparity in HSCT, greatly expand access
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Key takeaways:
- Post-transplant cyclophosphamide prophylaxis reduced the OS disparity in matched vs. mismatched unrelated donor hematopoietic stem cell transplant.
- The approach could expand access to HSCT.
Use of post-transplant cyclophosphamide prophylaxis to prevent graft-versus-host disease could greatly expand access to hematopoietic stem cell transplantation, according to results of a retrospective study.
An analysis of patients who received post-transplant cyclophosphamide (PTCy) showed no statistically significant difference in OS or GVHD-free RFS (GRFS) between patients with matched (8/8) or mismatched (7/8) unrelated donors.
The ability to find a suitable unrelated donor with a 7/8 HLA match is “much greater” than finding one with 8/8 HLA match, according to researcher Steven M. Devine, MD, chief medical officer at NMDP and senior scientific director at Center for International Blood and Marrow Transplant Research (CIBMTR), told Healio.
“For an African American patient, [chances] go from 30% to over 80%,” Devine said. “It’s even higher for Hispanic or Asian individuals — into the 90% range.
“If you can go even lower [to a 6/8 match or 5/8 match], you can pretty much find a volunteer unrelated donor for almost 100% of patients,” Devine added. “We are enabling a transplant for everyone, regardless of their ancestry.”
Access disparities
Allogeneic HSCT — used to treat multiple blood cancers and blood disorders — produces the best results when stem cells of a related or unrelated donor matches at 8/8 HLA markers at the HLA-A, -B, -C and -DRB1 genes, according to study background.
Only 30% of patients have siblings, who are HLA-identical matches and therefore could donate.
Non-Hispanic white individuals have a 79% likelihood of finding an unrelated matched donor in the NMDP registry. The rate is between 29% and 58% for people of other races and ethnicities.
“Historically, there’s been roughly a 10% lower chance of survival with each level of mismatch,” Devine said. “That’s why for years the focus has been on trying to find full matches for all patients.”
Cyclophosphamide, a chemotherapy drug used to treat a variety of solid tumors and hematologic cancers, has been repurposed for about 20 years to prevent GVHD after HSCT.
“It’s really revolutionized [stem cell transplant] because its use is associated with a much lower risk for both the acute and more chronic forms of GVHD,” Devine said. “It’s improved outcomes overall, and it’s allowed us to perform mismatched transplants both from related and unrelated donors. So, [for this study], we [wondered whether] those historical differences in outcomes between matched and mismatched transplant [are] as great as they were years ago now that we're using PTCy.”
Methods and results
Devine and colleagues used the CIBMTR database to evaluate outcomes among 10,025 adults (median age, 60.7 years; range, 18-82.7; 56.3% men; 90.1% white) who underwent HSCT between 2017 and 2021.
Patients either had acute leukemia (70.9%) or myelodysplastic syndrome (29.2%).
Nearly three-quarters (72.2%) received matched unrelated donor HSCT with calcineurin inhibitor-based prophylaxis (CNI), 16.7% underwent matched unrelated donor HSCT with PTCy, 6.1% underwent mismatched unrelated HSCT with CNI and 4.5% underwent mismatched unrelated donor HSCT with PTCy.
Median follow-up was 36.6 months (range, 3-77.8).
Patients who underwent mismatched unrelated donor HSCT with PTCy achieved similar OS (HR = 0.96; 95% CI, 0.82-1.18) and GRFS (HR = 0.9; 95% CI, 0.79-1.02) as those who underwent matched unrelated donor HSCT with PTCy.
Individuals who had matched unrelated donor HSCT with PTCy achieved longer OS (HR = 0.88; 95% CI, 0.8-0.96) and GRFS (HR = 0.61; 95% CI, 0.57-0.66) than those who underwent matched unrelated donor HSCT with CNI.
Patients who underwent mismatched unrelated donor HSCT with PTCy achieved longer GRFS than those who underwent matched unrelated donor HSCT with CNI (HR = 0.68; 95% CI, 0.6-0.76).
The benefit of PTCy persisted regardless of patient ancestry.
“We were very surprised and obviously very pleased that the PTCy had attenuated any differences that we had seen historically in those outcomes,” Devine said.
‘Everyone has a donor’
Researchers hope to build on these findings to further improve outcomes.
Incidence of infections is higher with PTCy, and so is risk for cardiac complications among older patients, Devine said.
“The current approaches with PTCy use high doses of cyclophosphamide,” Devine said. “We’re trying to ... lower the doses to see if we can still prevent GVHD but have fewer side effects.”
Dose modification and combination therapy with other immune-suppressive drugs are the next steps in this research.
“We’re trying to understand the science — what mechanistically does PTCy do within each patient?” Devine said. “We have some data suggesting how it acts on the T cells. Knowledge of that might help us develop new drugs that could replicate what it’s doing to the T cells, but maybe not have the same side effects.”
The goal is to develop a safe and effective treatment that would allow clinicians to administer HSCT with lower matching requirements.
Interim results from the ACCESS phase 2 study showed favorable survival outcomes for individuals who underwent peripheral blood HSCT for hematologic malignancies despite using grafts from mismatched unrelated donors.
“We didn’t see differences in outcomes between the [7/8 group and the 5/8 or 6/8 group],” Devine said. “It wasn’t a lot of patients but, between that and a prior study we did, we’re not seeing big differences in outcomes — at least overall survival — between the [7/8 and less than 7/8 groups]. That is really exciting because then it means everyone has a donor.”
For more information:
Steven M. Devine, MD, can be reached at sdevine2@nmdp.org.
References:
- Al Malki MM, et al. Abstract 6503. Presented at: ASCO Annual Meeting 2024; May 30-June 4, 2024; Chicago.
- Shaffer BC, et al. J Clin Oncol. 2024;doi:10.1200/JCO.24.00184.
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