Novel regimen reduces chronic GVHD after allogeneic stem cell transplantation
Key takeaways:
- The addition of post-transplant cyclophosphamide to sirolimus and cyclosporine reduced chronic GVHD.
- Efforts are needed to optimize cyclophosphamide dose to reduce toxicity.
A novel regimen significantly reduced risk for moderate to severe chronic graft-versus-host disease for certain patients who underwent allogeneic hematopoietic stem cell transplantation, according to randomized phase 2 study results.
The regimen also resulted in improved 1-year chronic GVHD-free RFS.
Prior research showed incidence of chronic GVHD after allogeneic HSCT ranges from 30% to 50% depending on the donor graft source and type of GVHD prophylaxis regimen used.
Use of post-transplant cyclophosphamide has greatly reduced incidence of severe acute and chronic GHVD.
Masumi Ueda Oshima, MD, MA, associate professor in the clinical research division at Fred Hutch Cancer Center, and colleagues conducted a single-center study to evaluate whether substituting cyclophosphamide for a standard post-transplant immunosuppressant could improve outcomes.
“This is an important area of research,” Ueda Oshima told Healio. “This trial was really focused on trying to prevent chronic GVHD and prevent patients from having a potentially debilitating condition even after they’re done with their treatment.”
The trial included 145 adults with hematologic malignancy who underwent HLA-matched or HLA-mismatched unrelated donor peripheral blood stem cell transplant at Fred Hutch Cancer Center between November 2017 and May 2024.
All participants had cardiac ejection fraction of 35% or greater. A majority (64.1%) of patients in the cohort had acute myeloid leukemia.
Conditioning regimens included fludarabine 90 mg/m2 with 2 Gy to 3 Gy total body irradiation, or fludarabine 120 mg/m2 with melphalan 100 mg/m2 and 2 Gy to 3 Gy total body irradiation.
Researchers randomly assigned 73 patients (median age, 66.3 years; range, 30.1-76.9) to sirolimus and cyclosporine plus mycophenolate mofetil. The other 72 patients (median age, 67.6 years; range, 37-77.4) received sirolimus and cyclosporine plus post-transplant cyclophosphamide.
Results showed a significant improvement in 1-year chronic GVHD-free RFS (73% vs. 48%; P = .005) — the study’s primary endpoint — and a significantly reduced rate of moderate to severe chronic GVHD (3% vs. 33%; P = .0004) in the post-transplant cyclophosphamide group.
Fifteen percent of patients assigned each regimen had relapsed at 1 year (HR = 1.03; P = .94).
Results showed no statistically significant difference in nonrelapse mortality (10% vs. 7%; P = .54) or 1-year OS (86% vs. 86%; HR = 1.05; P = .92) between the post-transplant cyclophosphamide and mycophenolate mofetil groups.
“We think this regimen deserves further study in a multicenter fashion, and we are exploring some potential opportunities for that,” Ueda Oshima told Healio.
A numerically higher percentage of patients assigned post-transplant cyclophosphamide experienced grade 3 or grade 4 respiratory (10% vs. 9%), cardiac (10% vs. 3%) and renal (19% vs. 14%) adverse events. Researchers reported three grade 5 respiratory toxicities — two in the post-transplant cyclophosphamide group and one in the mycophenolate mofetil group.
Higher percentages of patients assigned post-transplant cyclophosphamide also developed grade 3 or grade 4 increases in bilirubin, alanine aminotransferase or aspartate transferase (16% vs. 3%), as well as grade 3 hemolytic uremic syndrome (10% vs. 3%).
Grade 3 or higher infections occurred more frequently with post-transplant cyclophosphamide (44% vs. 19%; HR = 2.65; 95% CI, 1.41-4.97), with two grade 5 cases. BK Viruria also occurred more frequently with post-transplant cyclophosphamide (35% vs. 14%; HR = 2.96; 95% CI, 1.42-6.18).
“We do want to acknowledge that there were some higher toxicities and higher infection, so one next step would be to optimize the dose of the post-transplant cyclophosphamide,” Ueda Oshima said. “[This] has been an emerging area of research in GVHD prevention to see how much post-transplant cyclophosphamide you really need to ... still have this impact on GVHD but also not have the excess toxicities.”
References:
For more information:
Masumi Ueda Oshima, MD, MA, can be reached at mueda@fredhutch.org.
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