Novel regimen significantly lowers GVHD risk after reduced-intensity allogeneic HSCT
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NEW ORLEANS — A regimen containing post-transplant cyclophosphamide significantly lowered graft-versus-host disease risk among adults who underwent reduced-intensity allogeneic hematopoietic stem cell transplant, study results showed.
Data from the randomized, phase 3 BMT CTN 1703 study, presented at ASH Annual Meeting and Exposition, revealed those who received the GVHD prophylaxis regimen after transplantation with closely matched donor grafts had a twofold reduction in severe acute and chronic GVHD risk compared with a control group of patients who received standard therapy with tacrolimus and methotrexate.
The combination should serve as a new standard of care for GVHD prophylaxis after reduced-intensity allogeneic HSCT, the investigators concluded.
Background
Since the 1980s, standard GVHD prophylactic therapy after allogeneic HSCT included a doublet of a calcineurin inhibitor plus methotrexate, according to Shernan G. Holtan, MD, associate professor of medicine in the division of hematology, oncology and transplantation at University of Minnesota.
Several approaches have attempted to improve upon the combination of tacrolimus and methotrexate, but they have led to increased risk for serious infections or relapse with little effect on chronic GVHD rates, she added.
Results of the randomized, phase 2 BMT CTN 1203 study suggested the optimal treatment would be the combination of post-transplant cyclophosphamide, tacrolimus and mycophenolate mofetil (PTCy/Tac/MMF), which was the “clear winner” when compared with other experimental GVHD prophylactic treatment arms in the study, Holtan noted.
“Therefore, that treatment arm was carried forward into BMT CTN 1703, a randomized study comparing post-transplant cyclophosphamide, tacrolimus and mycophenolate mofetil with tacrolimus/methotrexate control,” she said during a presentation.
Methodology
BMT CTN 1703 included adults with hematologic malignancies undergoing reduced-intensity allogeneic HSCT with peripheral blood stem cell grafts from well-matched donors.
The study included 431 patients enrolled at 37 centers between June 25, 2019, and June 18, 2021, with a data cutoff date of Sept. 19, 2022.
Researchers randomly assigned study participants in a 1:1 ratio to receive either PTCy/Tac/MMF (n = 214; median age, 66.1 years; range, 20.7-78.6; 62.6% men) or tacrolimus plus methotrexate (n = 217; median age, 66.3 years; range, 26.3-77.4; 58.1% men).
One-year GVHD, disease relapse or PFS (GRFS) — defined as grade III or grade IV GVHD, chronic GVHD requiring systemic immune suppression, disease relapse, disease progression or death due to any cause — served as the study’s primary endpoint. Secondary endpoints included incidence and severity of acute or chronic GVHD, engraftment, disease relapse or progression, infections, transplant-related mortality, OS and patient-reported outcomes.
Key findings
The study met its primary endpoint, demonstrating a significantly higher adjusted 1-year GRFS rate of 52.7% (95% CI, 45.8-59.2) with PTCy/Tac/MMF compared with 34.9% (95% CI, 28.6-41.3) for the tacrolimus-plus-methotrexate control group.
Multivariate analysis showed significantly lower hazard of GRFS in the PTCy/Tac/MMF group compared with the control group (HR = 0.64; 95% CI, 0.49-0.83).
The investigators observed significantly lower rates of grade 3 or grade 4 acute GVHD at day 100 (6.3% vs. 14.7%; P = .001) and chronic GVHD requiring immunosuppression at 1 year (12.5% vs. 25%; P = .001) among patients who received PTCy/Tac/MMF compared with the control group.
Researchers noted no significant differences when comparing 1-year disease relapse/progression or OS rates between the treatment groups.
Grade 2 infections occurred more frequently in the PTCy/Tac/MMF group (33.7% vs. 23.5%; P= .002), whereas the two groups had similar grade 3 infection ratess.
Two deaths (4.2%) attributed to acute GVHD occurred in the PTCy/Tac/MMF group compared with eight acute GVHD-related (14.3%) deaths in the control group.
Clinical implications
The superior GRFS observed among patients who received PTCy/Tac/MMF vs. standard of care can be attributed to a substantial reduction in severe and acute chronic GVHD, with no increase in relapse or progression, only slightly delayed hematopoietic recovery and more grade 2 but not grade 3 infections, Holtan noted.
“Based on these results, we believe that post-transplant cyclophosphamide, tacrolimus and MMF should be standard GVHD prophylaxis in [adults undergoing] well-matched, reduced-intensity peripheral blood stem cell transplantation,” she told the audience. “We are looking forward to future planned analyses on patient-reported outcomes and microbiota studies.”
Perspective
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Ira Braunschweig, MD
PTCy is one of the most important advances ever in the field of stem cell transplantation. Pioneered by a group from Johns Hopkins, PTCy made haploidentical transplants feasible and successful from an engraftment, infection and GVHD perspective, making available a potentially curative modality to many patients with hematologic malignancies who otherwise could not get a transplant because of lack of an appropriate donor.
The question was, would PTCy make a positive impact on outcomes for matched transplants, as well? Based on phase 2 study data, the Blood and Marrow Transplant Clinical Trials Network initiated a prospective randomized study that showed superior GRFS for patients receiving PTCy/Tac/MMF when compared with the standard of tacrolimus plus methotrexate. This is especially gratifying because many previous attempts to improve on the standard have failed. Importantly, at 1 year, PTCy/Tac/MMF lowered the risk for both acute and chronic GVHD, with no difference in serious infections or relapse/progression.
I look forward to longer follow up on this study. There was no survival difference at 1 year, but will the difference in GVHD translate to better survival at 2 years? Conversely, will there be more late relapses when this regimen is used? Even if so, we are much better equipped to deal with the risk for relapse than we were 10 years ago, either with novel agents used in the maintenance setting, donor lymphocyte infusions based on sophisticated analysis of chimerism and better assessments of early relapse. Also, keep in mind, the patient cannot make it to 5 years if they are not alive at 2.
Indeed, it seems that we have a new standard for GVHD prophylaxis for reduced-intensity transplants. At long last, we are making an impact on “the fly in the ointment.”
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Holtan S, et al. Abstract LBA-4. Presented at: ASH Annual Meeting and Exposition; Dec. 10-13, 2022; New Orleans.
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