Post-Transplant Cyclophosphamide Regimen Yields Superior gRFS at 1 Year for GVHD


A 3-drug regimen with post-transplant cyclophosphamide may represent a new prophylactic option for well-matched adults with graft-versus-host disease who underwent reduced-intensity transplant.

The phase 3 BMT CTN 1703 trial (NCT03959241) met its primary endpoint of increasing 1-year graft-versus-host disease (GVHD) relapse-free survival (gRFS) with post-transplant, prophylactic cyclophosphamide, tacrolimus, and mycophenolate mofetil (CellCept) compared with tacrolimus plus methotrexate in patients with GVHD, according to data presented at the 2022 American Society for Hematology (ASH) Annual Meeting.

“Based upon these results, we believe that post-transplant cyclophosphamide, tacrolimus and [mycophenolate] should be the standard GVHD prophylaxis in well-matched adults [undergoing] reduced-intensity transplantation,” Shernan Holtan, MD, associate professor of medicine in the Division of Hematology, Oncology, and Transplantation at University of Minnesota Medical School in Minneapolis, Minnesota, said during her late-breaking abstract presentation on the findings.

Researchers enrolled 431 patients aged 18 years and older with hematologic malignancies who were undergoing reduced-intensity conditioning allogenic hematopoietic cell transplantation.

“The team completed enrollment 1 year ahead of schedule despite [COVID-19],” Holtan noted during the presentation.

Patients were randomized 1:1 to receive post-transplant cyclophosphamide, tacrolimus, and mycophenolate mofetil (n = 214; median age, 66.1 years; 62.6% men) or tacrolimus plus methotrexate (n = 217; median age, 66.3 years; 58.1% men).

The primary end point was gRFS and progression-free survival.

“This is a time-to-event end point, where the events are defined as grade 3 to 4 acute GVHD, chronic GVHD requiring systemic immunosuppression, relapse/progression, or death within the first year,” Holtan said during the presentation

Secondary endpoints of this study included engraftment/chimerism, incidence and severity of acute and chronic GVHD, infections, relapse/progression, and survival.

With a multivariate Cox regression model of the primary end point, researchers found that patients treated with post-transplant cyclophosphamide, tacrolimus, and mycophenolate mofetil had a significantly lower hazard for GVHD relapse or progression-free survival vs. those treated with tacrolimus plus methotrexate (HR = 0.641; 95% CI, 0.492-0.835; P = .001).

The post-transplant cyclophosphamide, tacrolimus, and mycophenolate mofetil group had a higher adjusted 1-year gRFS rate (52.7%; 95% CI, 45.8%-59.2%) compared with the tacrolimus plus methotrexate group (34.9%; 95% CI, 28.6%-41.3%).

“This was owed to a reduction in severe and acute and chronic [GVHD] approximately by two-fold in the arms,” Holtan said.

At day 100 of the study, grade III to IV acute GVHD accounted for 6.3% of patients in the post-transplant cyclophosphamide, tacrolimus, and mycophenolate mofetil group compared with 14.7% in the tacrolimus plus methotrexate group (P = .001). These rates for chronic GVHD requiring IST at 1 year was 12.5% in the triplet group vs 25.0% in the doublet group (P = .001).

At 1 year, both groups had similar rates of relapse/progression (20.8% vs. 20.2%; P = .906) and overall survival after transplant (77.0% vs. 72.2%; P = .252) when post-transplant cyclophosphamide, tacrolimus and mycophenolate mofetil was compared with tacrolimus plus methotrexate. Additionally, GVHD-free survival was 61.9% vs 44.9% in each respective arm (P = .0004) and transplant-related mortality rates were 12.3% vs 17.2% (P = .167).

“These improved [GVHD] outcomes did not come at the expense of relapse,” Holtan said.

Compared with the two-drug combination, patients treated with the three-drug combination had a lower cumulative incidence for engraftment, with neutrophils of at least 500/mm3 by day 28 (90.3% vs. 93.4%; P = .032) and platelet of over 20,000/mm3 by day 100 (90/3% vs 92.8%; P <.001).

The rates of grade 2/3 infection were similar in the three-drug and two-drug combination groups (40.0% vs. 30.4%; P = .018). Notably, most infections occurred early. Additionally, fewer patients who received prophylactic cyclophosphamide achieved an absolute lymphocyte count of over 1000/mm3 vs the doublet group (53.8% vs 63.2% (P <.001)

“We observed more grade 2 infections but not grade 3 infections, and most of these occurred in the first month,” Holtan explained.

She mentioned that further research is already underway.

“We're looking forward to future analyses where we will have patient-reported outcomes and microbiota studies from our companion protocol, BMT CTN 1801,” Holtan said.


Holtan SG, Hamadani M, Wu J, et al. Post-transplant cyclophosphamide, tacrolimus, and mycophenolate mofetil as the new standard for graft-versus-host disease (GVHD) prophylaxis in reduced intensity conditioning: results from phase III BMT CTN 1703. Presented at: 2022 ASH Annual Meeting and Exposition; December 10-13, 2022; New Orleans, LA. Abstract LBA-4.

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