GVHD Prophylactic Regimen Improves 1-Year GRFS Vs Standard in Patients With Hematologic Malignancies Post-HCT

Shernan Holtan, MD

Administration of a novel graft-versus-host-disease (GVHD) prophylaxis regimen consisting of cyclophosphamide, tacrolimus, and mycophenolate mofetil (CellCept) improved 1-year GVHD relapse-free survival (gRFS) compared with tacrolimus plus methotrexate in patients with hematologic malignancies undergoing reduced intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT), according to data from the phase 3 BMT CTN 1703 trial (NCT03959241) and were presented at the 2022 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 RIC allogenic HCT.

“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.

Reference

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.