October 2023

Katie Robinson

Patients undergoing a human leukocyte antigen (HLA)-matched allogeneic hematopoietic cell transplantation (alloHCT) with reduced-intensity conditioning who received a prophylaxis regimen of cyclophosphamide, tacrolimus, and mycophenolate mofetil had longer graft-versus-host disease (GVHD)-free, relapse-free survival than those who received standard prophylaxis of tacrolimus and methotrexate. These findings from a phase III study were published in the New England Journal of Medicine.

“The clinical implications are quite important,” said lead author Javier Bolaños-Meade, MD, of Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore. “We have, after several decades, a new standard for GVHD prophylaxis. The old standard, methotrexate with a calcineurin inhibitor, has been in use since the 1980s. Today, we have evidence from a phase III trial that there is a combination more effective than the old standard.”

A phase II trial by the Blood and Marrow Transplant Clinical Trials Network previously compared three different GVHD prophylaxis strategies with tacrolimus and methotrexate in patients undergoing alloHCT after reduced-intensity conditioning. The trial identified cyclophosphamide, tacrolimus, and mycophenolate mofetil as the most promising regimen to be studied in this phase III trial.

Between June 25, 2019, and June 18, 2021, 431 patients with hematologic cancers were randomized to receive experimental prophylaxis, comprising cyclophosphamide, tacrolimus, and mycophenolate mofetil (n=214; mean age = 64.2 years, 62.6% male), or standard prophylaxis of tacrolimus and methotrexate (n=217; mean age = 64.5 years, 58.1% male). Following reduced-intensity conditioning, the patients underwent alloHCT from an HLA-matched related donor or a matched or 7/8 mismatched unrelated donor.

The primary endpoint was GVHD-free, relapse-free survival at one year, with events defined as grade III or IV acute GVHD (aGVHD), chronic GVHD (cGVHD) requiring systemic immunosuppression, disease relapse or progression, and death from any cause. Secondary endpoints included the cumulative incidence of grades II to IV GVHD and of grade III or IV aGVHD, cGVHD, systemic immunosuppression-free survival, hematologic recovery, engraftment, disease relapse or progression, transplantation-related death, disease-free survival (DFS), overall survival (OS), post-transplantation lymphoproliferative disorders, infections, and other grade 3 to 5 toxic effects.

GVHD-free, relapse-free survival was significantly more common among patients who received experimental prophylaxis than among those who received standard prophylaxis (hazard ratio = 0.64; 95% CI 0.49-0.83; p=0.001). At one year, the adjusted GVHD-free, relapse-free survival was 52.7% (95% CI 45.8-59.2) and 34.9% (95% CI 28.6-41.3) with experimental and standard prophylaxis, respectively.

For the secondary endpoints, the incidence of grade II to IV aGVHD at day 100 was similar with both prophylaxis regimens. The incidence of grade III or IV aGVHD was lower in the experimental prophylaxis group than in the standard prophylaxis group (6.3% vs. 14.7%, respectively) as was the incidence of chronic GVHD (21.9% vs. 35.1%, respectively). A higher incidence of immunosuppression-free survival was seen with experimental prophylaxis than with standard prophylaxis (50.0% vs. 39.7%, respectively) at one year. The incidence of neutrophil recovery at day 28 was lower with experimental prophylaxis than with standard prophylaxis (90.3% vs. 93.4%, respectively), as was the incidence of platelet recovery to more than 20,000 platelets per microliter at day 100 (90.3% vs. 92.8%, respectively). The incidence of grade 2 or 3 infection at one year after transplantation was 40.0% versus 30.4%, respectively, while the incidence of cytomegalovirus reactivation at 100 days after transplantation was 7.3% versus 7.1%, respectively. For relapse and progression at one year, the incidence was 20.8% in the experimental prophylaxis group and 20.2% in the standard prophylaxis group. OS, DFS, and the incidence of transplantation-related death did not differ between the groups.

“The combination of cyclophosphamide, mycophenolate mofetil, and tacrolimus was more effective in achieving the combined endpoint (no severe aGVHD, no severe cGVHD, and no relapse or death) than methotrexate and a calcineurin inhibitor, without worsening other outcomes, such as more severe infections or relapse, for example,” Dr. Bolaños-Meade explained.

As many of the events were assessed at one year, data on late relapses and cGVHD were not fully captured. Further study is required to confirm the findings of a longer immunosuppression-free survival and a lower incidence of severe aGVHD and cGVHD with the cyclophosphamide, tacrolimus, and mycophenolate mofetil prophylaxis regimen.

Any conflicts of interest declared by the authors can be found in the original article.