New Prophylaxis Emerging in Graft Versus Host Disease

Shernan G. Holtan, MD

A novel treatment for graft versus host disease is showing a lot of promise in new data from a late-breaking abstract presented during American Society of Hematology (ASH) Annual Meeting and Exposition.

A team, led by Shernan G. Holtan, MD, University of Minnesota, compared the outcomes of alloHCT in a randomized phase 3 trial of patients treated with a new GVHD treatment compared to standard treatment.

Standard Therapy

Currently, the standard prophylaxis strategy to prevent GVHD is a calcineurin inhibitor like tacrolimus (Tac) plus methotrexate (MTX).

“Controlling both GVHD and disease relapse is essential for allogeneic hematopoietic cell transplantation (alloHCT) success,” the authors wrote.

While in recent years investigators have attempted several different alternative approaches to improve Tac/MTX treatment, intensifying immunosuppression often results in an increased risk of serious infections or relapse with no effect on chronic GVHD even if acute GVHD is reduced.

For example, a recent phase 2 trial conducted by the Blood and Marrow Transplant Clinical Trials Network compared 3 novel GVHD prophylaxis regimens to contemporaneous controls treated with Tac/MTX.

A Novel New Treatment

The most promising treatment to come out of that trial is BMT CTN 1203, a 3-drug combination of post-transplant cyclophosphamide (PTCy), tacrolimus, and mycophenolate mofetil (PTCy/Tac/MMF).

In the study, the investigators examined adult patients with hematologic malignancies undergoing RIC alloHCT with an 6/6 matched related (n = 128), 8/8 matched unrelated (n = 288), or 7/8 single mismatch (n = 15) peripheral blood stem cell donor, satisfactory organ function, and adequate performance status. Each participant was randomized to receive either PTCy/Tac/MMF (n = 214) or Tac/MTX (n = 217).

The patients were then stratified by transplant center and Disease Risk Index (DRI) and balanced by patient sex, age, Karnofsky performance status, disease risk, comorbidities, donor match, conditioning regimen, and post-transplant maintenance therapy.

The investigators sought primary endpoints of GVHD/relapse or progression-free survival (GRFS), a time-to-event outcome defined as grade III-IV acute GVHD, chronic GVHD requiring systemic immune suppression, disease relapse or progression, or death by any cause.

They also sought secondary endpoints of the incidence/severity of acute and chronic GVHD, engraftment/chimerism, relapse/progression, infections, and survival.

They also had a primary hypothesis that the novel treatment has at least a 15% higher GRFS at 1 year compared to the standard therapy in the intent-to-treat population.

Promising Results

The investigators used a multivariate Cox regression model and found the PTCy treatment group had a significantly lower hazard of GRFS than the standard therapy group (HR, 0.641; 95% CI, 0.492-0.835; P = 0.001).

The adjusted 1-year GRFS rates was 52.7% (95% CI, 45.8-59.1%) in the PTCy arm and 34.9% (95% CI, 28.6-41.3%) for the control arm.

However, there was a lower proportion of GRFS events in the treatment arm because of a reduction in both acute and chronic GVHD.

The day 100 grade 3-4 acute GVHD was 6.3% in the PTCy group compared to 14.7% in the standard group (P = 0.001), while the chronic GVHD at 1 year was 21.9% compared to 35.1% (P = 0.005).

There was no difference in the relapse/progression rate at 1 year (20.8% vs 20.2%; P = 0.9). There was also no differences in the OS rate at 1 year post transplant between the 2 groups (76.8% vs 72.6%; P = 0.3).

The cumulative incidence of engraftment was lower for the patients treated with PTCy for neutrophils at least 500/mm3 by day +28 (90.3% vs 93.4%, P = 0.03), platelets at least 50,000/mm3 by day +100 (79.5% vs 83.7%, P <0.001), and lymphocytes at least 1000/mm3 by 1 year (47.1% vs 63.2%, P <0.001).

For safety, the rate of grade 3 infections were similar between the 2 groups (12.2% vs 13.3%, P = 0.8). However, the PTCy group had more grade 2 infections (33.7% vs. 23.5%; P = 0.8).

There were no significant differences found in the proportion of chimerism at day 100 (>95% donor in 68.6% vs 67.8%, P = 0.2) or secondary graft failure between the arms (2.9% vs 0.9%, P = 0.2).

“BMT CTN 1703 met its primary endpoint, demonstrating a higher 1-year GRFS with PTCy/Tac/MMF compared to Tac/MTX owing to significant improvements in GVHD risk without increased risk of relapse or death,” the authors wrote. “PTCy/Tac/MMF, which has become standard of care for mismatched transplants, should also become the standard of care for GVHD prophylaxis from closely-matched donors receiving reduced intensity conditioning.”

The study, “LBA-4 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,” was published online by ASH 2022.