Objectives

To compare two graft-vs.-host-disease prophylaxis strategies in patients undergoing hematopoietic stem cell transplantation after reduced-intensity conditioning.

Background

The combination of methotrexate and a calcineurin inhibitor has been the standard of care for graft-vs.-host disease (GVHD) prevention in patients undergoing allogeneic transplantation. However, acute GVHD, chronic GVHD, or both develop in more than half of these patients, resulting in complications and death.

In 2013, the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) launched a phase 2 clinical trial (BMT CTN 1203) comparing three different GVHD prophylaxis strategies with a contemporaneous control regimen of tacrolimus/methotrexate (Tac/MTX) in patients undergoing hematopoietic stem cell transplantation (HSCT) after reduced-intensity conditioning (RIC). That trial identified the combination of cyclophosphamide/tacrolimus/mycophenolate mofetil (PTCy/Tac/MMF) as the most promising regimen. BMT CTN 1703 was a phase 3 follow up study initiated to compare PTCy/Tac/MMF to Tac/MTX.

Participants

Eligible participants were aged 18 years or older and undergoing their first allogeneic transplantation. Eligible diagnoses included: acute leukemia or chronic myeloid leukemia with no circulating blasts and less than 5% blasts in the bone marrow or myelodysplasia or chronic myelomonocytic leukemia with no circulating blasts and fewer than 10% blasts in the bone marrow, chronic lymphocytic leukemia or small lymphocytic lymphoma, or lymphomas that were sensitive to therapy.

A total of 431 participants were enrolled and underwent randomization. 214 participants were assigned to receive experimental prophylaxis and 217 participants were assigned to receive standard prophylaxis.

Design

The BMT-CTN 1703 study was a randomized, multicenter Phase 3 clinical trial. Participants with hematologic cancers were randomly assigned in a 1:1 ratio to receive PTCy/Tac/MMF (experimental prophylaxis) or Tac/MTX (standard prophylaxis). The participants underwent HSCT from an HLA-matched related donor or a matched or 7/8 mismatched (i.e., mismatched at only one of the HLA-A, HLA-B, HLA-C, and HLA-DRB1 loci) unrelated donor, after reduced-intensity conditioning.

The experimental prophylaxis regimen consisted of the following: cyclophosphamide (50 mg per kilogram per day on days 3 and 4 after HSCT); tacrolimus starting on day 5 (orally at a dose of 0.05 to 0.06 mg per kilogram per day or intravenously at a dose of 0.02 to 0.03 mg per kilogram per day; taper could start on day 90 with a goal of discontinuation by day 180); and mycophenolate mofetil (15 mg per kilogram per dose orally or intravenously), not to exceed 1 g thrice daily, starting on day 5 to day 35. The standard-prophylaxis regimen consisted of methotrexate (an intravenous bolus of 15 mg per square meter on day 1 and an intravenous bolus of 10 mg per square meter on days 3, 6, and 11) and tacrolimus (dose as above, starting 3 days before HSCT; taper could start on day 90 with a goal of discontinuation by day 180).

The primary end point was GVHD-free, relapse-free survival at 1 year, assessed in a time-to-event analysis, with events defined as grade III or IV acute GVHD, chronic GVHD warranting systemic immunosuppression, disease relapse or progression, and death from any cause.

Conclusions

Among patients undergoing allogeneic HLA-matched HSCT with reduced-intensity conditioning, GVHD-free, relapse-free survival at 1 year was significantly more common among those who received cyclophosphamide/tacrolimus/mycophenolate mofetil than among those who received tacrolimus/methotrexate.

Bolaños-Meade J, Hamadani M, Wu J, et al. Post-Transplantation Cyclophosphamide-Based Graft-versus-Host Disease Prophylaxis. N Engl J Med. 2023;388(25):2338-2348. doi:10.1056/NEJMoa2215943

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