Objectives

To evaluate novel approaches for graft-versus-host disease prophylaxis using a composite endpoint to determine the most promising intervention to be further tested on a phase III clinical trial.

Background

Graft-versus-host disease (GVHD) is a frequent cause of morbidity and mortality after allogenic hematopoietic cell transplantation (HCT). Over the last few decades, the combination of methotrexate and a calcineurin inhibitor have been the standard treatment for GVHD prevention. However, over 50% of patients develop GVHD after HCT. Moreover, in patients who develop GVHD and fail to respond to treatment, survival is poor due to infectious complications, organ failure and toxicity of immunosuppressive agents. Therefore, a strategy is needed that minimizes the incidence of GVHD, without other adverse effects.

The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 1203 trial was initiated to prospectively study three promising interventions for GVHD prevention compared to a contemporary control.

Participants

Eligible patients were 18–75 years old, candidates for a reduced intensity conditioning, and had a related 6/6 match for HLA-A and -B at intermediate resolution, and –DRB1 at high resolution; or unrelated donor who is HLA-matched 7/8 or 8/8 HLA-A, -B, -C and –DRB1 at high resolution using DNA-based typing. Patients with acute leukemia, chronic myelogenous leukemia, or myelodysplasia with no circulating blasts and with less than 5% blasts in the bone marrow; chronic lymphocytic leukemia/small lymphocytic lymphoma, as well as follicular, marginal zone, diffuse large-B cell, Hodgkin, or mantle cell lymphoma with chemosensitive disease at time of transplant were eligible to participate.

273 patients were randomly assigned to the three study arms: 89 to tacrolimus, methotrexate, and bortezomib (TAC/MTX/BOR); 92 to tacrolimus, methotrexate, and maraviroc (TAC/MTX/MVC); and 92 to tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide (TAC/MMF/PTCy). The 224 patients in the control group received tacrolimus and methotrexate (TAC/MTX).

Design

The BMT CTN 1203 study was a randomized phase II, open label, multicenter trial comparing each of three novel treatment arms to a nonrandomized prospective contemporary control. Randomization was performed in a 1:1:1 ratio using permuted blocks with random block sizes, stratified by donor type (HLA-matched sibling vs. matched unrelated vs. mismatched unrelated) and disease risk (high vs. low). HCT centers not participating in the clinical trial were recruited to participate in the control arm using data collected by the Center for International Blood and Marrow Transplant Research (CIBMTR).

Patients in the clinical trial were randomized to one of three GVHD prophylaxis regimens: TAC/MTX/BOR (bortezomib 1.3mg/m2 intravenously on days +1, +4 and +7 post HCT), TAC/MTX/MVC (maraviroc 300 mg orally twice daily from day -3 to day +30 post HCT), or TAC/MMF/PTCy (cyclophosphamide 50mg/kg on days +3 and +4 followed by TAC starting on day +5, and mycophenolate mofetil 15mg/kg three times a day from day +5 to day +35). MTX was administered at doses of 15 mg/m2 IV bolus on day +1, and 10 mg/m2 IV bolus on days +3, +6 and +11 post HCT. TAC was given intravenously at a dose of 0.05 mg/kg twice daily (or oral equivalent) starting day -3, with a target level of 5–15 ng/mL. TAC was recommended to continue at least until day +90 and to be completely tapered off by day +180. Dose adjustments were allowed when specific criteria were met. Other supportive care was provided per institutional standards.

The primary endpoint of GVHD-free, relapse-free survival (GFRS) was measured as the time from HCT to the first of four events: onset of grade III-IV acute GVHD, chronic GVHD requiring systemic immunosuppression, disease relapse, or death.

Conclusions

The tacrolimus/mycophenolate mofetil/post-transplant cyclophosphamide intervention had better GVHD-free, relapse-free survival compared to the control. Based on these findings, a phase III clinical trial will be launched to compare high-dose post-transplant cyclophosphamide with methotrexate and calcineurin inhibitor for graft-versus-host disease prophylaxis.

Bolaños-Meade J, Reshef R, Fraser R, et al. Three prophylaxis regimens (tacrolimus, mycophenolate mofetil, and cyclophosphamide; tacrolimus, methotrexate, and bortezomib; or tacrolimus, methotrexate, and maraviroc) versus tacrolimus and methotrexate for prevention of graft-versus-host disease with haemopoietic cell transplantation with reduced-intensity conditioning: a randomised phase 2 trial with a non-randomised contemporaneous control group (BMT CTN 1203). Lancet Haematol. 2019;6(3):e132-e143. doi:10.1016/S2352-3026(18)30221-7

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