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)

Abstract

Background. Prevention of GVHD without malignant relapse reflects the overall goal of allogeneic hematopoietic cell transplantation (HCT). Novel regimens utilizing either maraviroc (MVC), bortezomib (BOR), or post-transplant cyclophosphamide (PTCy) have been reported to modulate GVHD and were tested against commonly used combination of tacrolimus (TAC) and methotrexate (MTX). The study aim was to evaluate each of these novel approaches for GvHD prophylaxis compared to contemporary controls using a novel composite primary endpoint to determine the most promising intervention to be further tested on a phase III clinical trial. Methods. This completed prospective multicenter phase II trial randomly assigned adult patients, aged 18–75, who received reduced intensity conditioning HCT to TAC/MMF/PTCy (Cy 50mg/kg on days +3 and +4, followed by TAC starting on day +5 and MMF starting on day +5 at 15mg/kg every 8 hours from day +5 to day +35); TAC/MTX/BOR (BOR 1.3mg/m2 IV on days +1, +4 and +7 post HCT); or TAC/MTX/MVC (MVC 300 mg PO twice daily from day –3 to day +30 post HCT). MTX was administered at 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 (except the PTCy as indicated), with a target level of 5–15 ng/mL. TAC continued at least until day +90 and was tapered off by day 180. Each compared separately to a contemporary nonrandomized prospective cohort of patients who fulfilled the same eligibility criteria as the trial but treated with TAC/MTX at centers not participating in the trial. The primary endpoint (GFRS) was measured as the time from HCT to first of four events: onset of grade III-IV acute GVHD (aGVHD), chronic GVHD (cGVHD) requiring systemic immunosuppression (IS), disease relapse, or death. Randomization was performed in a 1:1:1 ratio using random block sizes for the three arms. The study was analyzed as a modified intent to treat. The study is closed to accrual and this is the study planned analysis. (ClinicalTrials.gov NCT#02208037). Findings. 273 patients were randomized between the 3 study arms; 224 controls received Tac/MTX. Controls were generally well balanced except for more frequent comorbidities and type of conditioning regimens utilized. Compared to controls, hazard ratio (HR) for GRFS were 0.72 (90% CI 0.54, 0.94) (p=0.04), 0.98 (90% CI 0.76, 1.27) (p=0.92) and 1.11 (90% CI 0.86, 1.41)(p=0.45) for TAC/MMF/PTCy, TAC/MTX/BOR and TAC/MTX/MVC, respectively. Overall, 238 patients experienced grades 3 and 4 toxicities: TAC/MMF/PTCy 12 (13%) and 67 (72.8%), TAC/MTX/BOR 10 (11.2%) and 68 (76.4%), and TAC/MTX/MVC 18 (19.6%) and 63 (68.5%) respectively. The most common toxicities where hematological: TAC/MMF/PTCy 77(83.7%), TAC/MTX/BOR 73 (82%), TAC/MTX/MVC 78 (84.8%) and cardiac: TAC/MMF/PTCy 43(46.7%), TAC/MTX/BOR 44 (49.4%), TAC/MTX/MVC 43 (46.7%).Interpretation. TAC/MMF/PTCy was the most promising intervention yielding the best GRFS; and the best to prospectively compare to TAC/MTX in a phase III randomized trial.