GVHD PROPHYLAXIS WITH METHOTREXATE IN HAPLOIDENTICAL HCT USING POSTTRANSPLANT CYCLOPHOSPHAMIDE: A PHASE IB/II CLINICAL TRIAL (NCT04622956)

Abstract

Introduction: In haploidentical hematopoietic cell transplantation (Haplo-HCT), the prevailing Graft-Versus-Host Disease (GVHD) prophylaxis in Brazil consists of posttransplant cyclophosphamide (PTCY) with cyclosporine and Mycophenolate Mofetil (MMF). While comparisons between MMF and Methotrexate (MTX) for GVHD prophylaxis have sparked debate in other donor types, some large studies indicate that MTX is linked to a reduced risk of GVHD and improved long-term outcomes. It's worth noting that MMF, a potent inhibitor of NK cells, could potentially interfere with the graft-versus-leukemia effect in Haplo-HCT. Additionally, IV MMF is not available in Brazil, which poses challenges for patients undergoing HCT. Objective: Our aim was to conduct a phase Ib/II study to assess the efficacy of MTX in adult patients with hematologic malignancies undergoing Haplo-HCT with PTCY. Herein, we present the findings from the phase I portion of this investigation. Methods: This ongoing single-arm, multicenter phase 1/2 study evaluates MTX administered on D+6 and +9 alongside PTCY at 50 mg/kg/day on D+3 and +4, with cyclosporine starting on day +5 until D +90 or beyond in the event of GVHD. The phase 1 part enrolled eligible adult patients with hematologic malignancies undegoing myeloablative Haplo-HCT. A 3+3 escalation design was employed to assess the safety and tolerability of three MTX dose levels: 0 (10 mg/m2 on D+6 and 7.5 mg/m2 on D+9), +1 (10 mg/m2 on D+6 and +9), and +2 (15 mg/m2 on D+6 and 10 mg/m2 on D+9). The primary objective was to determine the MTX dose for the phase 2 part of the study. Results: A total of 15 patients were enrolled: 6 at Level 0, 6 at Level +1, and 3 at Level +2. Most patients had acute leukemia or chronic myeloid leukemia. All patients received mobilized peripheral stem cells, except for two patients in the Level +1 group who received bone marrow grafts. Dose-Limiting Toxicities (DLTs) included transient increases in ALT/AST or total bilirubin at Level 0 and Level +1. The Maximum Tolerated Dose (MTD) was not reached. Febrile neutropenia and grade 3‒4 transplant-related toxicities occurred in 6/6, 4/6, and 3/3 patients at Levels 0, +1, and +2, respectively. The rates of grade 3-4 infectious complications, excluding febrile neutropenia and CMV reactivation, were 0.43 and 0.21, 0.37 and 0.34, and 0.23 and 0.46 events per patient per 100 days at risk at Levels 0, +1, and +2, respectively. Other adverse events were consistent with this patient population. Neutrophil engraftment was achieved in all patients, with median times of 19.5 days (range 17‒25), 19 days (17‒22), and 20 days (17‒22) for Levels 0, +1, and +2, respectively. Grades 2 and 3 acute GVHD up to day +90 occurred in 3 (50%)/2 (33%), 1 (17%)/1 (17%), and 1 (33%)/1 (33%) patients at Levels 0, +1, and +2, respectively. Moderate to severe chronic GVHD was diagnosed in one patient (17%) at Level 0 and two patients (34%) at Level +1. One patient at Level 0 with ALL who had prior anthracycline exposure developed heart failure on day +6 and died on day +56. Another patient at Level +2 experienced disease relapse and died. To date, all other patients are alive and remain disease-free. Conclusions: GVHD prophylaxis with MTX in Haplo-PTCY appears to be safe and well-tolerated in this myeloablative HCT population, with no MTD reached. These findings support the continuation of the phase II portion of the study, which is currently accruing with MTX doses of 15 mg/m2 on day +6 and 10 mg/m2 on day +9. Updated data will be presented at the forthcoming meeting.