Paper Details

ABSTRACT

Introduction:

Methotrexate, a well-established immunosuppressive agent widely used in graft-versus-host disease (GVHD) prophylaxis, has demonstrated activity in the treatment of steroid-refractory acute (a) and chronic (c) GVHD. Here we present the final analysis of MTX-aGVHD (EudraCT 2017-002691-98), a randomized Phase 3 study evaluating the add-on of methotrexate with corticosteroids (CS) as first-line treatment of patients with aGVHD.

 Methods:

Adult with newly diagnosed grade II-IV aGVHD, were randomized 1:1 within 72 hours of initiating 2 mg/Kg/d prednisone, to receive either methotrexate (3 mg/m² weekly for 4 weeks, followed by 3 mg/m² x 6 doses Q2) or placebo (weekly for 4 weeks, followed by 6 doses Q2). Patients were stratified by grade of aGVHD (II vs. III-IV) at study entry and by transplant center. Participants were followed for up to 1 year after randomization. GVHD-free and CS-free survival (EFS) at 1 year after randomization was the primary endpoint; key secondary endpoints were overall response rate (ORR) at Day 28 and 56, and best response within the first 12 months after randomization. Additional endpoints included overall survival (OS), and non-relapse mortality (NRM). Efficacy analyses were performed in the intention-to-treat population (all randomized subjects). This study was supported by the French Hospital Clinical Research Program in Cancer (PHRC-K).

Results:

A total of 104 patients were randomized to methotrexate (n=48) or placebo (n=56). Baseline characteristics were balanced between treatment groups. Median age was 59 years (range: 18-75); 63% of patients were male; 33% had grade III-IV aGVHD, and 55% had gastrointestinal involvement.

In the intention-to-treat population, 1 year EFS was 58% with methotrexate and 47% with placebo (p=0.43). ORR at Day 28 was 71% versus 75% (p=0.66) and ORR at Day 56 was 65% versus 63% for methotrexate vs. placebo respectively (p=0.84). One-year OS rates was 75% with methotrexate and 65% with placebo (p=0.62), while 1-year NRM was 29% and 34%, respectively (P=0.70). Relapse incidence was similar between groups: 6% versus. 5% (p=0.93). The one-year cumulative incidence of moderate to severe chronic GVHD was 7.4% with methotrexate and 10% with placebo  (p=0.50). 1 year cumulative incidence of primary disease

Among patients with grade II acute GVHD, methotrexate resulted in significantly higher 1-year EFS than placebo: 72% vs. 42%, representing an absolute improvement of 30 percentage points (P=0.046). Day 28 ORR was 80% versus 78%, respectively. One-year OS was also numerically higher with methotrexate: 84% vs. 62% (P=0.057). No benefit was observed among patients with grade III–IV acute GVHD, in whom EFS was 39% versus 56% (P=0.39) and OS was 50% versus 70% (P=0.26).

Seventy-five patients (72%) experienced at least one serious adverse event. Serious adverse events occurred in 36 patients receiving methotrexate (75%) and 39 receiving placebo (70%). Infections were the most common serious adverse events, occurring in 27 patients (56%) and 26 patients (46%), respectively. No new safety signal was identified.

Conclusions:

Although the primary endpoint was not met in the overall grade II–IV population, methotrexate produced a clinically meaningful 30-percentage-point improvement in 1-year GVHD-free and corticosteroid-free survival among patients with grade II acute GVHD, accompanied by a strong trend toward improved overall survival and no new safety signal. These findings identify grade II acute GVHD as a promising setting in which early low-dose methotrexate can provide an effective and readily available first-line partner to corticosteroids.