To Compare the Efficacy of the Addition of Methotrexate (MTX) to Current Standard Acute Graft-versus-host Disease (GVHD) First-line Treatment With Corticosteroids

Phase III randomized double-blinded trial designed to compare the efficacy of the addition of MTX to current standard acute GVHD first-line treatment with corticosteroids. The protocol will use a novel endpoint for benchmarking interventions based on a composite primary endpoint of GVHD-free and corticosteroids-free survival. The primary endpoint of the trial will be the assessment of a composite endpoint of graft-versus-host disease-free and corticosteroids-free survival at 12 months after randomization

Inclusion Criteria: * Adults patients (\>=18 years old) with hematological diseases, who develop a first episode of acute GVHD (grade II-IV) requiring systemic therapy * First allo-SCT, with any type of donor, stem cell source, GVHD prophylaxis or conditioning regimen * Biopsy of acute GVHD target organ is recommended, but not required. Enrollment should not be delayed awaiting biopsy or pathology results * The patient must have received no previous systemic immune suppressive therapy for treatment of acute GVHD, except for a maximum 72 hours of prior corticosteroid therapy * Absolute neutrophil count (ANC) greater than 0.5 G/L * Platelets count greater than 20 G/L * Signed informed consent * Affiliation to a social security system (recipient or assign) * Women who are of childbearing potential must have a negative serum pregnancy test and agree to use a medically acceptable method of contraception until 6 months after the end of treatment. Men with a partner of childbearing potential must agree to use a medically acceptable method of contraception until 6 months after the end of treatment. Exclusion Criteria: * Hyper-acute GVHD as defined by the MD Anderson's criteria (Saliba, de Lima et al. 2007) * Flare of GVHD in a patient already on corticosteroid treatment * Overlap chronic GVHD as defined by the NIH Consensus Criteria (Jagasia, Greinix et al. 2015) * MTX given within 7 days of enrollment * Active uncontrolled infection * Relapsed/persistent malignancy requiring rapid immune suppression withdrawal * Acute GVHD after donor lymphocytes infusion (DLI) * Other systemic drugs for GVHD treatment (including extra-corporeal photopheresis) * If any prior steroid therapy (for indication other than GVHD), treatment at doses \> 0.5 mg/kg/day methyl-prednisolone within 7 days prior to onset of acute GVHD * Patients who are pregnant, breast feeding, or if sexually active, unwilling to use effective birth control for the duration of the study * Patient on dialysis * Patients with veno-occlusive disease of the liver or with significant liver abnormalities who in the judgment of the treating physician cannot receive MTX * Patients requiring after inclusion in the protocol the continuation of one or more of the following medication: probenecide, trimethoprime (alone or in combination with sulfametoxazole), phenylbutazone or yellow fever vaccine * Patients with a history of intolerance/allergy to MTX * Hypersensitivity to the active substance or to any of the excipients