to compare the efficacy of the addition of methotrexate (mtx) to current standard acute graft-versus-host disease (gvhd) first-line treatment with corticosteroids

Conditions: Allogeneic Disease; GVH - Graft Versus Host Reaction; GVHD, Acute; Stem Cell Transplant Complications

Summary: 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

this is a phase iii randomized, multicenter, double blinded controlled study. patients who develop clinically meaningful acute gvhd and who meet all other entry criteria will be randomized 1:1 to receive either corticosteroids and placebo ("standard of care", control arm) or the combination of low-dose mtx with corticosteroids as first-line therapy for acute gvhd (mtx; "experimental arm"). the primary analysis of this hypothesis generation study is to estimate the composite endpoint of gvhd-free and corticosteroids-free survival at 12 months after randomization in both treatment arms. in fact, it is more and more established that such composite endpoint is a clinically very relevant one because it represents ideal recovery from allo-sct (stem cell transplantation) (at 1 year after acute gvhd diagnosis) and a measure of cure without ongoing morbidity.

Eligibility criteria:
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

Keywords: hematopoietic stem cell methotrexate corticosteroids therapy acute gvhd allogenic stem cell transplantation