The purpose of this study is to assess the impact of folinic acid (FA) -rescue following methotrexate (MTX) graft-versus-host disease (GVHD) prophylaxis on regimen related toxicity and transplantation outcomes after allogeneic hematopoietic cell transplantation (alloHCT) in a double blind randomized controlled trial.

A regimen consisted on a combination of a calcineurin inhibitor (CNI) with a short course of methotrexate (MTX) is the most widely used regimen for the prevention of GVHD after allogeneic hematopoietic cell transplantation (alloHCT). While the CNI is given in an adjusted dose, based on blood levels, MTX is given at a fixed 3 or 4 doses (15 mg/m2 on day +1, 10 mg/m2 on days +3, +6 +/- day +11). However, its use may be associated with considerable toxicity, including delayed engraftment, hepatotoxicity, nephrotoxicity and particularly oral mucositis (OM). The basis for OM is integrated: conditioning regimen and MTX prophylaxis for acute GVHD. OM has been shown to be associated with increased mortality and morbidity (principally from infection), significant pain, dysgeusia, difficulty speaking, difficulty receiving nutrition, hydration and oral medications, prolonged hospitalization and increased costs of care.

Reducing and even omitting doses of MTX due to regimen related toxicities (mucositis, hepatic and renal toxicities) is common. However, dose reduction of MTX may be associated with increased risk of acute GVHD and early death. Several non-randomized studies have shown that folinic acid (FA, leucovorin) administration may reduce MTX toxicity. Nevertheless, the efficacy and safety of its administration remain controversial. Despite limited and uncontrolled data, the European Group for Blood and Marrow Transplantation (EBMT) and the European LeukemiaNet working group recently recommended the use of FA-rescue and proposed a uniform policy of FA-rescue 24h after each MTX dose: 15mg every 8h after MTX administration on day 1, and every 6h on days 3, 6 and 11. Yet, according to several surveys (including by EBMT-ELN) only half of bone marrow transplantation (BMT) centers use to give post MTX FA-rescue.

The aim of this study is to assess the impact of FA-rescue following MTX GVHD prophylaxis on regimen related toxicity and transplantation outcomes after alloHCT in a double blind randomized controlled trial.

Inclusion Criteria:

• Acute leukemia in complete remission (CR) or myelodysplastic syndrome;
• First transplantation;
• Peripheral blood graft;
• Matched sibling or unrelated donor or one antigen or allelic mismatched sibling or unrelated donor (10/10 or 9/10 human leukocyte antigen match );
• Myeloablative or reduced intensity preparative regimen;
• Post-transplant GVHD prophylaxis consisting of a calcineurin inhibitor (CSA or tacrolimus) and methotrexate;
• Glutamate Pyruvate Transaminase (GPT) < 3 times upper normal limit (UNL) and creatinine ≤ 1.4 mg%;
• Written informed consent;

Exclusion Criteria:

• True non-myeloablative preparative regimen (TBI 200 +/- fludarabine);
• Acute leukemia not in remission;
• GPT > 3 times upper normal limit or creatinine > 1.4 mg%;
• Bone marrow, haploidentical or cord blood grafts;