The Effect of Folinic Acid Rescue Following MTX GVHD Prophylaxis on Regimen Related Toxicity and Transplantation Outcome
- Conditions
- MucositisGraft vs Host DiseaseAllogeneic Hematopoietic Cell Transplantation
- Interventions
- Drug: Placebo
- Registration Number
- NCT02506231
- Lead Sponsor
- Rabin Medical Center
- Brief Summary
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.
- Detailed Description
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.
Recruitment & Eligibility
- Status
- UNKNOWN
- Sex
- All
- Target Recruitment
- 160
- 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;
- 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;
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo Placebo Patients will be randomly assigned by central randomization in a 1:1 ratio to receive folinic acid (FA) or placebo starting 24h after each MTX dose for 24h. Oral FA 15 mg/dose or placebo will be given every 8h after MTX administration on day 1 (3 doses), and every 6h (4 doses) on days 3 and 6. Folinic acid Folinic acid Patients will be randomly assigned by central randomization in a 1:1 ratio to receive folinic acid (FA) or placebo starting 24h after each MTX dose for 24h. Oral FA 15 mg/dose or placebo will be given every 8h after MTX administration on day 1 (3 doses), and every 6h (4 doses) on days 3 and 6.
- Primary Outcome Measures
Name Time Method Incidence of severe (grade 3-4) oral mucositis according to the WHO scale 30 days According to the WHO (world health organization) oral mucositis grading scale
Duration (in days) of severe (grade 3-4) oral mucositis according to the WHO scale 30 days According to the WHO (world health organization) oral mucositis grading scale
- Secondary Outcome Measures
Name Time Method Incidence of relapse 24 months Non relapse mortality 24 months Disease free survival 24 months Overall survival 24 months Incidence of renal toxicity 30 days Creatinine \> 2 mg%
Incidence of oral mucositis 30 days Grade of oral mucositis 30 days According to the WHO (world health organization) oral mucositis grading scale
Time to neutrophil recovery 30 days Time to platelet recovery 60 days Adherence to methotrexate schedule 14 days Number of methotrexate doses that were actually given (out of 3 doses on days 1, 3 and 6)
Adherence to methotrexate doses 14 days Actual methotrexate doses given in mg/sqm divided by scheduled doses in mg/sqm X 100
Days of opiate use 30 days Days of total parenteral nutrition use 100 days Incidence of veno-occlusive disease of the liver (VOD) 30 days Severity of veno-occlusive disease of the liver (VOD) 30 days According to the Seattle criteria
Incidence of hepatic toxicity 30 days total bilirubin \> 2 mg%, unless mostly indirect
Incidence of febrile neutropenia 30 days Duration of febrile neutropenia 30 days Documented infections 30 days Time from transplantation to discharge 60 days Incidence of acute graft-versus-host disease 100 days Severity of acute graft-versus-host disease 100 days According to the consensus grading system
Incidence of chronic graft-versus-host disease 24 months Severity of chronic graft-versus-host disease 24 months According to the National Institutes of Health (NIH) consensus criteria