The Effect of Folinic Acid Rescue Following MTX GVHD Prophylaxis on Regimen Related Toxicity and Transplantation Outcome

Study Overview
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Brief Summary
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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
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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.

Official Title
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The Effect of Folinic Acid Rescue Following Methotrexate (MTX) Graft-versus-host Disease (GVHD) Prophylaxis on Regimen Related Toxicity and Transplantation Outcome: a Double Blind Randomized Controlled Study

Conditions
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Graft vs Host Disease, Allogeneic Hematopoietic Cell Transplantation, Mucositis

Intervention / Treatment
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* Drug: Folinic acid
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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;

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Folinic acid<br>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. | Drug: Folinic acid<br> <br> * Other names: leucovorin;|
| Placebo Comparator: Placebo<br>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. | Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of severe (grade 3-4) oral mucositis according to the WHO scale | According to the WHO (world health organization) oral mucositis grading scale | 30 days | 
| Duration (in days) of severe (grade 3-4) oral mucositis according to the WHO scale | According to the WHO (world health organization) oral mucositis grading scale | 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of oral mucositis |  | 30 days | 
| Grade of oral mucositis | According to the WHO (world health organization) oral mucositis grading scale | 30 days | 
| Time to neutrophil recovery |  | 30 days | 
| Time to platelet recovery |  | 60 days | 
| Adherence to methotrexate schedule | Number of methotrexate doses that were actually given (out of 3 doses on days 1, 3 and 6) | 14 days | 
| Adherence to methotrexate doses | Actual methotrexate doses given in mg/sqm divided by scheduled doses in mg/sqm X 100 | 14 days | 
| 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) | According to the Seattle criteria | 30 days | 
| Incidence of renal toxicity | Creatinine > 2 mg% | 30 days | 
| Incidence of hepatic toxicity | total bilirubin > 2 mg%, unless mostly indirect | 30 days | 
| 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 | According to the consensus grading system | 100 days | 
| Incidence of chronic graft-versus-host disease |  | 24 months | 
| Severity of chronic graft-versus-host disease | According to the National Institutes of Health (NIH) consensus criteria | 24 months | 
| Incidence of relapse |  | 24 months | 
| Non relapse mortality |  | 24 months | 
| Disease free survival |  | 24 months | 
| Overall survival |  | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Allogeneic hematopoietic cell transplantation, GVHD prophylaxis, Methotrexate, Folinic acid, Leucovorin, Mucositis