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

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

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.

Study Overview

• Status: Unknown
• Conditions: Mucositis; Graft vs Host Disease; Allogeneic Hematopoietic Cell Transplantation
• Intervention / Treatment: Drug: Placebo; Drug: Folinic acid

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.

• Study Type: Interventional
• Enrollment (Anticipated): 160
• Phase: Phase 2; Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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;

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: Folinic acid; Other Names: leucovorin
Placebo Comparator: 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.	Drug: Placebo

What is the study measuring?

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
Overall survival		24 months
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

Collaborators and Investigators

• Sponsor: Rabin Medical Center

Publications and helpful links

General Publications

• Yeshurun M, Rozovski U, Pasvolsky O, Wolach O, Ram R, Amit O, Zuckerman T, Pek A, Rubinstein M, Sela-Navon M, Raanani P, Shargian-Alon L. Efficacy of folinic acid rescue following MTX GVHD prophylaxis: results of a double-blind, randomized, controlled study. Blood Adv. 2020 Aug 25;4(16):3822-3828. doi: 10.1182/bloodadvances.2020002039.

Study record dates

Study Major Dates

• Study Start: October 1, 2015
• Primary Completion (Anticipated): October 1, 2017

Study Registration Dates

• First Submitted: July 13, 2015
• First Submitted That Met QC Criteria: July 22, 2015
• First Posted (Estimate): July 23, 2015

Study Record Updates

• Last Update Posted (Estimate): July 24, 2015
• Last Update Submitted That Met QC Criteria: July 23, 2015
• Last Verified: June 1, 2015

More Information

Terms related to this study

• Keywords: Methotrexate; Mucositis; Leucovorin; GVHD prophylaxis; Folinic acid; Allogeneic hematopoietic cell transplantation
• Additional Relevant MeSH Terms: Digestive System Diseases; Immune System Diseases; Gastrointestinal Diseases; Gastroenteritis; Stomatognathic Diseases; Mouth Diseases; Mucositis; Graft vs Host Disease; Physiological Effects of Drugs; Protective Agents; Micronutrients; Vitamins; Antidotes; Vitamin B Complex; Hematinics; Leucovorin; Levoleucovorin; Folic Acid
• Other Study ID Numbers: 0197-15-RMC