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Mycophenolate mofetil versus methotrexate for prevention of graft-versus-host disease in people receiving allogeneic hematopoietic stem cell transplantation.

Abstract

BACKGROUND

Allogeneic hematopoietic stem cell transplantation (allo-HCT) is associated with improved outcomes for people with various hematologic diseases; however, the morbidity and mortality resulting from acute and subsequently chronic graft-versus-host disease (GVHD) pose a serious challenge to wider applicability of allo-HCT. Intravenous methotrexate in combination with a calcineurin inhibitor, cyclosporine or tacrolimus, is a widely used regimen for the prophylaxis of acute GVHD, but the administration of methotrexate is associated with a number of adverse events. Mycophenolate mofetil, in combination with a calcineurin inhibitor, has been used extensively in people undergoing allo-HCT. Conflicting results regarding various clinical outcomes following allo-HCT have been observed when comparing mycophenolate mofetil-based regimens against methotrexate-based regimens for acute GVHD prophylaxis.

PRIMARY OBJECTIVE

to assess the effect of mycophenolate mofetil versus methotrexate for prevention of acute GVHD in people undergoing allo-HCT.

SECONDARY OBJECTIVES

to evaluate the effect of mycophenolate mofetil versus methotrexate for overall survival, prevention of chronic GVHD, incidence of relapse, treatment-related harms, nonrelapse mortality, and quality of life.

SEARCH METHODS

We searched Cochrane Central Register of Controlled Trials (CENTRAL) and MEDLINE from inception to March 2014. We handsearched conference abstracts from the last two meetings (2011 and 2012) of relevant societies in the field. We searched ClinicalTrials.gov, Novartis clinical trials database (www.novctrd.com), Roche clinical trial protocol registry (www.roche-trials.com), Australian New Zealand Clinical Trials Registry (ANZCTR), and the metaRegister of Controlled Trials for ongoing trials.

SELECTION CRITERIA

Two review authors independently reviewed all titles/abstracts and selected full-text articles for inclusion. We included all references that reported results of randomized controlled trials (RCTs) of mycophenolate mofetil versus methotrexate for the prophylaxis of GVHD among people undergoing allo-HCT in this review.

DATA COLLECTION AND ANALYSIS

Two review authors independently extracted data on outcomes from all studies and compared prior to data entry and analysis. We expressed results as risk ratios (RR) and 95% confidence intervals (CI) for dichotomous outcomes and hazard ratios (HR) and 95% CIs for time-to-event outcomes. We pooled the individual study effects using the random-effects model. Estimates lower than one indicate that mycophenolate mofetil was favored over methotrexate.

MAIN RESULTS

We included three trials enrolling 177 participants (174 participants analyzed). All participants in the trials by Keihl et al. and Bolwell et al. received cyclosporine while all participants enrolled in the trial by Perkins et al. received tacrolimus. However, the results did not differ by the type of calcineurin inhibitor employed (cyclosporine versus tacrolimus). There was no evidence for a difference between mycophenolate mofetil versus methotrexate for the outcomes of incidence of acute GVHD (RR 1.25; 95% CI 0.75 to 2.09; P value = 0.39, very low quality evidence), overall survival (HR 0.73; 95% CI 0.45 to 1.17; P value = 0.19, low-quality evidence), median days to neutrophil engraftment (HR 0.77; 95% CI 0.51 to 1.17; P value = 0.23, low-quality evidence), incidence of relapse (RR 0.84; 95% CI 0.52 to 1.38; P value = 0.50, low-quality evidence), non-relapse mortality (RR 1.21; 95% CI 0.62 to 2.36; P value = 0.57, low-quality evidence), and incidence of chronic GVHD (RR 0.92; 95% CI 0.65 to 1.30; P value = 0.62, low-quality evidence). There was low-quality evidence that mycophenolate mofetil compared with methotrexate improved platelet engraftment period (HR 0.87; 95% CI 0.81 to 0.93; P value < 0.0001, low-quality evidence). There was low-quality evidence that mycophenolate mofetil compared with methotrexate resulted in decreased incidence of severe mucositis (RR 0.48; 95% CI 0.32 to 0.73; P value = 0.0006, low-quality evidence), use of parenteral nutrition (RR 0.48; 95% CI 0.26 to 0.91; P value = 0.02, low-quality evidence), and medication for pain control (RR 0.76; 95% CI 0.63 to 0.91; P value = 0.002, low-quality evidence). Overall heterogeneity was not detected in the analysis except for the outcome of neutrophil engraftment. None of the included studies reported any outcomes related to quality of life. Overall quality of evidence was low.

AUTHORS' CONCLUSIONS

The use of mycophenolate mofetil compared with methotrexate for primary prevention of GVHD seems to be associated with a more favorable toxicity profile, without an apparent compromise on disease relapse, transplant-associated mortality, or overall survival. The effects on incidence of GVHD between people receiving mycophenolate mofetil compared with people receiving methotrexate were uncertain. There is a need for additional high-quality RCTs to determine the optimal GVHD prevention strategy. Future studies should take into account a comprehensive view of clinical benefit, including measures of morbidity, symptom burden, and healthcare resource utilization associated with interventions.

Authors+Show Affiliations

Department of Blood and Marrow Transplantation, H. Lee Moffitt Cancer Center, Division of Oncologic Sciences, University of South Florida, Tampa, Florida, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Meta-Analysis
Review
Systematic Review

Language

eng

PubMed ID

25061777

Citation

Kharfan-Dabaja, Mohamed, et al. "Mycophenolate Mofetil Versus Methotrexate for Prevention of Graft-versus-host Disease in People Receiving Allogeneic Hematopoietic Stem Cell Transplantation." The Cochrane Database of Systematic Reviews, 2014, p. CD010280.
Kharfan-Dabaja M, Mhaskar R, Reljic T, et al. Mycophenolate mofetil versus methotrexate for prevention of graft-versus-host disease in people receiving allogeneic hematopoietic stem cell transplantation. Cochrane Database Syst Rev. 2014.
Kharfan-Dabaja, M., Mhaskar, R., Reljic, T., Pidala, J., Perkins, J. B., Djulbegovic, B., & Kumar, A. (2014). Mycophenolate mofetil versus methotrexate for prevention of graft-versus-host disease in people receiving allogeneic hematopoietic stem cell transplantation. The Cochrane Database of Systematic Reviews, (7), CD010280. https://doi.org/10.1002/14651858.CD010280.pub2
Kharfan-Dabaja M, et al. Mycophenolate Mofetil Versus Methotrexate for Prevention of Graft-versus-host Disease in People Receiving Allogeneic Hematopoietic Stem Cell Transplantation. Cochrane Database Syst Rev. 2014 Jul 25;(7)CD010280. PubMed PMID: 25061777.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mycophenolate mofetil versus methotrexate for prevention of graft-versus-host disease in people receiving allogeneic hematopoietic stem cell transplantation. AU - Kharfan-Dabaja,Mohamed, AU - Mhaskar,Rahul, AU - Reljic,Tea, AU - Pidala,Joseph, AU - Perkins,Janelle B, AU - Djulbegovic,Benjamin, AU - Kumar,Ambuj, Y1 - 2014/07/25/ PY - 2014/7/26/entrez PY - 2014/7/26/pubmed PY - 2015/1/13/medline SP - CD010280 EP - CD010280 JF - The Cochrane database of systematic reviews JO - Cochrane Database Syst Rev IS - 7 N2 - BACKGROUND: Allogeneic hematopoietic stem cell transplantation (allo-HCT) is associated with improved outcomes for people with various hematologic diseases; however, the morbidity and mortality resulting from acute and subsequently chronic graft-versus-host disease (GVHD) pose a serious challenge to wider applicability of allo-HCT. Intravenous methotrexate in combination with a calcineurin inhibitor, cyclosporine or tacrolimus, is a widely used regimen for the prophylaxis of acute GVHD, but the administration of methotrexate is associated with a number of adverse events. Mycophenolate mofetil, in combination with a calcineurin inhibitor, has been used extensively in people undergoing allo-HCT. Conflicting results regarding various clinical outcomes following allo-HCT have been observed when comparing mycophenolate mofetil-based regimens against methotrexate-based regimens for acute GVHD prophylaxis. PRIMARY OBJECTIVE: to assess the effect of mycophenolate mofetil versus methotrexate for prevention of acute GVHD in people undergoing allo-HCT. SECONDARY OBJECTIVES: to evaluate the effect of mycophenolate mofetil versus methotrexate for overall survival, prevention of chronic GVHD, incidence of relapse, treatment-related harms, nonrelapse mortality, and quality of life. SEARCH METHODS: We searched Cochrane Central Register of Controlled Trials (CENTRAL) and MEDLINE from inception to March 2014. We handsearched conference abstracts from the last two meetings (2011 and 2012) of relevant societies in the field. We searched ClinicalTrials.gov, Novartis clinical trials database (www.novctrd.com), Roche clinical trial protocol registry (www.roche-trials.com), Australian New Zealand Clinical Trials Registry (ANZCTR), and the metaRegister of Controlled Trials for ongoing trials. SELECTION CRITERIA: Two review authors independently reviewed all titles/abstracts and selected full-text articles for inclusion. We included all references that reported results of randomized controlled trials (RCTs) of mycophenolate mofetil versus methotrexate for the prophylaxis of GVHD among people undergoing allo-HCT in this review. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data on outcomes from all studies and compared prior to data entry and analysis. We expressed results as risk ratios (RR) and 95% confidence intervals (CI) for dichotomous outcomes and hazard ratios (HR) and 95% CIs for time-to-event outcomes. We pooled the individual study effects using the random-effects model. Estimates lower than one indicate that mycophenolate mofetil was favored over methotrexate. MAIN RESULTS: We included three trials enrolling 177 participants (174 participants analyzed). All participants in the trials by Keihl et al. and Bolwell et al. received cyclosporine while all participants enrolled in the trial by Perkins et al. received tacrolimus. However, the results did not differ by the type of calcineurin inhibitor employed (cyclosporine versus tacrolimus). There was no evidence for a difference between mycophenolate mofetil versus methotrexate for the outcomes of incidence of acute GVHD (RR 1.25; 95% CI 0.75 to 2.09; P value = 0.39, very low quality evidence), overall survival (HR 0.73; 95% CI 0.45 to 1.17; P value = 0.19, low-quality evidence), median days to neutrophil engraftment (HR 0.77; 95% CI 0.51 to 1.17; P value = 0.23, low-quality evidence), incidence of relapse (RR 0.84; 95% CI 0.52 to 1.38; P value = 0.50, low-quality evidence), non-relapse mortality (RR 1.21; 95% CI 0.62 to 2.36; P value = 0.57, low-quality evidence), and incidence of chronic GVHD (RR 0.92; 95% CI 0.65 to 1.30; P value = 0.62, low-quality evidence). There was low-quality evidence that mycophenolate mofetil compared with methotrexate improved platelet engraftment period (HR 0.87; 95% CI 0.81 to 0.93; P value < 0.0001, low-quality evidence). There was low-quality evidence that mycophenolate mofetil compared with methotrexate resulted in decreased incidence of severe mucositis (RR 0.48; 95% CI 0.32 to 0.73; P value = 0.0006, low-quality evidence), use of parenteral nutrition (RR 0.48; 95% CI 0.26 to 0.91; P value = 0.02, low-quality evidence), and medication for pain control (RR 0.76; 95% CI 0.63 to 0.91; P value = 0.002, low-quality evidence). Overall heterogeneity was not detected in the analysis except for the outcome of neutrophil engraftment. None of the included studies reported any outcomes related to quality of life. Overall quality of evidence was low. AUTHORS' CONCLUSIONS: The use of mycophenolate mofetil compared with methotrexate for primary prevention of GVHD seems to be associated with a more favorable toxicity profile, without an apparent compromise on disease relapse, transplant-associated mortality, or overall survival. The effects on incidence of GVHD between people receiving mycophenolate mofetil compared with people receiving methotrexate were uncertain. There is a need for additional high-quality RCTs to determine the optimal GVHD prevention strategy. Future studies should take into account a comprehensive view of clinical benefit, including measures of morbidity, symptom burden, and healthcare resource utilization associated with interventions. SN - 1469-493X UR - https://www.unboundmedicine.com/medline/citation/25061777/Mycophenolate_mofetil_versus_methotrexate_for_prevention_of_graft_versus_host_disease_in_people_receiving_allogeneic_hematopoietic_stem_cell_transplantation_ L2 - https://doi.org/10.1002/14651858.CD010280.pub2 DB - PRIME DP - Unbound Medicine ER -