Inferior Outcomes with Cyclosporine and Mycophenolate Mofetil after Myeloablative Allogeneic Hematopoietic Cell Transplantation

• Type of Material: Article
• Authors: Betty K. Hamilton, Cleveland Clinic Taussig Cancer Institute; Ying Liu, Medical College of Wisconsin; Michael T. Hemmer, Medical College of Wisconsin; Navneet Majhail, Cleveland Clinic Taussig Cancer Institute; Olle Ringden, Karolinska Institutet; Dennis Kim, Princess Margaret Cancer Centre; Luciano Costa, University of Alabama Birmingham; Robert Stuart, Medical University of South Carolina; Amin Alousi, University of Texas MD Anderson Cancer Center; Joseph A. Pidala, H. Lee Moffitt Cancer Center and Research Institute; Daniel R. Couriel, Utah Blood & Marrow Transplant Program Adults; Mahmoud Aljurf, King Faisal Specialist Hospital Center & Research; Joseph H. Antin, Dana Farber Cancer Institute; Christopher Bredeson, Ottawa Hospital Research Institute; Jean-Yves Cahn, CHU Grenoble Alpes; Mitchell Cairo, New York Medical College; Sung Won Choi, University of Michigan; Christopher Dandoy, Cincinnati Childrens Hospital Medical Center; Robert Peter Gale, Imperial College London; Usama Gergis, Weill Cornell Medical College; Peiman Hematti, University of Wisconsin; Yoshihiro Inamoto, National Cancer Center; Rammurti T. Kamble, Baylor College of Medicine; Margaret MacMillan, University of Minnesota; David I. Marks, University Hospital Bristol NHS Trust; Eneida Nemecek, Doernbecher Childrens Hospital; Taiga Nishihori, H. Lee Moffitt Cancer Center & Research Institute; Ayman Saad, Ohio State University; Bipin N. Savani, Vanderbilt University; Jeff Schriber, Virginia G. Piper Cancer Center; Sachiko Seo, Dokkyo Medical University; Gerard Socie, Hopital St Louis; Takanori Teshima, Hokkaido University Hospital; Leo F. Verdonck, Isala Clinics; Edmund Waller, Emory University; Mona Wirk, Seattle Cancer Care Alliance; Stephen R. Spellman, CIBMTR – Minneapolis; Mukta Arora, University of Minnesota; Saurabh Chhabra, Medical College of Wisconsin
• Language: English
• Date: 2019-09-01
• Publisher: Elsevier Science Inc.
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2019 Published by Elsevier Inc. on behalf of the American Society for Transplantation and Cellular Therapy.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.bbmt.2019.05.019
• Title of Journal or Parent Work: Biology of Blood and Marrow Transplantation
• Volume: 25
• Issue: 9
• Start Page: 1744
• End Page: 1755
• Grant/Funding Information: None declared
• Keywords: Science & Technology; Term follow-up; Transplantation; Hematology; Comparing methotrexate; GVHD Prophylaxis; Phase III; Versus host disease; Bone-marrow; Acid exposure; Life Sciences & Biomedicine; Allogeneic hematopoietic cell transplantation; Minidose methotrexate; Mycophenolate mofetil; Peripheral blood; Graft; Methotrexate; Myeloablative; Graft-versus-host disease; Immunology
• Research Categories: Health Sciences, Immunology; Health Sciences, Medicine and Surgery; Health Sciences, Oncology

Abstract

The combination of a calcineurin inhibitor (cyclosporine [CSA] or tacrolimus [Tac]) and methotrexate (MTX) or mycophenolate mofetil (MMF) are widely used approaches to graft-versus-host disease (GVHD) prevention. There is limited and conflicting data, however, on the comparative effectiveness of MMF compared to MTX We analyzed data from the CIBMTR for adult patients undergoing first myeloablative hematopoietic cell transplant (HCT) from an HLA-identical matched related (MRD) (N=3979) or matched unrelated donor (URD) (N=4163) using CSA+MMF, CSA+MTX, Tac+MMF or Tac+MTX for GVHD prevention from 2000–2013. Within the MRD cohort, 2252 received CSA+MTX, 1391 Tac+MTX, 114 CSA+MMF, and 222 Tac+MMF. Recipients of CSA+MMF had a higher incidence of acute grade 2–4 (HR 1.65, 95% CI 1.24–2.20, P<0.001) and grade 3–4 (HR 1.92, 95% CI 1.31–2.83, P<0.001) GVHD compared to Tac+MTX. The use of CSA+MMF was also associated with inferior overall survival (OS) (HR 2.31, 95% CI 1.73–3.09, P<0.001) due to higher transplant-related mortality (TRM) (HR 4.03, 95% CI 2.61–6.23, P<0.001) versus Tac+MTX. Within the URD cohort, 974 received CSA+MTX, 2697 Tac+MTX, 68 CSA+MMF, and 424 Tac+MMF. CSA+MMF was again significantly associated with a higher incidence of grade 3–4 acute GVHD (HR 2.31, 95% CI 1.57–3.42, P<0001), worse OS (HR 2.36, 95% CI 1.67–3.35, P<0.001), and higher TRM (HR 3.09, 95% CI 2.00–4.77, P<0.001), compared to Tac+MTX, and other regimens. This large retrospective comparison of MMF versus MTX in combination with CSA or Tac thus demonstrates significantly worse GVHD and survival outcomes with CSA+MMF compared to Tac+MTX.