Influence of Age on Acute and Chronic GVHD in Children Undergoing HLA-Identical Sibling Bone Marrow Transplantation for Acute Leukemia: Implications for Prophylaxis

• Type of Material: Article
• Authors: Muna Qayed, Emory University; Tao Wang, Medical College of Wisconsin; Michael T. Hemmer, Medical College of Wisconsin; Stephen Spellman, Natl Marrow Donor Program Be Match; Mukta Arora, University of Minnesota; Daniel Couriel, Utah Blood & Marrow Transplant Program; Amin Alousi, University of Texas MD Anderson Cancer Center; Joseph Pidala, H. Lee Moffitt Cancer Center and Research Institute; Hisham Abdel-Azim, University of Southern California; Mahmoud Aljurf, King Faisal Specialist Hospital Center & Research; Mouhab Ayas, King Faisal Specialist Hospital Center & Research; Menachem Bitan, Tel Aviv Sourasky Medical Center; Mitchell Cairo, New York Medical College; Sung Won Choi, University of Michigan; Christopher Dandoy, Cincinnati Childrens Hospital Medical Center; David Delgado, Indiana University Hospital; Robert Peter Gale, Imperial College London; Gregory Hale, Johns Hopkins All Children's Hospital; Haydar Frangoul, TriStar Centennial; Rammurti T. Kamble, Baylor College of Medicine; Mohamed Kharfan-Dabaja, H. Lee Moffitt Cancer Center and Research Institute; Leslie Lehman, Dana Farber Cancer Institute; John Levine, Icahn School of Medicine at Mount Sinai; Margaret MacMillan, University of Minnesota; David I. Marks, University Hospital Bristol NHS Trust; Taiga Nishihori, H. Lee Moffitt Cancer Center and Research Institute; Richard F. Olsson, Karolinska Institutet; Peiman Hematti, University of Wisconsin Hospital and Clinics; Olov Ringden, Karolinska Institutet; Ayman Saad, University of Alabama Birmingham; Prakash Satwani, Columbia University; Bipin N. Savani, Vanderbilt University; Kirk R. Schultz, University of British Columbia; Sachiko Seo, East Hospital; Shalini Shenoy, Washington University; Edmund Waller, Emory University; Lolie Yu, Louisiana State University; Mary M. Horowitz, Medical College of Wisconsin; John Horan, Emory University
• Language: English
• Date: 2018-03-01
• Publisher: Elsevier: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017 The American Society for Blood and Marrow Transplantation
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.bbmt.2017.11.004
• Title of Journal or Parent Work: Biology of Blood and Marrow Transplantation
• ISSN: 1083-8791
• Volume: 24
• Issue: 3
• Start Page: 521
• End Page: 528
• Grant/Funding Information: The CIBMTR is supported primarily by Public Health Service Grant/Cooperative Agreement 5U24-CA076518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI) and the National Institute of Allergy and Infectious Diseases (NIAID); a Grant/Cooperative Agreement 5U10HL069294 from NHLBI and NCI; a contract HHSH250201200016C with Health Resources and Services Administration (HRSA/DHHS); two Grants N00014-15-1-0848 and N00014-16-1-2020 from the Office of Naval Research; and grants from * Actinium Pharmaceuticals, Inc.; Alexion; * Amgen, Inc.; Anonymous donation to the Medical College of Wisconsin; Astellas Pharma US; AstraZeneca; Atara Biotherapeutics, Inc.; Be the Match Foundation; * Bluebird Bio, Inc.; * Bristol Myers Squibb Oncology; * Celgene Corporation; Cellular Dynamics International, Inc.; Cerus Corporation; * Chimerix, Inc.; Fred Hutchinson Cancer Research Center; Gamida Cell Ltd.; Genentech, Inc.; Genzyme Corporation; Gilead Sciences, Inc.; Health Research, Inc. Roswell Park Cancer Institute; HistoGenetics, Inc.; Incyte Corporation; Janssen Scientific Affairs, LLC; * Jazz Pharmaceuticals, Inc.; Jeff Gordon Children’s Foundation; The Leukemia & Lymphoma Society; Medac, GmbH; MedImmune; The Medical College of Wisconsin; * Merck & Co, Inc.; * Mesoblast; MesoScale Diagnostics, Inc.; * Miltenyi Biotec, Inc.; National Marrow Donor Program; Neovii Biotech NA, Inc.; Novartis Pharmaceuticals Corporation; Onyx Pharmaceuticals; Optum Healthcare Solutions, Inc.; Otsuka America Pharmaceutical, Inc.; Otsuka Pharmaceutical Co, Ltd. – Japan; PCORI; Perkin Elmer, Inc.; Pfizer, Inc; * Sanofi US; * Seattle Genetics; * Spectrum Pharmaceuticals, Inc.; St. Baldrick’s Foundation; * Sunesis Pharmaceuticals, Inc.; Swedish Orphan Biovitrum, Inc.; Takeda Oncology; Telomere Diagnostics, Inc.; University of Minnesota; and * Wellpoint, Inc.; This work is supported in part by the National Center for Advancing Translational Sciences of the National Institutes of Health UL1TR000454 and KL2TR000455 (MQ)
• Keywords: Immunology; Matched sibling donor transplantation; RISK-FACTORS; Science & Technology; Recipient age; HIGH-DOSE CYCLOSPORINE; VERSUS-HOST-DISEASE; CHRONIC GRAFT; HEMATOPOIETIC-CELL TRANSPLANTATION; UNRELATED DONOR; Leukemia; IMPACT; Life Sciences & Biomedicine; FOLLOW-UP; Hematology; RELAPSE; Transplantation; GVHD; METHOTREXATE; Children
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Immunology; Health Sciences, Oncology

Abstract

Relapse remains the major cause of mortality after hematopoietic cell transplantation (HCT) for pediatric acute leukemia. Previous research has suggested that reducing the intensity of calcineurin inhibitor-based graft-versus-host disease (GVHD) prophylaxis may be an effective strategy for abrogating the risk of relapse in pediatric patients undergoing matched sibling donor (MSD) HCT. We reasoned that the benefits of this strategy could be maximized by selectively applying it to those patients least likely to develop GVHD. We conducted a study of risk factors for GVHD, to risk-stratify patients based on age. Patients age <18 years with leukemia who received myeloablative, T cell-replete MSD bone marrow transplantation and calcineurin inhibitor-based GVHD prophylaxis between 2000 and 2013 and were entered into the Center for International Blood and Marrow Transplant Research registry were included. The cumulative incidence of grade II-IV acute GVHD (aGVHD) was 19%, that of grade II-IV aGVHD 7%, and that of chronic GVHD (cGVHD) was 16%. Compared with age 13 to 18 years, age 2 to 12 years was associated with a lower risk of grade II-IV aGVHD (hazard ratio [HR],.42; 95% confidence interval [CI],.26 to.70; P =.0008), grade II-IV aGVHD (HR,.24; 95% CI,.10 to.56; P =.001), and cGVHD (HR,.32; 95% CI,.19 to.54; P <.001). Compared with 2000-2004, the risk of grade II-IV aGVHD was lower in children undergoing transplantation in 2005-2008 (HR,.36; 95% CI,.20 to.65; P =.0007) and in 2009-2013 (HR,.24; 95% CI..11 to.53; P =.0004). Similarly, the risk of grade III-IV aGVHD was lower in children undergoing transplantation in 2005-2008 (HR,.23; 95% CI,.08 to.65; P =.0056) and 2009-2013 (HR,.16; 95% CI,.04 to.67; P =.0126) compared with those doing so in 2000-2004. We conclude that aGVHD rates have decreased significantly over time, and that children age 2 to 12 years are at very low risk for aGVHD and cGVHD. These results should be validated in an independent analysis, because these patients with high-risk malignancies may be good candidates for trials of reduced GVHD prophylaxis.