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Transplant Toxicities

Identification of high-risk amino-acid substitutions in hematopoietic cell transplantation: a challenging task

Bone Marrow Transplantation volume 51, pages 1342–1349 (2016)Cite this article

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Abstract

Allogeneic hematopoietic cell transplantation (HCT) offers the potential to cure hematologic malignancies. In the absence of an HLA-matched donor, HLA mismatched unrelated donors may be used, although risks of GvHD and treatment-related mortality (TRM) are higher. Identification and avoidance of amino-acid substitution and position types (AASPT) conferring higher risks of TRM and GvHD would potentially improve the success of transplantation from single HLA mismatched unrelated donors. Using random forest and logistic regression analyses, we identified 19 AASPT associated with greater risks for at least one adverse transplant outcome: grade III-IV acute GvHD, TRM, lower disease-free survival or worse overall survival relative to HLA-matched unrelated donors and to other AASPT. When tested in an independent validation cohort of 3530 patients, none of the AASPT from the training set were validated as high risk, however. Review of the literature shows that failure to validate original observations is the rule and not the exception in immunobiology and emphasizes the importance of independent validation before clinical application. Our current data do not support avoiding any specific class I AASPT for unrelated donors. Additional studies should be performed to fully understand the role of AASPT in HCT outcomes.

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Acknowledgements

This study was partially supported by the University of Chicago Cancer Research Center, Chicago, Illinois (Fund-6-33573 to SRM). The CIBMTR is supported by Public Health Service Grant/Cooperative Agreement U24-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 N00014-13-1-0039 and N00014-14-1-0028 from the Office of Naval Research; and grants from Actinium Pharmaceuticals; Allos Therapeutics, Inc.; Amgen, Inc.; Anonymous donation to the Medical College of Wisconsin; Ariad; Be the Match Foundation; Blue Cross and Blue Shield Association; Celgene Corporation; Chimerix, Inc.; Fred Hutchinson Cancer Research Center; Fresenius-Biotech North America, Inc.; Gamida Cell Teva Joint Venture Ltd.; Genentech, Inc.; Gentium SpA; Genzyme Corporation; GlaxoSmithKline; Health Research, Inc. Roswell Park Cancer Institute; HistoGenetics, Inc.; Incyte Corporation; Jeff Gordon Children’s Foundation; Kiadis Pharma; the Leukemia & Lymphoma Society; Medac GmbH; The Medical College of Wisconsin; Merck & Co, Inc.; Millennium: The Takeda Oncology Co.; Milliman USA, Inc.; Miltenyi Biotec, Inc.; National Marrow Donor Program; Onyx Pharmaceuticals; Optum Healthcare Solutions, Inc.; Osiris Therapeutics, Inc.; Otsuka America Pharmaceutical, Inc.; Perkin Elmer, Inc.; Remedy Informatics; Sanofi US; Seattle Genetics; Sigma-Tau Pharmaceuticals; Soligenix, Inc.; St. Baldrick’s Foundation; StemCyte, A Global Cord Blood Therapeutics Co.; Stemsoft Software, Inc.; Swedish Orphan Biovitrum; Tarix Pharmaceuticals; TerumoBCT; Teva Neuroscience, Inc.; THERAKOS, Inc.; University of Minnesota; University of Utah and Wellpoint, Inc. The views expressed in this article do not reflect the official policy or position of the National Institute of Health, the Department of the Navy, the Department of Defense, Health Resources and Services Administration or any other agency of the US Government.

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Authors and Affiliations

  1. Department of Pathology, University of Chicago Medical Center, Chicago, IL, USA

    S R Marino

  2. Department of Public Health Sciences, University of Chicago, Chicago, IL, USA

    S M Lee & T Karrison

  3. Center for Structural Genomics of Infectious Diseases and Midwest Center for Structural Genomics, Argonne National Laboratory, Argonne, IL, USA

    T A Binkowski

  4. Division of Biostatistics, Medical College of Wisconsin, Milwaukee, WI, USA

    T Wang & H-L Wang

  5. Center for International Blood and Marrow Transplant Research, Milwaukee, WI, USA

    T Wang, H-L Wang & S J Lee

  6. Center for International Blood and Marrow Transplant Research, Minneapolis, MN, USA

    M Haagenson

  7. National Marrow Donor Program, Minneapolis, MN, USA

    M Maiers & S Spellman

  8. Division of Hematology, Weill-Cornell Medical College, New York, NY, USA

    K van Besien

  9. Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    S J Lee

  10. Department of Medicine, University of Chicago Medical Center, Chicago, IL, USA

    A Artz

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Correspondence to S R Marino.

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Marino, S., Lee, S., Binkowski, T. et al. Identification of high-risk amino-acid substitutions in hematopoietic cell transplantation: a challenging task. Bone Marrow Transplant 51, 1342–1349 (2016). https://doi.org/10.1038/bmt.2016.142

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