A Personalized Prediction Model for Outcomes after Allogeneic Hematopoietic Cell Transplant in Patients with Myelodysplastic Syndromes

Aziz Nazha, Zhen Huan Hu, Tao Wang, R. Coleman Lindsley, Hisham Abdel-Azim, Mahmoud Aljurf, Ulrike Bacher, Asad Bashey, Jean Yves Cahn, Jan Cerny, Edward Copelan, Zachariah DeFilipp, Miguel Angel Diaz, Nosha Farhadfar, Shahinaz M. Gadalla, Robert Peter Gale, Biju George, Usama Gergis, Michael R. Grunwald, Betty HamiltonShahrukh Hashmi, Gerhard C. Hildebrandt, Yoshihiro Inamoto, Matt Kalaycio, Rammurti T. Kamble, Mohamed A. Kharfan-Dabaja, Hillard M. Lazarus, Jane L. Liesveld, Mark R. Litzow, Navneet S. Majhail, Hemant S. Murthy, Sunita Nathan, Taiga Nishihori, Attaphol Pawarode, David Rizzieri, Mitchell Sabloff, Bipin N. Savani, Levanto Schachter, Harry C. Schouten, Sachiko Seo, Nirav N. Shah, Melhem Solh, David Valcárcel, Ravi Vij, Erica Warlick, Baldeep Wirk, William A. Wood, Jean A. Yared, Edwin Alyea, Uday Popat, Ronald M. Sobecks, Bart L. Scott, Ryotaro Nakamura, Wael Saber

Research output: Contribution to journalArticlepeer-review

Abstract

Allogeneic hematopoietic stem cell transplantation (HCT) remains the only potentially curative option for myelodysplastic syndromes (MDS). Mortality after HCT is high, with deaths related to relapse or transplant-related complications. Thus, identifying patients who may or may not benefit from HCT is clinically important. We identified 1514 patients with MDS enrolled in the Center for International Blood and Marrow Transplant Research Registry and had their peripheral blood samples sequenced for the presence of 129 commonly mutated genes in myeloid malignancies. A random survival forest algorithm was used to build the model, and the accuracy of the proposed model was assessed by concordance index. The median age of the entire cohort was 59 years. The most commonly mutated genes were ASXL1(20%), TP53 (19%), DNMT3A (15%), and TET2 (12%). The algorithm identified the following variables prior to HCT that impacted overall survival: age, TP53 mutations, absolute neutrophils count, cytogenetics per International Prognostic Scoring System–Revised, Karnofsky performance status, conditioning regimen, donor age, WBC count, hemoglobin, diagnosis of therapy-related MDS, peripheral blast percentage, mutations in RAS pathway, JAK2 mutation, number of mutations/sample, ZRSR2, and CUX1 mutations. Different variables impacted the risk of relapse post-transplant. The new model can provide survival probability at different time points that are specific (personalized) for a given patient based on the clinical and mutational variables that are listed above. The outcomes’ probability at different time points may aid physicians and patients in their decision regarding HCT.

Original languageEnglish (US)
Pages (from-to)2139-2146
Number of pages8
JournalBiology of Blood and Marrow Transplantation
Volume26
Issue number11
DOIs
StatePublished - Nov 2020

Bibliographical note

Funding Information:
The authors acknowledge all participating centers and researchers from the CIBMTR. Financial disclosure: The CIBMTR is supported primarily by Public Health Service grant/cooperative agreement U24CA076518 with the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI), and the National Institute of Allergy and Infectious Diseases (NIAID); grant/cooperative agreement U24HL138660 with NHLBI and NCI; grant U24CA233032 from the NCI; grants OT3HL147741, R21HL140314, and U01HL128568 from the NHLBI; contract HHSH250201700006C with Health Resources and Services Administration (HRSA); grants N00014-18-1-2888 and N00014-17-1-2850 from the Office of Naval Research; subaward from prime contract award SC1MC31881-01-00 with HRSA; subawards from prime grant awards R01HL131731 and R01HL126589 from NHLBI; subawards from prime grant awards 5P01CA111412, 5R01HL129472, R01CA152108, 1R01HL131731, 1U01AI126612, and 1R01CA231141 from the NIH; and industry funds from Actinium Pharmaceuticals, Inc.; Adaptive Biotechnologies; Allovir, Inc.; Amgen, Inc.; anonymous donation to the Medical College of Wisconsin; Anthem, Inc.; Astellas Pharma US; Atara Biotherapeutics, Inc.; BARDA; Be the Match Foundation; bluebird bio, Inc.; Boston Children's Hospital; Bristol Myers Squibb Co.; Celgene Corp.; Children's Hospital of Los Angeles; Chimerix, Inc.; City of Hope Medical Center; CSL Behring; CytoSen Therapeutics, Inc.; Daiichi Sankyo Co. Ltd.; Dana Farber Cancer Institute; Enterprise Science and Computing, Inc.; Fred Hutchinson Cancer Research Center; Gamida-Cell, Ltd.; Genzyme; Gilead Sciences, Inc.; GlaxoSmithKline (GSK); HistoGenetics, Inc.; Immucor; Incyte Corporation; Janssen Biotech, Inc.; Janssen Pharmaceuticals, Inc.; Janssen Research & Development, LLC; Janssen Scientific Affairs, LLC; Japan Hematopoietic Cell Transplantation Data Center; Jazz Pharmaceuticals, Inc.; Karius, Inc.; Karyopharm Therapeutics, Inc.; Kite, a Gilead Company; Kyowa Kirin; Magenta Therapeutics; Mayo Clinic and Foundation Rochester; Medac GmbH; Mediware; Memorial Sloan Kettering Cancer Center; Merck & Company, Inc.; Mesoblast; MesoScale Diagnostics, Inc.; Millennium, Takeda Oncology Co.; Miltenyi Biotec, Inc.; Mundipharma EDO; National Marrow Donor Program; Novartis Oncology; Novartis Pharmaceuticals Corporation; Omeros Corporation; Oncoimmune, Inc.; OptumHealth; Orca Biosystems, Inc.; PCORI; Pfizer, Inc.; Phamacyclics, LLC; PIRCHE AG; Regeneron Pharmaceuticals, Inc.; REGiMMUNE Corp.; Sanofi Genzyme; Seattle Genetics; Shire; Sobi, Inc.; Spectrum Pharmaceuticals, Inc.; St. Baldrick's Foundation; Swedish Orphan Biovitrum, Inc.; Takeda Oncology; The Medical College of Wisconsin; University of Minnesota; University of Pittsburgh; University of Texas MD Anderson; University of Wisconsin, Madison; Viracor Eurofins; and Xenikos BV. The views expressed in this article do not reflect the official policy or position of the National Institutes of Health, the Department of the Navy, the Department of Defense, HRSA, or any other agency of the US government. Conflict of interest statement: A.N.: Incyte, Novartis, Karyopharma, Tolero, MEI, Jazz Pharma, Daiichi Sankyo. J.C.: Jazz Pharma, Daiichi Sankyo, Incyte. Robert Peter Gale: Celgene. U.G.: Astellas, Incyte, Merck, Jazz Pharma. M.R.G.: Agios, Abbvie, Amgen, Cardinal Health, Celgene, Incyte, Merck, Pfizer, Travagene, Daiichi Sankyo, Medtrnoic, Forma Theraputics, Amgen, Genentech, Janssen, Novartis. D.R.: Abbvie, Agios, Jazz Pharma, Novartis, Sanofi, Teva, AROG, Bayer, Pfizer, Celgene, Gilead, Stemline. G.H.: Sangamo Bioscience, Axim Biotechnology, Juno Theraputics, Kite Pharma, Novartis, insys Theraputics, Abbvie, GW Pharmaceuticals, Cardina health, Immunomedics, Endocyte, Clovis Oncology, Aetna, CSV health, Bleubird Bio, BMD, Crispr therapeutics, IDEXX laboratoris, Johnson & Johnson, Pfizer, Procter & Gamble, Vertex, Bayer, Scott-Miracle, Pfizer, Kite Pharma, Incyte, Jazz Pharmaceuticals, Astellas. D.V.: Celgene, Novartis, Jazz Pharma, Amgen, GSK, Takeda, Astellas Pharma. Authorship statement: A.N. W.S. Kenny, and T.W. conceived and designed the study; A.N. R.C.L. W.S. and Kenny acquired the data; A.N. W.S. T.W. and Kenny provided analysis; A.N. W.S. Kenny, and R.C.L. provided administrative, technical, or material support; all authors interpreted the data and wrote, reviewed, and revised the manuscript. Financial disclosure: See Acknowledgments on page 2146.

Funding Information:
Financial disclosure: The CIBMTR is supported primarily by Public Health Service grant/cooperative agreement U24CA076518 with the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI), and the National Institute of Allergy and Infectious Diseases (NIAID); grant/cooperative agreement U24HL138660 with NHLBI and NCI; grant U24CA233032 from the NCI; grants OT3HL147741, R21HL140314, and U01HL128568 from the NHLBI; contract HHSH250201700006C with Health Resources and Services Administration (HRSA); grants N00014-18-1-2888 and N00014-17-1-2850 from the Office of Naval Research; subaward from prime contract award SC1MC31881-01-00 with HRSA; subawards from prime grant awards R01HL131731 and R01HL126589 from NHLBI; subawards from prime grant awards 5P01CA111412, 5R01HL129472, R01CA152108, 1R01HL131731, 1U01AI126612, and 1R01CA231141 from the NIH; and industry funds from Actinium Pharmaceuticals, Inc.; Adaptive Biotechnologies; Allovir, Inc.; Amgen, Inc.; anonymous donation to the Medical College of Wisconsin; Anthem, Inc.; Astellas Pharma US; Atara Biotherapeutics, Inc.; BARDA; Be the Match Foundation; bluebird bio, Inc.; Boston Children's Hospital; Bristol Myers Squibb Co.; Celgene Corp.; Children's Hospital of Los Angeles; Chimerix, Inc.; City of Hope Medical Center; CSL Behring; CytoSen Therapeutics, Inc.; Daiichi Sankyo Co., Ltd.; Dana Farber Cancer Institute; Enterprise Science and Computing, Inc.; Fred Hutchinson Cancer Research Center; Gamida-Cell, Ltd.; Genzyme; Gilead Sciences, Inc.; GlaxoSmithKline (GSK); HistoGenetics, Inc.; Immucor; Incyte Corporation; Janssen Biotech, Inc.; Janssen Pharmaceuticals, Inc.; Janssen Research & Development, LLC; Janssen Scientific Affairs, LLC; Japan Hematopoietic Cell Transplantation Data Center; Jazz Pharmaceuticals, Inc.; Karius, Inc.; Karyopharm Therapeutics, Inc.; Kite, a Gilead Company; Kyowa Kirin; Magenta Therapeutics; Mayo Clinic and Foundation Rochester; Medac GmbH; Mediware; Memorial Sloan Kettering Cancer Center; Merck & Company, Inc.; Mesoblast; MesoScale Diagnostics, Inc.; Millennium, Takeda Oncology Co.; Miltenyi Biotec, Inc.; Mundipharma EDO; National Marrow Donor Program; Novartis Oncology; Novartis Pharmaceuticals Corporation; Omeros Corporation; Oncoimmune, Inc.; OptumHealth; Orca Biosystems, Inc.; PCORI; Pfizer, Inc.; Phamacyclics, LLC; PIRCHE AG; Regeneron Pharmaceuticals, Inc.; REGiMMUNE Corp.; Sanofi Genzyme; Seattle Genetics; Shire; Sobi, Inc.; Spectrum Pharmaceuticals, Inc.; St. Baldrick's Foundation; Swedish Orphan Biovitrum, Inc.; Takeda Oncology; The Medical College of Wisconsin; University of Minnesota; University of Pittsburgh; University of Texas MD Anderson; University of Wisconsin, Madison; Viracor Eurofins; and Xenikos BV. The views expressed in this article do not reflect the official policy or position of the National Institutes of Health, the Department of the Navy, the Department of Defense, HRSA, or any other agency of the US government.

Publisher Copyright:
© 2020 American Society for Transplantation and Cellular Therapy

Keywords

  • Genomic biomarkers
  • MDS
  • Mutations

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

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