Myeloablative Conditioning for Allogeneic Transplantation Results in Superior Disease-Free Survival for Acute Myelogenous Leukemia and Myelodysplastic Syndromes with Low/Intermediate but not High Disease Risk Index: A Center for International Blood and Marrow Transplant Research Study

Nelli Bejanyan, Meijie Zhang, Khalid Bo-Subait, Claudio Brunstein, Hailin Wang, Erica D. Warlick, Sergio Giralt, Taiga Nishihori, Rodrigo Martino, Jakob Passweg, Ajoy Dias, Edward Copelan, Gregory Hale, Robert Peter Gale, Melhem Solh, Mohamed A. Kharfan-Dabaja, Miguel Angel Diaz, Siddhartha Ganguly, Steven Gore, Leo F. VerdonckNasheed M. Hossain, Natasha Kekre, Bipin Savani, Michael Byrne, Christopher Kanakry, Mitchell S. Cairo, Stefan Ciurea, Harry C. Schouten, Christopher Bredeson, Reinhold Munker, Hillard Lazarus, Jean Yves Cahn, Marjolein van Der Poel, David Rizzieri, Jean A. Yared, Cesar Freytes, Jan Cerny, Mahmoud Aljurf, Neil D. Palmisiano, Attaphol Pawarode, Vera Ulrike Bacher, Michael R. Grunwald, Sunita Nathan, Baldeep Wirk, Gerhard C. Hildebrandt, Sachiko Seo, Richard F. Olsson, Biju George, Marcos de Lima, Christopher S. Hourigan, Brenda M. Sandmaier, Mark Litzow, Partow Kebriaei, Wael Saber, Daniel Weisdorf

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Abstract

BACKGROUND: Myeloablative (MAC) as compared to reduced-intensity conditioning (RIC) is generally associated with lower risk of relapse after allogeneic hematopoietic cell transplantation (HCT) for acute myeloid leukemia (AML), particularly with presence of pre-HCT measurable residual disease. However, other disease specific risk factors in AML and myelodysplastic syndromes (MDS) can further inform when MAC vs. RIC may yield differential clinical outcomes.

OBJECTIVE: We analyzed AML and MDS HCT outcomes stratified by the disease risk index (DRI) to identify the impact of transplant conditioning intensity.

STUDY DESIGN: Using the CIBMTR database we studied 4387 adult patients (age 40-65 years) receiving HCT (2009-2015) for AML (68%) or MDS (32%) with low/intermediate risk (1539 MAC and 999 RIC) and high/very high risk (1121 MAC and 728 RIC). Non-relapse mortality (NRM) and relapse probabilities were calculated using cumulative incidence estimator. The Kaplan-Meier method was used to estimate disease-free survival (DFS) and overall survival. Cox proportional hazards regression model was used to conduct the multivariable analyses.

RESULTS: In the low/intermediate risk DRI cohort, RIC was associated with lower risk of NRM (HR = 0.74, 95% CI 0.62-0.88; p<0.001), but significantly higher risk of relapse (HR = 1.54, 95% CI 1.35-1.76; p<0.001) with inferior DFS (HR = 1.19, 95% CI 1.07-1.33; p = 0.001). In the high/very high risk DRI cohort, RIC resulted in borderline lower NRM (HR = 0.83, 95% CI 0.68-1.00; p = 0.051), and significantly higher risk of relapse (HR = 1.23, 95% CI 1.08-1.41; p = 0.002) leading to similar DFS using RIC (HR 1.07 (0.96-1.19), p = 0.24) or MAC.

CONCLUSION: These data support MAC over RIC as the preferred conditioning intensity for AML/MDS in 40-65-years-old patients with low/intermediate risk DRI, but similar clinical benefit to RIC in high/very high risk DRI. Novel MAC regimens with less toxicity could benefit all, but particularly the high/very high risk DRI group.

Original languageEnglish (US)
Pages (from-to)68.e1-68.e9
JournalBiology of Blood and Marrow Transplantation
Volume27
Issue number1
Early online dateOct 1 2020
DOIs
StatePublished - Jan 2021

Bibliographical note

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 the NHLBI and NCI; Grant U24CA233032 from the NCI; Grants OT3 HL147741, R21 HL140314, and U01 HL128568 from the NHLBI; Contract HHSH250201700006C with the 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 the HRSA; subawards from Prime Grant awards R01 HL131731 and R01 HL126589 from the NHLBI; subawards from prime Grant Awards 5P01CA111412, 5R01 HL129472, R01 CA152108, 1R01 HL131731, 1U01 AI126612, and 1R01 CA231141 from the NIH; and commercial funds from Actinium Pharmaceuticals, Adaptive Biotechnologies, Allovir, Amgen, Anonymous donation to the Medical College of Wisconsin, Anthem, Astellas Pharma US, Atara Biotherapeutics, BARDA, Be the Match Foundation, bluebird bio, Boston Children's Hospital, Bristol Myers Squibb, Celgene, Children's Hospital of Los Angeles, Chimerix, City of Hope Medical Center, CSL Behring, CytoSen Therapeutics, Daiichi Sankyo, Dana-Farber Cancer Institute, Enterprise Science and Computing, Fred Hutchinson Cancer Research Center; Gamida-Cell, Genzyme, Gilead Sciences, GlaxoSmithKline, HistoGenetics, Immucor, Incyte, Janssen Biotech, Janssen Pharmaceuticals, Janssen Research & Development, Janssen Scientific Affairs, Japan Hematopoietic Cell Transplantation Data Center, Jazz Pharmaceuticals, Karius, Karyopharm Therapeutics, Kite Pharma, Kyowa Kirin, Magenta Therapeutics, Mayo Clinic and Foundation Rochester, Medac, Mediware, Memorial Sloan Kettering Cancer Center, Merck & Company, Mesoblast, MesoScale Diagnostics, Millennium, Miltenyi Biotec, Mundipharma EDO, National Marrow Donor Program, Novartis Oncology, Novartis Pharmaceuticals, Omeros, Oncoimmune, OptumHealth, Orca Biosystems, PCORI, Pfizer, Phamacyclics, PIRCHE, Regeneron Pharmaceuticals, REGiMMUNE, Sanofi Genzyme, Seattle Genetics, Shire; Sobi, Spectrum Pharmaceuticals, St Baldrick's Foundation, Swedish Orphan Biovitrum, 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 NIH, the Department of the Navy, the Department of Defense, HRSA, or any other agency of the US Government.

Funding Information:
Financial disclosyure: 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 the NHLBI and NCI; Grant U24CA233032 from the NCI; Grants OT3 HL147741, R21 HL140314, and U01 HL128568 from the NHLBI; Contract HHSH250201700006C with the 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 the HRSA; subawards from Prime Grant awards R01 HL131731 and R01 HL126589 from the NHLBI; subawards from prime Grant Awards 5P01CA111412, 5R01 HL129472, R01 CA152108, 1R01 HL131731, 1U01 AI126612, and 1R01 CA231141 from the NIH; and commercial funds from Actinium Pharmaceuticals, Adaptive Biotechnologies, Allovir, Amgen, Anonymous donation to the Medical College of Wisconsin, Anthem, Astellas Pharma US, Atara Biotherapeutics, BARDA, Be the Match Foundation, bluebird bio, Boston Children's Hospital, Bristol Myers Squibb, Celgene, Children's Hospital of Los Angeles, Chimerix, City of Hope Medical Center, CSL Behring, CytoSen Therapeutics, Daiichi Sankyo, Dana-Farber Cancer Institute, Enterprise Science and Computing, Fred Hutchinson Cancer Research Center; Gamida-Cell, Genzyme, Gilead Sciences, GlaxoSmithKline, HistoGenetics, Immucor, Incyte, Janssen Biotech, Janssen Pharmaceuticals, Janssen Research & Development, Janssen Scientific Affairs, Japan Hematopoietic Cell Transplantation Data Center, Jazz Pharmaceuticals, Karius, Karyopharm Therapeutics, Kite Pharma, Kyowa Kirin, Magenta Therapeutics, Mayo Clinic and Foundation Rochester, Medac, Mediware, Memorial Sloan Kettering Cancer Center, Merck & Company, Mesoblast, MesoScale Diagnostics, Millennium, Miltenyi Biotec, Mundipharma EDO, National Marrow Donor Program, Novartis Oncology, Novartis Pharmaceuticals, Omeros, Oncoimmune, OptumHealth, Orca Biosystems, PCORI, Pfizer, Phamacyclics, PIRCHE, Regeneron Pharmaceuticals, REGiMMUNE, Sanofi Genzyme, Seattle Genetics, Shire; Sobi, Spectrum Pharmaceuticals, St Baldrick's Foundation, Swedish Orphan Biovitrum, 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 NIH, the Department of the Navy, the Department of Defense, HRSA, or any other agency of the US Government. Conflict of interest statement: There are no conflicts of interest to disclose. Financial disclosure: See Acknowledgments on page XXX.

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

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