Fludarabine and Melphalan Compared with Reduced Doses of Busulfan and Fludarabine Improve Transplantation Outcomes in Older Patients with Myelodysplastic Syndromes

Betül Oran, Kwang Woo Ahn, Caitrin Fretham, Amer Beitinjaneh, Asad Bashey, Attaphol Pawarode, Baldeep Wirk, Bart L. Scott, Bipin N. Savani, Christopher Bredeson, Daniel Weisdorf, David I. Marks, David Rizzieri, Edward Copelan, Gerhard C. Hildebrandt, Gregory A. Hale, Hemant S. Murthy, Hillard M. Lazarus, Jan Cerny, Jane L. LiesveldJean A. Yared, Jean Yves-Cahn, Jeffrey Szer, Leo F. Verdonck, Mahmoud Aljurf, Marjolein van der Poel, Mark Litzow, Matt Kalaycio, Michael R. Grunwald, Miguel Angel Diaz, Mitchell Sabloff, Mohamed A. Kharfan-Dabaja, Navneet S. Majhail, Nosha Farhadfar, Ran Reshef, Richard F. Olsson, Robert Peter Gale, Ryotaro Nakamura, Sachiko Seo, Saurabh Chhabra, Shahrukh Hashmi, Shatha Farhan, Siddhartha Ganguly, Sunita Nathan, Taiga Nishihori, Tania Jain, Vaibhav Agrawal, Ulrike Bacher, Uday Popat, Wael Saber

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Reduced-intensity conditioning (RIC) regimens developed to extend the use of allogeneic hematopoietic stem cell transplantation (HSCT) to older patients have resulted in encouraging outcomes. We aimed to compare the 2 most commonly used RIC regimens, i.v. fludarabine with busulfan (FluBu) and fludarabine with melphalan (FluMel), in patients with myelodysplastic syndrome (MDS). Through the Center for International Blood and Marrow Transplant Research (CIBMTR), we identified 1045 MDS patients age ≥60 years who underwent first HSCT with a matched related or matched (8/8) unrelated donor using an RIC regimen. The CIBMTR's definition of RIC was used: a regimen that incorporated an i.v. busulfan total dose ≤7.2 mg/kg or a low-dose melphalan total dose ≤150 mg/m2. The 2 groups, recipients of FluBu (n = 697) and recipients of FluMel (n = 448), were comparable in terms of disease- and transplantation-related characteristics except for the more frequent use of antithymocyte globulin or alemtuzumab in the FluBu group (39% versus 31%). The median age was 67 years in both groups. FluMel was associated with a reduced relapse incidence (RI) compared with FluBu, with a 1-year adjusted incidence of 26% versus 44% (P ≤. 0001). Transplantation-related mortality (TRM) was higher in the FluMel group (26% versus 16%; P ≤. 0001). Because the magnitude of improvement with FluMel in RI was greater than the improvement in TRM with FluBu, disease-free survival (DFS) was better at 1 year and beyond with FluMel compared with FluBu (48% versus 40% at 1 year [P = .02] and 35% versus 27% at 3 years [P = .01]). Overall survival was comparable in the 2 groups at 1 year (63% versus 61%; P = .4) but was significantly improved with FluMel compared with FluBu at 3 years (46% versus 39%; P = .03). Our results suggest that FluMel is associated with superior DFS compared with FluBu owing to reduced RI in older patients with MDS patients.

Original languageEnglish
Pages (from-to)921.e1-921.e10
JournalTransplantation and Cellular Therapy
DOIs
StatePublished - Nov 1 2021

Bibliographical note

Funding Information:
Financial disclosure: The CIBMTR is supported primarily by Public Health Service Grant U24CA076518 from the National Cancer Institute, the National Heart, Lung and Blood Institute, and the National Institute of Allergy and Infectious Diseases; Grant HHSH250201700006C from the Health Resources and Services Administration; and Awards N00014-20-1-2705 and N00014-20-1-2832 from the Office of Naval Research. Support is also provided by Be the Match Foundation, the Medical College of Wisconsin, the National Marrow Donor Program, and from the following commercial entities: AbbVie, Accenture, Actinium Pharmaceuticals, Adaptive Biotechnologies, Adienne, Allovir, Amgen, Astellas Pharma US, bluebird bio, Bristol Myers Squibb, CareDx, CSL Behring, CytoSen Therapeutics, Daiichi Sankyo, Eurofins Viracor, ExcellThera, Fate Therapeutics, Gamida Cell, Genentech, Gilead, GlaxoSmithKline, Incyte, Janssen/Johnson & Johnson, Jasper Therapeutics, Jazz Pharmaceuticals, Karyopharm Therapeutics, Kiadis Pharma; Kite Pharma, Kyowa Kirin, Magenta Therapeutics, Medac, Merck & Co, Millennium, Miltenyi Biotec, MorphoSys, Novartis, Omeros, Oncopeptides, Orca Biosystems, Pfizer, Pharmacyclics, Sanofi Genzyme, Seagen, Stemcyte, Takeda Pharmaceuticals, Tscan, Vertex, Vor Biopharma, and Xenikos.

Funding Information:
Financial disclosure: The CIBMTR is supported primarily by Public Health Service Grant U24CA076518 from the National Cancer Institute, the National Heart, Lung and Blood Institute, and the National Institute of Allergy and Infectious Diseases; Grant HHSH250201700006C from the Health Resources and Services Administration; and Awards N00014-20-1-2705 and N00014-20-1-2832 from the Office of Naval Research. Support is also provided by Be the Match Foundation, the Medical College of Wisconsin, the National Marrow Donor Program, and from the following commercial entities: AbbVie, Accenture, Actinium Pharmaceuticals, Adaptive Biotechnologies, Adienne, Allovir, Amgen, Astellas Pharma US, bluebird bio, Bristol Myers Squibb, CareDx, CSL Behring, CytoSen Therapeutics, Daiichi Sankyo, Eurofins Viracor, ExcellThera, Fate Therapeutics, Gamida Cell, Genentech, Gilead, GlaxoSmithKline, Incyte, Janssen/Johnson & Johnson, Jasper Therapeutics, Jazz Pharmaceuticals, Karyopharm Therapeutics, Kiadis Pharma; Kite Pharma, Kyowa Kirin, Magenta Therapeutics, Medac, Merck & Co, Millennium, Miltenyi Biotec, MorphoSys, Novartis, Omeros, Oncopeptides, Orca Biosystems, Pfizer, Pharmacyclics, Sanofi Genzyme, Seagen, Stemcyte, Takeda Pharmaceuticals, Tscan, Vertex, Vor Biopharma, and Xenikos. Conflict of interest statement: D.R. reports receiving personal fees from Amgen, Kite Pharma, AROG, Pharmacyclics, Seattle Genetics, Pfizer, Novartis, Sanofi-Aventis, Incyte, Gilead, Jazz Pharmaceuticals, AbbVie and Celgene and other remuneration from Celltron/Teva, Mustang, Bayer, and Stemline. G.C.H. reports receiving honoraria from Pfizer, Kite Pharma, Incyte, Jazz Pharmaceuticals, Pharmacyclics, Takeda, the Falk Foundation, and Astellas Pharma. G.A.H. reports receiving honoraria from Medpace. J.C. reports receiving personal fees from Jazz Pharmaceuticals and Amgen. J.L.L. reports receiving honoraria from Onconova. J.A.Y. reports receiving honoraria from Kite Pharma and Jazz Pharmaceutical. J.Y.-C. reports receiving honoraria from Agios, AbbVie, Otsuka and Race Oncology. J.S. reports receiving personal fees from Alexion Pharmaceuticals, Takeda Pharmaceuticals, Pfizer, Apellis Pharmaceuticals, Novartis, and Sanofi. M.R.G. reports receiving personal fees from AbbVie, Agios, Amgen, Cardinal Health, BMS/Celgene, Daiichi Sankyo, Incyte, Merck, Pfizer, Premier, Karius, Astellas, and Trovagene and honoraria from Incyte, Forma Therapeutics, Genentech/Roche, and Janssen. M.S. reports receiving personal fees from Astellas Pharma, Celgene, Pfizer, Jazz Pharmaceuticals, AbbVie, Taiho, Novartis, and Roche. N.F. reports receiving grants from CSL Behring and honoraria from Incyte. M.A.K.-D. reports receiving honoraria from Daiichi Sankyo and Pharmacyclics. N.F.M. reports receiving personal fees from Anthem, Incyte, and Nkarta. R.R. reports receiving personal fees from Gilead, Bristol Myers Squibb, Monsanto, Incyte, Magenta, Pharmacyclics, Atara, and Novartis. R.F.O. reports receiving personal fees from AstraZeneca. R.P.G. reports receiving personal fees from BeiGene, Kite Pharma, Fusion Pharma, La Jolla NanoMedical, MingSight Pharmaceuticals, CStone Pharmaceuticals, Antengene Biotech, FFF Enterprises, AZCA, the Rak Fond Foundation, and StemRad. R.N. reports receiving grants from Miyarisan and personal fees from NapaJen, Kadmon, Viracor, and Magenta. S.S. reports receiving personal fees from Janssen Pharmaceutical KK, outside the submitted work. S.H. reports receiving grants and honoraria from Pfizer, Novartis, Therakos, Janssen, and MSD. S.G. reports receiving personal fees from Seattle Genetics, Kite Pharma, and Kadmon. T.N. reports receiving honoraria from Karyopharm, Novartis, and Null Pharma. T.J. reports receiving honoraria from Takeda Oncology, CareDx, and Bristol Myers Squibb. Authorship statement: B.O. W.S. and U.P. developed the design and concept of the study; C.F. and K.W.A. performed the statistical analysis; B.O. W.S. U.P. C.F. and K.W.A. critically reviewed the data and analysis; and all authors were involved in interpretation of the data and analysis. B.O. wrote the first draft of the manuscript. All authors reviewed/revised the manuscript. Financial disclosure: See Acknowledgments on page 921.e8.

Publisher Copyright:
© 2021

Keywords

  • MDS
  • Melphalan
  • Relapse
  • Survival
  • Transplantation

ASJC Scopus subject areas

  • Hematology
  • Transplantation
  • Immunology and Allergy
  • Cell Biology
  • Molecular Medicine
  • Medicine (all)

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