Reduced intensity conditioning for acute myeloid leukemia using melphalan-vs busulfan-based regimens: A CIBMTR report

Zheng Zhou; Rajneesh Nath; Jan Cerny; Hai Lin Wang; Mei Jie Zhang; Hisham Abdel-Azim; Vaibhav Agrawal; Gulrayz Ahmed; A. Samer Al-Homsi; Mahmoud Aljurf; Hassan B. Alkhateeb; Amer Assal; Ulrike Bacher; Ashish Bajel; Qaiser Bashir; Minocher Battiwalla; Vijaya Raj Bhatt; Michael Byrne; Jean Yves Cahn; Mitchell Cairo; Hannah Choe; Edward Copelan; Corey Cutler; Moussab B. Damlaj; Zachariah Defilipp; Marcos De Lima; Miguel Angel Diaz; Nosha Farhadfar; James Foran; C. Esar O. Freytes; Aaron T. Gerds; Usama Gergis; Michael R. Grunwald; Zartash Gul; Mehdi Hamadani; Shahrukh Hashmi; Mark Hertzberg; Gerhard C. Hildebrandt; Nasheed Hossain; Yoshihiro Inamoto; Luis Isola; Tania Jain; Rammurti T. Kamble; Muhammad Waqas Khan; Mohamed A. Kharfan-Dabaja; Partow Kebriaei; Natasha Kekre; Nandita Khera; Hillard M. Lazarus; Jane L. Liesveld; Mark Litzow; Hongtao Liu; David I. Marks; Rodrigo Martino; Vikram Mathews; Asmita Mishra; Hemant S. Murthy; Arnon Nagler; Ryotaro Nakamura; Sunita Nathan; Taiga Nishihori; Rebecca Olin; Richard F. Olsson; Neil Palmisiano; Sagar S. Patel; Mrinal M. Patnaik; Attaphol Pawarode; Miguel Angel Perales; Ioannis Politikos; Uday Popat; David Rizzieri; Brenda M. Sandmaier; Bipin N. Savani; Sachiko Seo; Nirav N. Shah; Geoffrey L. Uy; David Valc A. Arcel; Leo F. Verdonck; Edmund K. Waller; Youjin Wang; Daniel Weisdorf; Baldeep Wirk; Eric Wong; Jean A. Yared; Wael Saber

doi:10.1182/bloodadvances.2019001266

Reduced intensity conditioning for acute myeloid leukemia using melphalan-vs busulfan-based regimens: A CIBMTR report

Zheng Zhou, Rajneesh Nath, Jan Cerny, Hai Lin Wang, Mei Jie Zhang, Hisham Abdel-Azim, Vaibhav Agrawal, Gulrayz Ahmed, A. Samer Al-Homsi, Mahmoud Aljurf, Hassan B. Alkhateeb, Amer Assal, Ulrike Bacher, Ashish Bajel, Qaiser Bashir, Minocher Battiwalla, Vijaya Raj Bhatt, Michael Byrne, Jean Yves Cahn, Mitchell CairoHannah Choe, Edward Copelan, Corey Cutler, Moussab B. Damlaj, Zachariah Defilipp, Marcos De Lima, Miguel Angel Diaz, Nosha Farhadfar, James Foran, C. Esar O. Freytes, Aaron T. Gerds, Usama Gergis, Michael R. Grunwald, Zartash Gul, Mehdi Hamadani, Shahrukh Hashmi, Mark Hertzberg, Gerhard C. Hildebrandt, Nasheed Hossain, Yoshihiro Inamoto, Luis Isola, Tania Jain, Rammurti T. Kamble, Muhammad Waqas Khan, Mohamed A. Kharfan-Dabaja, Partow Kebriaei, Natasha Kekre, Nandita Khera, Hillard M. Lazarus, Jane L. Liesveld, Mark Litzow, Hongtao Liu, David I. Marks, Rodrigo Martino, Vikram Mathews, Asmita Mishra, Hemant S. Murthy, Arnon Nagler, Ryotaro Nakamura, Sunita Nathan, Taiga Nishihori, Rebecca Olin, Richard F. Olsson, Neil Palmisiano, Sagar S. Patel, Mrinal M. Patnaik, Attaphol Pawarode, Miguel Angel Perales, Ioannis Politikos, Uday Popat, David Rizzieri, Brenda M. Sandmaier, Bipin N. Savani, Sachiko Seo, Nirav N. Shah, Geoffrey L. Uy, David Valc A. Arcel, Leo F. Verdonck, Edmund K. Waller, Youjin Wang, Daniel Weisdorf, Baldeep Wirk, Eric Wong, Jean A. Yared, Wael Saber

Medicine - Hematology, Oncology, Transplant

Research output: Contribution to journal › Article › peer-review

17 Scopus citations

Abstract

There is a lack of large comparative study on the outcomes of reduced intensity conditioning (RIC) in acute myeloid leukemia (AML) transplantation using fludarabine/busulfan (FB) and fludarabine/melphalan (FM) regimens. Adult AML patients from Center for International Blood and Marrow Transplant Research who received first RIC allo-transplant between 2001 and 2015 were studied. Patients were excluded if they received cord blood or identical twin transplant, total body irradiation in conditioning, or graft-versus-host disease (GVHD) prophylaxis with in vitro T-cell depletion. Primary outcome was overall survival (OS), secondary end points were leukemia-free survival (LFS), nonrelapse mortality (NRM), relapse, and GVHD. Multivariate survival model was used with adjustment for patient, leukemia, and transplant-related factors. A total of 622 patients received FM and 791 received FB RIC. Compared with FB, the FM group had fewer transplant in complete remission (CR), fewer matched sibling donors, and less usage of anti-thymocyte globulin or alemtuzumab. More patients in the FM group received marrow grafts and had transplantation before 2005. OS was significantly lower within the first 3 months posttransplant in the FM group (hazard ratio [HR] 5 1.82, P , .001), but was marginally superior beyond 3 months (HR 5 0.87, P 5 .05). LFS was better with FM compared with FB (HR 5 0.89, P 5 .05). NRM was significantly increased in the FM group during the first 3 months of posttransplant (HR 5 3.85, P , .001). Long-term relapse was lower with FM (HR 5 0.65, P , .001). Analysis restricted to patients with CR showed comparable results. In conclusion, compared with FB, the FM RIC showed a marginally superior long-term OS and LFS and a lower relapse rate. A lower OS early posttransplant within 3 months was largely the result of a higher early NRM.

Original language	English (US)
Pages (from-to)	3180-3190
Number of pages	11
Journal	Blood Advances
Volume	4
Issue number	13
DOIs	https://doi.org/10.1182/bloodadvances.2019001266
State	Published - Jul 14 2020

Bibliographical note

Funding Information:
The CIBMTR is supported primarily by grants from the National Institutes of Health, National Cancer Institute (NCI), the National Heart, Lung, and Blood Institute (NHLBI), and the National Institute of Allergy and Infectious Diseases (NIAID) via a Public Health Service grant/cooperative agreement (U24CA076518); NHLBI and NCI (U24HL138660); NHLBI (OT3HL147741, R21HL140314, U01HL128568); Health Resources and Services Administration (HHSH250201700006C); Office of Naval Research (N00014-18-1-2888, N00014-17-1-2850); HRSA subaward (prime contract award SC1MC31881-01-00); NHLBI subawards (prime grant awards R01HL131731, R01HL126589); and subawards from NCI (prime grant awards 5P01CA111412, R01CA152108, 1R01CA231141), NHLBI (prime grant awards 5R01HL129472, 1R01HL131731), and National Institute of Allergy and Infectious Diseases (prime grant award 1U01AI126612). The CIBMTR was also supported by commercial funds from Actinium Pharmaceuticals Inc., Adaptive Biotechnologies, Allovir Inc., Amgen Inc., an 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, 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, the 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.,

Funding Information:
Authorship Contribution: Z.Z., R.N., J.C., and W.S. conceived and designed the study; CIBMTR and collaborative transplant centers provided study materials and patients; H.-L.W., M.-J.Z., and W.S. collected and assembled data; Z.Z., R.N., J.C., H.-L.W., M.-J.Z., W.S. analyzed and interpreted the data; Z.Z., R.N., J.C., and W.S. wrote the manuscript; and all coauthors are leading physicians at respective transplant centers that made significant contributions to data collection and submission to the CIBMTR, and participated substantively in the writing of this manuscript Conflict-of-interest disclosure: R.N. serves on the advisory boards of, was paid travel fees to the advisory board, and is a consultant for Actinum, Astellas, Daiichi Sankyo. N.N.S. has received honoraria and/or travel support from Incyte, Celgene, and Miltenyi Biotec; serves on scientific advisory boards for Kite, Celgene, and Cellectar; has equity ownership in Geron, Exelexis, Oncosec, and Cell Vault;, and has received institutional research support for clinical trials from BMS and Miltenyi Biotec. D.R. is an advisory board member for AbbVie, Agios, Jazz Novartis, Sanofi, Teva; a consultant advisory board member for AROG, Bayer, Pfizer; a speaker, advisory board member for Celgene and Gilead; and a speaker, advisory board member, consultant, and has received research funding from Stemline. I.P. is a data and safety monitoring board member for ExcellThera; and has received an educational grant from Merck. M.-A.P. is an ad hoc advisory board member for AbbVie, Bellicum, Bristol-Myers Squibb; a member of the scientific advisory board for MolMed and Nex-Immune; is a consultant for Merck; and has received research funding from Incyte (clinical trial) and Kite/Gilead (clinical trial). R.F.O. reports personal fees from AstraZeneca, outside the submitted work. M. Hertzberg receives speaker fees from and is on the advisory boards for Takeda and Roche; is on the advisory board for MSD; and receives speaker fees from Celgene. M.R.G. is a consultant for Agios, AbbVie, Amgen, Cardinal Health, Celgene, Incyte, Merck, Pfizer, Travagene, and Daischi Dankyo; owns stock in Medtronic; and receives research

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© 2020 American Society of Hematology. All rights reserved.

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Zhou, Z., Nath, R., Cerny, J., Wang, H. L., Zhang, M. J., Abdel-Azim, H., Agrawal, V., Ahmed, G., Al-Homsi, A. S., Aljurf, M., Alkhateeb, H. B., Assal, A., Bacher, U., Bajel, A., Bashir, Q., Battiwalla, M., Bhatt, V. R., Byrne, M., Cahn, J. Y., ... Saber, W. (2020). Reduced intensity conditioning for acute myeloid leukemia using melphalan-vs busulfan-based regimens: A CIBMTR report. Blood Advances, 4(13), 3180-3190. https://doi.org/10.1182/bloodadvances.2019001266

Zhou, Z, Nath, R, Cerny, J, Wang, HL, Zhang, MJ, Abdel-Azim, H, Agrawal, V, Ahmed, G, Al-Homsi, AS, Aljurf, M, Alkhateeb, HB, Assal, A, Bacher, U, Bajel, A, Bashir, Q, Battiwalla, M, Bhatt, VR, Byrne, M, Cahn, JY, Cairo, M, Choe, H, Copelan, E, Cutler, C, Damlaj, MB, Defilipp, Z, Lima, MD, Diaz, MA, Farhadfar, N, Foran, J, Freytes, CEO, Gerds, AT, Gergis, U, Grunwald, MR, Gul, Z, Hamadani, M, Hashmi, S, Hertzberg, M, Hildebrandt, GC, Hossain, N, Inamoto, Y, Isola, L, Jain, T, Kamble, RT, Khan, MW, Kharfan-Dabaja, MA, Kebriaei, P, Kekre, N, Khera, N, Lazarus, HM, Liesveld, JL, Litzow, M, Liu, H, Marks, DI, Martino, R, Mathews, V, Mishra, A, Murthy, HS, Nagler, A, Nakamura, R, Nathan, S, Nishihori, T, Olin, R, Olsson, RF, Palmisiano, N, Patel, SS, Patnaik, MM, Pawarode, A, Perales, MA, Politikos, I, Popat, U, Rizzieri, D, Sandmaier, BM, Savani, BN, Seo, S, Shah, NN, Uy, GL, Arcel, DVA, Verdonck, LF, Waller, EK, Wang, Y, Weisdorf, D, Wirk, B, Wong, E, Yared, JA & Saber, W 2020, 'Reduced intensity conditioning for acute myeloid leukemia using melphalan-vs busulfan-based regimens: A CIBMTR report', Blood Advances, vol. 4, no. 13, pp. 3180-3190. https://doi.org/10.1182/bloodadvances.2019001266

@article{f9979e79aed04e7e886118e9d164aeb4,

title = "Reduced intensity conditioning for acute myeloid leukemia using melphalan-vs busulfan-based regimens: A CIBMTR report",

abstract = "There is a lack of large comparative study on the outcomes of reduced intensity conditioning (RIC) in acute myeloid leukemia (AML) transplantation using fludarabine/busulfan (FB) and fludarabine/melphalan (FM) regimens. Adult AML patients from Center for International Blood and Marrow Transplant Research who received first RIC allo-transplant between 2001 and 2015 were studied. Patients were excluded if they received cord blood or identical twin transplant, total body irradiation in conditioning, or graft-versus-host disease (GVHD) prophylaxis with in vitro T-cell depletion. Primary outcome was overall survival (OS), secondary end points were leukemia-free survival (LFS), nonrelapse mortality (NRM), relapse, and GVHD. Multivariate survival model was used with adjustment for patient, leukemia, and transplant-related factors. A total of 622 patients received FM and 791 received FB RIC. Compared with FB, the FM group had fewer transplant in complete remission (CR), fewer matched sibling donors, and less usage of anti-thymocyte globulin or alemtuzumab. More patients in the FM group received marrow grafts and had transplantation before 2005. OS was significantly lower within the first 3 months posttransplant in the FM group (hazard ratio [HR] 5 1.82, P , .001), but was marginally superior beyond 3 months (HR 5 0.87, P 5 .05). LFS was better with FM compared with FB (HR 5 0.89, P 5 .05). NRM was significantly increased in the FM group during the first 3 months of posttransplant (HR 5 3.85, P , .001). Long-term relapse was lower with FM (HR 5 0.65, P , .001). Analysis restricted to patients with CR showed comparable results. In conclusion, compared with FB, the FM RIC showed a marginally superior long-term OS and LFS and a lower relapse rate. A lower OS early posttransplant within 3 months was largely the result of a higher early NRM.",

author = "Zheng Zhou and Rajneesh Nath and Jan Cerny and Wang, {Hai Lin} and Zhang, {Mei Jie} and Hisham Abdel-Azim and Vaibhav Agrawal and Gulrayz Ahmed and Al-Homsi, {A. Samer} and Mahmoud Aljurf and Alkhateeb, {Hassan B.} and Amer Assal and Ulrike Bacher and Ashish Bajel and Qaiser Bashir and Minocher Battiwalla and Bhatt, {Vijaya Raj} and Michael Byrne and Cahn, {Jean Yves} and Mitchell Cairo and Hannah Choe and Edward Copelan and Corey Cutler and Damlaj, {Moussab B.} and Zachariah Defilipp and Lima, {Marcos De} and Diaz, {Miguel Angel} and Nosha Farhadfar and James Foran and Freytes, {C. Esar O.} and Gerds, {Aaron T.} and Usama Gergis and Grunwald, {Michael R.} and Zartash Gul and Mehdi Hamadani and Shahrukh Hashmi and Mark Hertzberg and Hildebrandt, {Gerhard C.} and Nasheed Hossain and Yoshihiro Inamoto and Luis Isola and Tania Jain and Kamble, {Rammurti T.} and Khan, {Muhammad Waqas} and Kharfan-Dabaja, {Mohamed A.} and Partow Kebriaei and Natasha Kekre and Nandita Khera and Lazarus, {Hillard M.} and Liesveld, {Jane L.} and Mark Litzow and Hongtao Liu and Marks, {David I.} and Rodrigo Martino and Vikram Mathews and Asmita Mishra and Murthy, {Hemant S.} and Arnon Nagler and Ryotaro Nakamura and Sunita Nathan and Taiga Nishihori and Rebecca Olin and Olsson, {Richard F.} and Neil Palmisiano and Patel, {Sagar S.} and Patnaik, {Mrinal M.} and Attaphol Pawarode and Perales, {Miguel Angel} and Ioannis Politikos and Uday Popat and David Rizzieri and Sandmaier, {Brenda M.} and Savani, {Bipin N.} and Sachiko Seo and Shah, {Nirav N.} and Uy, {Geoffrey L.} and Arcel, {David Valc A.} and Verdonck, {Leo F.} and Waller, {Edmund K.} and Youjin Wang and Daniel Weisdorf and Baldeep Wirk and Eric Wong and Yared, {Jean A.} and Wael Saber",

note = "Funding Information: The CIBMTR is supported primarily by grants from the National Institutes of Health, National Cancer Institute (NCI), the National Heart, Lung, and Blood Institute (NHLBI), and the National Institute of Allergy and Infectious Diseases (NIAID) via a Public Health Service grant/cooperative agreement (U24CA076518); NHLBI and NCI (U24HL138660); NHLBI (OT3HL147741, R21HL140314, U01HL128568); Health Resources and Services Administration (HHSH250201700006C); Office of Naval Research (N00014-18-1-2888, N00014-17-1-2850); HRSA subaward (prime contract award SC1MC31881-01-00); NHLBI subawards (prime grant awards R01HL131731, R01HL126589); and subawards from NCI (prime grant awards 5P01CA111412, R01CA152108, 1R01CA231141), NHLBI (prime grant awards 5R01HL129472, 1R01HL131731), and National Institute of Allergy and Infectious Diseases (prime grant award 1U01AI126612). The CIBMTR was also supported by commercial funds from Actinium Pharmaceuticals Inc., Adaptive Biotechnologies, Allovir Inc., Amgen Inc., an 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{\textquoteright}s Hospital, Bristol Myers Squibb Co., Celgene Corp., Children{\textquoteright}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, 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, the 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., Funding Information: Authorship Contribution: Z.Z., R.N., J.C., and W.S. conceived and designed the study; CIBMTR and collaborative transplant centers provided study materials and patients; H.-L.W., M.-J.Z., and W.S. collected and assembled data; Z.Z., R.N., J.C., H.-L.W., M.-J.Z., W.S. analyzed and interpreted the data; Z.Z., R.N., J.C., and W.S. wrote the manuscript; and all coauthors are leading physicians at respective transplant centers that made significant contributions to data collection and submission to the CIBMTR, and participated substantively in the writing of this manuscript Conflict-of-interest disclosure: R.N. serves on the advisory boards of, was paid travel fees to the advisory board, and is a consultant for Actinum, Astellas, Daiichi Sankyo. N.N.S. has received honoraria and/or travel support from Incyte, Celgene, and Miltenyi Biotec; serves on scientific advisory boards for Kite, Celgene, and Cellectar; has equity ownership in Geron, Exelexis, Oncosec, and Cell Vault;, and has received institutional research support for clinical trials from BMS and Miltenyi Biotec. D.R. is an advisory board member for AbbVie, Agios, Jazz Novartis, Sanofi, Teva; a consultant advisory board member for AROG, Bayer, Pfizer; a speaker, advisory board member for Celgene and Gilead; and a speaker, advisory board member, consultant, and has received research funding from Stemline. I.P. is a data and safety monitoring board member for ExcellThera; and has received an educational grant from Merck. M.-A.P. is an ad hoc advisory board member for AbbVie, Bellicum, Bristol-Myers Squibb; a member of the scientific advisory board for MolMed and Nex-Immune; is a consultant for Merck; and has received research funding from Incyte (clinical trial) and Kite/Gilead (clinical trial). R.F.O. reports personal fees from AstraZeneca, outside the submitted work. M. Hertzberg receives speaker fees from and is on the advisory boards for Takeda and Roche; is on the advisory board for MSD; and receives speaker fees from Celgene. M.R.G. is a consultant for Agios, AbbVie, Amgen, Cardinal Health, Celgene, Incyte, Merck, Pfizer, Travagene, and Daischi Dankyo; owns stock in Medtronic; and receives research Publisher Copyright: {\textcopyright} 2020 American Society of Hematology. All rights reserved.",

year = "2020",

month = jul,

day = "14",

doi = "10.1182/bloodadvances.2019001266",

language = "English (US)",

volume = "4",

pages = "3180--3190",

journal = "Blood Advances",

issn = "2473-9529",

publisher = "American Society of Hematology",

number = "13",

}

TY - JOUR

T1 - Reduced intensity conditioning for acute myeloid leukemia using melphalan-vs busulfan-based regimens

T2 - A CIBMTR report

AU - Zhou, Zheng

AU - Nath, Rajneesh

AU - Cerny, Jan

AU - Wang, Hai Lin

AU - Zhang, Mei Jie

AU - Abdel-Azim, Hisham

AU - Agrawal, Vaibhav

AU - Ahmed, Gulrayz

AU - Al-Homsi, A. Samer

AU - Aljurf, Mahmoud

AU - Alkhateeb, Hassan B.

AU - Assal, Amer

AU - Bacher, Ulrike

AU - Bajel, Ashish

AU - Bashir, Qaiser

AU - Battiwalla, Minocher

AU - Bhatt, Vijaya Raj

AU - Byrne, Michael

AU - Cahn, Jean Yves

AU - Cairo, Mitchell

AU - Choe, Hannah

AU - Copelan, Edward

AU - Cutler, Corey

AU - Damlaj, Moussab B.

AU - Defilipp, Zachariah

AU - Lima, Marcos De

AU - Diaz, Miguel Angel

AU - Farhadfar, Nosha

AU - Foran, James

AU - Freytes, C. Esar O.

AU - Gerds, Aaron T.

AU - Gergis, Usama

AU - Grunwald, Michael R.

AU - Gul, Zartash

AU - Hamadani, Mehdi

AU - Hashmi, Shahrukh

AU - Hertzberg, Mark

AU - Hildebrandt, Gerhard C.

AU - Hossain, Nasheed

AU - Inamoto, Yoshihiro

AU - Isola, Luis

AU - Jain, Tania

AU - Kamble, Rammurti T.

AU - Khan, Muhammad Waqas

AU - Kharfan-Dabaja, Mohamed A.

AU - Kebriaei, Partow

AU - Kekre, Natasha

AU - Khera, Nandita

AU - Lazarus, Hillard M.

AU - Liesveld, Jane L.

AU - Litzow, Mark

AU - Liu, Hongtao

AU - Marks, David I.

AU - Martino, Rodrigo

AU - Mathews, Vikram

AU - Mishra, Asmita

AU - Murthy, Hemant S.

AU - Nagler, Arnon

AU - Nakamura, Ryotaro

AU - Nathan, Sunita

AU - Nishihori, Taiga

AU - Olin, Rebecca

AU - Olsson, Richard F.

AU - Palmisiano, Neil

AU - Patel, Sagar S.

AU - Patnaik, Mrinal M.

AU - Pawarode, Attaphol

AU - Perales, Miguel Angel

AU - Politikos, Ioannis

AU - Popat, Uday

AU - Rizzieri, David

AU - Sandmaier, Brenda M.

AU - Savani, Bipin N.

AU - Seo, Sachiko

AU - Shah, Nirav N.

AU - Uy, Geoffrey L.

AU - Arcel, David Valc A.

AU - Verdonck, Leo F.

AU - Waller, Edmund K.

AU - Wang, Youjin

AU - Weisdorf, Daniel

AU - Wirk, Baldeep

AU - Wong, Eric

AU - Yared, Jean A.

AU - Saber, Wael

N1 - Funding Information: The CIBMTR is supported primarily by grants from the National Institutes of Health, National Cancer Institute (NCI), the National Heart, Lung, and Blood Institute (NHLBI), and the National Institute of Allergy and Infectious Diseases (NIAID) via a Public Health Service grant/cooperative agreement (U24CA076518); NHLBI and NCI (U24HL138660); NHLBI (OT3HL147741, R21HL140314, U01HL128568); Health Resources and Services Administration (HHSH250201700006C); Office of Naval Research (N00014-18-1-2888, N00014-17-1-2850); HRSA subaward (prime contract award SC1MC31881-01-00); NHLBI subawards (prime grant awards R01HL131731, R01HL126589); and subawards from NCI (prime grant awards 5P01CA111412, R01CA152108, 1R01CA231141), NHLBI (prime grant awards 5R01HL129472, 1R01HL131731), and National Institute of Allergy and Infectious Diseases (prime grant award 1U01AI126612). The CIBMTR was also supported by commercial funds from Actinium Pharmaceuticals Inc., Adaptive Biotechnologies, Allovir Inc., Amgen Inc., an 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, 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, the 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., Funding Information: Authorship Contribution: Z.Z., R.N., J.C., and W.S. conceived and designed the study; CIBMTR and collaborative transplant centers provided study materials and patients; H.-L.W., M.-J.Z., and W.S. collected and assembled data; Z.Z., R.N., J.C., H.-L.W., M.-J.Z., W.S. analyzed and interpreted the data; Z.Z., R.N., J.C., and W.S. wrote the manuscript; and all coauthors are leading physicians at respective transplant centers that made significant contributions to data collection and submission to the CIBMTR, and participated substantively in the writing of this manuscript Conflict-of-interest disclosure: R.N. serves on the advisory boards of, was paid travel fees to the advisory board, and is a consultant for Actinum, Astellas, Daiichi Sankyo. N.N.S. has received honoraria and/or travel support from Incyte, Celgene, and Miltenyi Biotec; serves on scientific advisory boards for Kite, Celgene, and Cellectar; has equity ownership in Geron, Exelexis, Oncosec, and Cell Vault;, and has received institutional research support for clinical trials from BMS and Miltenyi Biotec. D.R. is an advisory board member for AbbVie, Agios, Jazz Novartis, Sanofi, Teva; a consultant advisory board member for AROG, Bayer, Pfizer; a speaker, advisory board member for Celgene and Gilead; and a speaker, advisory board member, consultant, and has received research funding from Stemline. I.P. is a data and safety monitoring board member for ExcellThera; and has received an educational grant from Merck. M.-A.P. is an ad hoc advisory board member for AbbVie, Bellicum, Bristol-Myers Squibb; a member of the scientific advisory board for MolMed and Nex-Immune; is a consultant for Merck; and has received research funding from Incyte (clinical trial) and Kite/Gilead (clinical trial). R.F.O. reports personal fees from AstraZeneca, outside the submitted work. M. Hertzberg receives speaker fees from and is on the advisory boards for Takeda and Roche; is on the advisory board for MSD; and receives speaker fees from Celgene. M.R.G. is a consultant for Agios, AbbVie, Amgen, Cardinal Health, Celgene, Incyte, Merck, Pfizer, Travagene, and Daischi Dankyo; owns stock in Medtronic; and receives research Publisher Copyright: © 2020 American Society of Hematology. All rights reserved.

PY - 2020/7/14

Y1 - 2020/7/14

N2 - There is a lack of large comparative study on the outcomes of reduced intensity conditioning (RIC) in acute myeloid leukemia (AML) transplantation using fludarabine/busulfan (FB) and fludarabine/melphalan (FM) regimens. Adult AML patients from Center for International Blood and Marrow Transplant Research who received first RIC allo-transplant between 2001 and 2015 were studied. Patients were excluded if they received cord blood or identical twin transplant, total body irradiation in conditioning, or graft-versus-host disease (GVHD) prophylaxis with in vitro T-cell depletion. Primary outcome was overall survival (OS), secondary end points were leukemia-free survival (LFS), nonrelapse mortality (NRM), relapse, and GVHD. Multivariate survival model was used with adjustment for patient, leukemia, and transplant-related factors. A total of 622 patients received FM and 791 received FB RIC. Compared with FB, the FM group had fewer transplant in complete remission (CR), fewer matched sibling donors, and less usage of anti-thymocyte globulin or alemtuzumab. More patients in the FM group received marrow grafts and had transplantation before 2005. OS was significantly lower within the first 3 months posttransplant in the FM group (hazard ratio [HR] 5 1.82, P , .001), but was marginally superior beyond 3 months (HR 5 0.87, P 5 .05). LFS was better with FM compared with FB (HR 5 0.89, P 5 .05). NRM was significantly increased in the FM group during the first 3 months of posttransplant (HR 5 3.85, P , .001). Long-term relapse was lower with FM (HR 5 0.65, P , .001). Analysis restricted to patients with CR showed comparable results. In conclusion, compared with FB, the FM RIC showed a marginally superior long-term OS and LFS and a lower relapse rate. A lower OS early posttransplant within 3 months was largely the result of a higher early NRM.

AB - There is a lack of large comparative study on the outcomes of reduced intensity conditioning (RIC) in acute myeloid leukemia (AML) transplantation using fludarabine/busulfan (FB) and fludarabine/melphalan (FM) regimens. Adult AML patients from Center for International Blood and Marrow Transplant Research who received first RIC allo-transplant between 2001 and 2015 were studied. Patients were excluded if they received cord blood or identical twin transplant, total body irradiation in conditioning, or graft-versus-host disease (GVHD) prophylaxis with in vitro T-cell depletion. Primary outcome was overall survival (OS), secondary end points were leukemia-free survival (LFS), nonrelapse mortality (NRM), relapse, and GVHD. Multivariate survival model was used with adjustment for patient, leukemia, and transplant-related factors. A total of 622 patients received FM and 791 received FB RIC. Compared with FB, the FM group had fewer transplant in complete remission (CR), fewer matched sibling donors, and less usage of anti-thymocyte globulin or alemtuzumab. More patients in the FM group received marrow grafts and had transplantation before 2005. OS was significantly lower within the first 3 months posttransplant in the FM group (hazard ratio [HR] 5 1.82, P , .001), but was marginally superior beyond 3 months (HR 5 0.87, P 5 .05). LFS was better with FM compared with FB (HR 5 0.89, P 5 .05). NRM was significantly increased in the FM group during the first 3 months of posttransplant (HR 5 3.85, P , .001). Long-term relapse was lower with FM (HR 5 0.65, P , .001). Analysis restricted to patients with CR showed comparable results. In conclusion, compared with FB, the FM RIC showed a marginally superior long-term OS and LFS and a lower relapse rate. A lower OS early posttransplant within 3 months was largely the result of a higher early NRM.

UR - http://www.scopus.com/inward/record.url?scp=85088320644&partnerID=8YFLogxK

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U2 - 10.1182/bloodadvances.2019001266

DO - 10.1182/bloodadvances.2019001266

M3 - Article

C2 - 32663298

AN - SCOPUS:85088320644

SN - 2473-9529

VL - 4

SP - 3180

EP - 3190

JO - Blood Advances

JF - Blood Advances

IS - 13

ER -

Reduced intensity conditioning for acute myeloid leukemia using melphalan-vs busulfan-based regimens: A CIBMTR report

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