Abstract
Acute myeloid leukemia (AML) patients often undergo allogeneic hematopoietic cell transplantation (alloHCT) in first complete remission (CR). We examined the effect of depth of clinical response, including incomplete count recovery (CRi) and/or measurable residual disease (MRD), in patients from the Center for International Blood and Marrow Transplantation Research (CIBMTR) registry. We identified 2492 adult patients (1799 CR and 693 CRi) who underwent alloHCT between January 1, 2007 and December 31, 2015. The primary outcome was overall survival (OS). Multivariable analysis was performed to adjust for patient-, disease-, and transplant-related factors. Baseline characteristics were similar. Patients in CRi compared to those in CR had an increased likelihood of death (HR: 1.27; 95% confidence interval: 1.13–1.43). Compared to CR, CRi was significantly associated with increased non-relapse mortality (NRM), shorter disease-free survival (DFS), and a trend toward increased relapse. Detectable MRD was associated with shorter OS, shorter DFS, higher NRM, and increased relapse compared to absence of MRD. The deleterious effects of CRi and MRD were independent. In this large CIBMTR cohort, survival outcomes differ among AML patients based on depth of CR and presence of MRD at the time of alloHCT. Further studies should focus on optimizing post-alloHCT outcomes for patients with responses less than CR.
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Change history
20 May 2021
A Correction to this paper has been published: https://doi.org/10.1038/s41409-021-01353-3
References
Koreth J, Schlenk R, Kopecky KJ, Honda S, Sierra J, Djulbegovic BJ, et al. Allogeneic stem cell transplantation for acute myeloid leukemia in first complete remission: systematic review and meta-analysis of prospective clinical trials. JAMA. 2009;301:2349–61.
Appelbaum FR. Indications for allogeneic hematopoietic cell transplantation for acute myeloid leukemia in the genomic era. Am Soc Clin Oncol Educ Book. 2014;34:e327–33.
Dohner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Buchner T, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood 2017;129:424–47.
Chen X, Xie H, Wood BL, Walter RB, Pagel JM, Becker PS, et al. Relation of clinical response and minimal residual disease and their prognostic impact on outcome in acute myeloid leukemia. J Clin Oncol. 2015;33:1258–64.
Walter RB, Kantarjian HM, Huang X, Pierce SA, Sun Z, Gundacker HM, et al. Effect of complete remission and responses less than complete remission on survival in acute myeloid leukemia: a combined Eastern Cooperative Oncology Group, Southwest Oncology Group, and M. D. Anderson Cancer Center Study. J Clin Oncol. 2010;28:1766–71.
Vu K, Manjappa S, DiPersio JF, Gao F, Westervelt P, Vij R, et al. Hematologic recovery after pretransplant chemotherapy does not influence survival after allogeneic hematopoietic cell transplantation in acute myeloid leukemia patients. Biol Blood Marrow Transplant. 2015;21:1425–30.
Walter RB, Gooley TA, Wood BL, Milano F, Fang M, Sorror ML, et al. Impact of pretransplantation minimal residual disease, as detected by multiparametric flow cytometry, on outcome of myeloablative hematopoietic cell transplantation for acute myeloid leukemia. J Clin Oncol. 2011;29:1190–7.
Walter RB, Buckley SA, Pagel JM, Wood BL, Storer BE, Sandmaier BM, et al. Significance of minimal residual disease before myeloablative allogeneic hematopoietic cell transplantation for AML in first and second complete remission. Blood. 2013;122:1813–21.
Araki D, Wood BL, Othus M, Radich JP, Halpern AB, Zhou Y, et al. Allogeneic hematopoietic cell transplantation for acute myeloid leukemia: time to move toward a minimal residual disease-based definition of complete remission? J Clin Oncol. 2016;34:329–36.
Othus M, Wood BL, Stirewalt DL, Estey EH, Petersdorf SH, Appelbaum FR, et al. Effect of measurable (‘minimal’) residual disease (MRD) information on prediction of relapse and survival in adult acute myeloid leukemia. Leukemia. 2016;30:2080–3.
Versluis J, Cornelissen JJ. Risks and benefits in a personalized application of allogeneic transplantation in patients with AML in first CR. Semin Hematol. 2019;56:164–70.
Versluis J, Kalin B, Zeijlemaker W, Passweg J, Graux C, Manz MG, et al. Graft-versus-leukemia effect of allogeneic stem-cell transplantation and minimal residual disease in patients with acute myeloid leukemia in first complete remission. JCO Precis Oncol. 2017;1:1–13.
Slovak ML, Kopecky KJ, Cassileth PA, Harrington DH, Theil KS, Mohamed A, et al. Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group Study. Blood. 2000;96:4075–83.
Estey EH, Shen Y, Thall PF. Effect of time to complete remission on subsequent survival and disease-free survival time in AML, RAEB-t, and RAEB. Blood. 2000;95:72–7.
Inaba H, Coustan-Smith E, Cao X, Pounds SB, Shurtleff SA, Wang KY, et al. Comparative analysis of different approaches to measure treatment response in acute myeloid leukemia. J Clin Oncol. 2012;30:3625–32.
Zhou Y, Wood BL, Walter RB, Becker PS, Percival ME, Bar M, et al. Is there a need for morphologic exam to detect relapse in AML if multi-parameter flow cytometry is employed? Leukemia. 2017;31:2536–7.
Storb R, Gyurkocza B, Storer BE, Maloney DG, Sorror ML, Mielcarek M, et al. Allogeneic hematopoietic cell transplantation following minimal intensity conditioning: predicting acute graft-versus-host disease and graft-versus-tumor effects. Biol Blood Marrow Transplant. 2013;19:792–8.
Jongen-Lavrencic M, Grob T, Hanekamp D, Kavelaars FG, Al Hinai A, Zeilemaker A, et al. Molecular minimal residual disease in acute myeloid leukemia. N Engl J Med. 2018;378:1189–99.
Schuurhuis GJ, Heuser M, Freeman S, Bene MC, Buccisano F, Cloos J, et al. Minimal/measurable residual disease in AML: a consensus document from the European LeukemiaNet MRD Working Party. Blood. 2018;131:1275–91.
Othus M, Gale RP, Hourigan CS, Walter RB. Statistics and measurable residual disease (MRD) testing: uses and abuses in hematopoietic cell transplantation. Bone Marrow Transplant. 2020;55:843–50.
Armand P, Kim HT, Logan BR, Wang Z, Alyea EP, Kalaycio ME, et al. Validation and refinement of the disease risk index for allogeneic stem cell transplantation. Blood. 2014;123:3664–71.
Kongtim P, Parmar S, Milton DR, Perez JMR, Rondon G, Chen J, et al. Impact of a novel prognostic model, hematopoietic cell transplant-composite risk (HCT-CR), on allogeneic transplant outcomes in patients with acute myeloid leukemia and myelodysplastic syndrome. Bone Marrow Transplant. 2019;54:839–48.
Ustun C, Courville EL, DeFor T, Dolan M, Randall N, Yohe S, et al. Myeloablative, but not reduced-intensity, conditioning overcomes the negative effect of flow-cytometric evidence of leukemia in acute myeloid leukemia. Biol Blood Marrow Transplant. 2016;22:669–75.
Gilleece MH, Labopin M, Yakoub-Agha I, Volin L, Socie G, Ljungman P, et al. Measurable residual disease, conditioning regimen intensity, and age predict outcome of allogeneic hematopoietic cell transplantation for acute myeloid leukemia in first remission: a registry analysis of 2292 patients by the Acute Leukemia Working Party European Society of Blood and Marrow Transplantation. Am J Hematol. 2018;93:1142–52.
Hourigan CS, Dillon LW, Gui G, Logan BR, Fei M, Ghannam J, et al. Impact of conditioning intensity of allogeneic transplantation for acute myeloid leukemia with genomic evidence of residual disease. J Clin Oncol. 2020;38:1273–83.
Acknowledgements
The CIBMTR is supported primarily by Public Health Service U24CA076518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI) and the National Institute of Allergy and Infectious Diseases (NIAID); U24HL138660 from NHLBI and NCI; U01HL128568 from the NHLBI; HHSH250201700006C and HHSH250201700007C from the Health Resources and Services Administration (HRSA); and N00014-20-1-2705 and N00014-20-1-2832 from the Office of Naval Research; Additional federal support is provided by P01CA111412, R01CA152108, R01CA215134, R01CA218285, R01CA231141, R01AI128775, R01HL126589, R01HL129472, R01HL130388, R01HL131731, U01AI069197, U01AI126612, UG1HL06924, and BARDA. Support is also provided by Be the Match Foundation, Boston Children’s Hospital, Dana Farber, St. Baldrick’s Foundation, Stanford University, the Medical College of Wisconsin the National Marrow Donor Program, and from the following commercial entities: Actinium Pharmaceuticals, Inc.; Adienne SA; Allovir, Inc.; Amgen, Inc.; Angiocrine Bioscience; Astellas Pharma US; bluebird bio, Inc.; Bristol Myers Squibb Co.; Celgene Corp.; CSL Behring; CytoSen Therapeutics, Inc.; Daiichi Sankyo Co., Ltd.; ExcellThera; Fate Therapeutics; Gamida-Cell, Ltd.; Genentech Inc; Incyte Corporation; Janssen/Johnson & Johnson; Jazz Pharmaceuticals, Inc.; Kiadis Pharma; Kite, a Gilead Company; Kyowa Kirin; Legend Biotech; Magenta Therapeutics; Merck Sharp & Dohme Corp.; Millennium, the Takeda Oncology Co.; Miltenyi Biotec, Inc.; Novartis Pharmaceuticals Corporation; Omeros Corporation; Oncoimmune, Inc.; Orca Biosystems, Inc.; Pfizer, Inc.; Pharmacyclics, LLC; Sanofi Genzyme; Stemcyte; Takeda Pharma; Vor Biopharma; Xenikos BV. 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 (HRSA) or any other agency of the US Government.
Data sharing and declaration
CIBMTR supports accessibility of research in accord with the National Institutes of Health (NIH) Data Sharing Policy and the National Cancer Institute (NCI) Cancer Moonshot Public Access and Data Sharing Policy. The CIBMTR only releases de-identified data sets that comply with all relevant global regulations regarding privacy and confidentiality.
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WBR: Merck, Seattle Genetics, Spark Therapeutics; AK: Takeda, Jansen, Pfizer, Karyopharm, Celgene/BMS, Sanofi; TN: Novartis, Karyopharm; VB: Agios, Incyte, Takeda, Partner Therapeutics, Omeros, Abbvie, Jazz, Tolero Pharmaceuticals, National Marrow Donor Program, Oncoceutics, Partnership for health analytic research, LLC, Pfizer, CSL Behring; RS: Janssen; SG: Seattle Genetics, Kadmon; DAR: Amgen, Kite, AROG, Pharmacyclics, Seattle Genetics, Pfizer, Novartis, Sanofi-Aventis, Incyte, Gilead, Jazz, Abbvie, Celltron/Teva, Mustang, Bayer, Stemline, Celgene; MG: Incyte, Amgen, Alexion, ARIAD, Abbvie, Astellas, BMS/Celgene, Merck, Pfizer, Premier, Trovagene, Daiichi Sankyo, Cardinal Health, Novartis, Janssen, Genentech/Roche, Forma Therapeutics; MAK-D: Daiichi Sankyo; RFO: AstraZeneca; HL: BMS, Karyopharm, Agios.
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Percival, ME., Wang, HL., Zhang, MJ. et al. Impact of depth of clinical response on outcomes of acute myeloid leukemia patients in first complete remission who undergo allogeneic hematopoietic cell transplantation. Bone Marrow Transplant 56, 2108–2117 (2021). https://doi.org/10.1038/s41409-021-01261-6
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DOI: https://doi.org/10.1038/s41409-021-01261-6
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