Curative potential of fludarabine, melphalan, and non-myeloablative dosage of busulfan in elderly patients with myeloid malignancy
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Although the combination of fludarabine and high-dose melphalan (FLU/MEL) has been widely used in allogeneic stem cell transplantation, high-dose MEL causes life-threatening adverse events, especially in elderly patients. To reduce the toxicity of MEL without losing its antileukemic effect, we formulated a regimen comprising FLU (125 mg/m2), MEL (100 mg/m2), and a non-myeloablative busulfan dosage [4 mg/kg orally (oral) or 3.2 mg/kg intravenously (iv); FLU/MEL/BU]. We retrospectively analyzed 32 patients with myeloid malignancies who received FLU/MEL/BU at our institute. Median age was 59 years and the median observation period after allo-SCT was 8.2 years. The disease status of most of the patients (97%) at transplantation was controlled. The rate of neutrophil engraftment was 93.3%. The 5-year overall survival (OS), disease-free survival (DFS), non-relapse mortality (NRM), and relapse rate (RR) were 68.5%, 62.1%, 22.0%, and 15.9%, respectively, in all patients. Notably, the outcome of FLU/MEL/iv BU was excellent, with the 5-year OS and DFS being 75.6% and 70.8%, respectively, accompanied by a reduced 5-year NRM and RR of 19.3% and 9.8%, respectively. In conclusion, FLU/MEL/BU, particularly FLU/MEL/iv BU, has curative potential for controlled myeloid malignancies.
KeywordsAllogeneic stem cell transplantation Conditioning regimen Myeloid malignancy Busulfan Melphalan
This study was conducted at Kurashiki Central Hospital’s Department of Hematology/Oncology. We would like to thank all clinicians, medical staffs, and patients who contributed to this research.
TU and YU designed the study and analyzed the data. Transplantation was performed by TU, TJ, KO, YA, TS, TM, and TO with assistance from YU. The manuscript was written by TU and YU with assistance from TJ, KO, YA, TS, TM, and TO.
Compliance with ethical standards
Conflict of interest
The authors declare no conflict of interest.
- 1.Giralt S, Thall PF, Khouri I, Wang X, Braunschweig I, Ippolitti C, et al. Melphalan and purine analog-containing preparative regimens: reduced-intensity conditioning for patients with hematologic malignancies undergoing allogeneic progenitor cell transplantation. Blood. 2001;97(3):631–7.CrossRefGoogle Scholar
- 2.Kroger N, Sayer HG, Schwerdtfeger R, Kiehl M, Nagler A, Renges H, et al. Unrelated stem cell transplantation in multiple myeloma after a reduced-intensity conditioning with pretransplantation antithymocyte globulin is highly effective with low transplantation-related mortality. Blood. 2002;100(12):3919–24.CrossRefGoogle Scholar
- 4.Tauro S, Craddock C, Peggs K, Begum G, Mahendra P, Cook G, et al. Allogeneic stem-cell transplantation using a reduced-intensity conditioning regimen has the capacity to produce durable remissions and long-term disease-free survival in patients with high-risk acute myeloid leukemia and myelodysplasia. J Clin Oncol. 2005;23(36):9387–93.CrossRefGoogle Scholar
- 7.Shimoni A, Hardan I, Shem-Tov N, Rand A, Herscovici C, Yerushalmi R, et al. Comparison between two fludarabine-based reduced-intensity conditioning regimens before allogeneic hematopoietic stem-cell transplantation: fludarabine/melphalan is associated with higher incidence of acute graft-versus-host disease and non-relapse mortality and lower incidence of relapse than fludarabine/busulfan. Leukemia. 2007;21(10):2109–16.CrossRefGoogle Scholar
- 10.Kharfan-Dabaja MA, Labopin M, Bazarbachi A, Hamladji RM, Blaise D, Socie G et al. Comparing i.v. BU dose intensity between two regimens (FB2 vs FB4) for allogeneic HCT for AML in CR1: a report from the Acute Leukemia Working Party of EBMT. Bone Marrow Transpl. 2014;49(9):1170–1175.CrossRefGoogle Scholar
- 11.Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J et al. 1994 Consensus conference on acute GVHD grading. Bone Marrow Transpl. 1995;15(6): 825–828.Google Scholar
- 12.Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transpl. 2005;11(12):945–956.CrossRefGoogle Scholar
- 14.Oran B, Giralt S, Saliba R, Hosing C, Popat U, Khouri I, et al. Allogeneic hematopoietic stem cell transplantation for the treatment of high-risk acute myelogenous leukemia and myelodysplastic syndrome using reduced-intensity conditioning with fludarabine and melphalan. Biol Blood Marrow Transpl. 2007;13(4):454–62.CrossRefGoogle Scholar
- 15.Bryant A, Nivison-Smith I, Pillai ES, Kennedy G, Kalff A, Ritchie D, et al. Fludarabine melphalan reduced-intensity conditioning allotransplanation provides similar disease control in lymphoid and myeloid malignancies: analysis of 344 patients. Bone Marrow Transpl. 2014;49(1):17–23.CrossRefGoogle Scholar
- 18.Kekre N, Marquez-Malaver FJ, Cabrero M, Pinana J, Esquirol A, Soiffer RJ, et al. Fludarabine/busulfan versus fludarabine/melphalan conditioning in patients undergoing reduced-intensity conditioning hematopoietic stem cell transplantation for lymphoma. Biol Blood Marrow Transpl. 2016;22(10):1808–15.CrossRefGoogle Scholar
- 31.Ishida H, Adachi S, Hasegawa D, Okamoto Y, Goto H, Inagaki J, et al. Comparison of a fludarabine and melphalan combination-based reduced toxicity conditioning with myeloablative conditioning by radiation and/or busulfan in acute myeloid leukemia in Japanese children and adolescents. Pediatr Blood Cancer. 2015;62(5):883–9.CrossRefGoogle Scholar
- 32.Jaiswal SR, Chakrabarti A, Chatterjee S, Bhargava S, Ray K, O'Donnell P, et al. Haploidentical peripheral blood stem cell transplantation with post-transplantation cyclophosphamide in children with advanced acute leukemia with fludarabine-, busulfan-, and melphalan-based conditioning. Biol Blood Marrow Transpl. 2016;22(3):499–504.CrossRefGoogle Scholar
- 33.Yamamoto H, Uchida N, Yuasa M, Kageyama K, Ota H, Kaji D, et al. A novel reduced-toxicity myeloablative conditioning regimen using full-dose busulfan, fludarabine, and melphalan for single cord blood transplantation provides durable engraftment and remission in nonremission myeloid malignancies. Biol Blood Marrow Transpl. 2016;22(10):1844–50.CrossRefGoogle Scholar
- 34.Ueda T, Maeda T, Kusakabe S, Fujita J, Fukushima K, Yokota T, et al. Addition of melphalan to fludarabine/busulfan (FLU/BU4/MEL) provides survival benefit for patients with myeloid malignancy following allogeneic bone-marrow transplantation/peripheral blood stem-cell transplantation. Int J Hematol. 2019;109(2):197–205.CrossRefGoogle Scholar
- 35.Damlaj M, Alkhateeb HB, Hefazi M, Partain DK, Hashmi S, Gastineau DA, et al. Fludarabine-busulfan reduced-intensity conditioning in comparison with fludarabine-melphalan is associated with increased relapse risk in spite of pharmacokinetic dosing. Biol Blood Marrow Transpl. 2016;22(8):1431–9.CrossRefGoogle Scholar
- 37.Verhaak RG, Goudswaard CS, van Putten W, Bijl MA, Sanders MA, Hugens W, et al. Mutations in nucleophosmin (NPM1) in acute myeloid leukemia (AML): association with other gene abnormalities and previously established gene expression signatures and their favorable prognostic significance. Blood. 2005;106(12):3747–54.CrossRefGoogle Scholar
- 38.Kottaridis PD, Gale RE, Frew ME, Harrison G, Langabeer SE, Belton AA, et al. The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials. Blood. 2001;98(6):1752–9.CrossRefGoogle Scholar