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ORIGINAL ARTICLE
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Allogeneic Hematopoietic Stem Cell Transplantation after Conditioning Regimens with Fludarabine/melphalan or Fludarabine/busulfan for Patients with Hematological Malignancies: A Single-center Analysis Wataru Yamamoto, Taiki Andou, Megumi Itabashi, Satoshi Koyama, Yoshimi Ishii, Ayumi Numata, Kenji Motohashi, Maki Hagihara, Kenji Matsumoto and Shin Fujisawa
Abstract Objective Fludarabine plus melphalan (FM) and fludarabine plus busulfan (FB) are two major conditioning regimens for allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods We retrospectively analyzed patients who underwent allo-HSCT after a conditioning regimen consisting of FM or FB with/without total body irradiation for hematological malignancies between 2005 and 2014. Results There were 41 patients who met the criteria. The median follow-up time for the survivors was 3 years. Thirty-two patients received allo-HSCT after the FM regimen and nine patients received allo-HSCT after the FB regimen. Patients who received FB were older than those who received FM (p=0.041). There was no significant difference in the 3-year overall survival between patients who had received FB and those who had received FM (29.6% vs. 56.5%, p=0.267). The 3-year cumulative incidence of relapse was significantly higher in patients who had received FB than that in patients who had received FM (66.7% vs. 17.8%, p= 0.004), and FB was an independent prognostic factor for relapse by a multivariate analysis (hazard ratio, 9.8; 95% confidential interval, 2.5-39.3; p=0.001). When we restricted the evaluation to patients with acute myeloid leukemia and myelodysplastic syndrome, the 3-year cumulative incidence of relapse was also significantly higher in patients who had received FB than that in patients who had received FM (75.0% vs. 16.1%, p=0.004). Conclusion The results suggest that FM may provide better disease control than FB. Key words: allogeneic stem cell transplantation, conditioning regimen, busulfan, melphalan (Intern Med 55: 1721-1727, 2016) (DOI: 10.2169/internalmedicine.55.6094)
Introduction Allogeneic hematopoietic stem cell transplantation (alloHSCT) following reduced-intensity conditioning has been increasingly used in older patients or in patients who may be unsuitable for myeloablative conditioning with the aim of reducing non-relapse mortality (NRM) (1). Fludarabinebased regimens have been used as conditioning regimens for allo-HSCT in patients who must avoid cyclophosphamide toxicity or high-dose total body irradiation (TBI). Although
fludarabine-based regimens with melphalan or busulfan have been widely used (2-8), and there have been several retrospective reports comparing the two regimens (9-11), there have been no randomized, controlled trials to compare these two regimens. We believed that an understanding of the current status is important to conduct prospective trials in the future. Therefore, we retrospectively studied the outcomes of allo-HSCTs after fludarabine plus melphalan (FM) and fludarabine plus busulfan (FB) conditioning regimens in a single-center analysis.
Department of Hematology, Yokohama City University Medical Center, Japan Received for publication July 2, 2015; Accepted for publication September 23, 2015 Correspondence to Dr. Wataru Yamamoto,
[email protected]
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Intern Med 55: 1721-1727, 2016
DOI: 10.2169/internalmedicine.55.6094
Table 1. Patient Characteristics. Flu+Mel±TBI Flu+BU±TBI p (n=32) (n=9) 57 (32-64) 61 (50-65) 0.041
Age, median (range) Sex Male 24 4 Female 8 5 Disease Acute myelogenous leukemia 14 5 Acute lymphoblastic leukemia 7 0 Myelodysplastic syndrome 2 3 Non-Hodgkin lymphoma 4 0 Adult T-cell leukemia/lymphoma 4 0 Myelofibrosis 1 1 Disease risk at transplantation Standard risk 13 4 High risk 19 5 Performance status 0, 1 27 9 2, 3 5 0 Hematopoietic cell transplantation comorbidity index 16 6 0-2 3 16 3 Total body irradiation No 6 0 Yes 26 9 Donor type Related 8 0 Unrelated 24 9 Stem cell source Bone marrow 21 6 Peripheral blood 4 0 Cord blood 7 3 Human leukocyte antigen disparity Match 19 4 Mismatch 13 5 Antithymocyte globulin administration Absent 29 7 Present 3 2 Cytomegarovirus* Other 30 8 Recipient negative and donor positive 2 0 Sex mismatch Other 25 8 Female to male 7 1 *Data is uncertain in one case. Flu: fludarabine, Mel: melphalan, BU: busulfan, TBI: total body irradiation
Materials and Methods Patients who had received FM or FB with/without TBI for hematological malignancies from September 2005 to October 2014 at Yokohama City University Medical Center (Yokohama, Japan) were retrospectively investigated. The conditioning regimen consisted of FM or FB with or without low-dose TBI at 3 Gy. TBI was not administered when transplantation was completed using a human leukocyte antigen (HLA)-matched sibling donor. We defined an HLA match as a 6/6 antigen-matched donor (HLA-A, B, DR). Short-term treatment with methotrexate and calcineurin inhibitors was used as graft-versus-host disease (GVHD) prophylaxis. Grading of acute GVHD was performed according to established criteria (12). Acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) in the first complete remission or myelodysplastic syndrome (MDS) with refrac-
0.113
0.087
1.000
0.568
0.466
0.309
0.165
0.623
0.471
0.299
1.000
0.659
tory anemia was defined as a standard-risk disease. All other conditions were classified as a high-risk disease. We considered a negative cytomegalovirus serostatus for recipients and positive for donors to be a risk factor (13). All statistical analyses were performed with the R software program (version 3.0.1; R Development Core Team). The overall survival was calculated from the date of transplantation to the date of death from any cause or the date of the final follow-up. Survival curves were drawn according to the Kaplan-Meier method, and the significance for differences in the survival was assessed by the log-rank test. NRM was defined as death without disease relapse or the development of resistance. Death without relapse was considered to be a competing risk for relapse, relapse was a competing risk for NRM, and relapse and death without GVHD were competing risks for GVHD. NRM, relapse, and GVHD were estimated from the cumulative incidence curves, and the statistical significance of differences between
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Intern Med 55: 1721-1727, 2016
DOI: 10.2169/internalmedicine.55.6094
Table 2. Prognostic Factors for Overall Survival. Univariate analysis HR (95%CI) p
Variables
Age (years)
