Safety and Efficacy of Once-Daily Intravenous Busulfan in Allogeneic Transplantation: A Matched-Pair Analysis

[Background] Intravenous administration of busulfan (ivBU) has been widely used in conditioning regimens for allogeneic hematopoietic stem cell transplantation (HSCT), especially in patients with myeloid malignancies. IvBU was originally administered 4-times-daily (ivBU4) at 0.8 mg/kg over 2 hours according to the established way of administration in oral busulfan, but ivBU4 needs frequent preparations and a midnight administration. A once-daily infusion of ivBU (ivBU1) at 3.2 mg/kg over 3 hours seemed to be safe and convenient by resolving these problems, but clinical data of direct comparison of ivBU1 and ivBU4 has been scarce. We demonstrated that ivBU1 was safely performed based on a pharmacokinetic profile in a small cohort of Japanese patients (Int J Hematol. 2015;101:497-504), and therefore we planned a large matched-pair analysis using the nation-wide registry data to demonstrate the safety and efficacy of ivBU1 in Japanese patients.

[Methods] Patients aged more than 15 years with myeloid malignancies who underwent HSCT using ivBU1 in conditioning regimen were selected in our institutions. Control patients of ivBU4 matched for age, sex, performance status, disease risk, conditioning regimen, and donor type were selected from the Transplant Registry Unified Management Program (TRUMP), which is the registry data of the Japanese Society for Hematopoietic Cell Transplantation (JSHCT), using optimal matching algorithms in a 1:3 ratio. Patients who had ivBU for 2 days or 4 days were selected separately, and were combined when clinical outcomes were analyzed. Primary outcome measure was an overall survival after HSCT. This study was approved by the data management committee of TRUMP and the Institutional Review Board of Saitama Medical Center, Jichi Medical University.

[Results] A total of 91 patients who received ivBU1 for 2 days (n = 18) or 4 days (n = 73) after 2010 in our institutions were matched with 273 control patients who received ivBU4 between 2007 and 2013 (Table 1). In patients who received ivBU for 2 days of both groups, ivBU was mainly combined with fludarabine (Flu). On the other hand, in patients who received ivBU for 4 days of both groups, half of them received ivBU combined with cyclophosphamide (CY), and the remaining patients did combined with Flu. Overall survival (1y OS: 56.8 % vs 57.1 %, P= 0.94, Figure 1), disease-free survival (1y DFS: 51.6 % vs 50.8 %, P= 0.73), relapse rate (1y RR: 28.5 % vs 26.2 %, P= 0.94), non-relapse mortality (1y NRM: 19.9 % vs 23.0 %, P= 0.71), and the incidence of graft-versus-host disease (grade 2-4 acute GVHD: 26.6 % vs 36.8 %, P= 0.07, chronic GVHD: 38.6 % vs 32.5 %, P= 0.46) were not significantly different between the ivBU1 and ivBU4 groups. In patients who received ivBU1, neutrophil recovery was slower (median days: 22 vs 17, P < 0.001), and incidence of veno-occlusive disease (VOD) was lower (2.6% vs 17.4%, P= 0.04) than in those who received ivBU4. The former might have resulted from the less frequent usage of granulocyte-colony stimulating factor (25.3 % vs 84.2 %, P < 0.01), and the latter from the different criteria used for the diagnosis of VOD (Seattle criteria vs Baltimore criteria). [Conclusion] IvBU1 can be safely administered in Japanese patients. Clinical outcomes were similar between ivBU1 and ivBU4 groups.

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