Haematologica 2002; 87:(02)ELT10
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Limitations of oral busulfan in preparative regimen before hematopoietic stem-cell transplantation
Masahiro Kami,*^ Tamae Hamaki,*^ Yumiko Maruta,° Shigesaburo Miyakoshi,° Yoshitomo Mutou*
*Dept. of Hematology and °Dept. of Nursing, Toranomon Hospital, Tokyo;. ^Hematopoietic Stem Cell Transplantation Unit, National Cancer Center Hospital, Tokyo, Japan

Correspondence:Masahiro Kami, M.D. Department of Medical Oncology, Hematopoietic Stem Cell Transplantation Unit, National Cancer Center Hospital, 1-1 Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045, Japan. Phone: +81.33542-2511, Fax: +81.3-3542-3815, E-mail: mkami@ncc.go.jp
Busulfan is an important component of myeloablative regimens for hematopoietic stem-cell transplantation (HSCT). While most cytotoxic agents are given parenterally before HSCT, busulfan is usually administered by mouth. Although an intravenous formulation of busulfan was recently developed,1 its clinical use is approved only in USA, Canada and Israel. Because of its high cost, the oral formulation is commonly used in these countries. However, oral busulfan is associated with nausea, vomiting and inter-patient variability of bioavailability,2 making it difficult to control its blood levels without monitoring.3 These factors contribute to the development of graft rejection,4 hepatic veno-occlusive disease5 and relapse.6 To clarify limitations of oral busulfan, we reviewed the records of patients receiving HSCT after busulfan-containing regimens for the treatment of hematologic malignancies between October 1998 and March 2001, and obtained complete clinical data during the four-day period in which busulfan was administered. All patients received 1 mg/kg busulfan orally every six hours for four consecutive days, followed by other cytotoxic agents, mainly 60 mg/kg cyclophosphamide on two consecutive days.7 Busulfan was administered prior to any other cytotoxic agents, and no anti-cancer drugs were used concomitantly. During the four-day period, patients received phenytoin or valproate for prophylaxis against convulsions. Patients who receive oral busulfan sometimes vomit its capsules, and we usually re-administer them according to the interval between administration of busulfan and vomiting. If patients vomit within 30 minutes of administration, they receive the same dose of busulfan again. If patients vomit 30 minutes or more after administration, busulfan is not re-administered.
We investigated 24 patients. Sixteen and eight received allogeneic or autologous HSCT, respectively. The median age was 50 (22-63). During the four-day periods, gastrointestinal and neurological symptoms were common. Twelve patients developed nausea. Vomiting occurred eleven times in seven patients. Three, one, and three patients vomited on the first, third and last day of busulfan administration, respectively. The interval between busulfan administration and vomiting was 30 to 60 minutes (n=2), 1-2 hours (n=4), 2-3 hours (n=3), and 5-6 hours (n=2). Twelve patients developed neurological signs including headache (n=6), paresthesia (n=5), generalized convulsion (n=3) and diminished taste sensation (n=1). Interestingly, patients who developed convulsions showed similar characteristics. All three patients vomited on the third or last day of oral busulfan, and two received busulfan again after vomiting. All three patients developed convulsions within four hours of busulfan administration on the last day of administration. Convulsions occurred in three of the seven patients who vomited during busulfan administration, while convulsion did not occur in any of the seventeen patients who did not vomit during busulfan administration. There was a significant correlation between vomiting and convulsion (p=0.0173).
This study suggests that vomiting during busulfan administration might reflect elevated serum busulfan levels. We should recognize that additional administration of oral busulfan following vomiting might enhance the busulfan toxicities in some patients. Monitoring of blood busulfan levels and dose adjustment in individual patients may be required when using oral busulfan.  

References

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