Recently, intravenous busulfan (iv-BU) has replaced oral-BU, which can suppress variety of bioavailability. Also, iv-BU showed less hepatic toxicity by avoiding the hepatic first-pass effect of oral-BU. Previous reports showed that the use of iv-BU reduced early complications and decreased early non-relapse mortality (NRM). Some reports demonstrated that iv-BU may provide better overall survival (OS) in adult with malignant diseases.

Although several reports have been published on pediatric patients using iv-BU, the number of patients included was small, and the reports mainly focused on acute toxicity or early clinical outcome because of a short follow-up period. Thus, the role of iv-BU in HSCT for pediatric patients with acute leukemia is yet to be determined.

In this study, to compare clinical outcome of HSCT with iv-BU and oral-BU, we retrospectively analyzed HSCT based on data reported to the Japan Society for Hematopoietic Cell Transplantation (JSHCT) registry. The patients were selected according to the following criteria: (1) patients diagnosed with either acute lymphoblastic leukemia (ALL) or acute myeloblastic leukemia (AML), (2) aged 15 years or younger when receiving HSCT, (3) BU-based myeloablative (more than 8 mg/kg) preconditioning regimens, and (4) HSCT performed between 2000 and 2010.

Therefore, we analyzed 460 children with iv-BU (n = 198) or oral busulfan (BU) (n = 262) receiving hematopoietic stem cell conditioning transplantation (HSCT) with BU-based myeloablative conditioning for acute leukemia. The median age at HSCT was 4 years (range, 0–15 years). The median follow-up period was 1,828 days (range, 85–4,619 days) after HSCT in all the surviving patients, and 1,185 days (range, 100–3,759 days) after HSCT in the iv-BU patients.

Although OS with iv-BU and oral-BU at day 100 after HSCT was 72.5 ± 3.2% and 66.9 ± 2.9%, respectively, OS at 3 years after HSCT was similar (iv-BU, 53.4 ± 3.7%; oral-BU, 55.1 ± 3.1% ), and the log-rank test for OS did not show statistically significant difference (p = 0.77) (Figure 1a). The result was concordant even when an analysis was limited to patients with ALL or AML. OS at 3 years for patients with ALL using iv-BU (n = 90) and oral-BU (n = 151) was 56.4 ± 5.5% and 54.6 ± 4.1, respectively (p = 0.51) (Figure 1b). OS at 3 years for patients with AML using iv-BU (n = 108) and oral-BU (n = 111) was 51.0 ± 5.0% and 55.8 ± 4.8%, respectively (p = 0.83) (Figure 1c).

The similarity of OS was reproduced even with the limited cohort of 247 patients who received HSCT after 1st CR or 2nd CR without prior HSCT. OS at 3 years was 78.3 ± 4.2% for iv-BU patients (n = 98) and 78.7 ± 3.4% for oral-BU patients (n = 149) and the difference was not statistically significant (p = 0.66). Multivariate analysis also showed no significant survival advantage with iv-BU.

Cumulative incidence of relapse at 3 years with iv-BU was similar with that of oral-BU (39.0 ± 3.6% and 36.4 ± 3.1%, respectively) (p = 0.67). Cumulative incidence of NRM at 3 years was 16.6 ± 2.7% with iv-BU and 18.3 ± 2.5% with oral-BU (p = 0.51). The iv-BU group showed a tendency toward higher engraftment probability at day 60 (96.0 ± 1.5%) compared with the oral-BU group (89.3 ± 2.0%), but the difference was not statistically significant (p = 0.22)

This study was a retrospective study using registry data, and there are some limitations of our data. For example, as selection of iv-BU or oral-BU was strongly associated with the transplantation period, which may have introduced bias. Further prospective studies are required to establish an optimal allogeneic HSCT treatment strategy for pediatric patients with acute leukemia.

In conclusion, our study provides valuable information on the role of iv-BU in myeloablative HSCT for pediatric acute leukemia. In children, iv-BU could not show significant survival improvement in outcome of acute leukemia.


No relevant conflicts of interest to declare.

Author notes


Asterisk with author names denotes non-ASH members.