Intravenous versus oral busulfan-based conditioning for pediatric allogeneic hematopoietic cell transplantations: did the pendulum swing too far, too fast?

Oral busulfan is an alkylating agent that provides good antileukemic activity and excellent CNS penetration. It was first introduced over 30 years ago by George Santos as an alternative to total body irradiation (TBI) for preallogeneic transplantation conditioning [1]. Since its introduction, it has had a mixed reputation. Oral busulfan (PO BU) proved an attractive alternative to TBI based on general availability, ease of administration, and low cost. Although the results of early randomized controlled trials were mixed, in some settings, such as sibling donor allogeneic bone marrow transplantations for chronic myeloid leukemia, PO BUand TBI-based conditioning regimen transplantations resulted in similar outcomes [2]. Since the mid-1990s, PO BU has been 1 of the main conditioning agents for allogeneic transplantation. Despite this, PO BU has always carried with it the shadow of significant intraand inter-patient variability in absorption and first pass metabolism that contributes to a risk of veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) that can result in significant morbidity and death in some patients. To address these metabolic limitations, an intravenous formulation of the drug was developed and approved for use in allogeneic transplantation in 1999. Compared to PO BU, the intravenous formulation of busulfan (IV BU) resulted in less patient-topatient variability in metabolism, drug exposure, and early toxicities [3]. Early reports suggested that compared with PO BU, IV BU resulted in lower early toxicities, such as VOD/ SOS, and decreased treatment-related mortality [4-6]. IV BU use has steadily increased at the expense of both PO BU and TBI. Novel dosing regimens, particularly once a day, became another attractive feature of IV BU. Although more expensive to purchase, the perceived advantages and convenience with IV BU has led many programs to switch from PO to IV BU. With experience, however, we learned that it was not as simple as we had hoped. There remains patient-to-patient