Busulfan Use in Hematopoietic Stem Cell Transplantation: Pharmacology, Dose Adjustment, Safety and Efficacy in Adults and Children

Abstract

Busulphan (1, 4-bis [methanesulfonyl-y] butane) is a bi-functional alkylating agent that, in combination with cyclophosphamide, has been commonly used in conditioning regimens before hematological stem cell transplantation (HSCT) for nearly 20 years. Busulfan has a very narrow therapeutic index, and acute toxicity may be related to absorption and disposition of the drug and metabolites. Precise delivery of the oral formulation is compromised by erratic gastrointestinal absorption, particularly in infants and small children. An intravenous busulfan formula was approved nearly 40 years after the approval of the oral formulation. Busulfan levels expressed as the area under the concentration-time curve (AUC) higher than 1500 microM* minute were reported to increase the risk of developing veno-occlusive disease (VOD), while low levels may result in engraftment failure or disease relapse. VOD occurs in 11-40% of patients undergoing HSCT and is associated with death in 3.3% of patients. Measurement of individual plasma busulfan levels during oral or intravenous dosing to obtain an AUC is likely to provide the necessary elements to monitor the drug disposition, ensuring efficacy and preventing toxicity of patients undergoing HSCT. It is also important to consider the busulfan drug-drug interactions and adverse drug reactions that can develop during the therapeutic process. Busulfan therapeutic drug monitoring and dose-adjustment should be performed in specialized laboratories staffed by well-trained personnel.

Busulfan 12 mg/kg plus melphalan 140 mg/m2 versus melphalan 200 mg/m2 as conditioning regimens for autologous transplantation in newly diagnosed multiple myeloma patients included in the PETHEMA/GEM2000 study

“…44 Use of high dose intravenous busulfan in combination with cyclophosphamide and other drugs in the context of autologous or allogeneic transplantation for acute leukemia and non-Hodgkin's lymphoma has drastically reduced the incidence of VOD while maintaining efficacy. 39 In a recent Spanish phase II pilot study 45 including both relapsed and newly diagnosed MM patients, none of the patients given intravenous BUMEL/SCT developed VOD and the complete/near complete response rate post-transplant was 49%. The possibility of maintaining efficacy with intravenous busulfan while reducing or eliminating VOD renewed our interest in the GEM2000 results, presented herein after a median follow-up of 48 months.…”

“…After this protocol amendment the incidence of VOD fell to 0.4%. The erratic pharmacokinetics of oral busulfan 39 and the altered clearance of melphalan caused by the depletion of intracellular glutathione, induced by busulfan, [40][41][42] may have caused this complication. Some studies have shown that adjusting the oral busulfan dose according to plasma levels may lead to a reduction in the frequency of VOD.…”

Comparison of LC-MS Assay and HPLC Assay of Busulfan in Clinical Pharmacokinetics Studies

“…The toxic effects were strongly related to high drug exposure by the steady-state plasma concentrations and/or area under the curve of busulfan. Therefore, therapeutic drug monitoring (TDM) has been considered of benefit for individual optimization of busulfan therapy [3].…”

Single center retrospective analysis of BU-based conditioning regimens in allogeneic transplantation

“…5 Variability in BU concentration has been linked to adverse outcomes, such as development of veno-occlusive disease (VOD) and engraftment failure or disease relapse. 6,7 The first preparation of i.v. BU was introduced in 1996 and since then, BU-based conditioning regimens using the i.v.…”