Introduction
Treatment for acute lymphoblastic leukemia (ALL) is based on established risk stratification criteria that also include response to therapy. Such measures have increased the rates of survival from less than 10% in the 1960s to over 90% today.1
Hematopoietic stem cell transplantation (HSCT) has a role in the management of difficult-to-treat leukemia by inducing cures in these children.2,3. One factor influencing outcomes is the choice of the conditioning regimen.2,4 HSCT regimens have utilised a combination of total body irradiation (TBI) and high dose cyclophosphamide (Cy) and/or other agents such as etoposide.5,6,19 However TBI has been associated with significant adverse effects including neurocognitive decline, endocrine and metabolic concerns as well as apprehensions in regards to secondary malignancies.7,19 Busulfan (Bu) is a bifunctional DNA alkylating agent that has been used to replace TBI. Initial studies that incorporated oral Bu in combination with Cy resulted in poor outcomes when compared with Cy/TBI.7 This was mainly attributed to the toxicity of oral Bu, specifically the incidence of sinusoidal obstructive syndrome (SOS).5,8 The erratic absorption of Bu following oral administration with resultant unpredictable exposure was another contributing factor. This was especially concerning in pediatric patients owing to their higher drug clearance and less predictable pharmacokinetic profiles. 9-11
The advent of an intravenous formulation of Bu solved the problem of erratic oral absorption however, interpatient variability in clearance was a persisting concern. Targeted drug monitoring (TDM) of Bu in children, once introduced, allowed for better prediction of serum drug levels.49 Although not consistently, subsequent studies have shown improvements in outcomes following TDM of Bu.12
At the Alberta Children’s Hospital, Bu (with comparatively lower pharmacokinetic target of 3750μmol*min/day for 4 days, with a preceding test dose) is combined with higher dose (250 mg/m2) fludarabine (Flu), 400 cGy of TBI and anti-thymocyte globulin (ATG) in a regimen that was initially used in adults and later adapted for HSCT in children.13
We report our experience with this conditioning regimen for children diagnosed with ALL requiring HSCT.