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.