Cyclophosphamide, an oxazaphosphorine prodrug is frequently used in treatment of neuroblastoma,
which is one of the most prevalent solid organ malignancies in infants and young children.
Cytochrome P450 2B6 (CYP2B6) is the major catalyst and CYP2C19 is the minor enzyme
in bioactivation and inactivation pathways of cyclophosphamide. CYP-mediated metabolism
may contribute to the variable pharmacokinetics of cyclophosphamide and its toxic
byproducts leading to insufficient response to the therapy and development of clinically
significant side effects. The aim of the study was to reveal the contribution of pharmacogenetic
variability in CYP2B6 and CYP2C19 to the treatment efficacy and cyclophosphamide-induced
side effects in pediatric neuroblastoma patients under cyclophosphamide therapy (N
= 50). Cyclophosphamide-induced hematologic toxicities were pivotal in all patients,
whereas only moderate hepatorenal toxicity was developed. The patients’ CYP2B6 metabolizer
phenotypes were associated with the occurrence of lymphopenia, thrombocytopenia, and
monocytopenia as well as of liver injury, but not with kidney or urinary bladder (hemorrhagic
cystitis) toxicities. Furthermore, the patients’ age (< 1.5 years, P = 0.03) and female
gender (P ≤ 0.02), but not CYP2B6 or CYP2C19 metabolizer phenotypes appeared as significant
prognostic factors in treatment outcomes. Our results may contribute to a better understanding
of the impact of CYP2B6 variability on cyclophosphamide-induced side effects.
