Genetic Variations in CYP2B6 and Risk of Cyclophosphamide Toxicity in Patients Undergoing Myeloablative Stem Cell Transplantation.

In myeloablative stem cell transplantation (SCT), most patients receive cyclophosphamide (CPA) conditioning based on body weight or body surface area, under the assumption that each individual will metabolize the drug with the same efficiency. However, CPA requires biological activation, primarily by cytochrome P450 2B6 (CYP2B6), to exert its effects; therefore, patients with increased protein activity, as reported for *4 and *6 allelic variants, may have an increased risk for CPA-associated toxicity compared to patients with decreased protein activity, as reported for *5 and *7 allelic variants. In this study, we determine the relationship between allelic variants of CYP2B6 and toxicity outcomes and attempt to clarify the influence of CYP2B6 on the development of severe cardiac toxicity, veno-occlusive disease (VOD), and idiopathic pneumonia syndrome (IPS) early after SCT. A total of 259 DNA samples were obtained from patients who received 3.6 g/m² or 120 mg/kg of CPA as part of a myeloablative allogeneic SCT between 2002 and 2006. Genotyping was performed using pyrosequencing to detect three SNPs, 516A>G, 785A>G and 1459C>T, associated with four allelic variants: *4 (785A>G), *5 (1459C>T), *6 (785A>G, 516G>T) and *7 (785A>G, 516G>T, 1459C>T). The patients’ clinical history was reviewed and any instance of hepatic VOD, severe cardiac toxicity (i.e. myopericarditis ≥ grade 3) or IPS from 0 to 100 days post-transplant was recorded. Overall, 60 (24%) patients experienced toxicity (cardiac = 20; VOD = 26; IPS = 14). The prevalence of the *4, *5, *6 and *7 alleles was 3%, 8%, 23% and 2%; respectively. Patients heterozygous for *4, *5, *6 and *7 allelic variants and homozygous for the *6 allelic variant had similar rates of toxicity to those patients without allelic variants of CYP2B6, even when comparing each toxicity separately (Table 1). However, patients with decreased protein activity, *1/*5 and *1/*7, had a lower rate of toxicity compared to those with wild-type or increased protein activity, *1/*1, *1/*4, *1/*6 and *6/*6 (14.6% (7/48) vs. 26.1% (53/203)). In conclusion, variant alleles of CYP2B6 may predict a decreased risk of VOD, IPS, or cardiac toxicity within the first 100 days of SCT, but do not appear to predict an increased risk of toxicity.

Table 1. Association of toxicities with genotypes