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Allelic variations in CYP2B6 and CYP2C19 and survival of patients receiving cyclophosphamide prior to myeloablative hematopoietic stem cell transplantation

In hematopoietic stem cell transplantation (HSCT), patients receive cyclophosphamide (CPA) conditioning based on body weight, under the assumption that each individual will metabolize the drug with the same efficiency [1-3]. However, up to 20% of patients experience adverse outcomes related to CPA [4-7]. We hypothesized that due to their effects on CPA metabolism certain allelic variations of cytochrome P450 (CYP) 2B6 and 2C19 enzymes would be associated with higher regimen-related toxicity and worse outcomes in patients. We genotyped 359 patients who received allogeneic HSCT with high dose CPA conditioning. We investigated the effect of allelic variants of CYP2B6 and CYP2C19 on toxicity outcomes, nonrelapse mortality (NRM), relapse, progression free survival (PFS) and overall survival (OS). Overall, 65 (18%) patients experienced toxicity. There was no significant difference in toxicity events in patients with allelic variants of CYP2B6 or CYP2C19. However, compared to poor metabolizers, ultrarapid CYP2B6 metabolizers had worse PFS (P = 0.04). In addition, patients homozygous for CYP2C19 *2 allele had significantly worse PFS (P = 0.008) and OS (P = 0.004). Our results suggest that genotyping may help to predict survival in patients receiving high dose CPA, guide patient management and improve outcomes.