CYP2B6 genetic variation in cyclophosphamide metabolism and hemorrhagic cystitis in Fanconi anemia patients undergoing allogeneic hematopoietic cell transplantation: A descriptive genetic association study

Fanconi anemia (FA) is an inherited disorder characterized by congenital malformations, bone marrow failure, and malignancies. Hematopoietic cell transplant (HCT) is the only proven cure for the hematological complications. FA patients have increased chromosomal instability and aberrant deoxyribonucleic acid repair and thus can only tolerate low doses of chemotherapy or radiation as part of conditioning prior to HCT. Yet, they are still prone to severe regimen related toxicities including hemorrhagic cystitis (HC) from cyclophosphamide (CY). As CYP2B6 is a primary enzyme responsible for the catalyzation of the prodrug form of CY, understanding the association between CYP2B6 genetic variants and HC in FA patients may predict which patients will be more susceptible to developing HC. A descriptive genetic association study was performed to identify genetic variants associated with HC in patients with FA who underwent HCT between 1999 and 2017. All patients received a CY-based preparative regimen and had pretransplant recipient deoxyribonucleic acid available for genomic analysis. Forty FA pediatric patients were eligible for this analysis. They had received HCT from matched sibling donors (n = 6) or alternative donors (n = 34) for marrow failure (n = 38) or myelodysplastic syndrome (n = 2). The incidence of HC was 32.5% which occurred at a median of 32 days (range 20-180) after HCT. 9 patients had a concomitant viral infection (BK virus, n = 8 both adenovirus and BK virus, n = 1). No genetic variants were significantly associated with HC. The top variants were rs2279343 (g.23060A > G), and rs2279344 (g.23280G > A) in the CYP2B6 gene. The incidence of HC among FA patients with the rs2279343 variant was 42% (CI 22%-62%) compared to 20% (CI 0%-40%) among those without the variant (P = .19). The incidence of HC among patients with the variant in rs2279344 was 40% (CI 22%-58%) compared to 10% (CI 0%-28%) among those without (P = .11). No variants in our analysis were statistically associated with HC. The data suggest that CYP2B6 variants may increase the risk for HC in FA patients who received a CY based preparative therapy but these risk variants must be further evaluated in a larger population.