A comparative study of patients with acute promyelocytic leukemia receiving all-trans retinoic acid with and without voriconazole: effect on differentiation syndrome

Purpose: Differentiation syndrome (DS) is a potentially fatal complication related to all trans-retinoic acid (ATRA) use in induction chemotherapy for acute promyelocytic leukemia (APL) patients. Metabolism of ATRA occurs through cytochrome P450 (CYP) enzyme pathways, mostly CYP2C9 and CYP3A4. Voriconazole is a strong inhibitor of CYP2C9 and CYP2C19.  We evaluated and contrasted the incidence and outcomes of ATRA-induced DS in APL patients.

Methods: Forty-six APL patients undergoing induction-phase chemotherapy utilized ATRA at Mayo Clinic from 2000-2011.  Comparisons between groups for categorical outcomes were made using Pearson's chi-square or Fisher's exact test.  Two-sample t-tests or Wilcoxon rank-sum tests were used for continuous outcomes.  Cox proportional hazards model measured association of voriconazole and body mass index (BMI) with DS occurrence, where voriconazole was considered a time-dependent covariate.

Results: Of the 46 patients, 27 were male with a median age of 56 years.  Thirty-one patients received chemotherapy including ATRA with voriconazole and 15 patients underwent chemotherapy including ATRA without fungal prophylaxis. There was no difference in age, gender, Sanz risk assessment, combination chemotherapy regimen, WBC, platelet count, creatinine clearance and LDH levels amongst patients in the two groups.  The only heterogeneity was BMI, which was higher in patients receiving voriconazole (HR 1.04, CI 1.001-1.078, p=0.0427).  Overall incidence of DS was 35%, with patients receiving voriconazole being more likely to experience the same (HR 2.31, CI 0.78-6.874, p=0.1308).  After adjusting for BMI, patients receiving voriconazole had a higher tendency to experience DS.  Due to small numbers this trend was not statistically significant (HR 1.96, CI 0.65-5.94, p=0.23).  Zero deaths were attributable to DS.

Conclusions:   A trend towards increased incidence and severity of ATRA-mediated DS was seen in APL patients receiving voriconazole as fungal prophylaxis during induction therapy, contributing to morbidity.  Statistical significance was not reached due to small sample size.  This finding warrants larger studies.