Pharmacogenetics of Response to Glucocorticosteroids in Adults with Acute Lymphoblastic Leukemia.

Glucocorticoids are crucial components of standard chemotherapy regimens used for the treatment of adult acute lymphoblastic leukemia (ALL). However, little is known on significance of the inherited genetic background for response to steroids in adult ALL. We hypothesized that functional single nucleotide polymorphisms (SNPs) in genes important for steroid pharmacokinetics and pharmacodynamics may contribute to sensitivity or resistance to steroids. In this study we investigated whether analysis of common functional SNP in drug transporter P-glycoprotein gene (MDR1 or ABCB1), phase I cytochrome P450A metabolizing enzymes genes (CYP3A4 and CYP3A5) and glucocorticoid receptor gene NR3C1 can be useful to predict response to induction chemotherapy and survival of adult ALL patients. Sixty-two uniformly treated adult ALL patients were investigated for 6 common SNPs affecting steroid pathway including MDR1 exon 26 C3435T, CYP3A4*1B, CYP3A5*3, CYP3A5*6, NR3C1 bcl I and NR3C1 N363S polymorphisms. Genotypes were identified using direct sequencing or restriction fragment length polymorphism (RFLP) method. In the genotyped cohort 60% patients achieved complete remission after first induction chemotherapy. The analysis of the prognostic impact of the genotyped SNPs on treatment response showed that carriers of the glucocorticoid receptor NR3C1 gene 363S allele had a significantly greater probability of achievement of complete remission as compared to the non-carriers, odds ratio(OR)=1.23, 95% confidence interval (95%CI) = 1.02 −1.47, p=0.042). None of the analyzed polymorphic variants showed significant impact on probability of progression-free and overall survival of the included patients. In conclusion, we found that glucocorticoid receptor NR3C1 gene N363S polymorphism contributes to the response to steroids in patients with adult ALL. Inherited functional polymorphisms in pharmacokinetic pathways of anti-leukemic drugs should be considered as determinants of response potentially useful for individualization of chemotherapy of adult ALL of in the future.