Pharmacogenetic Study of Deferasirox, An Iron Chelating Agent

Abstract 2060

Transfusion associated iron overload induce systemic toxicity. Deferoxamine had been used to reduce iron induced toxicities by chelating iron but it is a short acting drug and needs parenteral administration. Recently, deferasirox, a more convenient long acting oral agent, has been introduced in clinical practice with promising efficacy. However, some patients experienced drug-related toxicities and could not tolerate it. As the deferasirox is known to be metabolized primarily by glucuronidation and excreted mainly into the feces, the effect and toxicity of deferasirox may be influenced by the variability of uridine diphosphate glycosyltransferases (UGTs) and ATP-binding cassette transporters (multi-drug resistance-associated protein 2 (MRP2) and breast cancer resistance protein (BCRP)) which are important for intestinal drug absorption and hepatic drug elimination. To predict toxicities and find optimal target population, we analyzed the genetic polymorphisms of UGT1A subfamily, MRP2 and BCRP among pediatric patients received deferasirox. Total 20 functional genetic polymorphisms including BCRP (34G>A, 8191C>T, 8825C>A), MRP2 (-1774delG, -24C>T), UGTA1 (-3279T>G, -39insTA, 211G>A, 686C>A), UGT1A3 (17A>G, 31T>C, 81G>A, 133C>T, 140T>C, 477A>G), UGT1A7 (387T>G, 391C>A, 392G>A, 622T>C), and UGT1A9 (-118insT) were analyzed in 98 patients who received deferasirox to reduce transfusion induced iron overload (ferritin > 1,000 ng/ml). The median age of patients was 9 years (1-23 years) and the diagnosis were acute leukemia in 23, lymphoma in 4, solid tumor in 63, aplastic anemia in 5, and other hematologic disease in 3. Drug-related toxicities were defined by overall, hepatotoxicity, renal toxicity, GI toxicity and skin toxicity using NCI-CTC 3.0. The associations of genetic variability on the drug-related toxicities were evaluated by logistic regression models for the risk of toxicities as well as Cox-proportional hazard models focusing on times until toxicities occurred. Patients received median 29.4 (range 17.9–34.1) mg/kg of deferasirox. Total 39 patients discontinued deferasirox owing to drug-related toxicities at median 56 (range 6–583) days after the administration and the cumulative incidence (CI) was 39.8%. The most frequent toxicity was increased AST/ALT over Grade 3 in 15 patients with CI 15.3%. GI toxicity, skin toxicity and renal toxicity occurred with CIs of 12.2% (N=12), 9.2% (N=9), and 5.1% (N=5), respectively. Patients carrying two MRP2 haplotypes containing -1774del and/or -24T had more 7-fold risk as well as 5-fold hazard of hepatotoxicity compared to patients with the wild-type allele (OR=7.05, 95% CI=1.77-28.11; HR=5.17, 95% CI=1.64-16.29). The UGT1A7 haplotypes containing reduced activity allele also increased the risk and hazard of renal toxicity although the number of patients with renal toxicity was small (OR=41.10, 95% CI=2.00-842.98; HR=87.64, 95% CI=3.61-2126.06). Other genetic polymorphisms were not associated with any drug-related toxicity. This finding suggests that functional genetic variants of enzymes to metabolize and transport deferasirox were associated with drug-related toxicities. Further study is warranted to confirm the results as the pharmacogenetic biomarkers of deferasirox.