Abstract
Imatinib mesylate (IM) is highly efficacious in the treatment of chronic myeloid leukemia (CML). Therapeutic drug monitoring and pharmacogenetic screening are affirmed for better management of IM therapy. The goal of this study was to gain a greater mechanistic understanding of the factors controlling variability in IM level and its relation to the response. One hundred and two patients with CML at chronic phase were recruited in this study. Blood samples were withdrawn at least 30 days after drug administration, and trough and peak concentrations of imatinib, N-des-methyl imatinib, and pyridine-N-oxide imatinib were determined by HPLC/MS/MS. Genetic polymorphism of the genes ABCG2 SNPs 34 G>A and 421C >A; ABCB1 SNPs 2677 G>A/T, 1236 C>T, 3435 C>T; SLCO1B3 SNPs 334 T>G and CYP3A5 were studied using PCR-RFLP technique. Our study presented significant higher trough IM (1,281 ± 578 ng/ml), lower Peak/Trough ratio, clearance (Cl), and elimination rate constant, ke, among patients who achieved favorable responses (N = 64) than those for patients who suffered unfavorable response (N = 37). The P/T ratio was the only significant independent factor affecting response, as the P/T ratio increased by one, the risk of unfavorable response increased by more than double as compared to favorable response with 95% CI (1.28–3.92, P = 00.005). Moreover, like the results of IM, the trough concentration of Pyridine-N-oxide imatinib was significantly higher (P = 0.01) and its P/T ratio was significantly lower (P = 0.008) in patients achieved favorable response than those without. The wild GG genotype of the ABCG2.34 G>A gene was associated with favorable response (P = 0.01), lower Cl, Ke and high plasma IM trough level than both (AA+GA) genotypes. ABCG2.421C >A (CC) genotype had a significantly higher plasma peak of IM, N-des-methyl imatinib and higher Css. The GG and TG alleles of the SLCO1B3.334 T>G gene were significantly correlated to favorable response, while the wild allele TT was linked to unfavorable response (P = 0.03). In conclusion, the trough and P/ T ratio for both IM and Pyridine-N-oxide imatinib, in addition to Polymorphism of ABCG2 SNPs 34 G>A and SLCO1B3.334 T>G gene, is a good predictor for response of IM in CML Egyptian patients.
Highlights
Chronic myeloid leukemia (CML) is characterized by a chromosomal abnormality, the Philadelphia [Ph] chromosome, which resulted in a unique molecular event, BCR-ABL1 oncogene, which encodes the chimeric BCR-ABL1 protein with constitutive kinase activity [1, 2]
During the two years follow-up, 37 (36.6%) patients showed an unfavorable response
The individual variability in Imatinib mesylate (IM) pharmacokinetics often leads to an unsatisfactory clinical outcome in patients with CML [31]
Summary
Chronic myeloid leukemia (CML) is characterized by a chromosomal abnormality, the Philadelphia [Ph] chromosome, which resulted in a unique molecular event, BCR-ABL1 oncogene, which encodes the chimeric BCR-ABL1 protein with constitutive kinase activity [1, 2]. Imatinib mesylate (IM) is a tyrosine kinase inhibitor that selectively inhibits the BCR-ABL1 oncoprotein and induces effective and safe durable cytogenetic responses in most patients [3]. Imatinib has been found effective in the chronic and accelerated phases of CML, as well as in blast crisis [4]. The estimated rate of complete cytogenetic response (CCyR) to IM at 18 months was 76%. The 5-year follow-up analysis specified an estimated 87% cumulative CCyR and an estimated overall survival of 89% among 553 patients who received IM as first-line therapy [5]
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