Trough Plasma Imatinib Levels and ABCG2 Polymorphisms Are Correlated with Optimal Cytogenetic Responses at 6 Months After Treatment with Standard Dose of Imatinib In Newly Diagnosed CML

Abstract 2272

To test the correlation of trough plasma Imatinib Mesylate (IM) levels and pharmacogenomic variation with cytogenetic or molecular responses, we measured trough plasma IM levels and analyzed various genetic polymorphisms in newly diagnosed CML patients at 6 months of IM treatment and compared them with the likelihood of achieving cytogenetic complete response (CyCR) or major molecular response to standard dose of IM.

Newly diagnosed 94 CML patients were prospectively enrolled in the current study. CyCR was achieved in 71 patients (75.5%). Eighty-four patients (89.4%) showed optimal response (CyCR + cytogenetic partial response CyPR) at 6 months. Trough plasma IM levels were highly variable ranging from 203 to 4980 ng/ml: mean (±SD) was 1392±78.8 ng/ml. Among 47 patients with trough plasma IM level of <1320 ng/ml, 39 patients (83.0%) showed optimal response and 8 (17.0%) suboptimal response. Among 47 patients with trough plasma IM level of ≥1320 ng/ml, 45 patients (95.7%) showed optimal response and 2 (4.3%) suboptimal response (P=0.045). Trough plasma IM level was 1346.0±78.3 ng/ml for the group with non-hematologic toxicity of grade 0 or 1 and 1969.6±365.3 for the group with grade 2–4, which was statistically significant (p=0.038).

The impact of single nucleotide polymorphisms (SNPs) in cytochrome P450 (CYP) genes (CYP2D6, CYP3A4, CYP3A5, CYP2C9, CYP2C19, CYP2B6, CYP2C8, CYP1A2) and transporter genes (hOCT1, hOCT2, hOCT3, ABCG2, ABCC2, SLCO1B1, ABCB1) potentially associated with IM trough level was also investigated. The AA genotype in CYP2C19*2 (681G>A) was significantly associated with higher IM trough level than dominant genotype (p=0.021), whereas transporter genes did not show any significant results. The CC genotype of ABCG2 (421C>A) gene was related with CCyR (OR 3.47, 95% CI 1.09–11.05; p=0.030).

In conclusion, the incidence of optimal responses in newly diagnosed CML patients who had been treated with standard dose of IM for 6 months was significantly higher in the patient group with trough plasma IM level of ≥1320 ng/ml than the group with <1320 ng/ml, and the trough level of IM was influenced by CYP2C19 genotype. Checking trough plasma IM level together with cytogenetic and molecular data at milestone timing may guide the clinicians to adopt dose escalation or 2^nd tyrosine kinase inhibitors in CML patients showing suboptimal response or resistance to standard dose of IM.