High imatinib dose overcomes insufficient response associated with ABCG2 haplotype in chronic myelogenous leukemia patients

Abstract

Pharmacogenetic studies in chronic myelogenous leukemia (CML) typically use a candidate gene approach. In an alternative strategy, we analyzed the impact of single nucleotide polymorphisms (SNPs) in drug transporter genes on the molecular response to imatinib, using a DNA chip containing 857 SNPs covering 94 drug transporter genes. Two cohorts of CML patients treated with imatinib were evaluated: an exploratory cohort including 105 patients treated at 400 mg/d and a validation cohort including patients sampled from the 400 mg/d and 600 mg/d arms of the prospective SPIRIT trial (n=239). Twelve SNPs discriminating patients according to cumulative incidence of major molecular response (CI-MMR) were identified within the exploratory cohort. Three of them, all located within the ABCG2 gene, were validated in patients included in the 400 mg/d arm of the SPIRIT trial. We identified an ABCG2 haplotype (define as G-G, rs12505410 and rs2725252) as associated with significantly higher CI-MMR in patients treated at 400 mg/d. Interestingly, we found that patients carrying this ABCG2 “favorable” haplotype in the 400 mg arm reached similar CI-MMR rates that patients randomized in the imatinib 600 mg/d arm. Our results suggest that response to imatinib may be influenced by constitutive haplotypes in drug transporter genes. Lower response rates associated with “non-favorable” ABCG2 haplotypes may be overcome by increasing the imatinib daily dose up to 600 mg/d.

Pharmacogenetics of BCR/ABL Inhibitors in Chronic Myeloid Leukemia

“…Another trial demonstrated that patients carrying the c.421AA genotype achieved the major MR in a greater percentage ( n = 4, 100%) compared to individuals with other genotypes ( n = 73, 12.3%) [ 34 ], but the unbalanced number of patients between the two groups of this study should be taken into consideration. Finally, the cumulative incidence of major MR was the same in patients who received imatinib 600 or 400 mg/day, if the latter ones carried a favourable G-G haplotype composed by two SNPs (rs12505410 and rs2725252) of the ABCG2 gene [ 58 ]. Overall, all these clinical trials show that ABCG2 SNPs are predictive markers of imatinib efficacy and pharmacokinetics.…”

Genetic polymorphisms associated with increased risk of developing chronic myelogenous leukemia

“…Single association analysis identified 139 SNPs that were significantly associated with CML at an FDR < 0.01 (Figure 1 and Supplemental data in Table S1 ). We observed that among the 139 SNPs, 11 correspond to genes coding for detoxification proteins and 12 to genes coding for transporter proteins (two families well represented in the DNA chip) [ 6 ].…”

“…Peripheral blood samples for DNA extraction from patients and controls were collected at the time of recruitment in the respective trials. For individual genotyping we used a dedicated DNA chip (designed in 2006 by the French REPAC network) with 16 561 SNPs (mainly tag-SNPs) covering 1 916 genes (implicated in proliferation, apoptosis, immunity and metabolism [ 6 , 22 ]. Genotyping was performed by Integragen SA using the Illumina GoldenGate assay.…”

Effect of ABCC2 and ABCG2 Gene Polymorphisms and CSF‐to‐Serum Albumin Ratio on Ceftriaxone Plasma and Cerebrospinal Fluid Concentrations

“…ABCG2 1194+928 rs13120400 T>C SNP is localized in chromosome 4, and the C allele has been associated with enhanced molecular response in chronic myelogenous leukemia patients treated with imatinib . Furthermore, Lima et al suggested that the C allele may cause a reduced efflux capability, leading to less methotrexate elimination and higher drug bioavailability, with a higher risk of toxicity …”