Response: is there really a relationship between Multidrug Resistance Gene (MDR1) polymorphisms and major molecular response to imatinib in chronic myeloid leukemia?

We would like to thank Deenik et al for having given us the opportunity to discuss our results regarding multidrug resistance gene (MDR1) polymorphisms and insist on the difficulties associated with the interpretation of single-nucleotide polymorphism (SNP) studies. As cited by Deekik et al, we reported in 2008 the impact of the 3 most relevant polymorphisms of MDR1 (ABCB1) gene on major molecular response (MMR) in 90 CML patients treated for at least 12 months by a standard dose of imatinib (ie, 400 mg) in front-line treatment or in second line after interferon-α.¹  We found a significant difference in genotype frequencies at loci 1236 and 2677 between patients with and those without MMR. In our 2008 report, we concluded that studies in a separate and larger patient population with newly diagnosed CML would be necessary to confirm these preliminary results. In continuation of this, we have now analyzed these 3 SNPs (C1236T, G2677T/A, and C3435T) in 557 of the 636 patients included in the multicenter French SPIRIT trial.²  Patients were treated de novo by imatinib 400 mg (n = 139), or imatinib 400 mg + Pegylated interferon (IFN) (n = 139), or imatinib 400 mg + cytarabine (AraC) (n = 139), or imatinib 600 mg (n = 140). The proportion of patients in MMR at 12 months was, respectively, 43.9%, 64.7%, 54%, and 55% in the 4 arms. The genotype distributions of each polymorphism were similar to those previously reported, and the 3 variants appeared in partial linkage disequilibrium.¹  A χ² test was used to analyze the association between ABCB1 polymorphisms and MMR within the total cohort and in each arm. For the polymorphism C1236T, no significant difference was observed in genotype frequencies between patients with or without MMR (Table 1). Similarly, no significant difference in genotype frequencies between patients with or without MMR was observed for the G2677T/A polymorphism. However, for the imatinib 400 mg + AraC, the presence of allele G2677 (GA, GG, or GT) was associated with a higher rate of MMR (59.5% vs 32.1%, P = .009; not shown in the table). This protective effect of the allele 2677 G in the arm imatinib 400 mg + AraC remained significant after multivariate analysis using a logistic regression model adjusted for Sokal risk, age, and sex (HR = 3.39; 95% confidence interval, 1.37-8.43). This result, which is similar to that found by Deenik et al, is surprising because AraC is not a substrate of MDR1 protein. However, 2 other studies did not identify any association of ABCB1 gene polymorphisms MMR after imatinib therapy for CML.^3,4 

Such results highlight the importance of studying a large cohort of homogeneous CML patients in order to draw conclusions. Thus, caution is required in order to conclude on a real impact of MDR genotypes on imatinib response. To interpret the results we have to keep in mind that C_min of imatinib is the result of many other pharmacokinetic and genetic determinants in addition to MDR1, such as CYP3A5, hOCT, and plasmatic transporters.