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. 2010 Nov 30;2(11):85. doi: 10.1186/gm206

The pharmacogenetics of imatinib

Stéphanie Dulucq 1, Maja Krajinovic 2,✉
PMCID: PMC3016627  PMID: 21122163

Abstract

Imatinib mesylate (IM), a tyrosine kinase inhibitor, is one of the first molecularly targeted therapies to have been used in the clinic. It has proven to be efficient in the treatment of chronic myeloid leukemia and also in other malignancies that involve expression of a tyrosine kinase. However, some patients can develop resistance and others suffer from toxic side effects. The pharmacokinetics of IM depends on several enzymes and transporters, and several studies have attempted to identify genetic factors associated with variable drug levels and clinical responses using a candidate gene approach. Larger and more homogenous studies are still needed to replicate the findings obtained so far, or to analyze other genetic variations to get clearer insights into how IM treatment can be tailored to each patient's genetics. Here we summarize pharmacogenetic studies of IM and highlight the genetic markers that could be used to improve the treatment and management of diseases for which IM is used.

Introduction

Imatinib mesylate (IM, also known as STI571, Glivec or Gleevec) is a competitive tyrosine kinase inhibitor commonly used for treatment of chronic myeloid leukemia (CML). It has also proven efficient for the treatment of advanced gastrointestinal stromal tumors (GISTs), c-KIT mastocytosis and myeloproliferative disorders with rearrangement of the platelet derived growth factor receptor (PDGFR) gene. In CML, IM inhibits the tyrosine kinase activity of the fusion protein of breakpoint cluster region (BCR) gene and the ABL tyrosine kinase (BCR-ABL), which results from a t(9;22)(q34, q11) translocation known as the Philadelphia chromosome; this fusion protein has a role in leukemogenesis [1]. IM occupies the ATP-binding pocket of the ABL kinase domain; this prevents a change in conformation of the protein that would otherwise convert the molecule to its active form, and IM binding thereby leads to the apoptosis of target cells.

Three main criteria can be used to evaluate the response to CML treatment: complete hematological remission, defined as a normal peripheral blood count with normal spleen; complete cytogenetic response (CCyR), defined by absence of the Philadelphia chromosome in bone marrow metaphase analysis; and major molecular response (MMR), defined by the thousand-fold (3 log) reduction in BCR-ABL transcript levels relative to the standardized baseline [1]. Other levels of cytogenetic or molecular response can be used [1], as mentioned in Table 1. Despite outstanding results of IM in the treatment of chronic phase CML, some patients do not achieve response criteria (for example, about 25% of patients did not achieve CCyR at 18 months [2], and some patients (about 25%) who initially responded well subsequently acquired resistance [3]. Apart from dosage errors, drug interactions and non-compliance with treatment, several mechanisms can contribute to the development of resistance: changes to the target protein (occurring through mutations or BCR-ABL amplification); downstream BCR-ABL-independent pathways; and drug pharmacokinetics parameters (absorption, distribution, metabolism and excretion). In malignancies other than CML, IM inhibits the tyrosine kinase domains of KIT and PDGFRα/β. Myeloproliferative disorders with PDGFR rearrangement show great sensitivity to IM and mostly require a lower dose of IM; this is especially true of chronic eosinophilic leukemia, which involves a fusion transcript of FIP1-like1 and PDGFRA [4]. In mastocytosis, the overall response rate varies according to c-KIT mutational status and has been reported to be 18 to 36% [5]. In GISTs, IM leads to a response rate of 50 to 70%, with a 2-year overall survival rate of 70% [6].

Table 1.

Summary of studies of the efficacy of IM treatment in relation to pharmacokinetic genetic variants*

Genes SNP* Base substitution† Functional effect‡ No of patients Response criteria IM dosage Association References
ABCB1 rs1128503 C1236T + 90 French MMR at 12 months 400 mg in front line or 2nd line after IFN Higher MMR with 1236T allele [20]
- 62 Japanese MMR ≥400 and ≤300 mg No [26]
229 Canadian CyR and MR at 1, 1.5, 2, 3, 4 and 5 years§ 400, 600 or 800 mg No [25]
87 English MMRat 18 months 400 mg No [24]
46 Dutch Cumulative incidence of MMR and CMR at 12 months 800 mg Higher MMR and CMR with CC genotype [22]
557 French MMR at 12 months 400 mg; 400 mg + IFN 400 mg + AraC; 600 mg No [21]
52 Chinese CCyR at 12 months 400 mg Lower CCyR with TT genotype [23]
rs2032582 G2677T/A + 90 French MMR at 12 months 400 mg in front line or 2nd line after IFN Lower MMR with 2677G allele [20]
- 62 Japanese MMR ≥400 and ≤300 mg No [26]
229 Canadian CyR and MR at 1, 1.5, 2, 3, 4 and 5 years§ 400, 600 or 800 mg No [25]
46 Dutch Cumulative incidence of MMR and CMR at 12 months 800 mg Lower CMR with TT genotype [22]
557 French MMR at 12 months 400 mg; 400 mg + IFN 400 mg + AraC; 600 mg Higher MMR with 2677G allele in the arm 400 mg + AraC [21]
52 Chinese CCyR at 12 months 400 mg Higher CCyR with AG/AT/AA genotypes [23]
rs1045642 C3435T¥ - 90 French MMR at 12 months 400 mg in front line or 2nd line after IFN No [20]
- 62 Japanese MMR ≥400 and ≤300 mg No [26]
ABCB1 rs1045642 C3435T¥ 229 Canadian CyR and MR at 1, 1.5, 2, 3, 4 and 5 years§ 400, 600 or 800 mg Overall survival lower with TT genotype but not confirmed in multivariate analysis [25]
46 Dutch Cumulative incidence of MMR and CMR at 12 months 800 mg Lower CMR with TT genotype [22]
557 French MMR at 12 months 400 mg; 400 mg + IFN 400 mg + AraC; 600 mg No [21]
52 Chinese CCyR at 12 months 400 mg Higher CCyR with CC genotype [23]
ABCG2 rs717620 - 62 Japanese MMR ≥400 and ≤300 mg No [26]
rs2231142 C421A¥ + 62 Japanese MMR ≥400 and ≤300 mg No [26]
229 Canadian CyR and MR at 1, 1.5, 2, 3, 4 and 5 years§ 400, 600 or 800 mg Higher CMR with AA genotype; more frequent need for IM dose escalation for CC genotype [25]
rs2231137 G34A 229 Canadian CyR and MR at 1, 1.5, 2, 3, 4 and 5 years§ 400, 600 or 800 mg Lower MCyR and CCyR with GG genotypes [25]
SLC22A1 rs12208357 32 Austrian MMR at 18 months 400 mg No [52]
- 132 English MMR 400 mg No [37]
229 Canadian CyR and MR at 1, 1.5, 2, 3, 4 and 5 years§ 400, 600 or 800 mg No [25]
- 136 Australian MMR at 2 years < 600 mg or ≥600 mg No [38]
rs2282143 - 132 English MMR 400 mg No [37]
- 62 Japanese MMR ≥400 and ≤300 mg No [26]
229 Canadian CyR and MR at 1, 1.5, 2, 3, 4 and 5 years§ 400, 600 or 800 mg No [25]
rs34130495 G1201A¥ - 132 English MMR 400 mg Higher MMR with GA genotypes [37]
SLC22A1 - 136 Australian MMR at 2 years < 600 mg or ≥600 mg No [38]
rs622342 - 132 English MMR 400 mg No [37]
rs1867351 - 62 Japanese MMR ≥400 and ≤300 mg No [26]
229 Canadian CyR and MR at 1, 1.5, 2, 3, 4 and 5 years§ 400, 600 or 800 mg No [25]
rs683369 C480G - 62 Japanese MMR ≥400 and ≤300 mg No [26]
229 Canadian CyR and MR at 1, 1.5, 2, 3, 4 and 5 years§ 400, 600 or 800 mg Higher risk of loss of response and treatment failure with GG genotypes [25]
rs628031 A1222G - 62 Japanese MMR ≥400 and ≤300 mg Higher MMR with GG genotypes [26]
229 Canadian CyR and MR at 1, 1.5, 2, 3, 4 and 5 years§ 400, 600 or 800 mg No [25]
- 136 Australian MMR at 2 years < 600 mg or ≥600 mg No [38]
rs 72552763 - 136 Australian MMR at 2 years < 600 mg or ≥600 mg No [38]
SLCO1B3 rs4149117 - 62 Japanese MMR ≥400 and ≤300 mg No [26]
CYP3A5 rs776746 A6986G - 62 Japanese MMR ≥400 and ≤300 mg No [26]
229 Canadian CyR and MR at 1, 1.5, 2, 3, 4 and 5 years§ 400, 600 or 800 mg Lower MCyR and CCyR with AA genotypes [25]
265 Indian Hematological response (HR) 400 mg Lower HR with GG genotypes [41]
rs28383468 229 Canadian CyR and MR at 1, 1.5, 2, 3, 4 and 5 years§ 400, 600 or 800 mg No [25]
AGP rs3182041 229 Canadian CyR and MR at 1, 1.5, 2, 3, 4 and 5 years§ 400, 600 or 800 mg No [25]
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*All patients were in chronic phase except for the study of Kim et al. [25], in which 203 patients were in chronic phase and 26 patients in accelerated phase or in blast crisis. †The base substitution and rs number taken from the National Centre for Biotechnology information SNP database [53] are indicated for polymorphisms positively associated with IM response. For the remaining SNPs for which no association was found, only the rs number is indicated. ‡Functional impact in vivo: association had been found between polymorphisms and transcript levels of candidate genes or with trough IM concentration. §CyR, cytogenetic response; MR, molecular response; the cumulative incidence of major cytogenetic response (MCyR), CCyR, MMR, complete molecular response (CMR), loss of response, treatment failure and overall survival was measured. MMR in patients with CCyR. ¥Polymorphisms with demonstrated functional effect in vitro.

In the conventional dose range, a fourfold inter-patient variability has been reported both in the systemic exposure for a given dose and in the dose required to achieve a specific target level [7]. Variation in drug concentration may result in excessive toxicity or suboptimal anticancer effect. Reduced IM efficacy has been linked to low drug exposure; the main reported toxicities of IM are neutropenia, superficial edema, nausea, muscle cramps and rashes [1-3]. Trough IM plasma levels (Cmin) have been reported to be associated with MMR in CML patients following standard drug dose [8,9] A plasma threshold of 1,002 ng/ml had the best sensitivity and specificity to predict MMR [8]. Patients with Cmin below this threshold have less chance to achieve MMR compared with patients with Cmin above it. Likewise, higher circulating levels of IM correlated with a better response rate and with a longer time to progression in patients with advanced GISTs with Cmin of more than 1,100 ng/ml [10].

Observed inter-patient pharmacokinetic variability may be due to patients' genetics. Polymorphisms in genes related to IM absorption, distribution, metabolism and excretion may affect the drug's bioavailability and consequently the response to the drug. The oral bioavailability of IM depends on its gastrointestinal absorption and on how much of it survives the extensive first pass metabolism that it encounters. Approximately 95% of IM in the human body is bound to plasma proteins, mainly serum albumin and α1 acid glycoprotein (AGP). Removal of IM is mediated by the P glycoprotein (P-gp, also called ABCB1 or MDR1) and breast cancer resistance protein (BCRP), and uptake is mediated by human organic cation transporter 1 (hOCT1). IM is mostly metabolized by the cytochrome P450 (CYP) proteins CYP3A4 and CYP3A5 [11]. Various studies have analyzed the polymorphisms in genes encoding these proteins in relation to IM pharmacokinetics and response, as detailed below and in Table 1.

Overview of pharmacogenetic studies

Pharmacokinetic determinants

Cancer cells have the ability to become resistant to multiple different drugs known as the multi drug resistance (MDR) phenomenon. This is due, among other mechanisms, to increased transport of drugs out of the cell. Mahon et al. [12] showed that IM is a substrate of P-gp and could thus be affected by MDR. This was confirmed by the facts that CML patients who did not achieve a CCyR had higher levels of expression of ABCB1 and that there was a correlation between BCR-ABL and ABCB1 transcript levels in these patients [13]. However, in GIST patients, the expression level of ABCB1 did not seem to impair the initial response to IM [14].

ABCB1 contains 28 exons and is located on chromosome 7q21.1. The silent C3435T polymorphism (rs1045642) in exon 26 of ABCB1 was the first polymorphism to be described; it was reported to modify P-gp expression [15] (Table 1). Decreased substrate specificity, lower levels of intestinal P-gp and reduced levels of ABCB1 mRNA in 3435TT individuals were reported [15-17]. Consistent with this, increased bioavailability of some P-gp substrates has been observed to be associated with the 3435TT genotype in several studies, although conflicting reports have subsequently appeared showing higher or no correlation with ABCB1 expression or P-gp activity [18]. The C3435T polymorphism is in linkage disequilibrium with a silent C1236T polymorphism (rs1128503) in exon 12 and a non-synonymous substitution G2677T/A (rs2032582) in exon 21, which leads to an amino acid change of Ala893 to serine or threonine; this may also contribute to the observed functional effect of variation at the C3435T polymorphism or at associated haplotypes.

Gurney et al. [19] reported a higher IM clearance in CML and GIST patients with the TT genotype at each of three positions in the ABCB1 gene (positions 1236, 2677 and 3435). Reduction in dose as a result of toxicity also tended to be less commonly needed in these individuals [19]. We and our colleagues [20] found a higher frequency of MMR in CML patients carrying the 1236T allele and in patients with non-G genotypes at position 2677. However, we could not confirm these results in a larger patient cohort [21]. Only in the subgroup of patients treated with both IM and cytarabine (also called AraC) was an association with the ABCB1 2677 polymorphism found, but, contrary to the initial finding [20], the presence of allele 2677G (GA or GG or GT) was associated with a higher rate of MMR [21]. This finding is surprising given that AraC is not a substrate of P-gp. The result is nevertheless similar to that reported by Deenik et al. [22], who observed a lower probability of cumulative MMR for CML patients who were homozygous for the ABCB1 alleles 3435T and 2677T, as well as for those having at least one 1236T allele. Finally, Ni et al. [23] reported a higher resistance rate in homozygous ABCB1 1236T patients and in those with at least one 3435T allele, whereas better CCyR was observed for patients with the AG/AT/AA genotype at position 2677. Three other studies conducted with CML patients did not find an association between ABCB1 polymorphisms and MMR [24-26].

BCRP, which, like P-gp, causes removal of IM, is encoded by the ABCG2 gene located on chromosome 4q22. BCRP is expressed not only in hematopoietic stem cells but also in hepatic and intestinal epithelial cells, and this affects the bioavailability of IM [27]. The SNPs G34A (rs2231137), which substitutes a valine for a methionine, and C421A (rs2231142), which substitutes a glutamine for a lysine, are the most frequent non-synonymous polymorphisms in ABCG2 across various populations (Table 1) [28]. Experiments in vitro using various drug substrates showed that the Gln141Lys substitution affects the transport efficiency of BCRP and may result in altered pharmacokinetics and drug-resistance profiles [28]. Human embryonic kidney cells transfected with the 141Lys variant of BCRP showed greater IM accumulation in vitro [29]. Consistent with this, a lower IM clearance and a higher dose-adjusted IM trough concentration were found in CML patients with the 141Lys variant [26,30], whereas the 141Gln variant reduced the response to IM [25]. In addition, the 34GG genotype was associated with a lower frequency of cytogenetic response [25], although the functional effect of this variant is less clear. In contrast to the reports on CML, pharmacokinetic IM parameters were not significantly different across genotypes of Gln141Lys polymorphism in patients with GISTs and KIT-positive soft tissue sarcoma [29].

The hOCT1 protein, encoded by the solute carrier family 22 gene (SLC22A1) on chromosome 6q26 [31], may also affect the response to IM by regulating its uptake. CML patients with low hOCT1 activity showed lower probability of achieving MMR [32], whereas those with high baseline level showed better survival and higher probability of achieving a cytogenetic or molecular response [24,33,34]. Given the important predictive role of SLC22A1 expression, some investigators have focused on gene variations that may affect hOCT1 function [35,36]. For example, the Arg61Cys, Cys88Arg and Gly401Ser amino acid replacements resulting from the corresponding genetic polymorphisms were shown to affect the transport of hOCT1 substrates [30]. Bazeos et al. [37] identified an association between Gly401Ser substitution (G1201A, rs34130495) and the transcription level of the SLC22A1 gene (Table 1). In addition, CML patients with the 1201GA genotype had higher probability of achieving MMR than patients with the 1201GG genotype. These results, however, need to be confirmed in a larger cohort given the low frequency of the A allele. Indeed, White et al. [38] were not able to replicate this finding. Kim et al. [25] showed instead that the SLC22A1 C480G polymorphism (rs683369), which leads to Leu160Phe replacement, is associated with IM response in CML. Patients with the 480GG genotype showed a higher risk of treatment failure or loss of response than other genotypes. Finally, Takahashi et al. [26] showed that the SLC22A1 A1222G polymorphism (rs628031), which leads to Met408Val replacement, is associated with molecular response in the group of patients treated with IM doses lower than 400 mg. Patients with the 1222GG genotype showed a higher MMR rate.

Uptake of imatinib has also been described, in vitro, to be mediated to a modest extent by SLCO1B3, which encodes the organic anion-transporting polypeptide 1B3 [39], but Takahashi et al. [26] did not find any association with IM response (Table 1).

Metabolizing enzymes

Among CYP3A5 polymorphisms, the CYP3A5*3 allele is particularly interesting, as it appears with a sufficiently high frequency and has a clear functional role. The CYP3A5*3 allele is defined by the A6986G substitution (rs776746), which generates a cryptic splice site and the introduction of a premature stop codon [40]. Individuals who are homozygous for this allele have reduced CYP3A5 levels and reduced metabolic capacity. In the study of Kim et al. [25], the 6986AA genotype had an adverse impact on achievement of CCyR, whereas Takahashi et al. [26] did not find an association between this allele and dose-adjusted IM trough concentration or clinical response (Table 1). In contrast, Sailaja et al. [41] found a higher frequency of the 6986GG genotype in CML patients with a minor or poor hematological response.

Binding proteins

The role of AGP in the mechanisms of IM resistance is not yet clear [42]. In GIST patients, an association was found between high plasma AGP levels and a lower clearance of IM and its metabolite [43]. Kim et al. [25] did not observe any association between AGP polymorphisms and IM response in CML patients.

Pharmacodynamic determinants

IM tyrosine kinase targets represent potential pharmacodynamic determinants. Any modification in these targets could modulate the efficacy of IM and affect its mechanism of action.

Acquired point mutations in the tyrosine kinase domain of BCR-ABL are the most frequent mechanism of acquired resistance to IM in CML [44]. These mutations should be distinguished from the polymorphisms in the ABL gene that could be responsible for primary resistance. However, their role is not yet clear. For example, the Lys247Arg amino acid replacement resulting from an adenine-to-guanine substitution does not seem to be functional [45]. Ernst et al. [46] found six different polymorphisms in CML patients with failure of treatment or suboptimal IM response, but the clinical impact of these variations still needs to be investigated.

Approximately 95% of GIST patients express the receptor tyrosine kinase KIT and 86% of GISTs contain c-KIT activating mutations that lead to a ligand-independent activation of the tyrosine kinase. These somatic mutations mostly occur in the juxtamembrane domain (encoded by exon 11) and extracellular domains (exon 9). The target kinase mutations in exon 11 are associated with a better overall partial response rate using standard Southwest oncology group response criteria [47].

Some GIST patients without c-KIT mutations show alterations in the juxtamembrane domain (encoded by exon 12) or activation loop domain (exon 18) of PDGFRA, with those with exon 18 mutations having a poor response to IM [47]. Resistance due to the somatic mutations in the tyrosine kinase domain of PDGFRA has also been described in a few cases of chronic eosinophilic leukemia [48]. IM-associated edema is believed to involve a disruption of PDGF signaling. The role of PDGFR polymorphisms in the risk of developing severe edema during IM treatment from CML was analyzed by Bruck et al. [49], but no significant association was found.

Dressman et al. [50] analyzed the effect of 68 polymorphisms in 26 genes on the cytogenetic response to IM. They found a significant association between the rs2290573 polymorphism located in an intron of a putative tyrosine kinase gene, DKFZP434C131, and the major cytogenetic response (MCyR) in a subset of IM-treated patients. Patients homozygous for the C allele had a significantly lower MCyR rate and a higher risk of disease progression than patients with other genotypes. It is unknown whether this polymorphism has a functional effect or whether it is a genetic marker in linkage disequilibrium with another polymorphism that is functional.

A substantial proportion of patients with IM resistance do not have BCR-ABL tyrosine kinase domain mutations, suggesting the involvement of additional mechanisms in IM resistance. Activation of other signaling pathways when IM blocks the BCR-ABL-mediated pathway might facilitate cell death avoidance in CML [51]. Recently, Kim et al. [51] analyzed a variety of polymorphisms in the genes of the apoptosis, angiogenesis, cell growth, Wilms tumor gene or interferon (IFN) signaling pathways in CML patients. An association obtained both in test and validation cohorts is particularly interesting. The CC genotype of the rs2069705 polymorphism in the IFNG (IFN-γ) gene was associated with a higher rate of molecular and cytogenetic response, suggesting a potential involvement of the IFN-γ signaling pathway in the mechanism of IM action in CML.

Clinical relevance of the pharmacogenetics of IM

Given that there is a large variability in response rate and IM systemic exposure following a standard drug dose, pharmacogenetic studies may provide insights into the role of genetic components in this variability. Focusing on a variety of genes whose products are essential for IM levels and action, these studies may identify potential pharmacokinetic and/or pharmacodynamic markers of IM response. These markers, complementing existing ones such as drug plasma concentrations, could allow the prediction, for each individual, of a lack of efficacy or excess toxicity, leading first to pharmacogenetically guided prospective clinical trials and ultimately to personalized treatment. Pharmacogenetic IM studies have been conducted so far mainly in patients diagnosed with CML or GIST, probably because of the higher incidence of these two diseases. The efficacy and toxicity of IM seem to depend on both IM pharmacokinetics, influenced by several enzymes and transporters, and IM pharmacodynamics, influenced by mutational status of the target. Several polymorphisms affecting the pharmacokinetic determinants of IM have been identified. Nevertheless, the data are not yet sufficiently conclusive to translate into individual drug dose adjustment (several reasons for this are outlined below). Meanwhile, trough IM plasma levels could help physicians to define the best IM dose [8]. In addition, the determination of hOCT1 activity before initiation of IM therapy may also be helpful [38].

Concluding remarks

Despite several groups attempting to demonstrate the impact of candidate gene polymorphisms, conflicting results remain. These discrepancies could be explained, at least in some cases, by different response criteria, study sample size, IM dosage and treatment protocols. Most studies have focused on ABCB1 polymorphisms, and constitutive or compensatory changes in expression of other ABC transporters, or IM-induced changes in ABCB1 expression, may confound the observed results in these studies. The results are not always supported by the expected functional effect of a given polymorphism, and they still require replication. It will be necessary to target other genotypes beyond those already analyzed to more comprehensively estimate the effect of the genes from the analysis of both individual polymorphisms and haplotypes.

It seems clear that the effect of IM depends on several genes. An approach involving multiple candidate genes may thus give the benefit of including the potential effects of gene-gene interactions, but this has not been much explored and usually requires larger studies. Further studies are clearly needed to elucidate the real impact of candidate gene polymorphisms on the IM response and to what extent the use of second generation tyrosine kinase inhibitors (nilotinib and dasatinib) may eventually overcome the resistance imposed by certain genetic variations.

Abbreviations

AGP: α1 acid glycoprotein; BCRP: breast cancer resistance protein; CCyR: complete cytogenetic response; CML: chronic myeloid leukemia; Cmin: trough imatinib plasma level; CMR: complete molecular response; CYP: cytochrome; GIST: gastrointestinal stromal tumor; hOCT1: human organic cation transporter 1; IM: imatinib mesylate; MCyR: major cytogenetic response; MDR: multidrug resistance; MMR: major molecular response; PDGFR: platelet-derived growth factor receptor; P-gp: P glycoprotein; SNP: single nucleotide polymorphism.

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

Both authors contributed equally to the writing of the manuscript.

Contributor Information

Stéphanie Dulucq, Email: maja.krajinovic@umontreal.ca.

Maja Krajinovic, Email: maja.krajinovic@umontreal.ca.

Acknowledgements

The authors are grateful to F-X Mahon for critical reading of the manuscript. MK is a Scholar of Fonds de Recherche en Santé du Quebec.

References

  1. Baccarani M, Cortes J, Pane F, Niederwieser D, Saglio G, Apperley J, Cervantes F, Deininger M, Gratwohl A, Guilhot F, Hochhaus A, Horowitz M, Hughes T, Kantarjian H, Larson R, Radich J, Simonsson B, Silver RT, Goldman J, Hehlmann R. European LeukemiaNet. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol. 2009;27:6041–6051. doi: 10.1200/JCO.2009.25.0779. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. O'Brien SG, Guilhot F, Larson RA, Gathmann I, Baccarani M, Cervantes F, Cornelissen JJ, Fischer T, Hochhaus A, Hughes T, Lechner K, Nielsen JL, Rousselot P, Reiffers J, Saglio G, Shepherd J, Simonsson B, Gratwohl A, Goldman JM, Kantarjian H, Taylor K, Verhoef G, Bolton AE, Capdeville R, Druker BJ. IRIS Investigators. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003;348:994–1004. doi: 10.1056/NEJMoa022457. [DOI] [PubMed] [Google Scholar]
  3. Hochhaus A, Kreil S, Corbin AS, La Rosee P, Muller MC, Lahaye T, Hanfstein B, Schoch C, Cross NC, Berger U, Gschaidmeier H, Druker BJ, Hehlmann R. Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia. 2002;16:2190–2196. doi: 10.1038/sj.leu.2402741. [DOI] [PubMed] [Google Scholar]
  4. Jovanovic JV, Score J, Waghorn K, Cilloni D, Gottardi E, Metzgeroth G, Erben P, Popp H, Walz C, Hochhaus A, Roche-Lestienne C, Preudhomme C, Solomon E, Apperley J, Rondoni M, Ottaviani E, Martinelli G, Brito-Babapulle F, Saglio G, Hehlmann R, Cross NC, Reiter A, Grimwade D. Low-dose imatinib mesylate leads to rapid induction of major molecular responses and achievement of complete molecular remission in FIP1L1-PDGFRA-positive chronic eosinophilic leukemia. Blood. 2007;109:4635–4640. doi: 10.1182/blood-2006-10-050054. [DOI] [PubMed] [Google Scholar]
  5. Pardanani A, Tefferi A. Systemic mastocytosis in adults: a review on prognosis and treatment based on 342 Mayo Clinic patients and current literature. Curr Opin Hematol. 2010;17:125–132. doi: 10.1097/MOH.0b013e3283366c59. [DOI] [PubMed] [Google Scholar]
  6. Verweij J, Casali PG, Zalcberg J, LeCesne A, Reichardt P, Blay JY, Issels R, van Oosterom A, Hogendoorn PC, Van Glabbeke M, Bertulli R, Judson I. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet. 2004;364:1127–1134. doi: 10.1016/S0140-6736(04)17098-0. [DOI] [PubMed] [Google Scholar]
  7. Peng B, Hayes M, Resta D, Racine-Poon A, Druker BJ, Talpaz M, Sawyers CL, Rosamilia M, Ford J, Lloyd P, Capdeville R. Pharmacokinetics and pharmacodynamics of imatinib in a phase I trial with chronic myeloid leukemia patients. J Clin Oncol. 2004;22:935–942. doi: 10.1200/JCO.2004.03.050. [DOI] [PubMed] [Google Scholar]
  8. Picard S, Titier K, Etienne G, Teilhet E, Ducint D, Bernard MA, Lassalle R, Marit G, Reiffers J, Begaud B, Moore N, Molimard M, Mahon FX. Trough imatinib plasma levels are associated with both cytogenetic and molecular responses to standard-dose imatinib in chronic myeloid leukemia. Blood. 2007;109:3496–3499. doi: 10.1182/blood-2006-07-036012. [DOI] [PubMed] [Google Scholar]
  9. Larson RA, Druker BJ, Guilhot F, O'Brien SG, Riviere GJ, Krahnke T, Gathmann I, Wang Y. Imatinib pharmacokinetics and its correlation with response and safety in chronic-phase chronic myeloid leukemia: a subanalysis of the IRIS study. Blood. 2008;111:4022–4028. doi: 10.1182/blood-2007-10-116475. [DOI] [PubMed] [Google Scholar]
  10. Demetri GD, Wang Y, Wehrle E, Racine A, Nikolova Z, Blanke C, Joensuu H, von Mehren M. Imatinib plasma levels are correlated with clinical benefit in patients with unresectable/metastatic gastrointestinal stromal tumors (GIST). J of Clin Oncol. 2009;27:3141–3147. doi: 10.1200/JCO.2008.20.4818. [DOI] [PubMed] [Google Scholar]
  11. Peng B, Lloyd P, Schran H. Clinical pharmacokinetics of imatinib. Clin Pharmacokinet. 2005;44:879–894. doi: 10.2165/00003088-200544090-00001. [DOI] [PubMed] [Google Scholar]
  12. Mahon FX, Belloc F, Lagarde V, Chollet C, Moreau-Gaudry F, Reiffers J, Goldman JM, Melo JV. MDR1 gene overexpression confers resistance to imatinib mesylate in leukemia cell line models. Blood. 2003;101:2368–2373. doi: 10.1182/blood.V101.6.2368. [DOI] [PubMed] [Google Scholar]
  13. Galimberti S, Cervetti G, Guerrini F, Testi R, Pacini S, Fazzi R, Simi P, Petrini M. Quantitative molecular monitoring of BCR-ABL and MDR1 transcripts in patients with chronic myeloid leukemia during Imatinib treatment. Cancer Genet Cytogenet. 2005;162:57–62. doi: 10.1016/j.cancergencyto.2005.01.015. [DOI] [PubMed] [Google Scholar]
  14. Theou N, Gil S, Devocelle A, Julie C, Lavergne-Slove A, Beauchet A, Callard P, Farinotti R, Le Cesne A, Lemoine A, Faivre-Bonhomme L, Emile JF. Multidrug resistance proteins in gastrointestinal stromal tumors: site-dependent expression and initial response to imatinib. Clin Cancer Res. 2005;11:7593–7598. doi: 10.1158/1078-0432.CCR-05-0710. [DOI] [PubMed] [Google Scholar]
  15. Hoffmeyer S, Burk O, von Richter O, Arnold HP, Brockmoller J, Johne A, Cascorbi I, Gerloff T, Roots I, Eichelbaum M, Brinkmann U. Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci USA. 2000;97:3473–3478. doi: 10.1073/pnas.050585397. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Wang D, Johnson AD, Papp AC, Kroetz DL, Sadee W. Multidrug resistance polypeptide 1 (MDR1, ABCB1) variant 3435C>T affects mRNA stability. Pharmacogenet Genomics. 2005;15:693–704. doi: 10.1097/01.fpc.0000178311.02878.83. [DOI] [PubMed] [Google Scholar]
  17. Kimchi-Sarfaty C, Oh JM, Kim IW, Sauna ZE, Calcagno AM, Ambudkar SV, Gottesman MM. A "silent" polymorphism in the MDR1 gene changes substrate specificity. Science. 2007;315:525–528. doi: 10.1126/science.1135308. [DOI] [PubMed] [Google Scholar]
  18. Sakaeda T, Nakamura T, Okumura K. Pharmacogenetics of MDR1 and its impact on the pharmacokinetics and pharmacodynamics of drugs. Pharmacogenomics. 2003;4:397–410. doi: 10.1517/phgs.4.4.397.22747. [DOI] [PubMed] [Google Scholar]
  19. Gurney H, Wong M, Balleine RL, Rivory LP, McLachlan AJ, Hoskins JM, Wilcken N, Clarke CL, Mann GJ, Collins M, Delforce SE, Lynch K, Schran H. Imatinib disposition and ABCB1 (MDR1, P-glycoprotein) genotype. Clin Pharmacol Ther. 2007;82:33–40. doi: 10.1038/sj.clpt.6100201. [DOI] [PubMed] [Google Scholar]
  20. Dulucq S, Bouchet S, Turcq B, Lippert E, Etienne G, Reiffers J, Molimard M, Krajinovic M, Mahon FX. Multidrug resistance gene (MDR1) polymorphisms are associated with major molecular responses to standard-dose imatinib in chronic myeloid leukemia. Blood. 2008;112:2024–2027. doi: 10.1182/blood-2008-03-147744. [DOI] [PubMed] [Google Scholar]
  21. Dulucq S, Preudhomme C, Guilhot F. Is there really a relationship between Multidrug resistance gene (MDR1) polymorphisms and major molecular response to imatinib in chronic myeloid leukemia. Blood. pp. 6145–6146. [DOI]
  22. Deenik W, Van der Holt B, Janseen J. Polymorphisms in the Multidrug Resistance gene MDR1(ABCB1) predict for molecular resistance in patients with newly diagnosed chronic myeloid leukemia (CML) receiving high-dose imatinib. Blood. pp. 6144–6145. [DOI] [PubMed]
  23. Ni LN, Li JY, Miao KR, Qiao C, Zhang SJ, Qiu HR, Qian SX. Multidrug resistance gene (MDR1) polymorphisms correlate with imatinib response in chronic myeloid leukemia. Med Oncol. 2010. [DOI] [PubMed]
  24. Marin D, Bazeos A, Mahon FX, Eliasson L, Milojkovic D, Bua M, Apperley JF, Szydlo R, Desai R, Kozlowski K, Paliompeis C, Latham V, Foroni L, Molimard M, Reid A, Rezvani K, de Lavallade H, Guallar C, Goldman J, Khorashad JS. Adherence is the critical factor for achieving molecular responses in patients with chronic myeloid leukemia who achieve complete cytogenetic responses on imatinib. J Clin Oncol. 2010;28:2381–2388. doi: 10.1200/JCO.2009.26.3087. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Kim DH, Sriharsha L, Xu W, Kamel-Reid S, Liu X, Siminovitch K, Messner HA, Lipton JH. Clinical relevance of a pharmacogenetic approach using multiple candidate genes to predict response and resistance to imatinib therapy in chronic myeloid leukemia. Clin Cancer Res. 2009;15:4750–4758. doi: 10.1158/1078-0432.CCR-09-0145. [DOI] [PubMed] [Google Scholar]
  26. Takahashi N, Miura M, Scott SA, Kagaya H, Kameoka Y, Tagawa H, Saitoh H, Fujishima N, Yoshioka T, Hirokawa M, Sawada K. Influence of CYP3A5 and drug transporter polymorphisms on imatinib trough concentration and clinical response among patients with chronic phase chronic myeloid leukemia. J Human Genet. 2010. doi:10.1038/jhg.2010.98. [DOI] [PubMed]
  27. Doyle LA, Ross DD. Multidrug resistance mediated by the breast cancer resistance protein BCRP (ABCG2). Oncogene. 2003;22:7340–7358. doi: 10.1038/sj.onc.1206938. [DOI] [PubMed] [Google Scholar]
  28. Morisaki K, Robey RW, Ozvegy-Laczka C, Honjo Y, Polgar O, Steadman K, Sarkadi B, Bates SE. Single nucleotide polymorphisms modify the transporter activity of ABCG2. Cancer Chemother Pharmacol. 2005;56:161–172. doi: 10.1007/s00280-004-0931-x. [DOI] [PubMed] [Google Scholar]
  29. Gardner ER, Burger H, van Schaik RH, van Oosterom AT, de Bruijn EA, Guetens G, Prenen H, de Jong FA, Baker SD, Bates SE, Figg WD, Verweij J, Sparreboom A, Nooter K. Association of enzyme and transporter genotypes with the pharmacokinetics of imatinib. Clin Pharmacol Ther. 2006;80:192–201. doi: 10.1016/j.clpt.2006.05.003. [DOI] [PubMed] [Google Scholar]
  30. Petain A, Kattygnarath D, Azard J, Chatelut E, Delbaldo C, Geoerger B, Barrois M, Seronie-Vivien S, LeCesne A, Vassal G. Population pharmacokinetics and pharmacogenetics of imatinib in children and adults. Clin Cancer Res. 2008;14:7102–7109. doi: 10.1158/1078-0432.CCR-08-0950. [DOI] [PubMed] [Google Scholar]
  31. Thomas J, Wang L, Clark RE, Pirmohamed M. Active transport of imatinib into and out of cells: implications for drug resistance. Blood. 2004;104:3739–3745. doi: 10.1182/blood-2003-12-4276. [DOI] [PubMed] [Google Scholar]
  32. White DL, Saunders VA, Dang P, Engler J, Venables A, Zrim S, Zannettino A, Lynch K, Manley PW, Hughes T. Most CML patients who have a suboptimal response to imatinib have low OCT-1 activity: higher doses of imatinib may overcome the negative impact of low OCT-1 activity. Blood. 2007;110:4064–4072. doi: 10.1182/blood-2007-06-093617. [DOI] [PubMed] [Google Scholar]
  33. Wang L, Giannoudis A, Lane S, Williamson P, Pirmohamed M, Clark RE. Expression of the uptake drug transporter hOCT1 is an important clinical determinant of the response to imatinib in chronic myeloid leukemia. Clin Pharmacol Ther. 2008;83:258–264. doi: 10.1038/sj.clpt.6100268. [DOI] [PubMed] [Google Scholar]
  34. Crossman LC, Druker BJ, Deininger MW, Pirmohamed M, Wang L, Clark RE. hOCT 1 and resistance to imatinib. Blood. 2005;106:1133–1134. doi: 10.1182/blood-2005-02-0694. author reply 1134. [DOI] [PubMed] [Google Scholar]
  35. Kerb R, Brinkmann U, Chatskaia N, Gorbunov D, Gorboulev V, Mornhinweg E, Keil A, Eichelbaum M, Koepsell H. Identification of genetic variations of the human organic cation transporter hOCT1 and their functional consequences. Pharmacogenetics. 2002;12:591–595. doi: 10.1097/00008571-200211000-00002. [DOI] [PubMed] [Google Scholar]
  36. Shu Y, Leabman MK, Feng B, Mangravite LM, Huang CC, Stryke D, Kawamoto M, Johns SJ, DeYoung J, Carlson E, Ferrin TE, Herskowitz I, Giacomini KM. Pharmacogenetics Of Membrane Transporters Investigators. Evolutionary conservation predicts function of variants of the human organic cation transporter, OCT1. Proc Natl Acad Sci USA. 2003;100:5902–5907. doi: 10.1073/pnas.0730858100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Bazeos A, Marin D, Reid AG, Gerrard G, Milojkovic D, May PC, de Lavallade H, Garland P, Rezvani K, Apperley JF, Goldman JM, Foroni L, Khorashad JS. hOCT1 transcript levels and single nucleotide polymorphisms as predictive factors for response to imatinib in chronic myeloid leukemia. Leukemia. 2010;24:1243–1245. doi: 10.1038/leu.2010.86. [DOI] [PubMed] [Google Scholar]
  38. White DL, Saunders VA, Dang P, Engler J, Hughes TP. OCT-1 activity measurement provides a superior imatinib response predictor than screening for single-nucleotide polymorphisms of OCT-1. Leukemia. 2010. [DOI] [PubMed]
  39. Hu S, Franke RM, Filipski KK, Hu C, Orwick SJ, de Bruijn EA, Burger H, Baker SD, Sparreboom A. Interaction of imatinib with human organic ion carriers. Clin Cancer Res. 2008;14:3141–3148. doi: 10.1158/1078-0432.CCR-07-4913. [DOI] [PubMed] [Google Scholar]
  40. Kuehl P, Zhang J, Lin Y, Lamba J, Assem M, Schuetz J, Watkins PB, Daly A, Wrighton SA, Hall SD, Maurel P, Relling M, Brimer C, Yasuda K, Venkataramanan R, Strom S, Thummel K, Boguski MS, Schuetz E. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet. 2001;27:383–391. doi: 10.1038/86882. [DOI] [PubMed] [Google Scholar]
  41. Sailaja K, Rao DN, Rao DR, Vishnupriya S. Analysis of CYP3A5*3 and CYP3A5*6 gene polymorphisms in Indian chronic myeloid leukemia patients. Asian Pac J Cancer Prev. 2010;11:781–784. [PubMed] [Google Scholar]
  42. Jorgensen HG, Elliott MA, Allan EK, Carr CE, Holyoake TL, Smith KD. Alpha1-acid glycoprotein expressed in the plasma of chronic myeloid leukemia patients does not mediate significant in vitro resistance to STI571. Blood. 2002;99:713–715. doi: 10.1182/blood.V99.2.713. [DOI] [PubMed] [Google Scholar]
  43. Delbaldo C, Chatelut E, Re M, Deroussent A, Seronie-Vivien S, Jambu A, Berthaud P, Le Cesne A, Blay JY, Vassal G. Pharmacokinetic-pharmacodynamic relationships of imatinib and its main metabolite in patients with advanced gastrointestinal stromal tumors. Clin Cancer Res. 2006;12:6073–6078. doi: 10.1158/1078-0432.CCR-05-2596. [DOI] [PubMed] [Google Scholar]
  44. Apperley JF. Part I: mechanisms of resistance to imatinib in chronic myeloid leukaemia. Lancet Oncol. 2007;8:1018–1029. doi: 10.1016/S1470-2045(07)70342-X. [DOI] [PubMed] [Google Scholar]
  45. Nicolini FE, Chabane K, Cayuela JM, Rousselot P, Thomas X, Hayette S. The role of the K247R substitution in the ABL tyrosine kinase domain in sensitivity to imatinib. Haematologica. 2006;91:137–138. [PubMed] [Google Scholar]
  46. Ernst T, Hoffmann J, Erben P, Hanfstein B, Leitner A, Hehlmann R, Hochhaus A, Muller MC. ABL single nucleotide polymorphisms may masquerade as BCR-ABL mutations associated with resistance to tyrosine kinase inhibitors in patients with chronic myeloid leukemia. Haematologica. 2008;93:1389–1393. doi: 10.3324/haematol.12964. [DOI] [PubMed] [Google Scholar]
  47. Corless CL, Fletcher JA, Heinrich MC. Biology of gastrointestinal stromal tumors. J Clin Oncol. 2004;22:3813–3825. doi: 10.1200/JCO.2004.05.140. [DOI] [PubMed] [Google Scholar]
  48. Gotlib J, Cools J. Five years since the discovery of FIP1L1-PDGFRA: what we have learned about the fusion and other molecularly defined eosinophilias. Leukemia. 2008;22:1999–2010. doi: 10.1038/leu.2008.287. [DOI] [PubMed] [Google Scholar]
  49. Bruck P, Wassmann B, Lopez ER, Hoelzer D, Ottmann OG. Development of hygromas or severe edema during treatment with the tyrosine kinase inhibitor STI571 is not associated with platelet-derived growth factor receptor (PDGFR) gene polymorphisms. Leuk Res. 2004;28:1153–1157. doi: 10.1016/j.leukres.2004.03.007. [DOI] [PubMed] [Google Scholar]
  50. Dressman MA, Malinowski R, McLean LA, Gathmann I, Capdeville R, Hensley M, Polymeropoulos MH. Correlation of major cytogenetic response with a pharmacogenetic marker in chronic myeloid leukemia patients treated with imatinib (STI571). Clin Cancer Res. 2004;10:2265–2271. doi: 10.1158/1078-0432.CCR-0785-3. [DOI] [PubMed] [Google Scholar]
  51. Kim DH, Kong JH, Byeun JY, Jung CW, Xu W, Liu X, Kamel-Reid S, Kim YK, Kim HJ, Lipton JH. The IFNG (IFN-{gamma}) genotype predicts cytogenetic and molecular response to imatinib therapy in chronic myeloid leukemia. Clin Cancer Res. 2010;16:5339–5350. doi: 10.1158/1078-0432.CCR-10-1638. [DOI] [PubMed] [Google Scholar]
  52. Zach O, Krieger O, Foedermayr M, Zellhofer B, Lutz D. OCT1 (SLC22A1) R61C polymorphism and response to imatinib treatment in chronic myeloid leukemia patients. Leuk Lymphoma. 2008;49:2222–2223. doi: 10.1080/10428190802322893. [DOI] [PubMed] [Google Scholar]
  53. Entrez SNP. http://www.ncbi.nlm.nih.gov/sites/entrez?db=snp

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