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Table 1 Summary of studies of the efficacy of IM treatment in relation to pharmacokinetic genetic variants*

From: The pharmacogenetics of imatinib

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 MMR at 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]
  1. *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.