The pharmacogenetics of imatinib

Dulucq, Stéphanie; Krajinovic, Maja

doi:10.1186/gm206

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]

*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.

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ISSN: 1756-994X

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