Background:

The intake of anthracyclines in blast cells could be affected by several transporters, including influx transporters (SLC22A16 and SLCO1B1) and efflux pumps of ABC family. Previous studies suggested that single nucleotide polymorphisms (SNPs) of genes coding for anthracyclines transporters may influence their effectiveness or toxicity, although their impact in acute myeloid leukemia (AML) induction therapy remains undetermined

Methods:

SNPs of anthracycline transporter genes (ABCB1: rs1128503, rs1045642, rs2032582 and haplotype; ABCC1: rs4148350; ABCC2: rs8187710; ABCG2: rs2231142, rs2231137; SLCO1B1: rs4149056; SLC22A16: rs12210538, rs714368) were evaluated in 225 adult patients at initial diagnosis from AML using a Sequenom (iPLEX) mass spectrometry-based multiplex genotyping assay (Sequenom, San Diego, CA). All patients received induction chemotherapy consisting of idarubicin plus cytarabine (PETHEMA-LMA 99, 2007 and 2010 trials).

Efficacy of first induction cycle was evaluated comparing complete remission (CR) vs. partial remission or resistance. Patients dying during induction were considered as no evaluable for efficacy. Based on WHO grading scale, toxicities were grouped as binary variables (grade 0-1 vs. grade 2-4). The grade of toxicity assigned to an organ group was the maximum grade of all the specific toxicities within that group. Renal and hepatic toxicities were also evaluated with analytic markers (renal function with urea and creatinine; hepatic function with bilirubin, AST, ALT, FA and GGT). Hematologic toxicity was measured with the time to neutropenia and thrombocytopenia recovery since first day of chemotherapy. Genotypes were studied with co-dominant model. Association between variables was assessed using linear and logistic regression adjusting for age, gender, ECOG, leukocyte and platelet count at diagnosis (R® version 3.1.2).

Results:

The median age of patients was 51.1 years (16-78 years). There were no statistically significant differences in CR or hematologic toxicities. Nevertheless, several associations were obtained between transporter genes polymorphisms and toxicities (significant toxicities were summarized in table 1 and 2). Variant allele of ABCB1 SNPs was previously related with lower activity of ABCB1 pump in kidney cells and lower anthracycline clearance. Accordingly, we obtained nephrotoxicity associated with these SNPs. Association between cardiac toxicity and ABCG2 polymorphisms was found in agreement with previously published works. The ocular toxicity associated with SLCO1B1 was also correlated with low platelet count at diagnosis in multivariable analysis.

Table 1.

Significant association between SNPs in gene transporters and different toxicities

ToxicityGene/SNPGenotypesGrade 0-1 n (%)Grade 2-4 n (%)OR (95%IC)P
Cardiotoxicity ABCG2 rs2231142 CC
CA 		171 (83.0)
9 (47.4) 		35 (17.0)
10 (52.6) 		5.64
(1.86-17.80) 		0.002 
Lung toxicity ABCG2 rs2231142 CC
CA 		174 (84.5)
12 (63.2) 		32 (15.5)
7 (36.8) 		3.37
(1.09-10.40) 		0.031 
Skin toxicity SLCO1B1 rs4149056 TT
TC 		112 (71.8)
21 (48.8) 		44 (28.2)
22 (51.2) 		2.43
(1.17-5.06) 		0.015 
Nephrotoxicity ABCB1 haplotype Other genotypes
TT/TT/TT 		175 (89.3)
21 (72.4) 		21 (10.7)
8 (27.6) 		3.74
(1.24-10.85) 		0.002 
Ocular toxicity ABCC1 rs4148350 GG
GT/TT 		205 (99.0)
16 (88.9) 		2 (1.0)
2 (11.1) 		13.7
(2.08-90.47) 		<0.001 
Ocular toxicity SLCO1B1 rs4149056 TT
CC 		155 (99.4)
23 (92.0) 		1 (0.6)
2 (8.0) 		9.97
(1.39-71.39) 		0.019 
ToxicityGene/SNPGenotypesGrade 0-1 n (%)Grade 2-4 n (%)OR (95%IC)P
Cardiotoxicity ABCG2 rs2231142 CC
CA 		171 (83.0)
9 (47.4) 		35 (17.0)
10 (52.6) 		5.64
(1.86-17.80) 		0.002 
Lung toxicity ABCG2 rs2231142 CC
CA 		174 (84.5)
12 (63.2) 		32 (15.5)
7 (36.8) 		3.37
(1.09-10.40) 		0.031 
Skin toxicity SLCO1B1 rs4149056 TT
TC 		112 (71.8)
21 (48.8) 		44 (28.2)
22 (51.2) 		2.43
(1.17-5.06) 		0.015 
Nephrotoxicity ABCB1 haplotype Other genotypes
TT/TT/TT 		175 (89.3)
21 (72.4) 		21 (10.7)
8 (27.6) 		3.74
(1.24-10.85) 		0.002 
Ocular toxicity ABCC1 rs4148350 GG
GT/TT 		205 (99.0)
16 (88.9) 		2 (1.0)
2 (11.1) 		13.7
(2.08-90.47) 		<0.001 
Ocular toxicity SLCO1B1 rs4149056 TT
CC 		155 (99.4)
23 (92.0) 		1 (0.6)
2 (8.0) 		9.97
(1.39-71.39) 		0.019 
View Large

Table 2.

Significant association between SNPs in gene transporters and analytic markers of renal and hepatic function

Hematologic toxicityGene/SNPGenotypesMean values (mg or U/dL)Logarithm of the difference (95%IC)P
Urea ABCB1 rs1045642 CC
TT 		57.98
70.89 		0.20
(0.01 to 0.40) 		0.044 
Urea ABCB1 rs2032582 GG
TT 		56.34
72.07 		0.23
(0.03 to 0.42) 		0.021 
Urea ABCB1 haplotype Other genotypes
TT/TT/TT 		59.29
78.14 		0.24
(0.04 to 0.43) 		0.019 
Bilirubin ABCB1 rs1045642 CC
CT
TT 		1.77
2.59
2.91 		0.021
(0.01 to 0.40)
0.39
(0.12 to 0.65) 		0.036
0.004 
ALT SLCO1B1 rs4149056 TT
TC 		90.92
161.02 		0.30
(0.01 to 0.60) 		0.049 
Hematologic toxicityGene/SNPGenotypesMean values (mg or U/dL)Logarithm of the difference (95%IC)P
Urea ABCB1 rs1045642 CC
TT 		57.98
70.89 		0.20
(0.01 to 0.40) 		0.044 
Urea ABCB1 rs2032582 GG
TT 		56.34
72.07 		0.23
(0.03 to 0.42) 		0.021 
Urea ABCB1 haplotype Other genotypes
TT/TT/TT 		59.29
78.14 		0.24
(0.04 to 0.43) 		0.019 
Bilirubin ABCB1 rs1045642 CC
CT
TT 		1.77
2.59
2.91 		0.021
(0.01 to 0.40)
0.39
(0.12 to 0.65) 		0.036
0.004 
ALT SLCO1B1 rs4149056 TT
TC 		90.92
161.02 		0.30
(0.01 to 0.60) 		0.049 
View Large

Conclusions:

This study shows a prognostic impact of transporter genes polymorphisms in adult AML patients regarding induction chemotherapy efficacy and toxicity. Further studies with larger population are needed to validate these associations, which could be useful biomarkers in clinical practice.

Disclosures

No relevant conflicts of interest to declare.

Topics:
genes, leukemia, myelocytic, acute, membrane transport proteins, polymorphism, toxic effect, p-glycoprotein, chief complaint, anthracycline antibiotics, urea, hematotoxicity

Author notes

*

Asterisk with author names denotes non-ASH members.

© 2015 by The American Society of Hematology
2015
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