Impact of Transporter Genes Polymorphisms in Standard Induction of Acute Myeloid Leukemia
Authors: Megías Juan Eduardo , Montesinos Pau , Herrero María José , Moscardó Federico , Bosó Virginia , Martínez-Cuadrón David , Rojas Luis , Rodríguez-Veiga Rebeca , Boluda Blanca , Martínez Jesús , Sanz Jaime , López Francisca , Cano Isabel , Lancharro Aima , Cervera Jose , Hervás David , Poveda José Luis , Aliño Salvador F , Sanz Miguel Ángel 
Published: October 2019

Abstract
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 Toxicity Gene/SNP Genotypes Grade 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
Table 2. Significant association between SNPs in gene transporters and analytic markers of renal and hepatic function Hematologic toxicity Gene/SNP Genotypes Mean 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
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.