Influence of Single Nucleotide Polymorphisms in Anthracycline Metabolism Pathway 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:
Single nucleotide polymorphisms (SNPs) within the genes involving drug detoxification enzymes of anthracyclines could lead to interindividual differences in treatment outcome. Several studies suggested, in different kinds of cancer, that SNPs of genes coding anthracyclines metabolism may influence their effectiveness or toxicity, being well-known their association with cardiotoxicity. The impact of these polymorphisms in adult acute myeloid leukemia (AML) patients treated with the combination of cytarabine and anthracyclines for induction remains undetermined.
Methods:
SNPs of anthracycline metabolism genes previously associated with clinical significance in other malignances (CBR3:rs1056892, rs8133052, NQO1 rs1800566, NQO2 rs1143684, NOS3:rs1799983, rs2070744, MnSOD rs4880) 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. 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. Nevertheless, several associations were obtained between NQO1, NQO2, NOS3 and MnSOD polymorphisms and toxicities (significant toxicities were summarized in table 1 and 2).
Table 1. Significant association between SNPs in gene metabolizers and different toxicities Toxicity Gene/SNP Genotypes Grade 0-1 n (%) Grade 2-4 n (%) OR (95%IC) P Cardiotoxicity NQO2 rs1143684 TT TC 119 (86.2) 74 (94.9) 19 (13.8) 4 (5.1) 0.26 (0.07-0.77) 0.025 Neurotoxicity NOS3 rs1799983 GG GT 71 (84.5) 101 (94.4) 13 (15.5) 6 (5.6) 0.28 (0.09-0.80) 0.022 Skin toxicity NOS3 rs1799983 GG GT TT 45 (53.6) 78 (72.9) 26 (76.5) 39 (46.4) 29 (27.1) 8 (23.5) 0.44 (0.24-0.82) 0.36 (0.14-0.88) 0.010 0.030 Skin toxicity NQO1 rs1800566 CC CT 78 (60.9) 64 (74.4) 50 (39.1) 29 (25.6) 0.53 (0.28-0.97) 0.042 Skin toxicity NQO2 rs1143684 TT CC 5.49 (1.19-38.9) 0.044 Gastrointestinal toxicity NQO2 rs1143684 TT CC 91 (65.9) 2 (25.0) 47 (34.1) 6 (75.0) 5.5 (1.19-38.99) 0.043 Mucositis NQO1 rs1800566 CC TT 119 (93.0) 8 (72.7) 9 (7.0) 3 (27.3) 6.1 (1.03-33.1) 0.035 Mucositis NQO2 rs1143684 TT CC 128 (92.8) 5 (62.5) 10 (7.2) 3 (37.5) 8.8 (1.53-45.60) 0.010 Nephrotoxicity MnSOD rs4880 TT CC 47 (81.0) 55 (94.8) 11 (19.0) 3 (5.2) 0.23 (0.05-0.86) 0.042 Nephrotoxicity NQO1 rs1800566 CC TT 114 (89.1) 8 (72.7) 14 (10.9) 3 (27.3) 6.66 (1.07-38.35) 0.033 Hepatotoxicity grades 3-4 NOS3 rs2070744 CC CT 19 (24.8) 100 (67.1) 20 (51.3) 49 (32.9) 0.44 (0.20-0.94) 0.035
Table 2. Significant association between SNPs in gene metabolizers and hematologic toxicities Hematologic toxicity Gene/SNP Genotypes Mean days Logarithm of the difference (95%IC) P Time to neutropenia recovery NOS3 rs2070744 CC TT 32.7 26.7 -0.17 (-0.35 to -0.01) 0.048 Time to thrombocytopenia recovery NOS3 rs1799983 GG GT TT 35.6 28.8 30.3 -0.17 (-0.17 to -0.06) -0.15 (-0.28 to -0.01) 0.002 0.034
Conclusions:
This study reveals that, as in other cancers, there is a prognostic impact of anthracycline metabolism gene polymorphisms in adult AML patients. 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.