Prognostic Impact of Anthracycline Metabolism Gene Polymorphisms in Newly Diagnosed Acute Myeloid Leukemia Adults

Background:

The genetic variability related with single nucleotide polymorphisms (SNPs) within the genes involving drug transport or metabolism, DNA repair and oxidative stress, could lead to interindividual differences in treatment outcome. Several studies suggested, in different kinds of cancer, that SNPs of genes coding for drug detoxification enzymes of anthracyclines may influence their effectiveness or toxicity. However the association of these polymorphisms in adult acute myeloid leukemia (AML) patients treated with the combination of cytarabine and anthracyclines for induction remains undetermined.

Methods:

The 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 109 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).

Genotypes were grouped as dichotomous variables (dominant and recessive model). 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. Overall toxicity was grouped with grade 3-4 assessment. Hematologic toxicity was measured with the time to neutropenia and thrombocytopenia recovery since first day of chemotherapy. Categorical and continuous variables were assessed using χ2 test with Yates correction if needed and Mann–Whitney U test, respectively.

Results:

The median age of patients was 53 years (17-78 years). There was no statistically significant difference in baseline characteristics (age, gender, leukocyte count, hemoglobin level, platelet count and percentage of peripheral or BM blasts) between the patients with the genotype distributions. There were lower CR rates among patients harboring CBR3 SNPs homozygous variant (rs1056892, AA: 37.5% vs. GA/AA: 76.5%, P=0.050; rs8133052, GG: 52.6% vs. GA/AA: 78.4%, P=0.049), both genotypes previously associated with higher enzymatic activity of CBR3 and higher anthracycline clearance. The variant allele (TC/CC) of NQO2 polymorphism was also associated with lower CR rates compared to TT genotype (45.2% vs. 69.2%, P=0.034). Skin toxicity was higher in wild genotypes of NQO1 (36.5% vs. 15.2%, P=0.025) and NOS3 rs1799983 (45.7% vs. 18.9%, P=0.007). Gastrointestinal toxicity was related with variant allele of NQO1 (69.2% vs. 45.2%, P=0.034). Regarding hematologic toxicity, time to thrombocytopenia recovery was delayed with variant alleles of NQO1 (29.1 vs. 43.2 days, P=0.004) and MnSOD (31.5 vs. 42.3 days, P=0.043).

Conclusions:

This study shows that, as in other cancers, there is a prognostic impact of anthracycline metabolism gene polymorphisms in adult AML patients. We obtained new associations of these anthracyclines metabolism pathways SNPs in relation to effectiveness and toxicity, which could be useful biomarkers in clinical practice.