Influence of Single Nucleotide Polymorphisms in Anthracycline Metabolism Pathway in Standard Induction of Acute Myeloid Leukemia

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).

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.