P443: IMPACT OF PHARMACOGENETIC VARIANTS ON CYTARABINE AND ANTHRACYCLINE EFFECT ON OUTCOMES IN ADULT AML PATIENTS

Abstract

Background: Acute myeloid leukaemia (AML) is primarily treated with combination of cytarabine and anthracyclines. Despite high remission rates, the 5-year overall survival (OS) is <50% and <20% for<60-year-old a ≥60-year-old patients, respectively. This grim clinical outcome could be partly explained by the patients’ genetic variability of proteins involved in metabolic paths of cytarabine and anthracyclines. Pharmacogenetic variants of the main cytarabine membrane transporter SLC29A1 (solute carrier family 29 member 1), DCK (Deoxycytidine kinase) the first enzyme in cytarabine stepwise activation process, genes coding main anthracycline efflux pump ABCB1 (ATP binding cassette) and genes coding glutathione S-transferases GSTM1 and GSTT1, main cytosolic detoxifiers od anthracycline-induced oxidative stress, are shown to influence clinical outcome in AML patients. Aims: to evaluate: 1) the effects of variants in pharmacogenes SLC29A1, DCK, ABCB1, GSTM1 and GSTT1, on complete remission (CR) and relapse rate (RR), disease free survival (DFS) and overall survival (OS), 2) the influence of demographic, laboratory and AML-related parameters on CR, RR, DFS and OS. Methods: 100 newly-diagnosed consenting adults (18-62 years old) diagnosed with AML, except acute promyelocytic leukaemia in Clinic of Haematology UCCS from January 2015 to January 2018, were included in retrospective cohort. Patients received one or two inductions ‘’3 + 7’’ cycles. In patients achieving CR either three consolidation cycles with high/intermediate doses of cytarabine or allogenic SCT in selected patients were performed. Demographic, standard laboratory and AML-related parameters (blood/bone marrow blast percentage, cytologic, flow cytometry and genetic markers enabling ELN risk stratification were collected from patients’ health records. Variants SLC29A1 rs9394992, DCK rs12648166, ABCB1 rs2032582 and GSTM1 and GSTT1 gene deletions were detected by methodology based on PCR, fragment analysis and direct sequencing. The study was approved by the Ethics Committee of the UCCS. The methods of descriptive and analytic statistics were used, while survival analysis was done by the Kaplan-Meier method using the Log-Rank test. Results: 100 patients (53 males) were included in the study, with the median age of 51 (range 18-62). Median laboratory parameters were: WBC 15.5x109/L (range 1-348.8), Hgb 97g/L (range 20-166), Plt 53.5 (range 1-422), LDH 249U/L (1-4169). CD34 was positive in 56% patients. According to ELN 15, 55 and 30 patients were classified in favorable, intermediate and adverse risk group, respectively. CR was achieved in 57 patients (41 after the first and 16 after the second induction cycle). A total of 34% of patients relapsed. Median DFS was 5.3 months (range 0.25-61.5), while median OS was 6 months (range 0.3-75). There was a significant difference in median DFS between CC, CT and TT genotype of SLC29A1: 13, 8 and 1.75 months, respectively (p=0.00037). Median DFS was significantly decreased in null genotype of GSTM1 (9.5 (null) vs 18 months (non-null); p=0.028). Significant difference in OS within ABCB1 genotypes TT, GG, GT and AG+AT was registered: 13, 7, 6.5 and 3 months, respectively (p=0.0036). Other parameters did not differ significantly. Summary/Conclusion: Our results, regarding impact of variants of SLC29A1, GSTM1 on DFS and impact of variant ABCB1 on OS in AML patients, are in line with previous studies. Although further studies, with larger cohorts, are needed, these pharmacogenetic variants show a potential to become prognostic markers in AML.