PKP-003 Influence of cytarabine metabolic pathway polymorphisms in effectiveness of acute myeloid leukaemia induction treatment

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Abstract

Background

Cytarabine is considered the most effective chemotherapeutic agent in the treatment of acute myeloid leukaemia (AML).

Purpose

Several studies suggest that single nucleotide polymorphisms (SNPs) in genes involving the metabolic pathway of cytarabine could influence treatment outcomes, although their clinical relevance remains undetermined.

Material and methods

The SNPs of cytarabine pathway (DCK:rs2306744, rs11544786, rs4694362; CDA:rs2072671, rs3215400, rs532545, rs602950; NT5C2:rs11598702; RRM1:rs9937; NME1:rs2302254) were evaluated in 225 adult patients at initial diagnosis of AML using a mass spectrometry based multiplex genotyping assay (Sequenom). All patients received induction chemotherapy consisting of idarubicin plus cytarabine (PETHEMA 99, 2007 and 2010 trials). The efficacy of the first induction cycle was evaluated comparing complete remission (CR) versus partial remission (PR) or resistance (patients dying during induction excluded), and overall survival (OS), event free survival (EFS), disease free survival (DFS) and relapse free survival (RFS) at 5 years. Genotypes were studied with the co-dominant model. Association between variables was assessed using logistic regression adjusting for age, gender, cytogenetic risk, ECOG, leukocyte and platelet count, haemoglobin, creatinine, bilirubin, albumin and LDH level at diagnosis (R V.3.1.2). The Kaplan–Meier method and Cox proportional were used for survival estimates.

Results

Median age of patients was 51.1 years (16–78). The variant allele of DCK SNP rs2306744, the enzyme that catalyses the limiting first phosphorylation in the activation of cytarabine, showed higher CR (OR 6.2; 95% CI 1.3–30.2; p=0.024). CDA is the main inactivating enzyme of cytarabine. The variant allele of rs602950 was related to higher CR (OR 3.0; 95% CI 1.02–8.8; p=0.045), OS (HR 1.7; 95% CI 1.03–2.6; p=0.039) and EFS (HR 0.4; 95% CI 0.2–0.7; p=0.014). However, the heterozygous genotype of CDA rs2072671 was associated with lower OS (HR 2.2; 95% CI 1.2–4.1; p=0.015), EFS (HR 1.9; 95% CI 1.01–3.4; p=0.045), DFS (HR 3.8; 95% CI 1.2–12.4; p=0.027) and RFS (HR 9.1; 95% CI 1.2–68.6; p=0.032), and heterozygous genotype of CDA rs3215400 with lower DFS (HR 2.9; 95% CI 1.4–6.3; p=0.006) and RFS (HR 3.3; 95% CI 1.1–9.9; p=0.033). The variant allele of RRM1 (rs9937), the enzyme directly associated with cytarabine sensitivity, was associated with lower OS (HR 2.0; 95% CI 1.1–3.5; p=0.021) and RFS (HR 3.8; 95% CI 1.02–14.3; p=0.047).

Conclusion

This study revealed the influence on cytarabine efficacy of DCK, CDA and RRM1 polymorphisms in AML adult patients, previously suggested in other studies. Further studies with a larger population are needed to validate these associations.

References and/or acknowledgements

Megías-Vericat JE, et al. Pharmacogenomics2016doi: 10.2217/pgs-2016-0055.

References and/or acknowledgements

No conflict of interest

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