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Pharmacokinetics and pharmacodynamics
PKP-003 Influence of cytarabine metabolic pathway polymorphisms in effectiveness of acute myeloid leukaemia induction treatment
  1. JE Megías-Vericat1,
  2. P Montesinos2,
  3. MJ Herrero3,
  4. V Bosó1,
  5. F Moscardó2,
  6. L Rojas4,
  7. D Martínez-Cuadrón2,
  8. SF Aliño5,
  9. MA Sanz2,
  10. JL Poveda6
  1. 1Hospital Universitario y Politécnico La Fe, Servicio de Farmacia-Área del Medicamento, Unidad de Farmacogenética-Instituto Investigación Sanitaria La Fe, Valencia, Spain
  2. 2Hospital Universitario y Politécnico La Fe, Servicio de Hematología y Hemoterapia, Valencia, Spain
  3. 3Hospital Universitario y Politécnico La Fe and Facultad de Medicina-Universidad de Valencia, Unidad de Farmacogenética-Instituto Investigación Sanitaria La Fe and Área del Medicamento and Departamento Farmacología, Valencia, Spain
  4. 4Hospital Universitario y Politécnico La Fe and Pontificia Universidad Católica de Chile, Unidad de Farmacogenética-Instituto Investigación Sanitaria La Fe and Área del Medicamento and Department of Internal Medicine, Faculty of Medicine, Valencia, Spain
  5. 5Hospital Universitario y Politécnico La Fe and Universidad de Valencia, Unidad de Farmacogenética and Unidad de Farmacología Clínica-Área del Medicamento-Instituto Investigación Sanitaria La Fe and Área del Medicamento and Departamento Farmacología, Valencia, Spain
  6. 6Hospital Universitario y Politécnico La Fe, Servicio de Farmacia- Área del Medicamento, Valencia, Spain

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.

No conflict of interest

http://dx.doi.org/10.1136/ejhpharm-2017-000640.431

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