Influence of cytarabine metabolic pathway polymorphisms in acute myeloid leukemia induction treatment

Abstract

Cytarabine is considered the most effective chemotherapeutic option in acute myeloid leukemia (AML). The impact of 10 polymorphisms in cytarabine metabolic pathway genes were evaluated in 225 adult de novo AML patients. Variant alleles of DCK rs2306744 and CDA rs602950 showed higher complete remission (p = .024, p = .045), with lower survival rates for variant alleles of CDA rs2072671 (p = .015, p = .045, p = .032), rs3215400 (p = .033) and wild-type genotype of rs602950 (p = .039, .014). Induction death (p = .033) and lower survival rates (p = .021, p = .047) were correlated to RRM1 rs9937 variant allele. In addition, variant alleles of CDA rs532545 and rs602950 were related to skin toxicity (p = .031, p = .049) and mucositis to DCK rs2306744 minor allele (p = .046). Other toxicities associated to variant alleles were hepatotoxicity to NT5C2 rs11598702 (p = .032), lung toxicity (p = .031) and thrombocytopenia to DCK rs4694362 (p = .046). This study supports the interest of cytarabine pathway polymorphisms regarding efficacy and toxicity of AML therapy in a coherent integrated manner.

Keywords:

• Cytarabine
• polymorphism
• CDA
• DCK
• acute myeloid leukemia
• efficacy

Acknowledgements

We are grateful to Dr. E. Busó from SCSIE (Universidad de Valencia) for his work and help with Mass Array Sequenom® genotyping, and Dr. D. Hervás from Unidad de Bioestadística (Instituto Investigación Sanitaria La Fe) for Biostatistical facilities.

Potential conflict of interest

Disclosure forms provided by the authors are available with the full text of this article online at https://doi.org/10.1080/10428194.2017.1323267.

Additional information

Funding

This study was supported by grants from the “Instituto Carlos III” (PIE13/00046) and the “Instituto Investigación Sanitaria La Fe” (2013/0331) assigned to the Pharmacy and Hematology Departments and the Pharmacogenetics Unit of the “Instituto Investigación Sanitaria La Fe” and the “Área del Medicamento” of the “Hospital Universitari i Politècnic La Fe”, Valencia, Spain. Besides, in part this work was supported by the Cooperative Research Thematic Network (RTICC), Grant RD12/0036/014 (ISCIII & ERDF). The study was performed on behalf of the PETHEMA cooperative group and IIS La Fe. Samples have been managed by the La Fe Biobank, licensed as required by Spanish Royal Decree 1716/2011 of 18 November (Ref.: PT13/0010/0026).