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Impact of NADPH oxidase functional polymorphisms in acute myeloid leukemia induction chemotherapy

The Pharmacogenomics Journal volume 18, pages 301–307 (2018)Cite this article

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Abstract

Efficacy and toxicity of anthracycline treatment in acute myeloid leukemia (AML) is mediated by reactive oxygen species (ROS). NADPH oxidase is the major endogenous source of ROS and a key mediator of oxidative cardiac damage. The impact of NADPH oxidase polymorphisms (CYBA:rs4673, NCF4:rs1883112, RAC2:rs13058338) was evaluated in 225 adult de novo AML patients. Variant alleles of NCF4 and RAC2 were related to higher complete remission (P=0.035, P=0.016), and CYBA homozygous variant showed lower overall survival with recessive model (P=0.045). Anthracycline-induced cardiotoxicity was associated to NCF4 homozygous variant (P=0.012) and CYBA heterozygous genotype (P=0.027). Novel associations were found between variant allele of CYBA and lower lung and gastrointestinal toxicities, and a protective effect in nephrotoxicity and RAC2 homozygous variant. Moreover, RAC2 homozygous variant was related to delayed thrombocytopenia recovery. This study supports the interest of NADPH oxidase polymorphisms regarding efficacy and toxicity of AML induction therapy, in a coherent integrated manner.

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Acknowledgements

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). We are grateful to Dr E Busó from SCSIE (Universidad de Valencia) for his work and help with MassArray Sequenom genotyping.

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Authors and Affiliations

  1. Unidad de Farmacogenética, Instituto Investigación Sanitaria La Fe and Área del Medicamento, Hospital Universitario y Politécnico La Fe, Valencia, Spain

    J E Megías-Vericat, M J Herrero, V Bosó, L Rojas, L Sendra & S F Aliño

  2. Servicio de Farmacia, Área del Medicamento, Hospital Universitario y Politécnico La Fe, Valencia, Spain

    J E Megías-Vericat, V Bosó & J L Poveda

  3. Servicio de Hematología y Hemoterapia, Hospital Universitario y Politécnico La Fe, Valencia, Spain

    P Montesinos, F Moscardó, D Martínez-Cuadrón, R Rodríguez-Veiga, J Cervera & M Á Sanz

  4. Departamento Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain

    M J Herrero, L Sendra & S F Aliño

  5. Department of Internal Medicine, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile

    L Rojas

  6. Unidad de Farmacología Clínica, Área del Medicamento, Hospital Universitario y Politécnico La Fe, Valencia, Spain

    S F Aliño

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  1. J E Megías-Vericat
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  2. P Montesinos
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  7. D Martínez-Cuadrón
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  10. J Cervera
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  11. J L Poveda
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Correspondence to J E Megías-Vericat or M J Herrero.

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Megías-Vericat, J., Montesinos, P., Herrero, M. et al. Impact of NADPH oxidase functional polymorphisms in acute myeloid leukemia induction chemotherapy. Pharmacogenomics J 18, 301–307 (2018). https://doi.org/10.1038/tpj.2017.19

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