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Profiling of drug-metabolizing enzymes/transporters in CD33+ acute myeloid leukemia patients treated with Gemtuzumab-Ozogamicin and Fludarabine, Cytarabine and Idarubicin

The Pharmacogenomics Journal volume 13, pages 335–341 (2013)Cite this article

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Abstract

Genetic heterogeneity in drug-metabolizing enzyme/transporter (DMET) genes affects specific drug-related cancer phenotypes. To investigate the relationships between genetic variation and response to treatment in acute myeloid leukemia (AML), we genotyped 1931 variants on DMET genes in 94 CD33-positive AML patients enrolled in a phase III multicenter clinical trial combining Gemtuzumab-Ozogamicin (GO) with Fludarabine–Cytarabine–Idarubicin (FLAI) regimen, with the DMET Plus platform. Two ADH1A variants showed statistically significant differences (odds ratio (OR)=5.68, P=0.0006; OR=5.35, P=0.0009) in allele frequencies between patients in complete/partial remission and patients without response, two substitutions on CYP2E1 (OR=0.13, P=0.001; OR=0.09, P=0.003) and one on SLCO1B1 (OR=4.68, P=0.002) were found to differently influence liver toxicity, and two nucleotide changes on SULTB1 and SLC22A12 genes correlated with response to GO (OR=0.24, P=0.0009; OR=2.75, P=0.0029). Genetic variants were thus found for the first time to be potentially associated with differential response and toxicity in AML patients treated with a combination of GO–FLAI regimen.

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Acknowledgements

This work was supported by the European LeukemiaNet, AIL, AIRC, Fondazione Del Monte di Bologna e Ravenna, FIRB 2006, PRIN 2008, Ateneo RFO grants, Project of Integrated Program (PIO) and Programma di Ricerca Regione – Università 2007–2009.

Author contributions: GM and II: project conception; II, MS, AL: manuscript writing; II, AL, SF, EA and AA: DMET array analysis; MS: statistical analyses; II, MS and GM: data interpretation; AL and AF: Sanger sequencing validation analysis; AC, CP, AM, ET, MCA, MM, FC, DR, DD, FG, MG and FP: clinical data and biological sample collection; GI MAR and MB: final approve.

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Authors and Affiliations

  1. Department of Hematology and Oncological Sciences ‘L. and A. Seràgnoli’ S.Orsola Malpighi Hospital, University of Bologna, Bologna, Italy

    I Iacobucci, A Lonetti, C Papayannidis, E Ottaviani, A Ferrari, M C Abbenante, S Parisi, F Cattina, M Baccarani & G Martinelli

  2. Department of Human Anatomy, University of Bologna, Cellular Signalling Laboratory, Bologna, Italy

    A Lonetti

  3. Division of Hematology and BMT, University of Udine, Udine, Italy

    A Candoni, A Michelutti, E Simeone, D Damiani & R Fanin

  4. Department of Experimental Evolutionary Biology, Laboratory of Molecular Anthropology, University of Bologna, Bologna, Italy

    M Sazzini

  5. Department of Pediatrics, Pediatric Oncology and Hematology ‘Lalla Seràgnoli’ Unit, University of Bologna, Bologna, Italy

    S Formica

  6. G.Prodi’ Cancer Research Center, University of Bologna, Bologna, Italy

    S Formica & A Astolfi

  7. Hematology and BMT Unit, University of Brescia, Brescia, Italy

    F Cattina, M Malagola & D Russo

  8. Unità Operativa Ematologia, Ospedale Ca’ Foncello, Treviso, Italy

    F Gherlinzoni & M Gottardi

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  1. I Iacobucci
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Correspondence to G Martinelli.

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Iacobucci, I., Lonetti, A., Candoni, A. et al. Profiling of drug-metabolizing enzymes/transporters in CD33+ acute myeloid leukemia patients treated with Gemtuzumab-Ozogamicin and Fludarabine, Cytarabine and Idarubicin. Pharmacogenomics J 13, 335–341 (2013). https://doi.org/10.1038/tpj.2012.13

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