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Association of the hOCT1/ABCB1 genotype with efficacy and tolerability of imatinib in patients affected by chronic myeloid leukemia

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Abstract

Purpose

The present study was aimed at investigating whether imatinib pharmacogenetics is related to its pharmacodynamics in patients affected by chronic myeloid leukemia.

Methods

Through a procedure based on a sequence of classical statistics methods, we investigated the possible relationships between treatment efficacy/tolerability and combinations of time-independent variables as gender and genetic covariates in the form of single nucleotide polymorphisms (SNPs) or combinations thereof. Moreover, since the drug tolerability has a strong incidence on the discontinuation of the therapy, we investigated whether the time of manifestation of the most frequent toxic effects can be related to time-independent patients’ characteristics or not.

Results

We found that a combination of two polymorphisms, namely hOCT1 c.480C>G (rs683369) and ABCB1 c.3435C>T (rs1045642), seems to play the role of predictor for imatinib in both efficacy and toxicity. Furthermore, the time of manifestation of edema toxicity is found to be associated to a combination of gender and ABCB1 c.3435C>T, whereas the time of manifestation of cramp toxicity appears related to gender.

Conclusions

The novelty of this study is dual: the achievement of results that potentially have a significant clinical interest and the demonstration that the adoption of composed covariates may represent a unique tool to study different aspects of the treatment with imatinib.

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Acknowledgements

We would like to thank all patients who accepted to participate in the TIKlet study. Funds from the Regione Toscana to G.C. and from University of Pisa (PRA grant) to A.D.P. are gratefully acknowledged.

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Authors and Affiliations

  1. Phymtech Srl, Via Giuntini 63, Navacchio, 56023, Pisa, Italy

    Laura Galeotti, Francesco Ceccherini, Dario Domingo, Marco Laurino & Fulvio Cornolti

  2. Section of Hematology, Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 55, 56126, Pisa, Italy

    Marialuisa Polillo, Antonello Di Paolo, Elena Arrigoni, Romano Danesi & Mario Petrini

  3. Section of Pharmacology, Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 55, 56126, Pisa, Italy

    Claudia Baratè, Giulia Cervetti, Francesca Guerrini, Giulia Fontanelli, Elena Ciabatti, Susanna Grassi & Sara Galimberti

  4. Department of Biological and Clinical Sciences, University of Torino, San Luigi Gonzaga Hospital, Regione Gonzole 10, 143 Orbassano, Turin, Italy

    Carmen Fava & Giuseppe Saglio

  5. Laboratory of Clinical Pharmacology and Pharmacogenetics, Department of Medical Sciences, Unit of Infectious Diseases, University of Torino, Amedeo di Savoia Hospital, Turin, Italy

    Antonio D’Avolio

  6. Department of Physics, University of Pisa, Largo Pontecorvo 3, 56127, Pisa, Italy

    Fulvio Cornolti

Authors
  1. Laura Galeotti
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  2. Francesco Ceccherini
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  3. Dario Domingo
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  4. Marco Laurino
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  5. Marialuisa Polillo
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  6. Antonello Di Paolo
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  7. Claudia Baratè
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  8. Carmen Fava
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  9. Antonio D’Avolio
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  10. Giulia Cervetti
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  11. Francesca Guerrini
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  12. Giulia Fontanelli
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  13. Elena Ciabatti
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  14. Susanna Grassi
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  15. Elena Arrigoni
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  16. Romano Danesi
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  17. Mario Petrini
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  18. Fulvio Cornolti
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  19. Giuseppe Saglio
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  20. Sara Galimberti
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Corresponding author

Correspondence to Antonello Di Paolo.

Ethics declarations

Conflict of interest

ADP and SG served as board members for Novartis Pharma SpA. The other Authors declare that they have no conflict of interest. Furthermore, the present study was performed according to the TIKlet protocol that was approved by the Ethics Committees and every patient gave his/her informed consent to the trial participation.

Additional information

L. Galeotti and F. Ceccherini have equally contributed to the study.

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Galeotti, L., Ceccherini, F., Domingo, D. et al. Association of the hOCT1/ABCB1 genotype with efficacy and tolerability of imatinib in patients affected by chronic myeloid leukemia. Cancer Chemother Pharmacol 79, 767–773 (2017). https://doi.org/10.1007/s00280-017-3271-3

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  • DOI: https://doi.org/10.1007/s00280-017-3271-3

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