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Metabolic shift of chronic myeloid leukemia patients under imatinib–pioglitazone regimen and discontinuation

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Abstract

The Estudo de Descontinuação de Imatinibe após Pioglitazona (EDI-PIO) is a single-center, longitudinal, prospective, phase 2, non-randomized, open, clinical trial (NCT02852486, August 2, 2016 retrospectively registered) for the discontinuation of imatinib after concomitant use of pioglitazone, being the first of its kind in a Brazilian population with chronic myeloid leukemia. Due to remaining of leukemic quiescent cells that are not affected by tyrosine kinase inhibitors, it has been suggested the use of pioglitazone, a PPARγ agonist, together with imatinib as a strategy for the maintenance of deep molecular response. The clinical benefit to this association is still controversial, and the metabolic alteration along this process remains unclear. Therefore, we applied a metabolomic protocol using high-resolution mass spectrometry to profile plasmatic metabolic response of a prospective cohort of ten individuals under discontinuation of imatinib and pioglitazone protocol. By comparing patients under pioglitazone and imatinib treatment with imatinib monotherapy and discontinuation phase, we were able to annotate 41 and 36 metabolites, respectively. The metabolic alterations observed during imatinib–pioglitazone combined therapy are associated with an extensive lipid remodeling, with activation of β-oxidation pathway, in addition to the presence of markers that suggest mitochondrial dysfunction.

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Data availability

Patients’ data are part of EDI-PIO clinical trial and will be available from KBBP (kborgia@unicamp.br) upon reasonable request. Mass spectrometry data is publicly available at Zenodo: https://zenodo.org/record/5116349.

Code availability

Use of MetaboAnalyst 4.0 online software (https://www.metaboanalyst.ca/) [26].

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Acknowledgements

We would like to thank the colleagues of the Oncohematology laboratory at the Hematology and Hemotherapy Center for their support, and the colleagues of Innovare biomarkers laboratory, who supported and encouraged this project. Hematology and Hemotherapy Center, University of Campinas would like to thank Coordination for the Improvement of Higher Education Personnel (CAPES) [Grant 88882.434900/2019‐01 for ABP]. Innovare Biomarkers Laboratory thank São Paulo Research Foundation (FAPESP) [Grant 2019/05718-3 for J.D], Coordination for the Improvement of Higher Education Personnel (CAPES) [Grant 88887.513974/2020-00 for A.N.O], and National Council for Scientific and Technological Development (CNPq) [Grant 141200/2018-9 for FD-A].

Funding

Hematology and Hemotherapy Center, University of Campinas would like to thank Coordination for the Improvement of Higher Education Personnel (CAPES) [Grant 88882.434900/2019‐01 for ABP]. Innovare Biomarkers Laboratory thank São Paulo Research Foundation (FAPESP) [Grant 2019/05718-3 for J.D], Coordination for the Improvement of Higher Education Personnel (CAPES) [Grant 88887.513974/2020-00 for A.N.O] and National Council for Scientific and Technological Development (CNPq) [Grant 141200/2018-9 for FD-A].

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Authors and Affiliations

  1. Hematology and Hemotherapy Center, University of Campinas, Campinas, Brazil

    Valquíria Mariane Oliveira Póvoa, Ana Beatriz Pascoal Lopes, Erich Vinícius de Paula & Katia Borgia Barbosa Pagnano

  2. INNOVARE Biomarkers Laboratory, School of Pharmaceutical Sciences, University of Campinas, Campinas, Brazil

    Valquíria Mariane Oliveira Póvoa, Jeany Delafiori, Flávia Luísa Dias-Audibert, Arthur Noin de Oliveira & Rodrigo Ramos Catharino

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  1. Valquíria Mariane Oliveira Póvoa
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  2. Jeany Delafiori
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  3. Flávia Luísa Dias-Audibert
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  4. Arthur Noin de Oliveira
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  5. Ana Beatriz Pascoal Lopes
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  6. Erich Vinícius de Paula
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  7. Katia Borgia Barbosa Pagnano
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  8. Rodrigo Ramos Catharino
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Contributions

Conceptualization—VMOP, KBBP, EVP, and RRC; Methodology—JD and FLD-A; Investigation—VMOP and JD; Resources—ABPL, VMOP, JD and FLD-A; Formal analysis—VMOP, JD and ANO; Data curation—VMOP, JD, ABPL and KBBP; Writing—Original Draft—VMOP and JD; Writing—Review & Editing—ANO, KBBP, and RRC; Visualization—JD; Supervision—RRC and KBBP; Project administration—RRC and KBBP.

Corresponding authors

Correspondence to Katia Borgia Barbosa Pagnano or Rodrigo Ramos Catharino.

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Conflict of interest

KBBP declares advisory board: Astellas, Abbvie, Novartis; lectures: EMS, Pintpharma, Jansen, and Astellas. The other authors declare no conflict of interests. All authors have read the journal’s policy on disclosure of potential conflicts of interest. The authors have full control of all primary data and agree to provide it to journal review if requested.

Ethical approval

The study was approved by the Ethics Committee of Unicamp (CEP-Unicamp: Comitê de Ética em Pesquisa da Unicamp—Campus Campinas), Number CAAE: 54899916.5.0000.5404.

Consent to participate

A written informed consent was obtained from all patients prior to enrollment.

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All authors approved the final version of the final manuscript and were responsible for the decision to submit for publication. The manuscript does not present identifiable patient data.

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Póvoa, V.M.O., Delafiori, J., Dias-Audibert, F.L. et al. Metabolic shift of chronic myeloid leukemia patients under imatinib–pioglitazone regimen and discontinuation. Med Oncol 38, 100 (2021). https://doi.org/10.1007/s12032-021-01551-5

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