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Renin angiotensin system inhibitors reduce the incidence of arterial thrombotic events in patients with hypertension and chronic myeloid leukemia treated with second- or third-generation tyrosine kinase inhibitors

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Abstract

Hypertension is a commonly reported comorbidity in patients diagnosed with chronic myeloid leukemia (CML), and its management represents a challenge in patients treated with 2nd- or 3rd-generation tyrosine kinase inhibitors (TKIs), considering their additional cardiovascular (CV) toxicity. The renin angiotensin system (RAS) contributes to hypertension genesis and plays an important role in atherosclerosis development, proliferation, and differentiation of myeloid hematopoietic cells. We analyzed a cohort of 192 patients with hypertension at CML diagnosis, who were treated with 2nd- or 3rd-generation TKIs, and evaluated the efficacy of RAS inhibitors (angiotensin-converting enzyme inhibitors (ACEi) and angiotensin-II receptor blockers (ARBs)) in the prevention of arterial occlusive events (AOEs), as compared with other drug classes. The 5-year cumulative incidence of AOEs was 32.7 ± 4.2%. Patients with SCORE ≥ 5% (high-very-high) showed a significantly higher incidence of AOEs (33.7 ± 7.6% vs 13.6 ± 4.8%, p = 0.006). The AOE incidence was significantly lower in patients treated with RAS inhibitors (14.8 ± 4.2% vs 44 ± 1%, p < 0.001, HR = 0.283). The difference in the low and intermediate Sokal risk group was confirmed but not in the high-risk group, where a lower RAS expression has been reported. Our data suggest that RAS inhibitors may represent an optimal treatment in patients with hypertension and CML, treated with 2nd or 3rdG TKIs.

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Acknowledgments

We are deeply grateful to the patients who participated in this study. We are grateful to Emanuela Morelli that was of great assistance in English editing the manuscript

Funding

This article was carried out within the framework of the research project financed by P.O.R. SARDEGNA F.S.E. 2014-2020 - Asse III “Istruzione e Formazione, Obiettivo Tematico: 10, Obiettivo Specifico: 10.5, Azione dell’accordo fi Partenariato:10.5.12 “Avviso di chiamata per il finanziamento di Progetti di ricerca – Anno 2017”.

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Author notes

  1. Olga Mulas and Giovanni Caocci contributed equally to this work.

Authors and Affiliations

  1. Department of Medical Sciences and Public Health, University of Cagliari, Hematology Businco Hospital, Cagliari, Italy

    Olga Mulas, Giovanni Caocci, Maria Pina Simula & Giorgio La Nasa

  2. SC Ematologia e CTMO, Ospedale Businco, Dipartimento di Scienze Mediche e Sanità Pubblica, Università di Cagliari, Via Jenner, sn, 09124, Cagliari, Italy

    Giovanni Caocci & Giorgio La Nasa

  3. Hematology, Section and BMT Unit, Rodolico Hospital, AOU Policlinico – V. Emanuele, Catania, Italy

    Fabio Stagno

  4. Department of Medicine, Section of Hematology, University of Verona, Verona, Italy

    Massimiliano Bonifacio & Luigi Scaffidi

  5. Haematology Unit, Cardarelli Hospital, Naples, Italy

    Mario Annunziata

  6. Haematology Unit, “Federico II” University of Naples, Naples, Italy

    Luigiana Luciano & Fiorenza De Gregorio

  7. Haematology Unit, “Fondazione IRCCS Policlinico S. Matteo” University Hospital, Pavia, Italy

    Ester Maria Orlandi & Chiara Elena

  8. Hematology Unit, Sant’Eugenio Hospital Tor Vergata University, Rome, Italy

    Elisabetta Abruzzese & Malgorzata Monika Trawinska

  9. Haematology and Transplant Center, Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy

    Nicola Sgherza

  10. Haematology Unit, Azienda Ospedaliera “Bianchi-Melacrino-Morelli”, Reggio Calabria, Italy

    Bruno Martino

  11. Haematology and Transplants Unit, University of Bari, Bari, Italy

    Francesco Albano & Imma Attolico

  12. Department of Clinical and Experimental Medicine, Section of Hematology, University of Pisa, Pisa, Italy

    Sara Galimberti & Claudia Baratè

  13. Haematology Unit, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza, Torino, Italy

    Patrizia Pregno & Francesca Pirillo

  14. Haematology Unit, Azienda Ospedaliera Universitaria Senese, University of Siena, Siena, Italy

    Monica Bocchia & Anna Sicuranza

  15. Department of Experimental, Diagnostic and Specialty Medicine, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy

    Fausto Castagnetti & Gabriele Gugliotta

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

    Mario Tiribelli & Rossella Stella

  17. Haematology Unit, University of Padova, Padua, Italy

    Gianni Binotto

  18. Haematology Unit, AOU Careggi, University of Florence, Florence, Italy

    Antonella Gozzini

  19. Hematology Unit, Azienda Unità Sanitaria Locale -IRCCS, Reggio Emilia, Italy

    Isabella Capodanno

  20. Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy

    Claudio Fozza

  21. Hematology Unit, Santa Maria Hospital, Terni, Italy

    Debora Luzi

  22. Data Center and Health Outcomes Research Unit, Italian Group for Adult Hematologic Diseases (GIMEMA), Rome, Italy

    Fabio Efficace

  23. Hematology Unit, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico, Milano, Italy

    Daniele Cattaneo & Alessandra Iurlo

  24. Department of tranlational and precision medicine, Sapienza University Policlinico Umberto 1, Rome, Italy

    Emilia Scalzulli, Robin Foà & Massimo Breccia

Authors
  1. Olga Mulas
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  2. Giovanni Caocci
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  3. Fabio Stagno
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  4. Massimiliano Bonifacio
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  5. Mario Annunziata
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  6. Luigiana Luciano
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  7. Ester Maria Orlandi
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  8. Elisabetta Abruzzese
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  9. Nicola Sgherza
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  10. Bruno Martino
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  11. Francesco Albano
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  15. Fausto Castagnetti
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  16. Mario Tiribelli
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  17. Gianni Binotto
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  18. Antonella Gozzini
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  19. Isabella Capodanno
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  20. Claudio Fozza
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  21. Debora Luzi
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  22. Fabio Efficace
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  23. Maria Pina Simula
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  25. Fiorenza De Gregorio
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  26. Chiara Elena
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  27. Malgorzata Monika Trawinska
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  28. Daniele Cattaneo
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  29. Imma Attolico
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  30. Claudia Baratè
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  31. Francesca Pirillo
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  32. Anna Sicuranza
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  33. Gabriele Gugliotta
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  34. Rossella Stella
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  35. Emilia Scalzulli
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  36. Alessandra Iurlo
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  37. Robin Foà
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  38. Massimo Breccia
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  39. Giorgio La Nasa
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Contributions

Conception and design: GC, OM

Collection and assembly of data: GC, OM, FS, MB, MA, LL, EO, EA, NS, BM, FA, SG, PP, MB, FC, MT, GB, AG, IC, CF, DL, FE, MPS, LS, FDG, CE, MMT, DC, IA, CB, FP, AS, GG, RS, ES, AI, RF, MB, GLN

Statistical analysis: GC, OM, FE

Manuscript writing: GC, MB

Corresponding author

Correspondence to Giovanni Caocci.

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The authors declare that they have no conflicts of interest.

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Data on patients were retrospectively collected in accordance with the 1975 guidelines of the Declaration of Helsinki.

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Mulas, O., Caocci, G., Stagno, F. et al. Renin angiotensin system inhibitors reduce the incidence of arterial thrombotic events in patients with hypertension and chronic myeloid leukemia treated with second- or third-generation tyrosine kinase inhibitors. Ann Hematol 99, 1525–1530 (2020). https://doi.org/10.1007/s00277-020-04102-6

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