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Hepatotoxicity as dose-limiting toxicity of the combination of bosutinib and atezolizumab in patients with chronic myeloid leukemia. Results of the ZEROLMC study

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Abstract

In the field of chronic myeloid leukemia (CML), new strategies are needed to increase the rate of successful treatment discontinuations, a crucial goal in this disease. Anti-PD-L1 checkpoint inhibitors are a promising therapeutic approach in CML after the demonstration of an increase of these inhibitory molecules in patients with CML. A phase Ib/II (NCT04793399, registration date March 11, 2021) open-label exploratory trial has been conducted to evaluate the safety of atezolizumab, a humanized anti-PD-L1 antibody, in combination with bosutinib in patients with newly diagnosed chronic phase CML. A total of 36 patients were planned to be enrolled, but the study had to be prematurely terminated due to safety concerns. Nine patients were included in the study, and only 8 went on to receive the combination with atezolizumab. There were a total of 44 adverse events (AEs) during the study period. The most frequent were gastrointestinal (50%), mostly mild (86% grade 1–2). The most serious AEs were hepatic. There were 17 hepatic AEs in 5 patients. Of the hepatic AEs 5 were during the bosutinib monotherapy phase and 12 during the combination phase (AST increase x4, ALT increase x4, blood bilirubin increase x1, alkaline phosphatase elevation x2, GGT increase x2), most of them grade 3–4. There were 2 patients who presented a dose-limiting toxicity; a grade 3 elevation of transaminases, that led to premature termination of the study. The combination of atezolizumab with bosutinib presents hepatotoxicity as a dose-limiting effect and therefore we do not recommend to explore this combination in future studies.

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Acknowledgements

We would like to thank Pfizer and Roche for providing the drugs for the study and to all the staff and patients who have made this study possible.

Funding

Pfizer SLU provided bosutinib, drug distribution, and funding for this trials and atezolizumab was provided by Roche Registration GmbH. The Contract Research Organization of the study is Fundación Teófilo Hernando.

Author information

Authors and Affiliations

  1. Hospital Universitario Doctor José Molina Orosa, Lanzarote, Spain

    Lucía Pérez-Lamas

  2. Hospital Universitario La Paz, Madrid, Spain

    Raquel de Paz Arias

  3. Hospital Universitario Doce de Octubre, Madrid, Spain

    Rosa Mª Ayala Díaz & Joaquín Martínez-López

  4. Hospital Virgen de la Salud, Toledo, Spain

    Luis Felipe Casado Montero

  5. Hospital Universitario Central de Asturias, Oviedo, Spain

    Ángel Ramírez Payer

  6. Hospital Universitario de Salamanca, Salamanca, Spain

    Magdalena Sierra

  7. Hospital General Universitario Morales Meseguer, CIBERER, UCAM, Murcia, Spain

    Francisca Ferrer Marín

  8. Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain

    Raúl Pérez López

  9. Institut Català d’Oncologia-Hospital germans Trias i Pujol, Universitat Autònoma de Barcelona, Josep Carreras Leukemia Research Institute, Badalona, Spain

    Blanca Xicoy Cirici

  10. Hospital de La Princesa, Madrid, Spain

    Juan Luis Steegmann

  11. Hospital Universitario de Gran Canaria Doctor Negrín, Las Palmas, Spain

    María Teresa Gómez Casares

  12. Hospital Universitario Ramón y Cajal, IRYCIS, Universidad de Alcalá, Madrid, Spain

    Valentín García-Gutiérrez

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  1. Lucía Pérez-Lamas
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Contributions

L.P.L.: Data collection and analysis, contribution in interpretation of results, original drafting of manuscript. R.P.A., R.M.A.D. and L.F.C.M.: Review of scientific literature, contribution in the elaboration of the methodology, critical revision of the manuscript. A.R.P, M. S., F.F.M.: Clinical data acquisition, statistical analysis, contribution in interpretation of results, critical revision of the manuscript. R.P.L., B.X.C., M.T.G.C., J.L.S.: Advice on data analysis, contribution in review of ethical and informed consent aspects, critical revision of the manuscript, final approval of the version to be published. J.M.L., V.G.G.: Conceptualization, study design, general supervision, contribution in interpretation of results, critical revision of manuscript. All authors have read and approved the final version of the manuscript and have contributed significantly to the study.

Corresponding author

Correspondence to Valentín García-Gutiérrez.

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Ethical Aproval

The design, submission and monitoring of this study was performed in collaboration with the Contract Research Organization Fundación Teófilo Hernando, in accordance with their standard operating procedures, which comply with the ethical principles of Good Clinical Practice, and in accordance with the current Declaration of Helsinki (Fortaleza, Brazil, October 2013). The study was approved by the independent ethics committee of each participating center and by the Spanish Agency of Medicines and Health Products (AEMPS). All patients gave written informed consent.

Competing interests

L. Pérez Lamas: Novartis; travel grants. Incyte; travel grants. B. Xicoy: Novartis, Incyte; travel grants, research funding, advisory board; BMS and Pfizer: travel grants, advisory board. R. Ayala: Advisory board member for BMS, Novartis and Incyte. Received speaker honoraria from Astellas, Novartis and BMS.F. Ferrer Marín: Advisory board member for BMS and Novartis. Received speaker honoraria from Novartis and BMS. Received grants from CTI and Incyte. V. Garcia-Gutierrez: Novartis; BMS; Incyte; Pfizer; travel grants, research funding, advisory board.

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Pérez-Lamas, L., de Paz Arias, R., Díaz, R.M.A. et al. Hepatotoxicity as dose-limiting toxicity of the combination of bosutinib and atezolizumab in patients with chronic myeloid leukemia. Results of the ZEROLMC study. Ann Hematol (2024). https://doi.org/10.1007/s00277-024-05662-7

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