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CHRONIC MYELOGENOUS LEUKEMIA

Are there new relevant therapeutic endpoints in the modern era of the BCR::ABL1 tyrosine kinase inhibitors in chronic myeloid leukemia?

Leukemia (2024)Cite this article

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The availability and affordability of multiple BCR::ABL1 tyrosine kinase inhibitors (TKIs) beginning in 2000 have changed the prognosis and treatment dynamics in Philadelphia-chromosome (Ph)-positive (or BCR::ABL1-positive) chronic myeloid leukemia (CML) [1,2,3]. Evolving discussions relate to the optimal biologic (lower) dose schedules; frontline versus later-line therapies; management of toxicities versus resistance; the benefit-risk of changing TKIs in patients in good molecular response in order to achieve treatment-free remission (TFR) status; and, with the availability of generic formulations, the cost or treatment value. These issues have been detailed elsewhere [4,5,6].

In the early days, with multiple unanswered questions, the main aims of TKI therapy were borrowed from the experience with interferon alpha. These focused on the achievement of hematologic response and cytogenetic response/complete cytogenetic response (CCyR). The latter endpoint, which required a bone marrow evaluation, was later replaced by its equivalent molecular endpoint, BCR::ABL1 transcripts on the International Scale (IS) of ≤1% (2-log reduction of BCR::ABL1 transcripts, or MR2). The achievement of major molecular response (MMR; BCR::ABL1 transcripts [IS] ≤0.1%), a deeper response than MR2, was later found to correlate with event-free survival (EFS) and has been used as an early surrogate endpoint for EFS improvement in clinical trials.

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Author information

Authors and Affiliations

  1. Leukemia Department, MD Anderson Cancer Center, Madrid, Spain

    Hagop Kantarjian, Fadi G. Haddad, Ghayas C. Issa, Elias Jabbour & Koji Sasaki

  2. SA Pathology, Centre For Cancer Biology Australia, Adelaide, SA, Australia

    Susan Branford

  3. Department of Translational and Precision Medicine, Sapienza University-Rome, Rome, Italy

    Massimo Breccia

  4. Georgia Cancer Center, Atlanta, GA, 30303, USA

    Jorge Cortes

  5. Universitatsklinikum Jena, Jena, Germany

    Andreas Hochhaus

  6. South Australian Health & Medical Institute, SAHMRI, Adelaide, SA, Australia

    Timothy Hughes

  7. Hematology Department and CRCL INSERM U 1052, Centre Léon Berard, Lyon, France

    Franck E. Nicolini

  8. Institut Bergonié or Bergonié Institute 229 cours de l’Argonne, 33076, Bordeaux, France

    Francois Xavier-Mahon

  9. INSERM U1312 Bordeaux University, Bordeaux, France

    Francois Xavier-Mahon

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All authors contributed equally to the concert and design of the perspective, writing and approving the final manuscript.

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Correspondence to Hagop Kantarjian.

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Competing interests

HK reports research grants and honoraria from AbbVie, Amgen, Amphista, Ascentage, Astellas, Biologix, Curis, Daiichi-Sankyo, Immunogen, Ipsen Biopharmaceuticals, Jazz, KAHR Medical, Labcorp, Novartis, Pfizer, Shenzhen Target Rx, Stemline, Takeda. SB reports research grants from Novartis and Cepheid, and honoraria from Novartis and Qiagen. FGH has no conflict of interest to disclose. G.C.I. received consultancy or advisory role fees from Novartis, Kura Oncology, Syndax Pharmaceuticals, Abbvie and NuProbe and received research funding from Celgene, Novartis, Kura Oncology, Syndax Pharmaceuticals, Merck, Cullinan Oncology, Astex and NuProbe. EJ reports research grants and honoraria from AbbVie, Amgen, Ascentage, Astex, Autolus, Bristol Myer-Squibb, Biologix, Daiichi-Sankyo, Genentech, Jazz, Kite, Novartis, Pfizer, Shenzhen Target Rx, TERNS, Takeda. MB received honoraria from Abbvie, AOP, Bristol Myer-Squibb, GSK, Incyte, Jazz, Novartis, Pfizer. FN is a consultant for Novartis and Sun Pharma Ltd, a board entity for Novartis, Incyte Biosciences, GSK, Bristol Myers Squibb-Celgene and Pfizer, and reports institutional grants from Novartis and Incyte Biosciences Europe. FXM reports honoraria from Ascentage Pharma Group. TPH reports research grants and honoraria from Novartis, Takeda, Pfizer, Terns, and Enliven. AH reports research support by Novartis, Incyte, BMS, Pfizer, Enliven and TERNS and honoraria by Novartis and Incyte.

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Kantarjian, H., Branford, S., Breccia, M. et al. Are there new relevant therapeutic endpoints in the modern era of the BCR::ABL1 tyrosine kinase inhibitors in chronic myeloid leukemia?. Leukemia (2024). https://doi.org/10.1038/s41375-024-02229-3

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