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CHRONIC MYELOGENOUS LEUKEMIA

Pathogenesis and management of accelerated and blast phases of chronic myeloid leukemia

Leukemia volume 37, pages 5–17 (2023)Cite this article

Subjects

Abstract

The treatment of chronic myeloid leukemia (CML) with tyrosine kinase inhibitors (TKIs) has been a model for cancer therapy development. Though most patients with CML have a normal quality and duration of life with TKI therapy, some patients progress to accelerated phase (AP) and blast phase (BP), both of which have a relatively poor prognosis. The rates of progression have reduced significantly from over >20% in the pre-TKI era to <5% now, largely due to refinements in CML therapy and response monitoring. Significant insights have been gained into the mechanisms of disease transformation including the role of additional cytogenetic abnormalities, somatic mutations, and other genomic alterations present at diagnosis or evolving on therapy. This knowledge is helping to optimize TKI therapy, improve prognostication and inform the development of novel combination regimens in these patients. While patients with de novo CML-AP have outcomes almost similar to CML in chronic phase (CP), those transformed from previously treated CML-CP should receive second- or third- generation TKIs and be strongly considered for allogeneic stem cell transplantation (allo-SCT). Similarly, patients with transformed CML-BP have particularly dismal outcomes with a median survival usually less than one year. Combination regimens with a potent TKI such as ponatinib followed by allo-SCT can achieve long-term survival in some transformed BP patients. Regimens including venetoclax in myeloid BP or inotuzumab ozogamicin or blinatumomab in lymphoid BP might lead to deeper and longer responses, facilitating potentially curative allo-SCT for patients with CML-BP once CP is achieved. Newer agents and novel combination therapies are further expanding the therapeutic arsenal in advanced phase CML.

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Fig. 1: Diagnostic criteria for accelerated phase and blast phase CML across different models.
Fig. 2: Risk factors for progression of chronic phase CML to advanced phases.
Fig. 3: Genomic, epigenetic and other intracellular and extracellular changes that drive progression from chronic phase CML to advanced phases.
Fig. 4: Genetic aberrations involved in blast phase CML and their association with immunophenotype.
Fig. 5: Proposed algorithm for the workup and management of advanced phase CML.

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Funding

NJS is supported by the K12 Paul Calabresi Clinical Oncology Scholar Award and the American Society of Hematology Junior Faculty Scholar Award in Clinical Research.

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  1. Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Jayastu Senapati, Elias Jabbour, Hagop Kantarjian & Nicholas J. Short

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JS analyzed the available data, wrote the first draft and subsequent versions, made the figures and tables; EJ and HK edited the manuscript and approved the final version; NJS conceptualized and designed the manuscript, analyzed the available data, edited the first draft and subsequent versions, edited the tables and figures and approved the final version Figures 2–5 created with BioRender.com.

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Correspondence to Nicholas J. Short.

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Competing interests

EJ received research grants from Abbvie, Adaptive biotechnologies, Amgen, Pfizer, and Takeda; and consultancy fees from Abbvie, adaptive biotechnologies, Amgen, BMS, Genentech, Incyte, Novartis, Pfizer, and Takeda. HK has received research grants from AbbVie, Agios, Amgen, Ariad, Astex, BMS, Cyclacel, Daiichi-Sankyo, Immunogen, Jazz Pharma, Novartis, Pfizer, Actinium, and Takeda. NJS has served as consultant for Takeda Oncology, Pfizer, Jazz Pharmaceuticals, and Sanofi, reports receiving research grants from Takeda Oncology, Astellas Pharma Inc., Stemline and Xencor, and has received honoraria from Amgen, Astellas Pharma Inc., and Sanofi.

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Senapati, J., Jabbour, E., Kantarjian, H. et al. Pathogenesis and management of accelerated and blast phases of chronic myeloid leukemia. Leukemia 37, 5–17 (2023). https://doi.org/10.1038/s41375-022-01736-5

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