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Teaching pack: Chronic myeloid leukaemia (CML)

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  1. Teaching pack · Cancer · haematologic

    Chronic myeloid leukaemia (CML)

    Chronic myeloid leukaemia is a blood cancer driven by a single fused gene, BCR-ABL. Imatinib in 2001 turned it from a disease with a median survival of about five years into one most people live with, and many can now stop treatment altogether.

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  2. What it is

    In two paragraphs

    CML is defined by the Philadelphia chromosome t(9;22) and its product, the constitutively active BCR-ABL1 tyrosine kinase. It is the paradigm of oncogene addiction: tyrosine kinase inhibitors (TKIs) restore near-normal life expectancy in chronic phase, and treatment response is tracked by quantitative BCR-ABL1 PCR on the International Scale (IS), with milestones at 3, 6 and 12 months (ELN 2020).

    First-line options are imatinib, the second-generation TKIs dasatinib, nilotinib and bosutinib, and since 2024 asciminib (ASC4FIRST), the first allosteric STAMP inhibitor. Second-generation drugs achieve deeper responses faster but have not improved overall survival over imatinib; choice is driven by comorbidity (cardiovascular risk with nilotinib and ponatinib, pleural effusions with dasatinib) and by the goal of treatment-free remission (TFR). Resistance is largely through ABL1 kinase-domain mutations; T315I is covered by ponatinib and asciminib. Allogeneic transplant is reserved for blast phase or multi-TKI failure.

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  3. Standard of care

    What is given today, by setting

    SettingApproachGuideline
    Chronic phase, first lineImatinib 400 mg, or a second-generation TKI (dasatinib, nilotinib, bosutinib), or asciminib (ASC4FIRST, approved 2024). Choice by comorbidity and treatment goal; monitor BCR-ABL1 IS at 3, 6, 12 months against ELN milestones.NCCN Category 1 (imatinib, dasatinib, nilotinib, bosutinib, asciminib)
    Resistance or intoleranceSwitch TKI guided by mutation analysis; ponatinib or asciminib for T315I; allogeneic HSCT if two or more TKIs fail or in advanced phase.not mapped
    Sustained deep molecular responseTreatment-free remission attempt after ≥3-5 years of TKI and ≥2 years of MR4 or better, with monthly PCR for the first six months (EURO-SKI); restart on loss of MMR.not mapped
    Blast phaseTKI plus acute-leukaemia-type induction (ponatinib or dasatinib with chemotherapy), then allogeneic HSCT.not mapped
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  4. State of the art

    Where the field stands

    • Life expectancy in chronic phase on TKI is close to the general population; the goal has moved from survival to deep molecular response and treatment-free remission.
    • Asciminib is the first allosteric BCR-ABL1 inhibitor and, since ASC4FIRST (2024), a first-line option with better tolerability than second-generation TKIs.
    • Roughly half of eligible patients maintain remission off therapy; predictors are duration of deep response and prior interferon exposure.
    • Blast-phase CML remains the unsolved problem, and TKI cost is the barrier in low- and middle-income countries despite generic imatinib.
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  5. History

    How we got here

    1. 1960Philadelphia chromosome
    2. 1973t(9;22) translocation
    3. 1990BCR-ABL causes CML in mice
    4. 1998Imatinib enters the clinic
    5. 2001Imatinib approved
    6. 2006Second-generation TKIs
    7. 2012Ponatinib covers T315I; bosutinib approved
    8. 2018Treatment-free remission validated
    9. 2021Asciminib: allosteric STAMP inhibitor approved
    10. 2024Asciminib first line
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  6. Pipeline

    What is coming

    • Asciminib (product)
    • Allogeneic stem cell transplantation (technology)
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  7. Open problems

    What nobody has solved

    • Blast-phase CML: median survival still under a year.
    • Predicting who can stop TKI safely; second TFR attempts.
    • Cardiovascular toxicity of nilotinib and ponatinib.
    • Access to any TKI and to PCR monitoring in LMICs.
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  8. Sources

    Read the primary sources

    • ELN 2020 recommendations: https://www.nature.com/articles/s41375-020-0776-2
    • NCI PDQ: CML: https://www.cancer.gov/types/leukemia/patient/cml-treatment-pdq
    • SEER: CML: https://seer.cancer.gov/statfacts/html/cmyl.html
    • Wikipedia: https://en.wikipedia.org/wiki/Chronic_myelogenous_leukemia
    • Guideline: https://www.nature.com/articles/s41375-020-0776-2
    • Guideline: https://doi.org/10.1016/S1470-2045(18)30192-X
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