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Teaching pack: Waldenström macroglobulinaemia

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9 slides generated from the cancer page, with a quiz from the open benchmark and speaker notes that cite the sources. Arrow keys move between slides; Print gives one slide per page.

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  1. Teaching pack · Cancer · haematologic

    Waldenström macroglobulinaemia

    A slow lymphoma that makes an abnormal IgM antibody, causing thick blood, anaemia and nerve damage. Nearly all cases share one mutation (MYD88 L265P), and BTK inhibitors control it for years.

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  2. What it is

    In two paragraphs

    Waldenström macroglobulinaemia (WM) is an IgM-secreting lymphoplasmacytic lymphoma with MYD88 L265P in ~95% and CXCR4 WHIM-like mutations in ~30-40%, the latter predicting slower BTK-inhibitor response. Symptoms come from marrow infiltration (cytopenias), IgM (hyperviscosity, neuropathy, cryoglobulinaemia, cold agglutinins) and adenopathy. Asymptomatic WM is observed.

    Treatment for symptomatic disease is rituximab-based chemo-immunotherapy (bendamustine-rituximab, DRC) or a covalent BTK inhibitor: ibrutinib (first WM approval 2015, iNNOVATE with rituximab), zanubrutinib (ASPEN 2021, fewer cardiac events than ibrutinib) or acalabrutinib. Plasmapheresis treats hyperviscosity before rituximab, which can transiently raise IgM (flare). Relapse options include the alternative class, proteasome inhibitors (bortezomib, carfilzomib), venetoclax, pirtobrutinib after covalent BTKi, and transplant in young fit patients. Bing-Neel syndrome (CNS involvement) responds to ibrutinib.

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  3. Standard of care

    What is given today, by setting

    SettingApproachGuideline
    AsymptomaticObservation; treat on symptoms, cytopenias, hyperviscosity or neuropathy, not on IgM level alone.not mapped
    Symptomatic, first lineBendamustine-rituximab or dexamethasone-rituximab-cyclophosphamide for fixed duration; or zanubrutinib / ibrutinib (± rituximab) continuously; plasmapheresis first for hyperviscosity.NCCN Category 1 (zanubrutinib, ibrutinib ± rituximab; BR)
    RelapsedSwitch class (BTKi ↔ chemo-immunotherapy); bortezomib- or carfilzomib-based regimens; venetoclax; pirtobrutinib after covalent BTKi; autologous transplant in selected young patients.NCCN Category 2A
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  4. State of the art

    Where the field stands

    • MYD88 L265P (2012) turned WM from a descriptive diagnosis into a genotype and made BTK inhibitors the rational therapy.
    • Zanubrutinib is the best-tolerated BTK inhibitor in head-to-head comparison (ASPEN) and is the preferred agent in many guidelines.
    • Median survival now exceeds 10 years; death from WM itself is uncommon in patients under 70.
    • Fixed-duration BTKi-venetoclax and CXCR4 antagonists are the next questions.
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  5. History

    How we got here

    1. 1944Waldenström describes the syndrome
    2. 2002Consensus diagnostic criteria (IWWM-2)
    3. 2012MYD88 L265P discovered
    4. 2014CXCR4 WHIM-like mutations
    5. 2015Ibrutinib: first drug ever approved for WM
    6. 2018iNNOVATE: ibrutinib-rituximab
    7. 2021Zanubrutinib approved (ASPEN)
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  6. Pipeline

    What is coming

    • Pirtobrutinib (product)
    • Venetoclax (product)
    • Zanubrutinib (product)
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  7. Open problems

    What nobody has solved

    • Indefinite BTKi therapy: cost, toxicity and resistance (BTK C481S).
    • CXCR4-mutant disease responds slower and shallower.
    • No approved therapy specific to IgM-related neuropathy.
    • Transformation to DLBCL (5-10%) carries poor prognosis.
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  8. Quiz

    Check understanding

    1. Why does venetoclax work in leukaemia?
      Answer
      It blocks BCL-2, the protein that stops leukaemia cells from self-destructing, so the built-in death programme (apoptosis) can run; used in CLL (fixed duration with obinutuzumab) and AML (with azacitidine).
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  9. Sources

    Read the primary sources

    • NCCN Guidelines: WM/LPL: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1475
    • IWMF (patient foundation): https://iwmf.com/
    • ASPEN (Blood 2020): https://doi.org/10.1182/blood.2020006844
    • Wikipedia: https://en.wikipedia.org/wiki/Waldenstr%C3%B6m_macroglobulinemia
    • Guideline: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1475
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