Waldenström macroglobulinaemia

Observation; treat on symptoms, cytopenias, hyperviscosity or neuropathy, not on IgM level alone.

Bendamustine-rituximab or dexamethasone-rituximab-cyclophosphamide for fixed duration; or zanubrutinib / ibrutinib (± rituximab) continuously; plasmapheresis first for hyperviscosity.

Switch class (BTKi ↔ chemo-immunotherapy); bortezomib- or carfilzomib-based regimens; venetoclax; pirtobrutinib after covalent BTKi; autologous transplant in selected young patients.

A lymphoplasmacytic lymphoma that secretes IgM. Two mutations, found by allele-specific PCR on a marrow aspirate, shape the whole plan. MYD88 L265P is present in more than 90 per cent and predicts response to BTK inhibitors; MYD88 wild-type disease responds much less well to them. CXCR4 mutations, present in about a third, predict slower and shallower responses to ibrutinib and a higher risk of a rise in IgM when treatment starts. Two complications need to be looked for because they change the urgency. Hyperviscosity, from a very high IgM, causes headache, blurred vision, nosebleeds and confusion, is confirmed on fundoscopy, and is treated with plasma exchange before anything else. IgM-related peripheral neuropathy, often anti-MAG positive, is a reason to treat even when other criteria are not met, because nerve damage does not reverse. Rituximab causes a transient rise in IgM, an IgM flare, in about half of patients, which can precipitate hyperviscosity; it is therefore held back or given after plasma exchange where the IgM is very high.

Treatment is for symptoms, not for a number: anaemia, thrombocytopenia, constitutional symptoms, symptomatic organ or node enlargement, hyperviscosity, neuropathy, cryoglobulinaemia or amyloidosis. An asymptomatic patient is watched. Two routes. Fixed-duration chemoimmunotherapy, usually bendamustine with rituximab for four to six cycles, gives deep responses and a treatment-free interval afterwards, and is the preference of many patients and many British units. Continuous BTK inhibition with zanubrutinib or ibrutinib gives high response rates without chemotherapy but is taken indefinitely. ASPEN, the only head-to-head trial, randomised 201 patients with MYD88-mutated disease to zanubrutinib or ibrutinib: the complete or very good partial response rate by independent review was 28.4 against 19.2 per cent, which did not reach statistical significance, but zanubrutinib caused markedly less atrial fibrillation, hypertension, bleeding and diarrhoea. A separate cohort treated MYD88 wild-type disease with zanubrutinib. Where a BTK inhibitor is chosen, zanubrutinib is therefore preferred. Rituximab with cyclophosphamide and dexamethasone is an alternative chemoimmunotherapy for patients in whom bendamustine is unsuitable. Proteasome-inhibitor regimens containing bortezomib are used where a rapid response is needed and neuropathy is absent.

The choice turns on what was used first and how long the remission lasted. After fixed-duration chemoimmunotherapy with a remission of two years or more, the same regimen can be repeated, or a BTK inhibitor started. After a BTK inhibitor, options are a different BTK inhibitor including the non-covalent pirtobrutinib, venetoclax, which has activity in this disease, proteasome-inhibitor regimens, chemoimmunotherapy if not previously used, and a clinical trial. Autologous transplant is occasionally used in younger patients with chemosensitive disease and multiple relapses. Transformation to diffuse large B-cell lymphoma is treated as aggressive lymphoma. Plasma exchange remains the immediate treatment for symptomatic hyperviscosity at any point.