Complications
May be due to lymphoplasmacytic infiltration of the nerve fibers, immunoglobulin M (IgM) deposition, autoantibodies, cryoglobulinemia, or amyloidosis.[41]
Neurologic antibody testing (including antimyelin-associated glycoprotein [anti-MAG] antibodies, antiganglioside M1 [anti-GM1] antibodies, antisulfatide IgM antibodies), nerve conduction study/electromyography, and referral to a neurologist are indicated if peripheral neuropathy is suspected.
The presence of anti-MAG, anti-GM1, or antisulfatide IgM antibodies support the diagnosis of IgM-related neuropathy. Their absence does not exclude the diagnosis.
Acquired Von Willebrand disease (VWD) has been described in patients with WM.[125][126] However the mechanism of low levels of Von Willebrand factor is not well understood. One retrospective study found low VW markers in 15% of selected patients but this is probably an overestimate.[127] There is an increased incidence in patients with CXCR4 mutation and in patients with high serum IgM levels. Levels of VM markers improve with treatment and the degree of improvement correlates with the depth of the response.
Patients with AL amyloidosis due to an IgM-producing monoclonal gammopathy of undetermined significance (MGUS)/WM show differences compared to the commoner AL amyloid in the context of a myeloma-type MGUS/MM clone. Patients with an IgM-related AL amyloid are reportedly less likely to have cardiac involvement, which is a poor prognostic feature. Despite this, overall, these patients probably do less well as complete remission is uncommon making regression of amyloid less likely. Patients with IgM amyloidosis are more likely to have soft tissue and peripheral nerve involvement and less commonly have the t (11;14) translocation (27% vs. 50%, p = 0.008), which is associated with a poorer response to bortezomib-based regimens.[128][129]
Hyperviscosity (due to elevated immunoglobulin M [IgM] in the serum) is a distinguishing feature of Waldenström macroglobulinemia. However, symptoms of hyperviscosity are observed in a minority of patients at diagnosis, and usually appear when serum IgM level is ≥3 g/dL.[34]
The clinical manifestations of hyperviscosity include skin and/or mucosal bleeding (purpura, epistaxis), headache, blurred vision, dizziness, vertigo, tinnitus, thrombosis (e.g., stroke, angina, myocardial infarction, pulmonary embolism, deep vein thrombosis).
Plasmapheresis (plasma exchange) can be used to urgently treat symptomatic hyperviscosity. See Management approach.
Long-standing hyperviscosity alters the vascular permeability and leads to perivascular malignant infiltration, giving rise to headache, vertigo, impaired hearing, ataxia, nystagmus, diplopia, and eventually coma.[32]
The syndrome does not include the neurologic manifestation from hyperviscosity syndrome. The central nervous system (CNS) damage can involve meninges (meningitis), cortical damage, and cranial and spinal cord involvement. There may be fast neurologic deterioration. Diagnostic workup includes histology, cerebrospinal fluid (CSF) analysis, molecular testing, radiology (neuroimaging), and blood analysis.[37]
There is no standard of treatment for Bing-Neel syndrome. Treatment with Bruton tyrosine kinase (BTK) inhibitors (e.g., ibrutinib) and chemotherapy may be considered, depending on the clinical situation and sites of CNS involvement.[37]
There is evidence of hemolysis. Direct antiglobulin test (DAT) is positive for anti-C3d; cold agglutinin titer is ≥1:64. Monoclonal IgM is present. There is evidence of lymphoma on bone marrow biopsy, but this is MYD88-negative and likely a distinct entity from WM.[120] There may be radiologic evidence of lymphoma, such as lymphadenopathy or splenomegaly. The therapeutic approach is to treat the underlying WM.[121]
WM is prone to Richter transformation, which is transformation to a high-grade lymphoma (most commonly a DLBCL, but other high-grade B-cell lymphomas have been reported). An increased incidence of Richter transformation has been reported in WM patients treated with nucleoside analogs, such as fludarabine either alone or in combination with other agents.
Transformation typically presents as a rapidly progressing tumor mass that is often extranodal and may be disseminated as widespread disease. A biopsy is required to confirm transformation to DLBCL. A positron emission tomography-computed tomography (PET-CT) scan is useful for directing biopsy and staging.
The prognosis is generally poor, and long-term survival is rare.
A retrospective study reported a higher incidence of treatment-related myelodysplastic syndrome/acute myeloid leukemia (1.6%) in WM patients treated with nucleoside analogs versus 0% in non-nucleoside analogs treated and 0% in untreated groups.[122]
In a trial of daily versus intermittent oral chlorambucil, 4 patients out of 46 (9%) in the intermittent chlorambucil group developed acute leukemia or myelodysplastic syndrome.[123]
Intravenous bortezomib causes significant neuropathy in 32% to 74% of patients, but, in up to 70% of instances, the neuropathy is reversible after discontinuation of treatment.[95][96][124]
The incidence of neuropathy has reduced now that bortezomib can be administered subcutaneously and with a once-weekly dosing.
Treating patients with preexisting neuropathy is a challenge, whereby an alternative treatment (i.e., a nonbortezomib-containing regimen) might be preferable.
There is an increased risk of fatal and serious cardiac arrhythmias, atrial fibrillation, cardiac failure, hypertension, and bleeding/bruising with ibrutinib.[18][75][76][80][81][82][83] Risk is increased in patients with cardiac comorbidities (e.g., hypertension, diabetes mellitus, history of cardiac arrhythmia) and those with acute infection or who are receiving warfarin.
Clinical evaluation of cardiac history and function should be performed prior to initiating ibrutinib. Patients should be carefully monitored during treatment for cardiac arrhythmias and signs of deterioration of cardiac function and clinically managed as appropriate. Blood pressure should be monitored and antihypertensive medication should be started or adjusted as needed.[84]
The risks and benefits of initiating or continued treatment with ibrutinib should be carefully assessed; alternative treatment may need to be considered.
Cardiac arrhythmias may occur with zanubrutinib; patients with cardiac comorbidities or acute infection may be at a higher risk.[85][86] Zanubrutinib may, however, cause less cardiovascular toxicity than ibrutinib.[78][79] Consider implementing ibrutinib safety precautions (described above) in patients receiving any BTK inhibitor. UK practice guidelines for managing cardiovascular complications associated with BTK inhibitors have been published.[81]
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