Waldenström Macroglobulinemia
What is it?
Waldenström's macroglobulinemia is a rare form of malignancy characterized by the uncontrolled proliferation of B lymphocytes, a particular type of immune system cells that produce in large quantities IgM-type immunoglobulins. The median age at diagnosis is 63-75 years.
Causes and risk factors
Waldenström's macroglobulinemia is more common in the elderly and Caucasian population and in the male sex (incidence of 3.4 per million for the male sex vs 1.7 per million in the female sex). There is an increased risk of developing the disease in patients with a family history of macroglobulinemia or other lymphoproliferative disorders and in patients with autoimmune diseases (Sjogren's syndrome, autoimmune hemolytic anemia, etc.) or chronic inflammatory diseases.
Which are the symptoms?
Waldenström's macroglobulinemia is an indolent lymphoproliferative disorder with a heterogeneous clinical presentation. Like other lymphoproliferative disorders, it may present with systemic symptoms such as unexplained weight loss, fever, and night sweats. The clinical manifestations can include:
- peripheral cytopenias and related complications, such as fatigue due to anemia or bleeding caused by thrombocytopenia;
- lymphadenopathy (enlarged lymph nodes);
- lplenomegaly (enlarged spleen) resulting from the infiltration of bone marrow and secondary lymphoid organs by tumor cells.
Other clinical manifestations may arise from the physicochemical properties of IgM immunoglobulins, leading to hyperviscosity syndrome, characterized by symptoms such as headache, blurred vision, confusion, and nosebleeds. Additionally, symptoms may result from IgM cryoglobulins—abnormal circulating antibodies that precipitate at temperatures below 37°C—causing conditions such as Raynaud’s phenomenon, ulcers on the extremities, and kidney damage.
Finally, IgM immunoglobulins can also develop autoimmune properties, leading to conditions such as:
- hemolytic anemia;
- hemorrhagic syndromes, including acquired von Willebrand disease, which may also have non-autoimmune causes;
- peripheral neuropathy.
In rare cases, the disease may involve the central nervous system (Bing-Neel syndrome), presenting with a range of neurological symptoms. Additionally, amyloid protein deposition can occasionally occur, leading to renal, cardiac, and hepatic damage.
How is it diagnosed?
The initial evaluation for Waldenström’s macroglobulinemia begins with blood tests, including serum protein electrophoresis and serum immunofixation, which help detect the presence of a monoclonal IgM component. To further assess potential signs or symptoms associated with the disease, the hematologist may also order:
- comprehensive blood tests, including complete blood count (CBC), biochemical profile, and electrolytes;
- urine analysis;
- imaging studies, such as ultrasound or CT scan, to evaluate lymph node enlargement, spleen or liver enlargement, and any indications of hyperviscosity (e.g., an eye fundus examination to check for retinal changes).
A confirmed diagnosis requires a bone marrow biopsy and bone marrow aspirate, along with testing for the MYD88 gene mutation, which is detected in over 90% of patients with Waldenström’s macroglobulinemia.
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How is it treated?
As with other indolent lymphomas, treatment is indicated only when the disease burden is such that it may result in impairment of the patient's quality of life, otherwise the patient is a candidate for periodic follow-up only.
In case of hyperviscosity syndrome, it is possible to subject the patient to plasmapheresis sessions to remove excess IgM antibodies quickly. The two most common therapy regimens used in the first-line setting are chemoimmunotherapy combinations comprising Rituximab (monoclonal anti-CD20 antibody) and chemotherapeutic drugs such as cyclophosphamide-dexamethasone (R-CD) or bendamustine (RB).
There are schemes including proteosome inhibitors (bortezomib). BTK inhibitors, which were previously reserved for relapsed/refractory cases, have also recently been approved for first-line use.
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Where do we treat it?
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