Waldenström Macroglobulinemia

What happens in Waldenström macroglobulinemia

WM starts in B lymphocytes that mature into cells between lymphocytes and plasma cells (lymphoplasmacytic cells). These abnormal cells collect in the bone marrow, lymph nodes and spleen, and produce a single type of IgM antibody (a monoclonal protein or paraprotein). IgM is a large molecule, so high levels can:

• make the blood thick (hyperviscosity), slowing flow in small vessels
• bind to nerves, causing peripheral neuropathy
• form cold-sensitive proteins (cryoglobulins or cold agglutinins), causing symptoms in the cold
• deposit as amyloid in organs, rarely

Marrow crowding causes anemia and, later, low platelets and white cells.

WM often develops from IgM MGUS, a harmless-looking precursor, and can stay "smoldering" (asymptomatic) for years.

Symptoms

• fatigue and weakness from anemia, the most common symptom
• bleeding: nosebleeds, bleeding gums, easy bruising
• hyperviscosity: blurred vision, headaches, dizziness, ringing in the ears, confusion
• peripheral neuropathy: numbness, tingling or pain in the feet, sometimes the hands. See peripheral neuropathy
• B symptoms: fever, night sweats, unintended weight loss
• swollen lymph nodes, enlarged spleen or liver
• cold-related symptoms: color changes in fingers, rash
• kidney problems, rarely

Diagnosis

• blood count: anemia and low platelets
• serum protein electrophoresis and immunofixation: detect and measure the IgM monoclonal protein
• serum viscosity when hyperviscosity is suspected
• bone marrow biopsy: confirms lymphoplasmacytic lymphoma
• MYD88 L265P and CXCR4 mutation testing: help confirm the diagnosis and guide treatment
• CT or PET-CT to check lymph nodes and spleen
• eye exam: to look for retinal vein swelling and bleeding from hyperviscosity
• tests for cryoglobulins, cold agglutinins and anti-MAG antibodies (in neuropathy)

Treatment

Watchful waiting

People without symptoms, even with high IgM levels, are usually monitored every few months. Early treatment does not improve survival in asymptomatic WM.

When to treat

Treatment is started for anemia, low platelets, hyperviscosity, significant neuropathy, bulky lymph nodes or spleen, B symptoms, amyloidosis or other complications.

Main treatment options

• BTK inhibitors: zanubrutinib, ibrutinib or acalabrutinib, oral targeted drugs taken continuously
• Chemoimmunotherapy: bendamustine with rituximab (BR) is widely used. Dexamethasone, rituximab and cyclophosphamide (DRC) is another option
• Rituximab alone in some people, though it can cause a temporary IgM "flare," so it is avoided first when IgM is very high
• Proteasome inhibitors such as bortezomib-based combinations
• Plasmapheresis: urgently removes IgM for symptomatic hyperviscosity, before other treatment
• Stem cell transplant in selected younger patients with relapsed disease
• Clinical trials of newer agents, including BCL2 inhibitors and non-covalent BTK inhibitors

Supportive care

Transfusions, vaccines, infection prevention and treatment of neuropathy symptoms.

Outlook

WM is generally not curable, but it is very treatable. Median survival is now often more than 10 years, and many people live much longer, often dying of unrelated causes. Outlook depends on age, blood counts, IgM level, albumin and beta-2 microglobulin (combined in the International Prognostic Scoring System for WM). A small number transform to a more aggressive lymphoma.

Frequently asked questions

What is Waldenström macroglobulinemia?

It is a rare, slow-growing type of non-Hodgkin lymphoma in which abnormal B cells in the bone marrow make large amounts of IgM antibody. The excess IgM can thicken the blood and damage nerves, and marrow crowding causes anemia.

What are the symptoms of Waldenström macroglobulinemia?

Common symptoms include fatigue from anemia, nosebleeds or bleeding gums, blurred vision, headaches, numbness in the feet, night sweats, weight loss and swollen lymph nodes. Many people have no symptoms when diagnosed.

Is Waldenström macroglobulinemia curable?

It is not usually curable, but it is highly treatable. Many people go years without needing treatment, and modern therapies such as BTK inhibitors and rituximab-based regimens keep the disease controlled for long periods.

What is the life expectancy with Waldenström macroglobulinemia?

Median survival is often more than 10 years, and many people live much longer. Outcomes depend on age, overall health, blood counts and other prognostic factors. Your hematologist can provide a more personal estimate.

What is hyperviscosity syndrome?

It occurs when very high IgM levels make the blood thick, slowing blood flow. Symptoms include blurred vision, headaches, dizziness, nosebleeds and confusion. It is an emergency treated with plasmapheresis to remove IgM quickly.