Waldenström's Macroglobulinemia

Waldenström's Macroglobulinemia (Lymphoplasmacytic Lymphoma) in brief

Waldenström's macroglobulinemia, also known as Waldenström's disease or lymphoplasmacytic lymphoma, is a rare form of lymphatic cancer. It shows features of both a lymphoma and a plasma cell disorder. In this disease, the cancer cells produce large amounts of an abnormal protein, which can lead to various symptoms. Waldenström's macroglobulinemia is a slowly progressing disease.

Waldenström's macroglobulinemia at a glance

Type of disease

Rare, slow-growing (indolent) non-Hodgkin lymphoma

Typical age

Mostly over 60 years

Sex

Men affected more often than women

Hallmark

Excess of IgM protein in the blood

What exactly is Waldenström's macroglobulinemia?

Waldenström's macroglobulinemia is a rare cancer that affects the lymphatic system, in particular a certain type of white blood cell, the B lymphocytes. These cells develop into plasma cells that overproduce the IgM protein. This leads to what is known as macroglobulinemia, in which the blood becomes thicker due to the excess protein. This can impair blood flow and strain various organs. The disease belongs to the indolent (slow-growing) non-Hodgkin lymphomas, and many patients live with it for a long time, often without needing immediate intensive treatment.

Why do I have Waldenström's macroglobulinemia?

The exact cause of Waldenström's macroglobulinemia is unknown. However, there are some risk factors:

• Genetic predisposition: Waldenström's macroglobulinemia occurs more frequently in people with a family history of the disease.
• Age: Most patients are older than 60, and the risk increases with advancing age.
• Sex: Men are affected more often than women.
• Ethnicity: Waldenström's macroglobulinemia occurs more frequently in people of Northern European descent.

However, no clear cause is known, and people without these risk factors can also develop the disease.

Symptoms of Waldenström's macroglobulinemia

The symptoms of Waldenström's macroglobulinemia vary. Some patients have no complaints at first. However, possible symptoms include:

• Fatigue and weakness (due to anemia)
• Weight loss
• Tendency to bleed (e.g. frequent nosebleeds)
• Blurred vision or visual disturbances (due to thickened blood)
• Dizziness and headaches
• Increased susceptibility to infections (due to a weakened immune system)
• Enlarged lymph nodes or spleen
• Polyneuropathy (disturbances of sensation in the legs and arms)

Because many of these symptoms are non-specific, the diagnosis is often only made after blood tests that reveal elevated IgM levels and other abnormalities.

When is Waldenström's macroglobulinemia treated?

Not all patients with Waldenström's macroglobulinemia need treatment right away. Often, watchful waiting (a watch-and-wait approach) is recommended, especially when the disease is not causing severe symptoms. Treatment then becomes necessary when symptoms such as anemia, a tendency to bleed, nerve damage, or dangerous thickening of the blood occur.

How is Waldenström's macroglobulinemia treated?

The treatment of Waldenström's macroglobulinemia is tailored to the individual needs of the patient. The most common therapies include:

• Immunotherapy and chemotherapy: Drugs such as rituximab (an antibody that specifically attacks cancer cells) combined with chemotherapy (e.g. bendamustine) help to slow the progression of the disease.
• Plasmapheresis: A procedure in which excess IgM protein is filtered out of the blood to relieve acute symptoms.
• Targeted therapies: Newer drugs such as ibrutinib block specific signaling pathways that control the growth of the cancer cells. These forms of therapy are increasingly used to control the disease.
• Stem cell transplantation: In rare cases, a transplant may be considered, especially in younger patients or when other treatments are not working.

How exactly have clinical trials changed the treatment landscape in Waldenström's macroglobulinemia?

In recent years, clinical trials have brought advances in the treatment of Waldenström's macroglobulinemia. Here are some important trials and their impact on treatment:

1. Targeted therapy with ibrutinib – The iNNOVATE trial

One of the biggest changes in the treatment of Waldenström's macroglobulinemia was the introduction of ibrutinib, a so-called "targeted" drug. Ibrutinib blocks a certain protein (BTK) that drives the growth of the cancer cells. Thanks to the iNNOVATE trial, it was shown that ibrutinib slows the progression of the disease and works very well in many patients – including those who no longer respond to other therapies. This trial led to ibrutinib being approved in many countries for the treatment of Waldenström's macroglobulinemia. It offers patients an effective therapy, often with fewer side effects than classic chemotherapy.

2. Improved combination therapies – R-bendamustine

Combination therapies consisting of immunotherapy and chemotherapy have also proven to be very effective. In a large German study, the drug bendamustine was tested together with rituximab (an antibody that specifically attacks lymphoma cells). The results showed that this combination was able to significantly delay the course of the disease in many patients. This form of therapy is now frequently used in patients with advanced Waldenström's macroglobulinemia, as it works well and is comparatively well tolerated.

3. Rituximab in long-term treatment – The rituximab maintenance trial

Rituximab is an antibody that specifically recognizes and destroys cancer cells. The rituximab maintenance trial investigated whether it makes sense to continue giving rituximab for longer after the initial treatment in order to secure treatment success. The trial showed that patients who received rituximab over a longer period lived longer without disease relapse. Today, this "maintenance therapy" is often used to slow the progression of the disease.

4. New treatment options for difficult-to-treat cases – The ASPEN trial

For patients who do not respond to conventional therapies, new drugs such as zanubrutinib were tested in the ASPEN trial. Zanubrutinib works similarly to ibrutinib but is often better tolerated and has fewer side effects. This trial showed that zanubrutinib is effective in many patients, particularly in those who have already tried several other treatments. It thus offers a new option for patients whose disease is difficult to treat.