BTK Inhibitors for Waldenström’s Macroglobulinemia: Comparisons, Benefits, and the Future

According to a story from AJMC, a recent critical review evaluated the class of therapies known as Bruton tyrosine kinase (BTK) inhibitors and their use in the treatment of Waldenström’s macroglobulinemia (WM) a type of rare hematologic cancer. These are the only therapeutics approved by the US Food and Drug Administration (FDA) specifically for treating this rare cancer. Examples of BTK inhibitors approved by the FDA include ibrutinib and zanubrutinib.

About Waldenström’s Macroglobulinemia (WM)

Waldenström’s macroglobulinemia, which is also known as lymphoplasmacytic lymphoma, is a rare type of blood cancer that affects two types of B lymphocytes, including plasma cells and lymphoplasmacytoid cells. A distinct characteristic of this type of cancer is the presence of a high concentration of IgM antibodies. It is a slow progressing form of blood cancer, and many patients can lead active lives. While it cannot be cured, it is treatable; some patients are able to experience years of remission without symptoms. There are only about 1,500 new cases per year in the U.S. Although it mostly occurs due to sporadic genetic mutations, a family history increases risk. Symptoms include vision loss, headaches, enlargement of the lymph nodes, liver, and spleen, bleeding nose and gums, weight loss, fatigue, and general weakness. To learn more about WM, click here.

BTK Inhibitors: A Standard of Care in WM

The review first compared ibrutinib and zanubrutinib as they are the current BTK inhibitor options available to US patients.


Ibrutinib was the first of this class to get approved and it has become a standard of care for WM. Three clinical trials have demonstrated its effectiveness as a single agent therapy. It is administered once daily as a pill, making it convenient for patients. Ibrutinib allows many patients to effectively treat their disease without having to deal with chemotherapy and its side effects.

Potential side effects include increased bleeding and cardiac toxicity, but the risks are tolerable for most patients. However, patients with other heart issues may have to avoid ibrutinib and in patients with the CXCR4 gene mutations, responses may not be as robust.


Zanubrutinib is a more recent development and has greater sensitivity to BTK. As a result, this drug should share similar performance to ibrutinib but with less adverse side effects. The drug is dosed as two or four pills taken daily. A noted side effect distinct to zanubrutinib is neutropenia, or low levels of neutrophils (a type of white blood cell) in the blood.

Overall, choosing one option over the other will generally happen on a case-by-case basis, and depends on other factors that could impact tolerability, such as comorbidities. Future BTK inhibitors that are in development include acalabrutinib, nemtabrutinib, tirabrutinib, pirtobrutinib, and orelabrutinib.

There is still a lot of room for improvement in treating WM, but there is no doubt that the BTK inhibitor class of agents will continue to play a vital role in the management of the disease.


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