Waldenstrom Macroglobulinemia: Subtype of non-Hodgkins

A rare blood cell cancer, Waldenstrom Macroglobulinemia is characterized by an excess of abnormal white blood cells in the bone marrow. These abnormal cells have characteristics of both white blood cells, #lymphocytes, also called B cells and more mature cells known as plasma cells. Having both lymphocyte and plasma characteristics, they cells are known as lymphoplasmacytic cells and ultimately lymphoplasmacytic lymphoma. In those with Waldenstrom Macroglobulinemia, these abnormal cells produce excess amounts of IgM, an immunoglobulin, and this overproduction contributes to the condition's name, Macroglobulinemia.


Waldenstrom macroglobulinemia usually begins in an individual's sixties, more often in Caucasian men. Waldenstrom macroglobulinemia is a slow-growing cancer. Some affected individuals have elevated levels of IgM and lymphoplasmacytic cells but no symptoms of the condition, which means these cases are caught kind of by accident, during a routine blood draw. These cases are often called smoldering (or asymptomatic) Waldenstrom macroglobulinemia. It can be many years before they develop any noticable signs and symptoms.


The most common signs and symptoms are weakness and extreme #fatigue caused by the #anemia from a short supply of red blood cells. Affected individuals can also experience general symptoms such as fever, night sweats, and weight loss. Some people with Waldenstrom macroglobulinemia develop a loss of sensation and weakness in the limbs, otherwise known as peripheral neuropathy. The belief is that the IgM protein in high supply attaches to the protective covering of nerve cells and breaks it down. The damaged nerves cannot carry signals normally, leading to neuropathy.


Other symptoms are related to the accumulation of lymphoplasmacytic cells in different tissues, such as an accumulation of cells in the liver leading to an enlarged liver, or spleen, or lymph nodes. In the bone marrow, the lymphoplasmacytic cells interfere with normal blood cell development, causing a shortage of healthy blood cells.


Symptoms more related to the excess amounts of IgM related to blood which is more viscous or thicker, ultimately impairing circulation. Bleeding in the nose or mouth may occur, blurring or loss of vision, #headache, dizziness, and confusion.


In some individuals, IgM and other immunoglobulins react to cold temperatures to form gel-like clumps that block blood flow in areas exposed to the cold, such as the hands and feet. This can lead to Raynaud phenomenon, in which the fingers and toes turn white or blue in response to cold temperatures.


Genetic Predisposition


Epigenetics is a big part of what we do in our practice, helping clients understand their own individual make-up and how they can optimize their health through understanding their polymorphisms. Waldenstrom macroglobulinemia is the result of a combination of genetic changes, most commonly a variant in the MYD88 gene, found in more than 90 percent of those affected.


Another gene commonly associated with Waldenstrom macroglobulinemia is the CXCR4, present in approximately 30 percent of those affected, and these individuals often also have the MYD88 gene variant.


The proteins produced from the MYD88 and CXCR4 genes are both involved in signaling within cells. The #MYD88 protein relays signals that help prevent the self-destruction of cells, thus aiding in cell survival. The #CXCR4 protein stimulates signaling pathways inside the cell that help regulate cell growth and division and cell survival. Variants of these genes lead to production of proteins that are constantly turned on, or overactive. Excessive signaling through these overactive proteins allows for survival and proliferation of abnormal cells that should undergo apoptosis, which likely contributes to the accumulation of lymphoplasmacytic cells in Waldenstrom macroglobulinemia.


Other genetic changes haven't been identified that may contribute to #Waldenstrom macroglobulinemia, but there have been some regions of DNA which are deleted or added in some people with the condition, yet researchers aren't sure which gene in these regions are important for the development of the condition. The variants that cause Waldenstrom macroglobulinemia are acquired during a person's lifetime and are present only in the abnormal blood cells.


These aren't necessary inherited, more so acquired during a person's lifetime from environmental exposures, whatever that might be for each person. Some families do have a predisposition to the condition, as about 20 percent of people with Waldenstrom macroglobulinemia have a family member with the condition or another disorder involving abnormal B cells.


Progression of Disease


About 20 percent of people are managed simply with careful watch-and-wait, but more often treatment is required. The current therapies available can control the disease for many years. The five-year-survival-rate is approximately 75 percent for individuals who are newly diagnosed. Newer therapies have increased success of treatment which has extended overall survival up to 15 years after diagnosis. Nevertheless, recurrence is common and the disease is still considered incurable. The overarching goal is to understand the molecular basis of the disease and develop new effective therapies that ultimately will lead to a cure for Waldenstrom macroglobulinemia.


Treatment for this disease changed dramatically once MYD88 mutations were discovered in 2012. Since MYD88 interacts with a protein called Bruton's Tyrosine Kinase (BTK), and BTK is known to promote other blood cancers and BTK inhibitors are highly effective in controlling chronic lymphocytic leukemia, the efficacy and safety of ibrutinib was explored for Waldenstrom macroglobulinemia. The estimated 2-year progression-free survival with no relapses and overall survival rates are 69 percent and 95 percent, respectively, with #ibrutinib. Those with both MYD88 and CXCR4 mutations tended to have slower, less robust responses to ibrutinib than those with only the MYD88 mutation. Unfortunately, ibrutinib is not effective in those without MYD88 mutation. Since FDA approval of ibrutinib, numerous BTK inhibitors have been developed and advanced into clinical trials, and multiple promising therapies are being developed.

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