Waldenstrom macroglobulinemia

Synonyms

5

Overview

Waldenström macroglobulinemia is a rare blood cell cancer characterized by an excess of abnormal white blood cells called lymphoplasmacytic cells in the bone marrow. This condition is classified as a lymphoplasmacytic lymphoma. The abnormal cells have characteristics of both white blood cells (lymphocytes) called B cells and of more mature cells derived from B cells known as plasma cells. These abnormal cells produce excess amounts of IgM, a type of protein known as an immunoglobulin; the overproduction of this large protein is how the condition got its name ("macroglobulinemia").

Waldenström macroglobulinemia usually begins in a person's sixties and is a slow-growing (indolent) cancer. Some affected individuals have elevated levels of IgM and lymphoplasmacytic cells but no symptoms of the condition; in these cases, the disease is usually found incidentally by a blood test taken for another reason. These individuals are diagnosed with smoldering (or asymptomatic) Waldenström macroglobulinemia. It can be several years before this form of the condition progresses to the symptomatic form.

People with Waldenström macroglobulinemia have an increased risk of developing other cancers of the blood or other tissues.

Symptoms

  • General weakness
  • Loss of appetite
  • Weight loss
  • Peripheral neuropathy
  • Fever
  • Change of mental status
  • Increase of viscosity of the blood leading to nosebleeds, headaches, dizziness, blaring or loss of vision

Causes

The cause of the condition is not known but environmental, genetic, and viral factors have been suggested as possible causes. There have been some reports of familial cases suggesting a genetic predisposition.

The most common known genetic change associated with this condition is a mutation in the MYD88 gene, which is found in more than 90 percent of affected individuals. Another gene commonly associated with Waldenström macroglobulinemia, CXCR4, is mutated in approximately 30 percent of affected individuals (most of whom also have the MYD88 gene mutation). Other genetic changes believed to be involved in Waldenström macroglobulinemia have not yet been identified. Studies have found that certain regions of DNA are deleted or added in some people with the condition; however, researchers are unsure which genes in these regions are important for development of the condition. The mutations that cause Waldenström macroglobulinemia are acquired during a person's lifetime and are present only in the abnormal blood cells.

Prevention

Not known.

Diagnosis

A distinguishing feature of WM is the presence of an IgM monoclonal protein (or paraprotein) that is produced by the cancer cells. The laboratory diagnosis of Waldenström macroglobulinemia is contingent on demonstrating a significant monoclonal IgM spike and identifying malignant cells consistent with Waldenström macroglobulinemia (usually found in bone marrow biopsy samples and aspirates). General studies include a full blood count, red cell indices, platelet count, and a peripheral smear. Normocytic normochromic anemia, leukopenia, and thrombocytopenia may be observed. Anemia is the most common finding, present in 8% of patients with symptomatic Waldenström macroglobulinemia. The peripheral smear may reveal plasmacytoid lymphocytes, normocytic normochromic red cells, and rouleaux formation. Neutropenia can be found in some patients. Thrombocytopenia is found in approximately 5% of patients with bleeding diathesis.

Chemistry tests include lactate dehydrogenase (LDH) levels, uric acid levels, erythrocyte sedimentation rate (ESR), renal and hepatic function, total protein levels, and an albumin-to-globulin ratio. The ESR and uric acid level may be elevated. Creatinine is occasionally elevated and electrolytes are occasionally abnormal. Hypercalcemia is noted in approximately 4% of patients. The LDH level is frequently elevated, indicating the extent of Waldenström macroglobulinemia–related tissue involvement. Rheumatoid factor, cryoglobulins, direct antiglobulin test and cold agglutinin titre results can be positive. Beta-2-microglobulin and C-reactive protein test results are not specific for Waldenström macroglobulinemia. Beta-2-microglobulin is elevated in proportion to tumor mass. Coagulation abnormalities may be present. Prothrombin time, activated partial thromboplastin time, thrombin time, and fibrinogen tests should be performed. Platelet aggregation studies are optional. Serum protein electrophoresis results indicate evidence of a monoclonal spike but cannot establish the spike as IgM. An M component with beta-to-gamma mobility is highly suggestive of Waldenström macroglobulinemia. Immunoelectrophoresis and immunofixation studies help identify the type of immunoglobulin, the clonality of the light chain, and the monoclonality and quantitation of the paraprotein. High-resolution electrophoresis and serum and urine immunofixation are recommended to help identify and characterize the monoclonal IgM paraprotein.

The light chain of the monoclonal protein is usually the kappa light chain. At times, patients with Waldenström macroglobulinemia may exhibit more than one M protein. Plasma viscosity must be measured. Results from characterization studies of urinary immunoglobulins indicate that light chains (Bence Jones protein), usually of the kappa type, are found in the urine. Urine collections should be concentrated.

Bence Jones proteinuria is observed in approximately 4% of patients and exceeds 1 g/d in approximately 3% of patients. Patients with findings of peripheral neuropathy should have nerve conduction studies and antimyelin associated glycoprotein serology.

Criteria for diagnosis of Waldenström's macroglobulinemia include:

  • IgM monoclonal gammopathy that excludes chronic lymphocytic leukemia and Mantle cell lymphoma.
  • Evidence of anemia, constitutional symptoms, hyperviscosity, swollen lymph nodes, or enlargement of the liver and spleen that can be attributed to an underlying lymphoproliferative disorder.

Prognosis

The prognosis varies from person to person, depending upon a variety of factors, including age at diagnosis and severity of symptoms.  Fortunately recent advances in research (much of which has been funded by the IWMF) have extended this diagnosis significantly.  

The International Prognostic Scoring System for Waldenström’s Macroglobulinemia (IPSSWM) is a predictive model to characterise long-term outcome. According to the model, factors predicting survival are: 

  • Age >65 years;
  • Hemoglobin ≥11.5 g/dL;
  • Platelet count ≤1×19/L;
  • B2-microglobulin >3 mg/L;
  • Serum monoclonal protein concentration >70 g/L


The risk categories are:

  • Low risk is defined by the presence of ≤1 adverse variable except age
  • High risk by the presence of >2 adverse characteristics 
  • Intermediate risk by the presence of 2 adverse characteristics or age >65 years

 
5-year survival rates are 87%, 68% and 36% respectively.

Treatment

There are no treatments that can cure WM, although in most cases the disease is indolent (slow growing) and can be effectively managed with appropriate therapies.

Ibrutinib (Imbruvica) is FDA approved, as the first drug specifically designated for the treatment of WM. While Ibruvica, an oral drug that targets the Bruton's tyrosine kinase (BTK) pathway in B-cell growth and development, is a very important step forward in treatment, it is not a cure for WM and not everyone responds to it.

Some affected individuals have a procedure called plasmapheresis, to reverse or prevent the symptoms associated with the thickening of the blood (hyperviscosity). This involves removing the blood, passing it through a machine that removes the part of the blood with the IgM antibody, and returning the blood to the body. This may be combined with other treatments such as various types of chemotherapy. Many different drugs can be used to manage this condition, both alone and/or in various combinations.