The disease, named after the Swedish oncologistJan G. Waldenström, was first identified in 1944. As with other lymphomas, the disease is characterized by an uncontrolled increase of B-cells, i.e., white blood cells formed in the bone marrow and lymph nodes. The proliferation of B-cells interferes with the production of red blood cells, resulting in anemia. A unique characteristic of the disease is that the B-cells produce excess amounts of immunoglobulin protein (IgM), thickening the blood, and requiring additional treatment. WM is a rare disease, with only about 1,500 cases per year in the U.S. While the disease is incurable, it is treatable. Because of its indolent nature, many patients are able to lead active lives, and, when treatment is required, may experience years of symptom-free remission.
For a time, WM was considered to be related to multiple myeloma due to the presence of monoclonal gammopathy and infiltration of the bone marrow and other organs by plasmacytoid lymphocytes. The new World Health Organization (WHO) classification, however, places WM under the category of lymphoplasmacytic lymphomas, itself a subcategory of the indolent (low-grade) non-Hodgkin lymphomas. In recent years, there have been significant advances in the understanding and treatment of WM.
Waldenström's macroglobulinemia is characterized by an uncontrolled clonal proliferation of terminally differentiated B lymphocytes. Somatic mutations in MYD88 causing a change from leucine to proline at amino acid position 265 occur in over 90% of patients. Recently, somatic mutations in the C-terminal domain of CXCR4 which are similar to those that appear in the germline of patients with WHIM syndrome were reported, along with small deletions affecting many genes involved in B-cell lymphoma genesis  There has been an association demonstrated with the locus 6p21.3 on chromosome 6. There is a 2- to 3-fold risk increase of developing WM in people with a personal history of autoimmune diseases with autoantibodies and particularly elevated risks associated with hepatitis, human immunodeficiency virus, and rickettsiosis.
There are genetic factors, with first-degree relatives shown to have a highly increased risk of also contracting Waldenström's. There is also evidence to suggest that environmental factors including exposure to farming, pesticides, wood dust, and organic solvents may influence the development of Waldenström's.
Although believed to be a sporadic disease, studies have shown increased susceptibility within families, indicating a genetic component. A mutation in gene MYD88 has been found to occur frequently in patients. WM cells show only minimal changes in cytogenetic and gene expression studies. Their miRNA signature however differs from their normal counterpart. It is therefore believed that epigenetic modifications play a crucial role in the disease.
The protein Src tyrosine kinase is overexpressed in Waldenström macroglobulinemia cells compared with control B cells. Inhibition of Src arrests the cell cycle at phase G1 and has little effect on the survival of WM or normal cells.
Symptoms include blurring or loss of vision, headache, and (rarely) stroke or coma are due to the effects of the IgMparaprotein, which may cause autoimmune phenomenon or cryoglobulinemia. Other symptoms of WM are due to the hyperviscosity syndrome, which is present in 6-20% of patients. This is attributed to the IgM monoclonal protein increasing the viscosity of the blood by forming aggregates to each other, binding water through their carbohydrate component and by their interaction with blood cells.
A diagnosis of Waldenström's macroglobulinemia depends on a significant monoclonal IgM spike evident in blood tests and malignant cells consistent with the disease in bone marrow biopsy samples. Blood tests show the level of IgM in the blood and the presence of proteins, or tumor markers, that are the key symptoms of WM. A bone marrow biopsy provides a sample of bone marrow, usually from the back of the pelvis bone. The sample is extracted through a needle and examined under a microscope. A pathologist identifies the particular lymphocytes that indicate WM. Flow cytometry may be used to examine markers on the cell surface or inside the lymphocytes.
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 40% 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 Waldenstrom macroglobulinemia 1. IgM monoclonal gammopathy that excludes CLL and Mantle cell lymphoma 2. Evidence of anemia , constitutional symptoms , hyperviscosity , lymphadenopathy , or hepatosplenomegaly that can be attributed to underlying lymphoproliferative disorder
Current medical treatments result in survival of some longer than 10 years; in part this is because better diagnostic testing means early diagnosis and treatments. Older diagnosis and treatments resulted in published reports of median survival of approximately 5 years from time of diagnosis. Currently, median survival is 6.5 years. In rare instances, WM progresses to multiple myeloma.
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 (n.b. the study quoted conversely refers to them as "5 adverse covariates") are:
Age >65 years
Haemoglobin ≤11.5 g/dL
Platelet count ≤100×109/L
B2-microglobulin >3 mg/L
Serum monoclonal protein concentration >70 g/L
The risk categories are:
Low: ≤1 adverse variable except age
Intermediate: 2 adverse characteristics or age >65 years
High: >2 adverse characteristics
Five-year survival rates for these categories are 87%, 68% and 36% respectively.
The IPSSWM has been shown to be reliable. It is also applicable to patients on a Rituximab-based treatment regimen. An additional predictive factor is elevated serum lactate dehydrogenase (LDH).
There is no single accepted treatment for WM. There is marked variation in clinical outcome due to gaps in knowledge of the disease's molecular basis. Objective response rates are high (>80%) but complete response rates are low (0-15%). Recently Yang et al. showed that the MYD88 L265P mutation induced activation of Bruton's Tyrosine Kinase, the target of the drug ibrutinib, which is in clinical trials in relapsed/refractory patient and has shown promising activity (Treon et al., Proceedings of the American Society of Hematology 2013). The FDA approved ibrutinib for use in WM in 2015.
There are different treatment flowcharts: Treon and mSMART.
WM patients are at higher risk of developing second cancers than the general population, however it is not yet clear whether treatments are contributory.
In the absence of symptoms, many clinicians will recommend simply monitoring the patient. Waldenström himself stated "let well do" referring to watch and wait for patients who can simply be monitored without treatment. But on occasion the disease can be fatal, as it was to the French president Georges Pompidou, who died in office in 1974. The Shah of Iran also suffered from Waldenstrom's Macroglobulinemia which resulted in his ill fated trip to the US for therapy in 1979, leading to the takeover of the US Embassy in Tehran.
Should treatment be started it should address both the paraprotein level and the lymphocytic B-cells.
As of October 2010, there have been a total of 44 clinical trials on Waldenstrom's macroglobulinemia, excluding transplantion treatments. Of these, 11 were performed on previously untreated patients, 14 in patients with relapsed or refractory Waldenstrom's. A database of clinical trials investigating Waldenström's macroglobulinemia is maintained by the National Institutes of Health in the US.
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