Waldenström macroglobulinemia (/ˈvældənstrɒmˌmækroʊˌɡlɒbjəlɪˈniːmiə/VAL-dən-stromMAK-roh-GLOB-yə-lin-EE-mee-ə,^[1][2]US also/ˈvɑːldənstrɛm-/VAHL-dən-strem -⁠^[3]) is a type ofcancer affecting two types ofwhite blood cells: lymphoplasmacytoid cells and plasma cells (bothB cells). It is characterized by having high levels of a circulatingantibody,immunoglobulin M (IgM), which is made and secreted by the cells involved in the disease. Waldenström macroglobulinemia is an "indolent lymphoma" (i.e., one that tends to grow and spread slowly) and a type oflymphoproliferative disease that shares clinical characteristics with the indolentnon-Hodgkin lymphomas.^[4] It is commonly classified as a form ofplasma cell dyscrasia, similar to other plasma cell dyscrasias that, for example, lead tomultiple myeloma. Waldenström macroglobulinemia is commonly preceded by two clinically asymptomatic but progressively morepre-malignant phases,IgM monoclonal gammopathy of undetermined significance andsmoldering Waldenström macroglobulinemia. The Waldenström macroglobulinemia spectrum of dysplasias differs from other spectrums of plasma cell dyscrasias in that it involves not only aberrant plasma cells but also aberrant lymphoplasmacytoid cells and that it involves IgM while other plasma dyscrasias involve other antibodyisoforms.^[5][6]

Waldenström macroglobulinemia is a rare disease, with only about 1,500 cases per year in theUnited States. It occurs more frequently in older adults.^[7] 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-freeremission.^[8]

Signs and symptoms of Waldenström macroglobulinemia includeweakness,fatigue,weight loss, and chronic oozing ofblood from the nose and gums.^[9]Peripheral neuropathy occurs in 10% of patients.Enlargement of the lymph nodes,spleen, and/orliver are present in 30–40% of cases.^[10] Other possible signs and symptoms include blurring or loss of vision,headache, and (rarely)stroke orcoma.^{[citation needed]}

Waldenström macroglobulinemia is characterized by an uncontrolled clonal proliferation of terminally differentiated B lymphocytes. The most commonly associated mutations, based on whole-genome sequencing of 30 patients, are asomatic mutation inMYD88 (90% of patients) and a somatic mutation inCXCR4 (27% of patients).^[11] CXCR4 mutations cause symptomatichyperviscosity syndrome and high bone marrow activity characteristic of the disease.^[12] However, CXCR4 mutation is not associated withsplenomegaly, high platelet counts, or different response to therapy, questioning the relevance of CXCR4 in treating patients.^[12] An association has been demonstrated with the locus 6p21.3 onchromosome 6.^[13] There is a two-to-threefold increased risk of Waldenström macroglobulinemia in people with a personal history ofautoimmune diseases withautoantibodies, and a particularly elevated risk associated withhepatitis,human immunodeficiency virus, andrickettsiosis.^[14]

There aregenetic factors with first-degree relatives of Waldenström macroglobulinemia patients shown to have a highly increased risk of also developing the disease.^[15] There is also evidence to suggest thatenvironmental factors, including exposure to farming, pesticides, wood dust, and organic solvents, may influence the development of Waldenström macroglobulinemia.^[16]

Although believed to be a sporadic disease, studies have shown increased susceptibility within families, indicating a genetic component.^[17][18] A mutation in geneMYD88 has been found to occur frequently in patients.^[19] Waldenström macroglobulinemia cells show only minimal changes incytogenetic andgene expression studies. However, theirmiRNA signature differs from their normal counterpart. Therefore,epigenetic modifications play a crucial role in the disease.^[20]

Comparative genomic hybridization identified the followingchromosomal abnormalities: deletions of 6q23 and 13q14, and gains of 3q13-q28, 6p and 18q.^[21]FGFR3 is overexpressed.^[22] The followingsignalling pathways have been implicated:

• CD154/CD40^[23]
• Akt^[24]
• ubiquitination,p53 activation, andcytochrome c release^[25]
• NF-κB^[26][27]
• Wnt/beta-catenin^[28]
• mTOR^[29]
• ERK^[26]
• MAPK^[30]
• Bcl-2^[31]

The proteinSrc tyrosine kinase is overexpressed in Waldenström macroglobulinemia cells compared with control B cells.^[32] Inhibition of Src arrests thecell cycle at phase G₁ and has little effect on the survival of Waldenström macroglobulinemia or normal cells.

MicroRNAs involved in Waldenström macroglobinemia:^[33][34]

• increased expression of miRNAs-363*,^[35] -206,^[36] -494,^[37] -155,^[38] -184,^[39] -542–3p.^[40]
• decreased expression of miRNA-9*^[41]
• microRNA-155 regulates the proliferation and growth of Waldenström macroglobulinemia cells in vitro and in vivo by inhibiting MAPK/ERK, PI3/AKT, and NF-κB pathways.^{[citation needed]}

In Waldenström macroglobulinemia cells,histone deacetylases and histone-modifying genes are de-regulated.^[42] Bone marrow tumor cells express the following antigen targetsCD20 (98.3%),CD22 (88.3%),CD40 (83.3%),CD52 (77.4%),IgM (83.3%),MUC1 core protein (57.8%), and 1D10 (50%).^[43]

Symptoms including blurring or loss of vision, headache, and (rarely)stroke orcoma are due to the effects of theIgMparaprotein, which may causeautoimmune phenomena orcryoglobulinemia. Other symptoms of Waldenström macroglobulinemia are due tohyperviscosity syndrome, which is present in 6–20% of patients.^{[44][45][46][47]} This is attributed to the IgM monoclonal protein molecules 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.^[48]

A diagnosis of Waldenström macroglobulinemia depends on a significant monoclonal IgM spike, which is evident in blood tests andmalignant cells consistent with the disease inbone marrow biopsy samples.^[49] Blood tests show the level of IgM in the blood and the presence of proteins, or tumor markers, that are the key signs of Waldenström macroglobulinemia. A bone marrow biopsy provides a sample of bone marrow, usually from the lower back of the pelvis bone. The sample is extracted through a needle and examined under a microscope. Apathologist identifies the particularlymphocytes that indicate Waldenström macroglobulinemia.Flow cytometry may be used to examine markers on the cell surface or inside the lymphocytes.^[50]

Additional tests such ascomputed tomography (CT or CAT) scan may be used to evaluate the chest, abdomen, and pelvis, particularly swelling of the lymph nodes, liver, and spleen. A skeletal survey can help distinguish between Waldenström macroglobulinemia andmultiple myeloma.^[50]Anemia occurs in about 80% of patients with Waldenström macroglobulinemia. Alow white blood cell count andlow platelet count in the blood may be observed. Alow level of neutrophils (a specific type of white blood cell) may also be found in some individuals with Waldenström macroglobulinemia.^[49]

Chemistry tests includelactate dehydrogenase (LDH) levels, uric acid levels,erythrocyte sedimentation rate (ESR), kidney and liver function, total protein levels, and an albumin-to-globulin ratio. The ESR anduric acid level may beelevated.Creatinine is occasionally elevated, and electrolytes are sometimes abnormal. Ahigh blood calcium level 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 titer results can be positive.Beta-2 microglobulin andC-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 light chain's clonality, and the paraprotein's monoclonality and quantitation. 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 one g/d in approximately 3%. Patients with findings ofperipheral neuropathy should havenerve conduction studies and antimyelin-associated glycoprotein serology.^{[citation needed]}

Criteria for diagnosis of Waldenström macroglobulinemia include:

1. IgM monoclonal gammopathy that excludeschronic lymphocytic leukemia andmantle cell lymphoma.
2. Evidence of anemia, constitutional symptoms, hyperviscosity,swollen lymph nodes, orenlargement of the liver and spleen that can be attributed to an underlying lymphoproliferative disorder.^[51]

There is no single accepted treatment for Waldenström macroglobulinemia.^[52] There is marked variation in clinical outcomes due to gaps in knowledge of the disease's molecular basis. Objectiveresponse rates are high (> 80%), but complete response rates are low (0–15%).^[53] The medicationibrutinib targets the MYD88 L265P mutation induced activation ofBruton's tyrosine kinase.^[54] In a cohort study of previously treated patients, ibrutinib induced responses in 91% of patients, and at 2 years 69% of patients had no progression of disease and 95% were alive.^[55] Based on this study, theFood and Drug Administration approved ibrutinib for use in Waldenström macroglobulinemia in 2015.^[56]

There are different treatment flowcharts: Treon^[57] and mSMART.^{[58][clarification needed]}

Patients with Waldenström macroglobulinemia are at higher risk of developing second cancers than the general population, but it is not yet clear whether treatments are contributory.^[59]

In the absence of symptoms, many clinicians will recommend simply monitoring the patient;^[60] Waldenström himself stated "let well do" for such patients. These asymptomatic cases are now classified as two successively morepre-malignant phases,IgM monoclonal gammopathy of undetermined significance andsmoldering Waldenström macroglobulinemia.^[5][6] But on occasion, the disease can be fatal, as it was to the French presidentGeorges Pompidou, who died in office in 1974, six years after the discovery of his cancer.Mohammad Reza Shah Pahlavi, the Shah of Iran, also had Waldenström macroglobulinemia, which resulted in his ill-fated trip to the United States for therapy in 1979, leading to theIran hostage crisis.^[61]

Should treatment be started it should address both the paraprotein level and the lymphocytic B-cells.^[62]

In 2002, a panel at the International Workshop on Waldenström's Macroglobulinemia agreed on criteria for the initiation of therapy. They recommended starting treatment in patients with constitutional symptoms such as recurrentfever,night sweats,fatigue due toanemia,weight loss, progressive symptomaticlymphadenopathy orspleen enlargement, andanemia due to bone marrow infiltration. Complications such as hyperviscosity syndrome, symptomatic sensorimotor peripheral neuropathy, systemicamyloidosis,kidney failure, or symptomaticcryoglobulinemia were also suggested as indications for therapy.^[63]

Treatment includes the monoclonal antibodyrituximab, sometimes in combination with chemotherapeutic drugs such aschlorambucil,cyclophosphamide, orvincristine or withthalidomide.^[64]Corticosteroids, such asprednisone, may also be used in combination.Plasmapheresis can be used to treat the hyperviscosity syndrome by removing the paraprotein from the blood, although it does not address the underlying disease.^[65]Ibrutinib is another agent that has been approved for use in this condition. Combination treatment with ibrutinib and rituximab showed significantly higher disease progression-free survival than with rituximab alone.^[66]

Autologousbone marrow transplantation is a treatment option.^{[67][68][69][70]}

Zanubrutinib, another BTK inhibitor, isindicated for the treatment of adults with Waldenström macroglobulinemia.^[71] For patients experiencing hyperviscosity syndrome, plasmapheresis is used to reduce IgM levels in the blood rapidly.^[72]

When primary or secondaryresistance invariably develops,salvage therapy is considered.Allogeneic stem cell transplantation can induce durable remissions for heavily pre-treated patients.^[73]

As of October 2010, there have been 44 clinical trials on Waldenström macroglobulinemia, excluding transplantation treatments. Of these, 11 were performed on previously untreated patients, 14 in patients with relapsed or refractory Waldenström.^[74] A database of clinical trials investigating Waldenström macroglobulinemia is maintained by theNational Institutes of Health in the U.S..^[75]

Patients withpolymorphic variants (alleles)FCGR3A-48 and -158 were associated with improved categorical responses to rituximab-based treatments.^[76]

Current medical treatments result in survival of some longer than 10 years, partly because better diagnostic capabilities mean early diagnosis and treatments. Older age at diagnosis and treatment resulted in published reports of median survival of approximately 5 years from diagnosis.^[4] Currently, median survival is 6.5 years.^[77] In rare instances, Waldenström macroglobulinemia progresses tomultiple myeloma.^[78]

The International Prognostic Scoring System for Waldenström's Macroglobulinemia is a predictive model to characterise long-term outcomes.^[79][80] According to the model, factors predicting reduced survival^[81] are:

• Age > 65 years
• Hemoglobin ≤ 11.5 g/dL
• Platelet count ≤ 100 billion/L
• B2-microglobulin > 3 mg/L
• Serum monoclonal protein concentration > 70 g/L

The risk categories are:

• Low: ≤ 1 adverse variable except for 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.^[82] The corresponding median survival rates are 12, 8, and 3.5 years.^[83]

The International Prognostic Scoring System for Waldenström's Macroglobulinemia has been shown to be reliable.^[84] It is also applicable to patients on a rituximab-based treatment regimen.^[82] An additional predictive factor is elevated serum lactate dehydrogenase (LDH).^[85]

Ofcancers involving the lymphocytes, 1% of cases are Waldenström macroglobulinemias.^[86] A rare disorder, there are fewer than 1,500 cases diagnosed in the United States annually.

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The median age of onset is between 60 and 65 years, with some cases occurring in late teens. Notable victims of the disease include dancer/choreographerGower Champion, who died of the disease in 1980, aged 61;^[4][10] and former French presidentGeorges Pompidou.

Waldenström macroglobulinemia was first described byJan G. Waldenström (1906–1996) in 1944 in two patients with bleeding from the nose and mouth,anemia, decreased levels offibrinogen in the blood (hypofibrinogenemia),swollen lymph nodes, neoplastic plasma cells in bone marrow, andincreased viscosity of the blood due to increased levels of a class of heavy proteins calledmacroglobulins.^[87]

For a time, Waldenström macroglobulinemia was considered to be related tomultiple myeloma because of the presence ofmonoclonal gammopathy and infiltration of the bone marrow and other organs by plasmacytoid lymphocytes. The newWorld Health Organization (WHO) classification, however, places Waldenström macroglobulinemia under the category of lymphoplasmacytic lymphomas, itself a subcategory of the indolent (low-grade) non-Hodgkin lymphomas.^[88] Since the 1990s, there have been significant advances in the understanding and treatment of Waldenström macroglobulinemia.^[53]

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