Waldenström's macroglobulinemia

Waldenström's macroglobulinemia
Classification and external resources
ICD-10 C88.0
ICD-9 273.3
ICD-O: M9761/3
OMIM 153600
DiseasesDB 14030
MedlinePlus 000588
eMedicine med/2395
MeSH D008258

Waldenström's macroglobulinemia (WM, also known as lymphoplasmacytic lymphoma) is cancer involving a subtype of white blood cells called lymphocytes. The main attributing antibody is Immunoglobulin M (IgM). WM is an "indolent lymphoma," (i.e., one that tends to grow and spread slowly). It is a type of lymphoproliferative disease, which shares clinical characteristics with the indolent non-Hodgkin lymphomas.[1]

The disease, named after the Swedish oncologist Jan 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.[2]

Contents

History and classification

WM was first described by Jan G. Waldenström (1906–1996) in 1944 in two patients with bleeding from the nose and mouth, anemia, decreased levels of fibrinogen in the blood (hypofibrinogenemia), swollen lymph nodes, neoplastic plasma cells in bone marrow, and increased viscosity of the blood due to increased levels of a class of heavy proteins called macroglobulins.[3]

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.[4] In recent years, there have been significant advances in the biology and treatment of WM.[5]

Causes

Waldenström's macroglobulinemia is characterized by an uncontrolled clonal proliferation of terminally differentiated B lymphocytes. The underlying etiology is not yet known but a number of risk factors have been identified. There has been an association demonstrated with the locus 6p21.3 on chromosome 6.[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.[7]

There are genetic factors, with first-degree relatives shown to have a highly increased risk of also contracting Waldenström's.[8] 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.[9]

Biochemistry

Although believed to be a sporadic disease, studies have shown increased susceptibility within families, indicating a genetic component.[10][11] However, genetic involvement is poorly understood. 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.[12]

Comparative genomic hybridization identified the following chromosomal abnormalities: deletions of 6q23 and 13q14, and gains of 3q13-q28, 6p and 18q.[13] FGFR3 is overexpressed.[14] The following signalling pathways have been implicated:

The protein Src tyrosine kinase is overexpressed in Waldenström macroglobulinemia cells compared with control B cells.[24] Inhibition of Src arrests the cell cycle at phase G1 and has little effect on the survival of WM or normal cells.

MicroRNAs involved in Waldenström's[25][26]:

MicroRNA-155 regulates the proliferation and growth of WM cells in vitro and in vivo, by inhibiting MAPK/ERK, PI3/AKT, and NF-κB pathways.

In WM-cells, histone deacetylases and histone-modifying genes are de-regulated.[34]

Bone marrow tumour cells express the following antigen targets CD20 (98.3%), CD22 (88.3%), CD40 (83.3%), CD52 (77.4%), IgM (83.3%), MUC1 core protein (57.8%), and 1D10 (50%).[35]

Epidemiology

Of all cancers involving the same class of blood cell, 1% of cases are WM.[36]

WM is a rare disorder, with fewer than 1,500 cases occurring in the United States annually.[1] The median age of onset of WM is between 60 and 65 years, with some cases occurring in late teens.[1][37]

Symptoms

Symptoms of WM include weakness, fatigue, weight loss and chronic oozing of blood from the nose and gums.[38] Peripheral neuropathy can occur in 10% of patients. Lymphadenopathy, splenomegaly, and/or hepatomegaly are present in 30-40% of cases.[37] Other possible symptoms include blurring or loss of vision, headache, and (rarely) stroke or coma.

Pathophysiology

Symptoms blurring or loss of vision, headache, and (rarely) stroke or coma are due to the effects of the IgM paraprotein, 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.[39][40][41][42] 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.[43]

Diagnosis

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.[44] 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.[45]

Additional tests such as computed 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 WM and multiple myeloma.[45] Anemia is typically found in 80% of patients with WM. Leukopenia, and thrombocytopenia may be observed. Neutropenia may also be found in some patients.[44]

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

Prognosis

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.[1] Currently, median survival is 6.5 years.[46] In rare instances, WM progresses to multiple myeloma.[47]

The International Prognostic Scoring System for Waldenström’s Macroglobulinemia (IPSSWM) is a predictive model to characterise long-term outcome.[48][49] According to the model, factors predicting survival (n.b. the study quoted conversely refers to them as "5 adverse covariates") are:

age >65 years;
hemoglobin ≤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.[50]

The IPSSWM has been shown to be reliable.[51] It is also applicable to patients on a Rituximab-based treatment regimen.[50] An additional predictive factor is elevated serum lactate dehydrogenase (LDH).[52]

Treatment

There is no single accepted treatment for WM.[53] 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%).[5]

There are different treatment flowcharts: Treon[54] and mSMART.[55]

WM patients are at higher risk of developing second cancers than the general population, however it is not yet clear whether treatments are contributory.[56]

Watchful waiting

In the absence of symptoms, many clinicians will recommend simply monitoring the patient.[57] But on occasion the disease can be fatal, as it was to its best known sufferer, the former French president Georges Pompidou, who died in 1974. Indeed, in 1991, Waldenström himself raised the question of the need for effective therapy.[58]

First-line

Should treatment be started it should address both the paraprotein level and the lymphocytic B-cells.[59]

In 2002, a panel at the International Workshop on Waldenström Macroglobulinemia agreed on criteria for the initiation of therapy. They recommended starting therapy in patients with constitutional symptoms such as recurrent fever, night sweats, fatigue due to anemia, weight loss, progressive symptomatic lymphadenopathy or splenomegaly, and anemia due to marrow infiltration. Complications such as hyperviscosity syndrome, symptomatic sensorimotor peripheral neuropathy, systemic amyloidosis, renal insufficiency, or symptomatic cryoglobulinemia were also suggested as indications for therapy.[60]

Treatment includes the monoclonal antibody rituximab, sometimes in combination with chemotherapeutic drugs such as chlorambucil, cyclophosphamide, or vincristine or with thalidomide.[61] Corticosteroids, such as Prednisone, 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.[62]

Recently, autologous bone marrow transplantation has been added to the available treatment options.[63][64][65][66]

Salvage therapy

When primary or secondary resistance invariably develops, salvage therapy is considered. Allogeneic stem cell transplantation can induce durable remissions for heavily pre-treated patients.[67]

Drug pipeline

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.[68] A database of clinical trials investigating Waldenström's macroglobulinemia is maintained by the National Institutes of Health in the US.[69]

Patient stratification

Patients with polymorphic variants (alleles) FCGR3A-48 and -158 were associated with improved categorical responses to Rituximab-based treatments.[70]

See also

References

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