Waldenström's macroglobulinemia

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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 IgM. It is a type of lymphoproliferative disease, and shares clinical characteristics with the indolent non-Hodgkin lymphomas.[1]

It is named after the Swedish physician Jan G. Waldenström, who first identified the condition.

Contents

[edit] 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.[2]

For a period of 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. [3]

[edit] Causes

Waldenstrom'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.[4] 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.[5]

There are genetic factors, with first-degree relatives shown to have a highly increased risk of also contracting Waldenstrom's.[6]

[edit] Biochemistry

The following pathways have been implicated:

The protein Src tyrosine kinase is overexpressed in Waldenstrom macroglobulinemia cells compared with control B cells.[15] 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 Waldenstrom's[16][17]:

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

[edit] Epidemiology

Of all cancers involving the same class of blood cell, 1% of cases are WM.[25]

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][26]

[edit] Symptoms

Symptoms of WM include weakness, fatigue, weight loss and chronic oozing of blood from the nose and gums.[27] Peripheral neuropathy can occur in 10% of patients. Lymphadenopathy, splenomegaly, and/or hepatomegaly are present in 30-40% of cases.[26] Some symptoms 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.[28][29][30][31] This is attributed to the IgM monoclonal protein increasing the viscosity of the blood. Symptoms of this are mainly neurologic and can include blurring or loss of vision, headache, and (rarely) stroke or coma.

[edit] Diagnosis

A distinguishing feature of WM is the presence of an IgM monoclonal protein (or paraprotein) that is produced by the cancer cells.

Lab Studies:

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 80% 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 50% 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 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

[edit] 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 [32]. In rare instances, WM progresses to multiple myeloma.[33]

The International Prognostic Scoring System for Waldenström’s Macroglobulinemia (IPSSWM) is a predictive model to characterise long-term outcome.[34] According to the model, factors predicting survival 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.[35]

The IPSSWM has been shown applicable to patients on a Rituximab-based treatment regimen.[35] An additional predictive factor is elevated serum lactate dehydrogenase (LDH).[36]

[edit] Treatment

There is no single accepted treatment for WM[37]. Indeed, in 1991, Waldenström himself raised the question of the need for effective therapy.[38] In the absence of symptoms, many clinicians will recommend simply monitoring the patient [39]. Should treatment be started it should address both the paraprotein level and the lymphocytic B-cells.[40]

In 2002, a panel at the International Workshop on Waldenstrom 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.[41]

Treatment includes the monoclonal antibody rituximab, sometimes in combination with chemotherapeutic drugs such as chlorambucil, cyclophosphamide, or vincristine or with thalidomide[42]. Corticosteroids 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.[43]

Recently, autologous bone marrow transplantation has been added to the available treatment options.[44][45][46][47]

[edit] Drug pipeline

A database of clinical trials investigating Waldenstrom's macroglobulinemia is maintained by the National Institutes of Health in the US.[48]

[edit] Phase IV

  • none

[edit] Phase III

  • Comparison between Chlorambucil and Fludarabine[49][50]

[edit] Phase II

There are over 100 active trials studying different interventions.[51] Interventions include either individually or combinations of Fludarabine, Perifosine, Bortezomib, Rituximab, Sildenafil citrate, CC-5013, Thalidomide, Simvastatin, Campath-1H, Dexamethasone, Antineoplaston, Beta Alethine, Dolastatin 10, Cyclophosphamide, Yttrium Y 90 Ibritumomab, ABT-263, Ofatumumab, Enzastaurin and Denileukin diftitox.

[edit] See also

[edit] References

  1. ^ a b c d Cheson BD (2006). "Chronic Lymphoid Leukemias and Plasma Cell Disorders". in Dale DD, Federman DD. ACP Medicine. New York, NY: WebMD Professional Publishing. ISBN 0974832715. 
  2. ^ Waldenstrom J (1944). "Incipient myelomatosis or "essential" hyperglobulinemia with fibrinognenopenia-a new syndrome?". Acta Med Scand 117: 216–247. 
  3. ^ Harris NL, Jaffe ES, Diebold J, Flandrin G, Muller-Hermelink HK, Vardiman J, Lister TA, Bloomfield CD (2000). "The World Health Organization classification of neoplastic diseases of the haematopoietic and lymphoid tissues: Report of the Clinical Advisory Committee Meeting, Airlie House, Virginia, November 1997". Histopathology 36 (1): 69–86. doi:10.1046/j.1365-2559.2000.00895.x. PMID 10632755. 
  4. ^ Schop RF, Van Wier SA, Xu R, et al. (2006). "6q deletion discriminates Waldenström macroglobulinemia from IgM monoclonal gammopathy of undetermined significance". Cancer Genet. Cytogenet. 169 (2): 150–3. doi:10.1016/j.cancergencyto.2006.04.009. PMID 16938573. 
  5. ^ PMID 18809818
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  7. ^ http://www.asco.org/ASCO/Abstracts+&+Virtual+Meeting/Abstracts?&vmview=abst_detail_view&confID=26&abstractID=4297
  8. ^ doi:10.1182/blood-2007-05-092098
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  18. ^ http://www.mirbase.org/cgi-bin/mirna_entry.pl?acc=MI0000764
  19. ^ http://www.mirbase.org/cgi-bin/mirna_entry.pl?acc=MI0000490
  20. ^ http://www.mirbase.org/cgi-bin/mirna_entry.pl?acc=MI0003134
  21. ^ http://www.mirbase.org/cgi-bin/mirna_entry.pl?acc=MI0000681
  22. ^ http://www.mirbase.org/cgi-bin/mirna_entry.pl?acc=MI0000481
  23. ^ http://www.mirbase.org/cgi-bin/mirna_entry.pl?acc=MI0003686
  24. ^ http://www.mirbase.org/cgi-bin/mirna_entry.pl?acc=MI0000466
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  26. ^ a b Raje N, Hideshima T, Anderson KC (2003). "Plasma Cell Tumors". in Kufe DW, Pollock RE, Weichselbaum RR, Bast RC, Gansler TS. Holland-Frei Cancer Medicine (6th ed.). New York, NY: B.C. Decker. ISBN 1550092138. 
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  29. ^ San Miguel JF, Vidriales MB, Ocio E, Mateo G, Sanchez-Guijo F, Sanchez ML, Escribano L, Barez A, Moro MJ, Hernandez J, Aguilera C, Cuello R, Garcia-Frade J, Lopez R, Portero J, Orfao A (2003). "Immunophenotypic analysis of Waldenstrom's macroglobulinemia". Semin Oncol 30 (2): 187–95. doi:10.1053/sonc.2003.50074. PMID 12720134. 
  30. ^ Ghobrial IM, Witzig TE (2004). "Waldenstrom macroglobulinemia". Curr Treat Options Oncol 5 (3): 239–47. doi:10.1007/s11864-004-0015-5. PMID 15115652. 
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  32. ^ http://emedicine.medscape.com/article/207097-overview
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  39. ^ http://emedicine.medscape.com/article/207097-treatment
  40. ^ PMID 18813229
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  42. ^ PMID 18713945
  43. ^ Gertz MA (2005). "Waldenstrom macroglobulinemia: a review of therapy". Am J Hematol 79 (2): 147–57. doi:10.1002/ajh.20363. PMID 15929102. 
  44. ^ Yang L, Wen B, Li H, Yang M, Jin Y, Yang S, Tao J (1999). "Autologous peripheral blood stem cell transplantation for Waldenstrom's macroglobulinemia". Bone Marrow Transplant 24 (8): 929–30. doi:10.1038/sj.bmt.1701992. PMID 10516708. 
  45. ^ Martino R, Shah A, Romero P, Brunet S, Sierra J, Domingo-Albos A, Fruchtman S, Isola L (1999). "Allogeneic bone marrow transplantation for advanced Waldenstrom's macroglobulinemia". Bone Marrow Transplant 23 (7): 747–9. doi:10.1038/sj.bmt.1701633. PMID 10218857. 
  46. ^ Anagnostopoulos A, Dimopoulos MA, Aleman A, Weber D, Alexanian R, Champlin R, Giralt S (2001). "High-dose chemotherapy followed by stem cell transplantation in patients with resistant Waldenstrom's macroglobulinemia". Bone Marrow Transplant 27 (10): 1027–9. doi:10.1038/sj.bmt.1703041. PMID 11438816. 
  47. ^ Tournilhac O, Leblond V, Tabrizi R, Gressin R, Senecal D, Milpied N, Cazin B, Divine M, Dreyfus B, Cahn JY, Pignon B, Desablens B, Perrier JF, Bay JO, Travade P (2003). "Transplantation in Waldenstrom's macroglobulinemia--the French experience". Semin Oncol 30 (2): 291–6. doi:10.1053/sonc.2003.50048. PMID 12720155. 
  48. ^ http://clinicaltrials.gov/ct2/results?term=Waldenstrom
  49. ^ ClinicalTrials.gov NCT00608374
  50. ^ ClinicalTrials.gov NCT00566332
  51. ^ [1]

[edit] External links

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