Waldenström's macroglobulinemia

Waldenström's macroglobulinemia

DiseaseDisorder infobox
Name = Waldenström's macroglobulinemia
ICD10 = ICD10|C|88|0|c|81
ICDO = ICDO|9761|3
ICD9 = ICD9|273.3
OMIM = 153600
MedlinePlus = 000588
eMedicineSubj = med
eMedicineTopic = 2395
DiseasesDB = 14030
MeshID = 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.cite book | author = Cheson BD | year = 2006 | title = ACP Medicine | chapter = Chronic Lymphoid Leukemias and Plasma Cell Disorders | editor = Dale DD, Federman DD | publisher = WebMD Professional Publishing | location = New York, NY | id = ISBN 0974832715 ]

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

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.cite journal | author= Waldenstrom J | title=Incipient myelomatosis or "essential" hyperglobulinemia with fibrinognenopenia-a new syndrome? | journal=Acta Med Scand| year=1944 | pages=216–247 | volume=117 ]

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. cite journal | author=Harris NL, Jaffe ES, Diebold J, Flandrin G, Muller-Hermelink HK, Vardiman J, Lister TA, Bloomfield CD | title=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 | journal=Histopathology | year=2000 | pages=69–86 | volume=36 | issue=1 | pmid=10632755 | doi=10.1046/j.1365-2559.2000.00895.x]


The underlying cause is not yet known. However, there has been an association demonstrated with the locus 6p21.3 on chromosome 6.cite journal |author=Schop RF, Van Wier SA, Xu R, "et al" |title=6q deletion discriminates Waldenström macroglobulinemia from IgM monoclonal gammopathy of undetermined significance |journal=Cancer Genet. Cytogenet. |volume=169 |issue=2 |pages=150–3 |year=2006 |pmid=16938573 |doi=10.1016/j.cancergencyto.2006.04.009]


Of all cancers involving the same class of blood cell, 1% of cases are WM.cite book
author=Turgeon, Mary Louise
title=Clinical hematology: theory and procedures
publisher=Lippincott Williams & Wilkins
location=Hagerstown, MD
quote=Frequency of lymphoid neoplasms. (Source: Modified from WHO Blue Book on Tumour of Hematopoietic and Lymphoid Tissues. 2001, p. 2001.)

WM is a rare disorder, with fewer than 1,500 cases occurring in the United States annually. The median age of onset of WM is between 60 and 65 years, with some cases occurring in late teens.cite book | author = Raje N, Hideshima T, Anderson KC | year = 2003 | title = Holland-Frei Cancer Medicine | chapter = Plasma Cell Tumors | edition=6th edition | editor = Kufe DW, Pollock RE, Weichselbaum RR, Bast RC, Gansler TS| publisher = B.C. Decker | location = New York, NY | id = ISBN 1550092138 ]


Symptoms of WM include weakness, fatigue, weight loss and chronic oozing of blood from the nose and gums.cite book | author =Kyle RA | year = 1998 | title = Internal Medicine | chapter = Chapter 94: Multiple Myeloma and the Dysproteinemias | editor = Stein JH | edition = 5th ed. | publisher = C.V.Mosby | location = New York | id = ISBN 0815186983 ] Peripheral neuropathy can occur in 10% of patients. Lymphadenopathy, splenomegaly, and/or hepatomegaly are present in 30-40% of cases. 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.cite journal | author=Owen RG, Barrans SL, Richards SJ, O'Connor SJ, Child JA, Parapia LA, Morgan GJ, Jack AS | title=Waldenstrom macroglobulinemia. Development of diagnostic criteria and identification of prognostic factors | journal=Am J Clin Pathol | year=2001 | pages=420–8 | volume=116 | issue=3 | pmid=11554171 | doi=10.1309/4LCN-JMPG-5U71-UWQB] cite journal | author=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 | title=Immunophenotypic analysis of Waldenstrom's macroglobulinemia | journal=Semin Oncol | year=2003 | pages=187–95 | volume=30 | issue=2 | pmid=12720134 | doi=10.1053/sonc.2003.50074] cite journal | author=Ghobrial IM, Witzig TE | title=Waldenstrom macroglobulinemia | journal=Curr Treat Options Oncol | year=2004 | pages=239–47 | volume=5 | issue=3 | pmid=15115652 | doi=10.1007/s11864-004-0015-5] cite journal | author=Dimopoulos MA, Kyle RA, Anagnostopoulos A, Treon SP | title=Diagnosis and management of Waldenstrom's macroglobulinemia | journal=J Clin Oncol | year=2005 | pages=1564–77 | volume=23 | issue=7 | pmid=15735132 | doi=10.1200/JCO.2005.03.144] 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.


A distinguishing feature of WM is the presence of an IgM monoclonal protein (or paraprotein) that is produced by the cancer cells, and a concurrent decrease in levels of uninvolved immunoglobulins (i.e., IgG and IgA).

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 CBC 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


Current medical treatments result in survival 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. New treatments have made longer term survival a reality for many with this condition. In rare instances, WM progresses to multiple myeloma.cite journal | author=Johansson B, Waldenstrom J, Hasselblom S, Mitelman F | title=Waldenstrom's macroglobulinemia with the AML/MDS-associated t(1;3)(p36;q21) | journal=Leukemia | year=1995 | pages=1136–8 | volume=9 | issue=7 | pmid=7630185]


There is no single accepted treatment for WM. Indeed, in 1991, Waldenström himself raised the question of the need for effective therapy. [cite journal | author=Waldenstrom J | title=To treat or not to treat, this is the real question | journal=Leuk Res | year=1991 | pages=407–8 | volume=15 | issue=6 | pmid=1907339 | doi=10.1016/0145-2126(91)90049-Y] In the absence of symptoms, many clinicians will recommend simply monitoring the patient.

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.cite journal | author=Kyle RA, Treon SP, Alexanian R, Barlogie B, Bjorkholm M, Dhodapkar M, Lister TA, Merlini G, Morel P, Stone M, Branagan AR, Leblond V | title=Prognostic markers and criteria to initiate therapy in Waldenstrom's macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom's Macroglobulinemia | journal=Semin Oncol | year=2003 | pages=116–20 | volume=30 | issue=2 | pmid=12720119 | doi=10.1053/sonc.2003.50038]

Treatment includes the monoclonal antibody rituximab, sometimes in combination with chemotherapeutic drugs such as chlorambucil, cyclophosphamide, or vincristine. 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.cite journal | author=Gertz MA | title=Waldenstrom macroglobulinemia: a review of therapy | journal=Am J Hematol | year=2005 | pages=147–57 | volume=79 | issue=2 | pmid=15929102 | doi=10.1002/ajh.20363]

Recently, autologous bone marrow transplantation has been added to the available treatment options.cite journal | author=Yang L, Wen B, Li H, Yang M, Jin Y, Yang S, Tao J | title=Autologous peripheral blood stem cell transplantation for Waldenstrom's macroglobulinemia | journal=Bone Marrow Transplant | year=1999 | pages=929–30 | volume=24 | issue=8 | pmid=10516708 | doi=10.1038/sj.bmt.1701992] cite journal | author=Martino R, Shah A, Romero P, Brunet S, Sierra J, Domingo-Albos A, Fruchtman S, Isola L | title=Allogeneic bone marrow transplantation for advanced Waldenstrom's macroglobulinemia | journal=Bone Marrow Transplant | year=1999 | pages=747–9 | volume=23 | issue=7 | pmid=10218857 | doi=10.1038/sj.bmt.1701633] cite journal | author=Anagnostopoulos A, Dimopoulos MA, Aleman A, Weber D, Alexanian R, Champlin R, Giralt S | title=High-dose chemotherapy followed by stem cell transplantation in patients with resistant Waldenstrom's macroglobulinemia | journal=Bone Marrow Transplant | year=2001 | pages=1027–9 | volume=27 | issue=10 | pmid=11438816 | doi=10.1038/sj.bmt.1703041] cite journal | author=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 | title=Transplantation in Waldenstrom's macroglobulinemia--the French experience | journal=Semin Oncol | year=2003 | pages=291–6 | volume=30 | issue=2 | pmid=12720155 | doi=10.1053/sonc.2003.50048]

Drug pipeline

A database of clinical trials investigating Waldenstrom's macroglobulinemia is maintained by the National Institutes of Health in the US. [http://clinicaltrials.gov/ct2/results?term=Waldenstrom]

Phase IV

* none

Phase III

* Comparison between Chlorambucil and Fludarabine [ClinicalTrialsGov|NCT00608374] [ClinicalTrialsGov|NCT00566332]

Phase II

There are over 100 active trials studying different interventions. [ [http://clinicaltrials.gov/ct2/results?term=Waldenstrom&recr=&type=Intr&cond=&intr=&spons=&id=&state1=&cntry1=&state2=&cntry2=&state3=&cntry3=&locn=&phase=1&rcv_s=&rcv_e=&lup_s=&lup_e=] ] 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, and Denileukin diftitox.


External links

* [http://www.iwmf.com/ The International Waldenström's Macroglobulinemia Foundation site]
* [http://www.cancer.gov/cancertopics/factsheet/Sites-Types/WM National Cancer Institute's Waldenström's Macroglobulinemia Q&A]
* [http://www.cancer.org/docroot/CRI/CRI_2_3x.asp?dt=76 American Cancer Society Detailed Guide: Waldenström's Macroglobulinemia]
* [http://www.waldenstromsresearch.org/ Research Fund for Waldenström's]

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