Waldenström's macroglobulinemia

From WikiProjectMed
Jump to navigation Jump to search
Waldenström's macroglobulinemia
Other names: Lymphoplasmacytic lymphoma
SpecialtyHematology, oncology

Waldenström's macroglobulinemia (/ˈvældənstrɛmz ˌmækrˌɡlɒbjələˈnmiə/;[1][2] WM) is a type of cancer affecting two types of B cells: lymphoplasmacytoid cells and plasma cells. Both cell types are white blood cells. WM is characterized by having high levels of a circulating antibody, immunoglobulin M (IgM), which is made and secreted by the cells involved in the disease. WM is an "indolent lymphoma" (i.e., one that tends to grow and spread slowly) and a type of lymphoproliferative disease which shares clinical characteristics with the indolent non-Hodgkin lymphomas.[3]

It may present with clear small bumps in skin where monoclonal IgM deposit.[4]

WM is commonly classified as a form of plasma cell dyscrasia, similar to other plasma cell dyscrasias that, for example, lead to multiple myeloma, WM is commonly preceded by two clinically asymptomatic but progressively more pre-malignant phases, IgM monoclonal gammopathy of undetermined significance (i.e. IgM MGUS) and smoldering Waldenström macroglobulinemia. The WM 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 antibody isoforms.[5][6]

WM is a rare disease, with only about 1,500 cases per year in the United States. WM 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-free remission.[8]

Signs and symptoms

Signs and symptoms of WM include weakness, fatigue, weight loss, and chronic oozing of blood from the nose and gums.[9] Peripheral neuropathy occurs in 10% of patients. Enlargement of the lymph nodes, spleen, and/or liver are present in 30–40% of cases.[10] Other possible signs and symptoms include blurring or loss of vision, headache, and (rarely) stroke or coma.[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 a somatic mutation in MYD88 (90% of patients) and a somatic mutation in CXCR4 (27% of patients).[11] An association has been demonstrated with the locus 6p21.3 on chromosome 6.[12] There is a two- to threefold increased risk of WM in people with a personal history of autoimmune diseases with autoantibodies, and a particularly elevated risk associated with liver inflammation, human immunodeficiency virus, and rickettsiosis.[13]

There are genetic factors, with first-degree relatives of WM patients shown to have a highly increased risk of also developing the disease.[14] There is also evidence to suggest that environmental factors, including exposure to farming, pesticides, wood dust, and organic solvents, may influence the development of WM.[15]


Although believed to be a sporadic disease, studies have shown increased susceptibility within families, indicating a genetic component.[16][17] A mutation in gene MYD88 has been found to occur frequently in patients.[18] 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.[19]

Comparative genomic hybridization identified the following chromosomal abnormalities: deletions of 6q23 and 13q14, and gains of 3q13-q28, 6p and 18q.[20] FGFR3 is overexpressed.[21] The following signalling pathways have been implicated:

The protein Src tyrosine kinase is overexpressed in Waldenström macroglobulinemia cells compared with control B cells.[31] 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:[32][33]

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.[41]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%).[42]


Symptoms include 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.[43][44][45][46] 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.[47]


An Eye angiography indicated mild central vein dilation.

A diagnosis of Waldenström macroglobulinemia depends on a significant monoclonal IgM spike evident in blood tests and malignant cells consistent with the disease in bone marrow biopsy samples.[48] Blood tests show the level of IgM in the blood and the presence of proteins, or tumor markers, that are the key signs of WM. 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. 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.[49]

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.[49] Anemia is typically found in 80% of patients with WM. A low white blood cell count, and low platelet count in the blood may be observed. A low level of neutrophils (a specific type of white blood cell) may also be found in some individuals with WM.[48]

Chemistry tests include lactate 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 and uric acid level may be elevated. Creatinine is occasionally elevated and electrolytes are occasionally abnormal. A high 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 titre results can be positive. Beta-2 microglobulin and C-reactive protein test results are not specific for Waldenström's 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's 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.[citation needed]

Criteria for diagnosis of Waldenström macroglobulinemia include:

  1. IgM monoclonal gammopathy that excludes chronic lymphocytic leukemia and Mantle cell lymphoma
  2. Evidence of anemia, constitutional symptoms, hyperviscosity, swollen lymph nodes, or enlargement of the liver and spleen that can be attributed to an underlying lymphoproliferative disorder.[50]


There is no single accepted treatment for WM.[51] 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%).[52] The medication ibrutinib targets the MYD88 L265P mutation induced activation of Bruton's tyrosine kinase.[53] 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.[54] Based on this study, the Food and Drug Administration approved ibrutinib for use in WM in 2015.[55]

There are different treatment flowcharts: Treon[56] and mSMART.[57]

WM patients are at higher risk of developing second cancers than the general population, but it is not yet clear whether treatments are contributory.[58]

Watchful waiting

In the absence of symptoms, many clinicians will recommend simply monitoring the patient;[59] Waldenström himself stated "let well do" for such patients. These asymptomatic cases are now classified as two successively more pre-malignant phases, IgM monoclonal gammopathy of undetermined significance (i.e. IgM MGUS) and smoldering Waldenström's macroglobulinemia.[5][6]

But on occasion, the disease can be fatal, as it was to the French president Georges Pompidou, who died in office in 1974. Mohammad Reza Shah Pahlavi, the Shah of Iran, also suffered from Waldenström macroglobulinemia, which resulted in his ill-fated trip to the United States for therapy in 1979, leading to the Iran hostage crisis.[60]


Should treatment be started it should address both the paraprotein level and the lymphocytic B-cells.[61]

In 2002, a panel at the International Workshop on Waldenström's 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 spleen enlargement, and anemia due to bone marrow infiltration. Complications such as hyperviscosity syndrome, symptomatic sensorimotor peripheral neuropathy, systemic amyloidosis, kidney failure, or symptomatic cryoglobulinemia were also suggested as indications for therapy.[62]

Treatment includes the monoclonal antibody rituximab, sometimes in combination with chemotherapeutic drugs such as chlorambucil, cyclophosphamide, or vincristine or with thalidomide.[63] 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.[64] 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 just Rituximab treatment.[65]

Autologous bone marrow transplantation is a treatment options.[66][67][68][69]

Zanubrutinib is indicated for the treatment of adults with Waldenström's macroglobulinemia.[70]

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.[71]

Drug pipeline

As of October 2010, there have been a total of 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's.[72] A database of clinical trials investigating Waldenström's macroglobulinemia is maintained by the National Institutes of Health in the US.[73]

Patient stratification

Patients with polymorphic variants (alleles) FCGR3A-48 and -158 were associated with improved categorical responses to rituximab-based treatments.[74]


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.[3] Currently, median survival is 6.5 years.[75] In rare instances, WM progresses to multiple myeloma.[76]

The International Prognostic Scoring System for Waldenström’s Macroglobulinemia (IPSSWM) is a predictive model to characterise long-term outcomes.[77][78] According to the model, factors predicting reduced survival[79] 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.[80] The corresponding median survival rates are 12, 8, and 3.5 years.[81]

The IPSSWM has been shown to be reliable.[82] It is also applicable to patients on a rituximab-based treatment regimen.[80] An additional predictive factor is elevated serum lactate dehydrogenase (LDH).[83]


Of all cancers involving the lymphocytes, 1% of cases are WM.[84]

WM is a rare disorder, with fewer than 1,500 cases occurring in the United States annually.[3] The median age of onset of WM is between 60 and 65 years, with some cases occurring in late teens.[3][10]


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.[85]

For a time, WM was considered to be related to multiple myeloma because of 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.[86] In recent years, there have been significant advances in the understanding and treatment of WM.[52]


One recent investigation showed that a population of cells, lacking both B-cell and plasma cell markers, has characteristics of cancer-initiating cells in Waldenström's macroglobulinemia.[87]

See also


  1. "Waldenström's macroglobulinemia". Merriam-Webster Dictionary. Retrieved 24 September 2020.
  2. "macroglobulinemia". Merriam-Webster Dictionary. Retrieved 24 September 2020.
  3. 3.0 3.1 3.2 3.3 Cheson BD (2006). "Chronic Lymphoid Leukemias and Plasma Cell Disorders". In Dale DD, Federman DD (eds.). ACP Medicine. New York, NY: WebMD Professional Publishing. ISBN 978-0-9748327-1-5.
  4. Johnstone, Ronald B. (2017). "14. Cutaneous deposits". Weedon's Skin Pathology Essentials (2nd ed.). Elsevier. p. 290. ISBN 978-0-7020-6830-0. Archived from the original on 2021-05-25. Retrieved 2022-09-28.
  5. 5.0 5.1 van de Donk NW, Mutis T, Poddighe PJ, Lokhorst HM, Zweegman S (2016). "Diagnosis, risk stratification and management of monoclonal gammopathy of undetermined significance and smoldering multiple myeloma". International Journal of Laboratory Hematology. 38 Suppl 1: 110–22. doi:10.1111/ijlh.12504. PMID 27161311.
  6. 6.0 6.1 Abeykoon JP, Yanamandra U, Kapoor P (2017). "New developments in the management of Waldenström macroglobulinemia". Cancer Management and Research. 9: 73–83. doi:10.2147/CMAR.S94059. PMC 5354523. PMID 28331368.
  7. "Waldenstrom macroglobulinemia | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Archived from the original on 2018-04-18. Retrieved 2018-04-17.
  8. International Waldenstrom's Macroglobulinemia Foundation (IWMF). "Living with Waldenstrom's Macroglobulinemia."
  9. Kyle RA (1998). "Chapter 94: Multiple Myeloma and the Dysproteinemias". In Stein JH (ed.). Internal Medicine (5th ed.). New York: C.V.Mosby. ISBN 978-0-8151-8698-4.
  10. 10.0 10.1 Raje N, Hideshima T, Anderson KC (2003). "Plasma Cell Tumors". In Kufe DW, Pollock RE, Weichselbaum RR, Bast RC, Gansler TS (eds.). Holland-Frei Cancer Medicine (6th ed.). New York, NY: B.C. Decker. ISBN 978-1-55009-213-4.
  11. Hunter, Z. R.; Xu, L.; Yang, G.; Zhou, Y.; Liu, X.; Cao, Y.; Manning, R. J.; Tripsas, C.; Patterson, C. J.; Sheehy, P.; Treon, S. P. (2013). "The genomic landscape of Waldenstrom macroglobulinemia is characterized by highly recurring MYD88 and WHIM-like CXCR4 mutations, and small somatic deletions associated with B-cell lymphomagenesis". Blood. 123 (11): 1637–46. doi:10.1182/blood-2013-09-525808. PMID 24366360.
  12. Schop, Roelandt F.J.; Van Wier, Scott A.; Xu, Ruifang; 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.
  13. Koshiol, J.; Gridley, G.; Engels, E.; McMaster, M.; Landgren, O. (2008). "Chronic immune stimulation and subsequent Waldenström macroglobulinemia". Archives of Internal Medicine. 168 (17): 1903–1909. doi:10.1001/archinternmed.2008.4. PMC 2670401. PMID 18809818.
  14. Kristinsson, S.; Björkholm, M.; Goldin, L.; McMaster, M.; Turesson, I.; Landgren, O. (2008). "Risk of lymphoproliferative disorders among first-degree relatives of lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia patients: a population-based study in Sweden". Blood. 112 (8): 3052–3056. doi:10.1182/blood-2008-06-162768. PMC 2569164. PMID 18703425.
  15. Royer, R.; Koshiol, J.; Giambarresi, T.; Vasquez, L.; Pfeiffer, R.; McMaster, M. (2010). "Differential characteristics of Waldenström macroglobulinemia according to patterns of familial aggregation". Blood. 115 (22): 4464–4471. doi:10.1182/blood-2009-10-247973. PMC 2881498. PMID 20308603.
  16. McMaster, M. (2003). "Familial Waldenstrom's macroglobulinemia". Seminars in Oncology. 30 (2): 146–152. doi:10.1053/sonc.2003.50063. PMID 12720125. Archived from the original on 2021-10-17. Retrieved 2021-10-01.
  17. McMaster, M.; Goldin, L.; Bai, Y.; Ter-Minassian, M.; Boehringer, S.; Giambarresi, T.; Vasquez, L.; Tucker, M. (2006). "Genomewide linkage screen for Waldenstrom macroglobulinemia susceptibility loci in high-risk families". American Journal of Human Genetics. 79 (4): 695–701. doi:10.1086/507687. PMC 1592553. PMID 16960805.
  18. Treon, S. P.; Xu, L.; Yang, G.; Zhou, Y.; Liu, X.; Cao, Y.; Sheehy, P.; Manning, R. J.; Patterson, C. J.; Tripsas, C.; Arcaini, L.; Pinkus, G. S.; Rodig, S. J.; Sohani, A. R.; Harris, N. L.; Laramie, J. M.; Skifter, D. A.; Lincoln, S. E.; Hunter, Z. R. (2012). "MYD88 L265P Somatic Mutation in Waldenström's Macroglobulinemia". New England Journal of Medicine. 367 (9): 826–833. doi:10.1056/NEJMoa1200710. PMID 22931316.
  19. Sacco, A.; Issa, G. C.; Zhang, Y.; Liu, Y.; Maiso, P.; Ghobrial, I. M.; Roccaro, A. M. (2010). "Epigenetic modifications as key regulators of Waldenstrom's Macroglobulinemia biology". Journal of Hematology & Oncology. 3: 38. doi:10.1186/1756-8722-3-38. PMC 2964547. PMID 20929526.
  20. Braggio, E.; Keats, J. J.; Leleu, X.; Van Wier, S. V.; Jimenez-Zepeda, V. H.; Schop, R. F. J.; Chesi, M.; Barrett, M.; Stewart, A. K.; Dogan, A.; Bergsagel, P. L.; Ghobrial, I. M.; Fonseca, R. (2009). "High-Resolution Genomic Analysis in Waldenström's Macroglobulinemia Identifies Disease-Specific and Common Abnormalities with Marginal Zone Lymphomas". Clinical Lymphoma, Myeloma & Leukemia. 9 (1): 39–42. doi:10.3816/CLM.2009.n.009. PMC 3646570. PMID 19362969.
  21. Azab, A. K.; Azab, F.; Quang, P.; Maiso, P.; Sacco, B.; Ngo, A.; Liu, H. T.; Zhang, Y.; Morgan, Y.; Roccaro, A. M.; Ghobrial, I. M. (2011). "FGFR3 is overexpressed Waldenstrom macroglobulinemia and its inhibition by Dovitinib induces apoptosis, and overcomes stroma-induced proliferation". Clinical Cancer Research. 17 (13): 4389–4399. doi:10.1158/1078-0432.CCR-10-2772. PMID 21521775.
  22. "Meeting Library Redesign". 2017-05-26.{{cite web}}: CS1 maint: url-status (link)
  23. Leleu, X.; Jia, X.; Runnels, J.; Ngo, H.; Moreau, A.; Farag, M.; Spencer, J.; Pitsillides, C.; Hatjiharissi, E.; Roccaro, A.; O'Sullivan, G.; McMillin, D. W.; Moreno, D.; Kiziltepe, T.; Carrasco, R.; Treon, S. P.; Hideshima, T.; Anderson, K. C.; Lin, C. P.; Ghobrial, I. M. (2007). "The Akt pathway regulates survival and homing in Waldenstrom macroglobulinemia". Blood. 110 (13): 4417–4426. doi:10.1182/blood-2007-05-092098. PMC 2234792. PMID 17761832.
  24. Mensah-Osman, E.; Al-Katib, A.; Dandashi, M.; Mohammad, R. (2003). "XK469, a topo IIbeta inhibitor, induces apoptosis in Waldenstrom's macroglobulinemia through multiple pathways". International Journal of Oncology. 23 (6): 1637–1644. doi:10.3892/ijo.23.6.1637. PMID 14612935.
  25. 25.0 25.1 Leleu, X.; Eeckhoute, J.; Jia, X.; Roccaro, A.; Moreau, A.; Farag, M.; Sacco, A.; Ngo, H.; Runnels, J.; Melhem, M. R.; Burwick, N.; Azab, A.; Azab, F.; Hunter, Z.; Hatjiharissi, E.; Carrasco, D. R.; Treon, S. P.; Witzig, T. E.; Hideshima, T.; Brown, M.; Anderson, K. C.; Ghobrial, I. M. (2008). "Targeting NF-kappaB in Waldenstrom macroglobulinemia". Blood. 111 (10): 5068–5077. doi:10.1182/blood-2007-09-115170. PMC 2384134. PMID 18334673.
  26. Braggio, E.; Keats, J.; Leleu, X.; Van Wier, S.; Jimenez-Zepeda, V.; Valdez, R.; Schop, R.; Price-Troska, T.; Henderson, K.; Sacco, A.; Azab, F.; Greipp, P.; Gertz, M.; Hayman, S.; Rajkumar, S. V.; Carpten, J.; Chesi, M.; Barrett, M.; Stewart, A. K.; Dogan, A.; Bergsagel, P. L.; Ghobrial, I. M.; Fonseca, R. (2009). "Identification of copy number abnormalities and inactivating mutations in two negative regulators of nuclear factor-kappaB signaling pathways in Waldenstrom's macroglobulinemia". Cancer Research. 69 (8): 3579–3588. doi:10.1158/0008-5472.CAN-08-3701. PMC 2782932. PMID 19351844.
  27. Gutiérrez, N.; Ocio, E.; De Las Rivas, J.; Maiso, P.; Delgado, M.; Fermiñán, E.; Arcos, M.; Sánchez, M.; Hernández, J.; San Miguel, J. F. (2007). "Gene expression profiling of B lymphocytes and plasma cells from Waldenström's macroglobulinemia: comparison with expression patterns of the same cell counterparts from chronic lymphocytic leukemia, multiple myeloma and normal individuals". Leukemia. 21 (3): 541–549. doi:10.1038/sj.leu.2404520. PMID 17252022.
  28. Burwick, N.; Roccaro, A.; Leleu, X.; Ghobrial, I. (2008). "Targeted therapies in Waldenström macroglobulinemia". Current Opinion in Investigational Drugs. 9 (6): 631–637. PMID 18516762.
  29. Chng, W.; Schop, R.; Price-Troska, T.; Ghobrial, I.; Kay, N.; Jelinek, D.; Gertz, M.; Dispenzieri, A.; Lacy, M.; Kyle, R. A.; Greipp, P. R.; Tschumper, R. C.; Fonseca, R.; Bergsagel, P. L. (2006). "Gene-expression profiling of Waldenstrom macroglobulinemia reveals a phenotype more similar to chronic lymphocytic leukemia than multiple myeloma". Blood. 108 (8): 2755–2763. doi:10.1182/blood-2006-02-005488. PMC 1895596. PMID 16804116.
  30. Nichols, G.; Stein, C. (2003). "Modulation of the activity of Bcl-2 in Waldenstrom's macroglobulinemia using antisense oligonucleotides". Seminars in Oncology. 30 (2): 297–299. doi:10.1053/sonc.2003.50045. PMID 12720156.
  31. Ngo, H.; Azab, A.; Farag, M.; Jia, X.; Melhem, M.; Runnels, J.; Roccaro, A.; Azab, F.; Sacco, A.; Leleu, X.; Anderson, K. C.; Ghobrial, I. M. (2009). "Src tyrosine kinase regulates adhesion and chemotaxis in Waldenstrom macroglobulinemia". Clinical Cancer Research. 15 (19): 6035–6041. doi:10.1158/1078-0432.CCR-09-0718. PMC 2990685. PMID 19755386.
  32. Vacca, A.; Dammacco, F. (2009). "MicroRNAs to know in Waldenstrom macroglobulinemia". Blood. 113 (18): 4133–4134. doi:10.1182/blood-2009-01-199828. PMID 19406998.
  33. Roccaro, A.; Sacco, A.; Chen, C.; Runnels, J.; Leleu, X.; Azab, F.; Azab, A.; Jia, X.; Ngo, H.; Melhem, M. R.; Burwick, N.; Varticovski, L.; Novina, C. D.; Rollins, B. J.; Anderson, K. C.; Ghobrial, I. M. (2009). "MicroRNA expression in the biology, prognosis, and therapy of Waldenström macroglobulinemia". Blood. 113 (18): 4391–4402. doi:10.1182/blood-2008-09-178228. PMC 2943754. PMID 19074725.
  34. "MiRNA Entry for MI0000764". Archived from the original on 2018-04-23. Retrieved 2021-10-01.
  35. "MiRNA Entry for MI0000490". Archived from the original on 2021-01-19. Retrieved 2021-10-01.
  36. "MiRNA Entry for MI0003134". Archived from the original on 2021-07-27. Retrieved 2021-10-01.
  37. "MiRNA Entry for MI0000681". Archived from the original on 2021-06-04. Retrieved 2021-10-01.
  38. "MiRNA Entry for MI0000481". Archived from the original on 2020-09-25. Retrieved 2021-10-01.
  39. "MiRNA Entry for MI0003686". Archived from the original on 2020-12-04. Retrieved 2021-10-01.
  40. "MiRNA Entry for MI0000466". Archived from the original on 2021-06-04. Retrieved 2021-10-01.
  41. Roccaro, A.; Sacco, A.; Jia, X.; Azab, A.; Maiso, P.; Ngo, H.; Azab, F.; Runnels, J.; Quang, P.; Ghobrial, I. M. (2010). "microRNA-dependent modulation of histone acetylation in Waldenström macroglobulinemia". Blood. 116 (9): 1506–1514. doi:10.1182/blood-2010-01-265686. PMC 2938840. PMID 20519629.
  42. Treon, S.; Kelliher, A.; Keele, B.; Frankel, S.; Emmanouilides, C.; Kimby, E.; Schlossman, R.; Mitsiades, N.; Mitsiades, C.; Preffer, F.; Anderson, K. C. (2003). "Expression of serotherapy target antigens in Waldenstrom's macroglobulinemia: therapeutic applications and considerations". Seminars in Oncology. 30 (2): 248–252. doi:10.1053/sonc.2003.50047. PMID 12720146.
  43. Owen RG, Barrans SL, Richards SJ, O'Connor SJ, Child JA, Parapia LA, Morgan GJ, Jack AS (2001). "Waldenstrom macroglobulinemia. Development of diagnostic criteria and identification of prognostic factors". Am J Clin Pathol. 116 (3): 420–8. doi:10.1309/4LCN-JMPG-5U71-UWQB. PMID 11554171.
  44. 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.
  45. Ghobrial IM, Witzig TE (2004). "Waldenstrom macroglobulinemia". Curr Treat Options Oncol. 5 (3): 239–47. doi:10.1007/s11864-004-0015-5. PMC 3133652. PMID 15115652.
  46. Dimopoulos MA, Kyle RA, Anagnostopoulos A, Treon SP (2005). "Diagnosis and management of Waldenstrom's macroglobulinemia". J Clin Oncol. 23 (7): 1564–77. doi:10.1200/JCO.2005.03.144. PMID 15735132.
  47. Morbidity Mediated By The Effects Of IgM Archived 2012-03-26 at the Wayback Machine From Chapter 88 – Waldenström Macroglobulinemia/Lymphoplasmacytic Lymphoma. Hoffman, Ronald (2009). Hematology : basic principles and practic. Philadelphia, PA: Churchill Livingstone/Elsevier. ISBN 978-0-443-06715-0.
  48. 48.0 48.1 Waldenstrom Macroglobulinemia~workup at eMedicine
  49. 49.0 49.1 National Cancer Institute. Waldenström Macroglobulinemia: Questions and Answers Archived 2013-01-28 at the Wayback Machine. Retrieved on: 2011-08-14.
  50. Criteria for diagnosis of WM- IMWG 2009 guidelines
  51. Leleu, X.; Gay, J.; Roccaro, A.; Moreau, A.; Poulain, S.; Dulery, R.; Champs, B.; Robu, D.; Ghobrial, I. (2009). "Update on therapeutic options in Waldenström macroglobulinemia". European Journal of Haematology. 82 (1): 1–12. doi:10.1111/j.1600-0609.2008.01171.x. PMC 3133624. PMID 19087134.
  52. 52.0 52.1 Neparidze, N.; Dhodapkar, M. (2009). "Waldenstrom's macroglobulinemia: Recent advances in biology and therapy". Clinical Advances in Hematology & Oncology. 7 (10): 677–681, 687–681. PMC 3612541. PMID 20040909.
  53. Yang, G.; Zhou, Y.; Liu, X.; Xu, L.; Cao, Y.; Manning, R. J.; Patterson, C. J.; Buhrlage, S. J.; Gray, N.; Tai, Y.-T.; Anderson, K. C.; Hunter, Z. R.; Treon, S. P. (2013). "A mutation in MYD88 (L265P) supports the survival of lymphoplasmacytic cells by activation of Bruton tyrosine kinase in Waldenstrom macroglobulinemia". Blood. 122 (7): 1222–1232. doi:10.1182/blood-2012-12-475111. ISSN 0006-4971. PMID 23836557.
  54. Treon, Steven P.; Tripsas, Christina K.; Meid, Kirsten; Warren, Diane; Varma, Gaurav; Green, Rebecca; Argyropoulos, Kimon V.; Yang, Guang; Cao, Yang; Xu, Lian; Patterson, Christopher J.; Rodig, Scott; Zehnder, James L.; Aster, Jon C.; Harris, Nancy Lee; Kanan, Sandra; Ghobrial, Irene; Castillo, Jorge J.; Laubach, Jacob P.; Hunter, Zachary R.; Salman, Zeena; Li, Jianling; Cheng, Mei; Clow, Fong; Graef, Thorsten; Palomba, M. Lia; Advani, Ranjana H. (2015). "Ibrutinib in Previously Treated Waldenström's Macroglobulinemia". New England Journal of Medicine. 372 (15): 1430–1440. doi:10.1056/NEJMoa1501548. ISSN 0028-4793. PMID 25853747.
  55. Goodin, Tara (29 January 2015). "FDA expands approved use of Imbruvica for rare form of non-Hodgkin lymphoma". FDA. Archived from the original on 2 April 2015. Retrieved 29 January 2015.
  56. Treon, S. P. (2009). "How I treat Waldenström macroglobulinemia". Blood. 114 (12): 2375–2385. doi:10.1182/blood-2009-05-174359. PMID 19617573.
  57. Ansell, S. M.; Kyle, R. A.; Reeder, C. B.; Fonseca, R.; Mikhael, J. R.; Morice, W. G.; Bergsagel, P. L.; Buadi, F. K.; Colgan, J. P.; Dingli, D.; Dispenzieri, A.; Greipp, P. R.; Habermann, T. M.; Hayman, S. R.; Inwards, D. J.; Johnston, P. B.; Kumar, S. K.; Lacy, M. Q.; Lust, J. A.; Markovic, S. N.; Micallef, I. N. M.; Nowakowski, G. S.; Porrata, L. F.; Roy, V.; Russell, S. J.; Short, K. E. D.; Stewart, A. K.; Thompson, C. A.; Witzig, T. E.; Zeldenrust, S. R. (2010). "Diagnosis and Management of Waldenström Macroglobulinemia: Mayo Stratification of Macroglobulinemia and Risk-Adapted Therapy (mSMART) Guidelines". Mayo Clinic Proceedings. 85 (9): 824–833. doi:10.4065/mcp.2010.0304. PMC 2931618. PMID 20702770.
  58. Varettoni, M.; Tedeschi, A.; Arcaini, L.; Pascutto, C.; Vismara, E.; Orlandi, E.; Ricci, F.; Corso, A.; Greco, A.; Mangiacavalli, S.; Lazzarino, M.; Morra, E. (2011). "Risk of second cancers in Waldenstrom macroglobulinemia". Annals of Oncology. 23 (2): 411–415. doi:10.1093/annonc/mdr119. PMID 21525403.
  59. Waldenstrom Macroglobulinemia~treatment at eMedicine
  60. Waldenström J (1991). "To treat or not to treat, this is the real question". Leuk Res. 15 (6): 407–8. doi:10.1016/0145-2126(91)90049-Y. PMID 1907339.
  61. Baehring, J.; Hochberg, E.; Raje, N.; Ulrickson, M.; Hochberg, F. (2008). "Neurological manifestations of Waldenström macroglobulinemia". Nature Clinical Practice Neurology. 4 (10): 547–556. doi:10.1038/ncpneuro0917. PMID 18813229.
  62. Kyle RA, Treon SP, Alexanian R, Barlogie B, Bjorkholm M, Dhodapkar M, Lister TA, Merlini G, Morel P, Stone M, Branagan AR, Leblond V (2003). "Prognostic markers and criteria to initiate therapy in Waldenstrom's macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom's Macroglobulinemia". Semin Oncol. 30 (2): 116–20. doi:10.1053/sonc.2003.50038. PMID 12720119.
  63. Treon, S.; Soumerai, J.; Branagan, A.; Hunter, Z.; Patterson, C.; Ioakimidis, L.; Briccetti, F.; Pasmantier, M.; Zimbler, H.; Cooper, R. B.; Moore, M.; Hill j, J.; Rauch, A.; Garbo, L.; Chu, L.; Chua, C.; Nantel, S. H.; Lovett, D. R.; Boedeker, H.; Sonneborn, H.; Howard, J.; Musto, P.; Ciccarelli, B. T.; Hatjiharissi, E.; Anderson, K. C. (2008). "Thalidomide and rituximab in Waldenstrom macroglobulinemia". Blood. 112 (12): 4452–4457. doi:10.1182/blood-2008-04-150854. PMC 2597120. PMID 18713945.
  64. Gertz MA (2005). "Waldenstrom macroglobulinemia: a review of therapy". Am J Hematol. 79 (2): 147–57. doi:10.1002/ajh.20363. PMID 15929102.
  65. Dimopoulos, Meletios A.; Tedeschi, Alessandra; Trotman, Judith; García-Sanz, Ramón; Macdonald, David; Leblond, Veronique; Mahe, Beatrice; Herbaux, Charles; Tam, Constantine; Orsucci, Lorella; Palomba, M. Lia; Matous, Jeffrey V.; Shustik, Chaim; Kastritis, Efstathios; Treon, Steven P.; Li, Jianling; Salman, Zeena; Graef, Thorsten; Buske, Christian (21 June 2018). "Phase 3 Trial of Ibrutinib plus Rituximab in Waldenström's Macroglobulinemia". New England Journal of Medicine. 378 (25): 2399–2410. doi:10.1056/NEJMoa1802917. PMID 29856685.
  66. 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.
  67. 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.
  68. 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.
  69. 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.
  70. "FDA approves zanubrutinib for Waldenström's macroglobulinemia". U.S. Food and Drug Administration (FDA). 1 September 2021. Archived from the original on 1 September 2021. Retrieved 1 September 2021. Public Domain This article incorporates text from this source, which is in the public domain.
  71. Kyriakou, C.; Canals, C.; Cornelissen, J. J.; Socie, G.; Willemze, R.; Ifrah, N.; Greinix, H. T.; Blaise, D.; Deconinck, E.; Ferrant, A.; Schattenberg, A.; Harousseau, J. -L.; Sureda, A.; Schmitz, N. (2010). "Allogeneic Stem-Cell Transplantation in Patients with Waldenstrom Macroglobulinemia: Report from the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation". Journal of Clinical Oncology. 28 (33): 4926–4934. doi:10.1200/JCO.2009.27.3607. PMID 20956626.
  72. Rourke, M.; Anderson, K. C.; Ghobrial, I. M. (2010). "Review of clinical trials conducted in Waldenstrom macroglobulinemia and recommendations for reporting clinical trial responses in these patients". Leukemia & Lymphoma. 51 (10): 1779–1792. doi:10.3109/10428194.2010.499977. PMID 20795787.
  73. "Archive copy". Archived from the original on 2011-06-13. Retrieved 2021-10-01.{{cite web}}: CS1 maint: archived copy as title (link)
  74. Treon, S. P.; Yang, G.; Hanzis, C.; Ioakimidis, L.; Verselis, S. J.; Fox, E. A.; Xu, L.; Hunter, Z. R.; Tseng, H.; Manning, R. J.; Patterson, C. J.; Sheehy, P.; Turnbull, B. (2011). "Attainment of complete/very good partial response following rituximab-based therapy is an important determinant to progression-free survival, and is impacted by polymorphisms in FCGR3A in Waldenstrom macroglobulinaemia". British Journal of Haematology. 154 (2): 223–228. doi:10.1111/j.1365-2141.2011.08726.x. PMID 21564078.
  75. Waldenstrom Macroglobulinemia at eMedicine
  76. Johansson B, Waldenstrom J, Hasselblom S, Mitelman F (1995). "Waldenstrom's macroglobulinemia with the AML/MDS-associated t(1;3)(p36;q21)". Leukemia. 9 (7): 1136–8. PMID 7630185.
  77. Morel P, Duhamel A, Gobbi P, Dimopoulos M, Dhodapkar M, McCoy J, et al. International Prognostic Scoring System for Waldenström’s Macroglobulinemia. XIth International Myeloma Workshop & IVth International Workshop on Waldenstrom's Macroglobulinemia 25 30 June 2007 Kos Island, Greece. Haematologica 2007;92(6 suppl 2):1–229.
  78. Kastritis, E.; Kyrtsonis, M.; Hadjiharissi, E.; Symeonidis, A.; Michalis, E.; Repoussis, P.; Tsatalas, C.; Michael, M.; Sioni, A.; Kartasis, Z.; Stefanoudaki, E.; Voulgarelis, M.; Delimpasi, S.; Gavriatopoulou, M.; Koulieris, E.; Gika, D.; Zomas, A.; Roussou, P.; Anagnostopoulos, N.; Economopoulos, T.; Terpos, E.; Zervas, K.; Dimopoulos, M. A.; Greek Myeloma Study, G. (2010). "Validation of the International Prognostic Scoring System (IPSS) for Waldenstrom's macroglobulinemia (WM) and the importance of serum lactate dehydrogenase (LDH)". Leukemia Research. 34 (10): 1340–1343. doi:10.1016/j.leukres.2010.04.005. PMID 20447689.
  79. N.B. The article refers to them as "adverse covariates".
  80. 80.0 80.1 Dimopoulos, M.; Kastritis, E.; Delimpassi, S.; Zomas, A.; Kyrtsonis, M.; Zervas, K. (2008). "The International Prognostic Scoring System for Waldenstrom's macroglobulinemia is applicable in patients treated with rituximab-based regimens". Haematologica. 93 (9): 1420–1422. doi:10.3324/haematol.12846. PMID 18641029.
  81. "Survival Rates for Waldenstrom Macroglobulinemia". Archived from the original on 2016-11-19. Retrieved 2021-10-01.
  82. Hivert, B.; Tamburini, J.; Vekhoff, A.; Tournilhac, O.; Leblond, V.; Morel, P. (2011-03-10). "Prognostic value of the International Scoring System and response in patients with advanced Waldenström macroglobulinemia". Haematologica. 96 (5): 785–788. doi:10.3324/haematol.2010.029140. PMC 3084930. PMID 21393333.
  83. Dhodapkar, M.; Hoering, A.; Gertz, M.; Rivkin, S.; Szymonifka, J.; Crowley, J.; Barlogie, B. (2009). "Long-term survival in Waldenstrom macroglobulinemia: 10-year follow-up of Southwest Oncology Group-directed intergroup trial S9003". Blood. 113 (4): 793–796. doi:10.1182/blood-2008-07-172080. PMC 2630265. PMID 18931340.
  84. Turgeon, Mary Louise (2005). Clinical hematology: theory and procedures. Hagerstown, MD: Lippincott Williams & Wilkins. p. 283. ISBN 978-0-7817-5007-3. Frequency of lymphoid neoplasms. (Source: Modified from WHO Blue Book on Tumour of Hematopoietic and Lymphoid Tissues. 2001, p. 2001.)
  85. Waldenstrom J (1944). "Incipient myelomatosis or "essential" hyperglobulinemia with fibrinognenopenia-a new syndrome?". Acta Med Scand. 117 (3–4): 216–247. doi:10.1111/j.0954-6820.1944.tb03955.x.
  86. 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.
  87. Wada N (Jan 2014). "Characterization of subpopulation lacking both B-cell and plasma cell markers in Waldenstrom macroglobulinemia cell line". Lab. Invest. 94 (1): 79–88. doi:10.1038/labinvest.2013.129. PMID 24189269.
External resources