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Macroglobulinemia, Waldenstrom, 1(WM1)

MedGen UID:
320546
Concept ID:
C1835192
Disease or Syndrome
Synonyms: Macroglobulinemia, Waldenstrom, susceptibility to, 1; Waldenstrom's syndrome
 
Gene (location): MYD88 (3p22.2)
 
Monarch Initiative: MONDO:0100281
OMIM®: 153600

Definition

Waldenstrom macroglobulinemia (WM) is a malignant B-cell neoplasm characterized by lymphoplasmacytic infiltration of the bone marrow and hypersecretion of monoclonal immunoglobulin M (IgM) protein (review by Vijay and Gertz, 2007). The importance of genetic factors is suggested by the observation of familial clustering of WM (McMaster, 2003). Whereas WM is rare, an asymptomatic elevation of monoclonal IgM protein, termed 'IgM monoclonal gammopathy of undetermined significance' (IgM MGUS) is more common. Patients with IgM MGUS can progress to develop WM, at the rate of 1.5% to 2% per year (Kyle et al., 2003). Genetic Heterogeneity of Waldenstrom Macroglobulinemia A locus for susceptibility to Waldenstrom macroglobulinemia (WM2; 610430) has been mapped to chromosome 4q. [from OMIM]

Additional description

From MedlinePlus Genetics
Waldenström macroglobulinemia is a rare blood cell cancer characterized by an excess of abnormal white blood cells in the bone marrow.  These abnormal cells have characteristics of both white blood cells (lymphocytes) called B cells and more mature cells derived from B cells known as plasma cells. These abnormal cells with both lymphocyte and plasma characteristics are known as lymphoplasmacytic cells. Due to these cells, Waldenström macroglobulinemia is classified as a lymphoplasmacytic lymphoma. In Waldenström macroglobulinemia, these abnormal cells produce excess amounts of IgM, the largest of a type of protein known as an immunoglobulin; the overproduction of this large protein contributes to the condition's name (macroglobulinemia). 

Waldenström macroglobulinemia usually begins in a person's sixties and is a slow-growing (indolent) cancer. Some affected individuals have elevated levels of IgM and lymphoplasmacytic cells but no symptoms of the condition; in these cases, the disease is usually found incidentally by a blood test taken for another reason. These individuals are diagnosed with smoldering (or asymptomatic) Waldenström macroglobulinemia. It can be many years before a person with the condition develops noticable signs and symptoms.

The most common signs and symptoms to first appear in people with Waldenström macroglobulinemia are weakness and extreme tiredness (fatigue) caused by a shortage of red blood cells (anemia). Affected individuals can also experience general symptoms such as fever, night sweats, and weight loss. Some people with Waldenström macroglobulinemia develop a loss of sensation and weakness in the limbs (peripheral neuropathy). Doctors are unsure why this feature occurs, although they speculate that the IgM protein attaches to the protective covering of nerve cells (myelin) and breaks it down. The damaged nerves cannot carry signals normally, leading to neuropathy.

Other features of Waldenström macroglobulinemia are due to the accumulation of lymphoplasmacytic cells in different tissues. For example, accumulation of these cells can lead to an enlarged liver (hepatomegaly), spleen (splenomegaly), or lymph nodes (lymphadenopathy). In the bone marrow, the lymphoplasmacytic cells interfere with normal blood cell development, causing a shortage of healthy blood cells (pancytopenia). 

Several other signs and symptoms of Waldenström macroglobulinemia are related to the excess amounts of IgM. Increased IgM can thicken blood and impair circulation, causing a condition known as hyperviscosity syndrome. Features related to hyperviscosity syndrome include bleeding in the nose or mouth, blurring or loss of vision, headache, dizziness, and confusion. In some affected individuals, IgM and other immunoglobulins react to cold temperatures to form gel-like clumps that block blood flow in areas exposed to the cold, such as the hands and feet. These clumped proteins are referred to as cryoglobulins, and their clumping causes a condition known as cryoglobulinemia. Cryoglobulinemia can lead to pain in the hands and feet or episodes of Raynaud phenomenon, in which the fingers and toes turn white or blue in response to cold temperatures. The IgM protein, along with another protein called amyloid, can build up in organs and interfere with their normal function. This buildup causes a condition called amyloidosis. Organs that are typically affected by amyloidosis include the heart, kidneys, liver or spleen. Affected individuals can experience weakness, fatigue, shortness of breath, irregular heartbeat, or joint pain. 

  https://medlineplus.gov/genetics/condition/waldenstrom-macroglobulinemia

Clinical features

From HPO
Leukemia
MedGen UID:
9725
Concept ID:
C0023418
Neoplastic Process
A cancer of the blood and bone marrow characterized by an abnormal proliferation of leukocytes.
Lymphoma
MedGen UID:
44223
Concept ID:
C0024299
Neoplastic Process
A cancer originating in lymphocytes and presenting as a solid tumor of lymhpoid cells.
Polyneuropathy
MedGen UID:
57502
Concept ID:
C0152025
Disease or Syndrome
A generalized disorder of peripheral nerves.
Polyclonal elevation of IgM
MedGen UID:
871141
Concept ID:
C4025612
Finding
A heterogeneous increase in IgM immunoglobulins characterized by a diffuse band on serum electrophoresis.
Impaired lymphocyte transformation with phytohemagglutinin
MedGen UID:
871152
Concept ID:
C4025625
Finding
Normal peripheral blood lymphocytes, when stimulated by phytohemagglutinin (PHA) are cytotoxic for homologous and heterologous cells but not for autologous cells in monolayer culture. The cytotoxic effect is thought to be indicative of the immunological competence of the lymphocytes.
Monoclonal immunoglobulin M proteinemia
MedGen UID:
1381967
Concept ID:
C4477091
Neoplastic Process
Presence of a monoclonal immunoglobulin M protein in the serum.

Professional guidelines

PubMed

Castillo JJ, Branagan AR, Sermer D, Flynn CA, Meid K, Little M, Stockman K, White T, Canning A, Guerrera ML, Kofides A, Liu S, Liu X, Richardson K, Tsakmaklis N, Patterson CJ, Hunter ZR, Treon SP, Sarosiek S
Blood 2024 Feb 15;143(7):582-591. doi: 10.1182/blood.2023022420. PMID: 37971194Free PMC Article
Treon SP, Tedeschi A, San-Miguel J, Garcia-Sanz R, Anderson KC, Kimby E, Minnema MC, Benevolo G, Qiu L, Yi S, Terpos E, Tam CS, Castillo JJ, Morel P, Dimopoulos M, Owen RG
Semin Hematol 2023 Mar;60(2):97-106. Epub 2023 Apr 20 doi: 10.1053/j.seminhematol.2023.03.009. PMID: 37173155
Kyle RA, Durie BG, Rajkumar SV, Landgren O, Blade J, Merlini G, Kröger N, Einsele H, Vesole DH, Dimopoulos M, San Miguel J, Avet-Loiseau H, Hajek R, Chen WM, Anderson KC, Ludwig H, Sonneveld P, Pavlovsky S, Palumbo A, Richardson PG, Barlogie B, Greipp P, Vescio R, Turesson I, Westin J, Boccadoro M; International Myeloma Working Group
Leukemia 2010 Jun;24(6):1121-7. Epub 2010 Apr 22 doi: 10.1038/leu.2010.60. PMID: 20410922Free PMC Article

Curated

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®), Waldenström Macroglobulinemia/Lymphoplasmacytic Lymphoma, 2023

Recent clinical studies

Etiology

Dimopoulos MA, Opat S, D'Sa S, Jurczak W, Lee HP, Cull G, Owen RG, Marlton P, Wahlin BE, Garcia-Sanz R, McCarthy H, Mulligan S, Tedeschi A, Castillo JJ, Czyz J, Fernández de Larrea C, Belada D, Libby E, Matous J, Motta M, Siddiqi T, Tani M, Trněný M, Minnema MC, Buske C, Leblond V, Treon SP, Trotman J, Chan WY, Schneider J, Allewelt H, Patel S, Cohen A, Tam CS
J Clin Oncol 2023 Nov 20;41(33):5099-5106. Epub 2023 Jul 21 doi: 10.1200/JCO.22.02830. PMID: 37478390Free PMC Article
Buske C, Jurczak W, Salem JE, Dimopoulos MA
Leukemia 2023 Jan;37(1):35-46. Epub 2022 Nov 19 doi: 10.1038/s41375-022-01732-9. PMID: 36402930Free PMC Article
Castillo JJ, Allan JN, Siddiqi T, Advani RH, Meid K, Leventoff C, White TP, Flynn CA, Sarosiek S, Branagan AR, Demos MG, Guerrera ML, Kofides A, Liu X, Munshi M, Tsakmaklis N, Xu L, Yang G, Patterson CJ, Hunter ZR, Davids MS, Furman RR, Treon SP
J Clin Oncol 2022 Jan 1;40(1):63-71. Epub 2021 Nov 18 doi: 10.1200/JCO.21.01194. PMID: 34793256Free PMC Article
Tam CS, Opat S, D'Sa S, Jurczak W, Lee HP, Cull G, Owen RG, Marlton P, Wahlin BE, Sanz RG, McCarthy H, Mulligan S, Tedeschi A, Castillo JJ, Czyz J, Fernández de Larrea C, Belada D, Libby E, Matous JV, Motta M, Siddiqi T, Tani M, Trneny M, Minnema MC, Buske C, Leblond V, Trotman J, Chan WY, Schneider J, Ro S, Cohen A, Huang J, Dimopoulos M
Blood 2020 Oct 29;136(18):2038-2050. doi: 10.1182/blood.2020006844. PMID: 32731259Free PMC Article
Treon SP, Tripsas CK, Meid K, Warren D, Varma G, Green R, Argyropoulos KV, Yang G, Cao Y, Xu L, Patterson CJ, Rodig S, Zehnder JL, Aster JC, Harris NL, Kanan S, Ghobrial I, Castillo JJ, Laubach JP, Hunter ZR, Salman Z, Li J, Cheng M, Clow F, Graef T, Palomba ML, Advani RH
N Engl J Med 2015 Apr 9;372(15):1430-40. doi: 10.1056/NEJMoa1501548. PMID: 25853747

Diagnosis

Derman B, Castillo JJ, Sarosiek S, Beksac M
Am Soc Clin Oncol Educ Book 2022 Apr;42:1-10. doi: 10.1200/EDBK_349643. PMID: 35394823
Castillo JJ, Allan JN, Siddiqi T, Advani RH, Meid K, Leventoff C, White TP, Flynn CA, Sarosiek S, Branagan AR, Demos MG, Guerrera ML, Kofides A, Liu X, Munshi M, Tsakmaklis N, Xu L, Yang G, Patterson CJ, Hunter ZR, Davids MS, Furman RR, Treon SP
J Clin Oncol 2022 Jan 1;40(1):63-71. Epub 2021 Nov 18 doi: 10.1200/JCO.21.01194. PMID: 34793256Free PMC Article
Castillo JJ, Treon SP
Br J Haematol 2019 Nov;187(3):277-285. Epub 2019 Aug 20 doi: 10.1111/bjh.16167. PMID: 31430829
Kasi PM, Ansell SM, Gertz MA
Clin Adv Hematol Oncol 2015 Jan;13(1):56-66. PMID: 25679974
Gertz MA, Fonseca R, Rajkumar SV
Oncologist 2000;5(1):63-7. doi: 10.1634/theoncologist.5-1-63. PMID: 10706651

Therapy

Tam CS, Muñoz JL, Seymour JF, Opat S
Blood Cancer J 2023 Sep 11;13(1):141. doi: 10.1038/s41408-023-00902-x. PMID: 37696810Free PMC Article
Buske C, Jurczak W, Salem JE, Dimopoulos MA
Leukemia 2023 Jan;37(1):35-46. Epub 2022 Nov 19 doi: 10.1038/s41375-022-01732-9. PMID: 36402930Free PMC Article
Castillo JJ, Allan JN, Siddiqi T, Advani RH, Meid K, Leventoff C, White TP, Flynn CA, Sarosiek S, Branagan AR, Demos MG, Guerrera ML, Kofides A, Liu X, Munshi M, Tsakmaklis N, Xu L, Yang G, Patterson CJ, Hunter ZR, Davids MS, Furman RR, Treon SP
J Clin Oncol 2022 Jan 1;40(1):63-71. Epub 2021 Nov 18 doi: 10.1200/JCO.21.01194. PMID: 34793256Free PMC Article
Tam CS, Opat S, D'Sa S, Jurczak W, Lee HP, Cull G, Owen RG, Marlton P, Wahlin BE, Sanz RG, McCarthy H, Mulligan S, Tedeschi A, Castillo JJ, Czyz J, Fernández de Larrea C, Belada D, Libby E, Matous JV, Motta M, Siddiqi T, Tani M, Trneny M, Minnema MC, Buske C, Leblond V, Trotman J, Chan WY, Schneider J, Ro S, Cohen A, Huang J, Dimopoulos M
Blood 2020 Oct 29;136(18):2038-2050. doi: 10.1182/blood.2020006844. PMID: 32731259Free PMC Article
Castillo JJ, Treon SP
Br J Haematol 2019 Nov;187(3):277-285. Epub 2019 Aug 20 doi: 10.1111/bjh.16167. PMID: 31430829

Prognosis

Tam CS, Opat S, D'Sa S, Jurczak W, Lee HP, Cull G, Owen RG, Marlton P, Wahlin BE, Sanz RG, McCarthy H, Mulligan S, Tedeschi A, Castillo JJ, Czyz J, Fernández de Larrea C, Belada D, Libby E, Matous JV, Motta M, Siddiqi T, Tani M, Trneny M, Minnema MC, Buske C, Leblond V, Trotman J, Chan WY, Schneider J, Ro S, Cohen A, Huang J, Dimopoulos M
Blood 2020 Oct 29;136(18):2038-2050. doi: 10.1182/blood.2020006844. PMID: 32731259Free PMC Article
Durie BGM, Hoering A, Sexton R, Abidi MH, Epstein J, Rajkumar SV, Dispenzieri A, Kahanic SP, Thakuri MC, Reu FJ, Reynolds CM, Orlowski RZ, Barlogie B
Blood Cancer J 2020 May 11;10(5):53. doi: 10.1038/s41408-020-0311-8. PMID: 32393732Free PMC Article
Castillo JJ, Treon SP
Br J Haematol 2019 Nov;187(3):277-285. Epub 2019 Aug 20 doi: 10.1111/bjh.16167. PMID: 31430829
Treon SP, Tripsas CK, Meid K, Warren D, Varma G, Green R, Argyropoulos KV, Yang G, Cao Y, Xu L, Patterson CJ, Rodig S, Zehnder JL, Aster JC, Harris NL, Kanan S, Ghobrial I, Castillo JJ, Laubach JP, Hunter ZR, Salman Z, Li J, Cheng M, Clow F, Graef T, Palomba ML, Advani RH
N Engl J Med 2015 Apr 9;372(15):1430-40. doi: 10.1056/NEJMoa1501548. PMID: 25853747
O'Connell TX, Horita TJ, Kasravi B
Am Fam Physician 2005 Jan 1;71(1):105-12. PMID: 15663032

Clinical prediction guides

Röth A, Berentsen S, Barcellini W, D'Sa S, Jilma B, Michel M, Weitz IC, Yamaguchi M, Nishimura JI, Vos JMI, Storek M, Wong N, Patel P, Jiang X, Vagge DS, Wardęcki M, Shafer F, Lee M, Broome CM
Blood 2022 Sep 1;140(9):980-991. doi: 10.1182/blood.2021014955. PMID: 35687757Free PMC Article
Buske C, Tedeschi A, Trotman J, García-Sanz R, MacDonald D, Leblond V, Mahe B, Herbaux C, Matous JV, Tam CS, Heffner LT, Varettoni M, Palomba ML, Shustik C, Kastritis E, Treon SP, Ping J, Hauns B, Arango-Hisijara I, Dimopoulos MA
J Clin Oncol 2022 Jan 1;40(1):52-62. Epub 2021 Oct 4 doi: 10.1200/JCO.21.00838. PMID: 34606378Free PMC Article
Le Cann M, Bouhour F, Viala K, Simon L, Tard C, Rossi C, Morel G, Lagrange E, Magy L, Créange A, Michaud M, Franques J, Echaniz-Laguna A, Antoine JC, Baron M, Arnulf B, Puma A, Delmont E, Maisonobe T, Leblond V, Roos-Weil D
Blood 2020 Nov 19;136(21):2428-2436. doi: 10.1182/blood.2020007092. PMID: 32959046
Davids MS, Roberts AW, Seymour JF, Pagel JM, Kahl BS, Wierda WG, Puvvada S, Kipps TJ, Anderson MA, Salem AH, Dunbar M, Zhu M, Peale F, Ross JA, Gressick L, Desai M, Kim SY, Verdugo M, Humerickhouse RA, Gordon GB, Gerecitano JF
J Clin Oncol 2017 Mar 10;35(8):826-833. Epub 2017 Jan 17 doi: 10.1200/JCO.2016.70.4320. PMID: 28095146Free PMC Article
O'Connell TX, Horita TJ, Kasravi B
Am Fam Physician 2005 Jan 1;71(1):105-12. PMID: 15663032

Recent systematic reviews

Chan WL, Chong VCL, Wee IJY, Poon LM, Chan EHL, Lee J, Chee YL, Jeyasekharan AD, Chng WJ, Samuel M, de Mel S
Blood Cancer J 2023 Sep 7;13(1):140. doi: 10.1038/s41408-023-00916-5. PMID: 37679351Free PMC Article
Abushukair H, Syaj S, Ababneh O, Qarqash A, Schinke C, Thanendrarajan S, Zangari M, van Rhee F, Al Hadidi S
Am J Hematol 2022 Jul;97(7):942-950. Epub 2022 Apr 8 doi: 10.1002/ajh.26552. PMID: 35358350
Parrondo RD, Reljic T, Iqbal M, Ayala E, Tun HW, Kharfan-Dabaja MA, Kumar A, Murthy HS
Clin Lymphoma Myeloma Leuk 2020 Oct;20(10):e694-e711. Epub 2020 Jun 2 doi: 10.1016/j.clml.2020.05.021. PMID: 32616401
Yun S, Vincelette ND, Acharya U, Abraham I
Clin Lymphoma Myeloma Leuk 2017 Jan;17(1):31-37.e13. Epub 2016 Sep 19 doi: 10.1016/j.clml.2016.09.010. PMID: 27780690
Yang K, Tan J, Wu T
Cochrane Database Syst Rev 2009 Jan 21;(1):CD006719. doi: 10.1002/14651858.CD006719.pub3. PMID: 19160296

Supplemental Content

Table of contents

    Clinical resources

    Practice guidelines

    • PubMed
      See practice and clinical guidelines in PubMed. The search results may include broader topics and may not capture all published guidelines. See the FAQ for details.

    Curated

    • NCCN, 2023
      NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®), Waldenström Macroglobulinemia/Lymphoplasmacytic Lymphoma, 2023

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