|
|
| Line 1: |
Line 1: |
| {{Infobox medical condition (new)
| | #REDIRECT [[Waldenström macroglobulinemia]] |
| | name = Waldenström macroglobulinemia
| |
| |
| |
| | synonyms = '''Lymphoplasmacytic lymphoma'''
| |
| | field = [[Hematology]] and [[oncology]]
| |
| | symptoms =
| |
| | complications =
| |
| | onset =
| |
| | duration =
| |
| | types =
| |
| | causes =
| |
| | risks =
| |
| | diagnosis =
| |
| | differential =
| |
| | prevention =
| |
| | treatment =
| |
| | medication =
| |
| | prognosis =
| |
| | frequency =
| |
| | deaths =
| |
| }}
| |
| | |
| '''Waldenström macroglobulinemia''' ('''WM'''), is a type of [[cancer]] affecting two types of [[B cells]]: lymphoplasmacytoid cells and plasma cells. Both cell types are [[white blood cell]]s. 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 lymphoma]]s.<ref name="Cheson">{{cite book | author = Cheson BD | year = 2006 | title = ACP Medicine | chapter = Chronic Lymphoid Leukemias and Plasma Cell Disorders |veditors=Dale DD, Federman DD | publisher = WebMD Professional Publishing | location = New York, NY | isbn = 978-0-9748327-1-5 }}</ref> 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, [[Plasma cell dyscrasia#IgM MGUS|IgM monoclonal gammopathy of undetermined significance]] (i.e. IgM MGUS) and [[plasma cell dyscrasia#Smoldering Waldenström macroglobulinemia|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]].<ref name="pmid27161311">{{cite journal | vauthors = van de Donk NW, Mutis T, Poddighe PJ, Lokhorst HM, Zweegman S | title = Diagnosis, risk stratification and management of monoclonal gammopathy of undetermined significance and smoldering multiple myeloma | journal = International Journal of Laboratory Hematology | volume = 38 Suppl 1 | issue = | pages = 110–22 | year = 2016 | pmid = 27161311 | doi = 10.1111/ijlh.12504 | url = | doi-access = free }}</ref><ref name="pmid28331368">{{cite journal | vauthors = Abeykoon JP, Yanamandra U, Kapoor P | title = New developments in the management of Waldenström macroglobulinemia | journal = Cancer Management and Research | volume = 9 | issue = | pages = 73–83 | year = 2017 | pmid = 28331368 | pmc = 5354523 | doi = 10.2147/CMAR.S94059 | url = }}</ref>
| |
| | |
| WM is a rare disease, with only about 1,500 cases per year in the [[United States]]. WM occurs more frequently in older adults.<ref>{{Cite web|url=https://rarediseases.info.nih.gov/diseases/7872/waldenstrom-macroglobulinemia|title=Waldenstrom macroglobulinemia {{!}} Genetic and Rare Diseases Information Center (GARD) – an NCATS Program|website=rarediseases.info.nih.gov|language=en|access-date=2018-04-17}}</ref> 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 (medicine)|remission]].<ref>International Waldenstrom's Macroglobulinemia Foundation (IWMF). "Living with Waldenstrom's Macroglobulinemia."</ref>
| |
| | |
| ==Signs and symptoms==
| |
| Signs and symptoms of WM include [[weakness]], [[fatigue (physical)|fatigue]], [[weight loss]], and chronic oozing of [[epistaxis|blood from the nose]] and gums.<ref name="Kyle1988">{{cite book | author =Kyle RA | year = 1998 | title = Internal Medicine | chapter = Chapter 94: Multiple Myeloma and the Dysproteinemias | editor = Stein JH | edition = 5th | publisher = C.V.Mosby | location = New York | isbn = 978-0-8151-8698-4 }}</ref> [[Peripheral neuropathy]] occurs in 10% of patients. [[Lymphadenopathy|Enlargement of the lymph nodes]], [[splenomegaly|spleen]], and/or [[hepatomegaly|liver]] are present in 30–40% of cases.<ref name="Raje" /> Other possible signs and symptoms include blurring or loss of vision, [[headache]], and (rarely) [[stroke]] or [[coma]].{{citation needed|date=July 2020}}
| |
| | |
| ==Causes==
| |
| 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).<ref>{{Cite journal | doi = 10.1182/blood-2013-09-525808| title = 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| journal = Blood| volume = 123| issue = 11| pages = 1637–46| year = 2013| last1 = Hunter | first1 = Z. R.| last2 = Xu | first2 = L.| last3 = Yang | first3 = G.| last4 = Zhou | first4 = Y.| last5 = Liu | first5 = X.| last6 = Cao | first6 = Y.| last7 = Manning | first7 = R. J.| last8 = Tripsas | first8 = C.| last9 = Patterson | first9 = C. J.| last10 = Sheehy | first10 = P.| last11 = Treon | first11 = S. P. | pmid=24366360}}</ref> An association has been demonstrated with the locus 6p21.3 on [[chromosome 6]].<ref name="pmid16938573">{{cite journal |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 |last1=Schop |first1= Roelandt F.J. |last2=Van Wier |first2=Scott A. |last3=Xu |first3=Ruifang |display-authors=3 |last4=Ghobrial |first4=I. |last5=Ahmann |first5=G. |last6=Greipp |first6=P. |last7=Kyle |first7=R. |last8=Dispenzieri |first8=A. |last9=Lacy |first9=M. |last10=Rajkumar |first10=S. |last11=Gertz |first11=M. |last12=Fonseca |first12=R.}}</ref> There is a two- to threefold increased risk of WM in people with a personal history of [[autoimmune disease]]s with [[autoantibodies]], and a particularly elevated risk associated with [[hepatitis|liver inflammation]], [[human immunodeficiency virus]], and [[rickettsiosis]].<ref>{{Cite journal| last1 = Koshiol | first1 = J.| last2 = Gridley | first2 = G.| last3 = Engels | first3 = E.| last4 = McMaster | first4 = M.| last5 = Landgren | first5 = O.| title = Chronic immune stimulation and subsequent Waldenström macroglobulinemia| journal = Archives of Internal Medicine| volume = 168| issue = 17| pages = 1903–1909| year = 2008| pmid = 18809818| pmc = 2670401| doi = 10.1001/archinternmed.2008.4}}</ref>
| |
| | |
| There are [[genetic disorder|genetic factors]], with first-degree relatives of WM patients shown to have a highly increased risk of also developing the disease.<ref>{{Cite journal| last1 = Kristinsson | first1 = S.| last2 = Björkholm | first2 = M.| last3 = Goldin | first3 = L.| last4 = McMaster | first4 = M.| last5 = Turesson | first5 = I.| last6 = Landgren | first6 = O.| title = Risk of lymphoproliferative disorders among first-degree relatives of lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia patients: a population-based study in Sweden| journal = Blood| volume = 112| issue = 8| pages = 3052–3056| year = 2008| pmid = 18703425| pmc = 2569164| doi = 10.1182/blood-2008-06-162768}}</ref> 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.<ref>{{Cite journal| last1 = Royer | first1 = R.| last2 = Koshiol | first2 = J.| last3 = Giambarresi | first3 = T.| last4 = Vasquez | first4 = L.| last5 = Pfeiffer | first5 = R.| last6 = McMaster | first6 = M.| title = Differential characteristics of Waldenström macroglobulinemia according to patterns of familial aggregation| journal = Blood| volume = 115| issue = 22| pages = 4464–4471| year = 2010| pmid = 20308603| pmc = 2881498| doi = 10.1182/blood-2009-10-247973}}</ref>
| |
| | |
| ===Genetics===
| |
| Although believed to be a sporadic disease, studies have shown increased susceptibility within families, indicating a genetic component.<ref>{{Cite journal| last1 = McMaster | first1 = M.| title = Familial Waldenstrom's macroglobulinemia| journal = Seminars in Oncology| volume = 30| issue = 2| pages = 146–152| year = 2003| pmid = 12720125| doi = 10.1053/sonc.2003.50063| url = https://zenodo.org/record/1236002}}</ref><ref>{{Cite journal| last1 = McMaster | first1 = M.| last2 = Goldin | first2 = L.| last3 = Bai | first3 = Y.| last4 = Ter-Minassian | first4 = M.| last5 = Boehringer | first5 = S.| last6 = Giambarresi | first6 = T.| last7 = Vasquez | first7 = L.| last8 = Tucker | first8 = M.| title = Genomewide linkage screen for Waldenstrom macroglobulinemia susceptibility loci in high-risk families| journal = American Journal of Human Genetics| volume = 79| issue = 4| pages = 695–701| year = 2006| pmid = 16960805| pmc = 1592553| doi = 10.1086/507687}}</ref> A mutation in gene [[MYD88]] has been found to occur frequently in patients.<ref>{{Cite journal | last1 = Treon | first1 = S. P. | last2 = Xu | first2 = L. | last3 = Yang | first3 = G. | last4 = Zhou | first4 = Y. | last5 = Liu | first5 = X. | last6 = Cao | first6 = Y. | last7 = Sheehy | first7 = P. | last8 = Manning | first8 = R. J. | last9 = Patterson | first9 = C. J. | last10 = Tripsas | doi = 10.1056/NEJMoa1200710 | first10 = C. | last11 = Arcaini | first11 = L. | last12 = Pinkus | first12 = G. S. | last13 = Rodig | first13 = S. J. | last14 = Sohani | first14 = A. R. | last15 = Harris | first15 = N. L. | last16 = Laramie | first16 = J. M. | last17 = Skifter | first17 = D. A. | last18 = Lincoln | first18 = S. E. | last19 = Hunter | first19 = Z. R. | title = MYD88 L265P Somatic Mutation in Waldenström's Macroglobulinemia | journal = New England Journal of Medicine | volume = 367 | issue = 9 | pages = 826–833 | year = 2012 | pmid = 22931316 | pmc = | doi-access = free }}</ref> WM cells show only minimal changes in [[cytogenetic]] and [[gene expression profiling|gene expression studies]]. Their [[miRNA]] signature however differs from their normal counterpart. It is therefore believed that [[Epigenetics|epigenetic]] modifications play a crucial role in the disease.<ref>{{Cite journal | doi = 10.1186/1756-8722-3-38 | last1 = Sacco | first1 = A. | last2 = Issa | first2 = G. C. | last3 = Zhang | first3 = Y. | last4 = Liu | first4 = Y. | last5 = Maiso | first5 = P. | last6 = Ghobrial | first6 = I. M. | last7 = Roccaro | first7 = A. M. | title = Epigenetic modifications as key regulators of Waldenstrom's Macroglobulinemia biology | journal = Journal of Hematology & Oncology | volume = 3 | pages = 38 | year = 2010 | pmid = 20929526 | pmc = 2964547}}</ref>
| |
| | |
| [[Comparative genomic hybridization]] identified the following [[chromosomal abnormalities]]: deletions of 6q23 and 13q14, and gains of 3q13-q28, 6p and 18q.<ref>{{Cite journal| last1 = Braggio | first1 = E.| last2 = Keats | first2 = J. J.| last3 = Leleu | first3 = X.| last4 = Van Wier | first4 = S. V.| last5 = Jimenez-Zepeda | first5 = V. H.| last6 = Schop | first6 = R. F. J.| last7 = Chesi | first7 = M.| last8 = Barrett | first8 = M.| last9 = Stewart | first9 = A. K.| last10 = Dogan | first10 = A.| last11 = Bergsagel | first11 = P. L.| last12 = Ghobrial | first12 = I. M.| last13 = Fonseca | first13 = R.| title = High-Resolution Genomic Analysis in Waldenström's Macroglobulinemia Identifies Disease-Specific and Common Abnormalities with Marginal Zone Lymphomas| journal = Clinical Lymphoma, Myeloma & Leukemia| volume = 9| issue = 1| pages = 39–42| year = 2009| pmid = 19362969| pmc = 3646570| doi = 10.3816/CLM.2009.n.009}}</ref> [[FGFR3]] is overexpressed.<ref>{{Cite journal | last1 = Azab | first1 = A. K. | last2 = Azab | first2 = F. | last3 = Quang | first3 = P. | last4 = Maiso | first4 = P. | last5 = Sacco | first5 = B. | last6 = Ngo | first6 = A. | last7 = Liu | first7 = H. T. | last8 = Zhang | first8 = Y. | last9 = Morgan | first9 = Y. | last10 = Roccaro | first10 = A. M. | last11 = Ghobrial | first11 = I. M. | title = FGFR3 is overexpressed Waldenstrom macroglobulinemia and its inhibition by Dovitinib induces apoptosis, and overcomes stroma-induced proliferation | doi = 10.1158/1078-0432.CCR-10-2772 | journal = Clinical Cancer Research | year = 2011 | pmid = 21521775 | volume=17 | issue=13 | pages=4389–4399| doi-access = free }}</ref> The following [[signalling pathway]]s have been implicated:
| |
| *[[CD154]]/[[CD40]]<ref>{{Cite web | url=http://www.asco.org/ASCO/Abstracts+&+Virtual+Meeting/Abstracts?&vmview=abst_detail_view&confID=26&abstractID=4297 | title=Meeting Library Redesign| date=2017-05-26}}</ref>
| |
| *[[Akt]]<ref>{{Cite journal| last1 = Leleu | first1 = X.| last2 = Jia | first2 = X.| last3 = Runnels | first3 = J.| last4 = Ngo | first4 = H.| last5 = Moreau | first5 = A.| last6 = Farag | first6 = M.| last7 = Spencer | first7 = J.| last8 = Pitsillides | first8 = C.| last9 = Hatjiharissi | first9 = E.| last10 = Roccaro | first10 = A.| last11 = O'Sullivan | first11 = G.| last12 = McMillin | first12 = D. W.| last13 = Moreno | first13 = D.| last14 = Kiziltepe | first14 = T.| last15 = Carrasco | first15 = R.| last16 = Treon | first16 = S. P.| last17 = Hideshima | first17 = T.| last18 = Anderson | first18 = K. C.| last19 = Lin | first19 = C. P.| last20 = Ghobrial | first20 = I. M.| title = The Akt pathway regulates survival and homing in Waldenstrom macroglobulinemia| journal = Blood| volume = 110| issue = 13| pages = 4417–4426| year = 2007| pmid = 17761832| pmc = 2234792| doi = 10.1182/blood-2007-05-092098}}</ref>
| |
| *[[ubiquitination]], [[p53]] activation, [[cytochrome c]] release<ref>{{Cite journal| last1 = Mensah-Osman | first1 = E.| last2 = Al-Katib | first2 = A.| last3 = Dandashi | first3 = M.| last4 = Mohammad | first4 = R.| title = XK469, a topo IIbeta inhibitor, induces apoptosis in Waldenstrom's macroglobulinemia through multiple pathways| journal = International Journal of Oncology| volume = 23| issue = 6| pages = 1637–1644| year = 2003| pmid = 14612935 | doi=10.3892/ijo.23.6.1637}}</ref>
| |
| *[[NF-κB]]<ref name="PMID 18334673">{{Cite journal| last1 = Leleu | first1 = X.| last2 = Eeckhoute | first2 = J.| last3 = Jia | first3 = X.| last4 = Roccaro | first4 = A.| last5 = Moreau | first5 = A.| last6 = Farag | first6 = M.| last7 = Sacco | first7 = A.| last8 = Ngo | first8 = H.| last9 = Runnels | first9 = J.| last10 = Melhem | first10 = M. R.| last11 = Burwick | first11 = N.| last12 = Azab | first12 = A.| last13 = Azab | first13 = F.| last14 = Hunter | first14 = Z.| last15 = Hatjiharissi | first15 = E.| last16 = Carrasco | first16 = D. R.| last17 = Treon | first17 = S. P.| last18 = Witzig | first18 = T. E.| last19 = Hideshima | first19 = T.| last20 = Brown | first20 = M.| last21 = Anderson | first21 = K. C.| last22 = Ghobrial | first22 = I. M.| title = Targeting NF-kappaB in Waldenstrom macroglobulinemia| journal = Blood| volume = 111| issue = 10| pages = 5068–5077| year = 2008| pmid = 18334673| pmc = 2384134| doi = 10.1182/blood-2007-09-115170}}</ref><ref>{{Cite journal| last1 = Braggio | first1 = E.| last2 = Keats | first2 = J.| last3 = Leleu | first3 = X.| last4 = Van Wier | first4 = S.| last5 = Jimenez-Zepeda | first5 = V.| last6 = Valdez | first6 = R.| last7 = Schop | first7 = R.| last8 = Price-Troska | first8 = T.| last9 = Henderson | first9 = K.| last10 = Sacco | first10 = A.| last11 = Azab | first11 = F.| last12 = Greipp | first12 = P.| last13 = Gertz | first13 = M.| last14 = Hayman | first14 = S.| last15 = Rajkumar | first15 = S. V.| last16 = Carpten | first16 = J.| last17 = Chesi | first17 = M.| last18 = Barrett | first18 = M.| last19 = Stewart | first19 = A. K.| last20 = Dogan | first20 = A.| last21 = Bergsagel | first21 = P. L.| last22 = Ghobrial | first22 = I. M.| last23 = Fonseca | first23 = R.| title = Identification of copy number abnormalities and inactivating mutations in two negative regulators of nuclear factor-kappaB signaling pathways in Waldenstrom's macroglobulinemia| journal = Cancer Research| volume = 69| issue = 8| pages = 3579–3588| year = 2009| pmid = 19351844| pmc = 2782932| doi = 10.1158/0008-5472.CAN-08-3701}}</ref>
| |
| *[[Wnt signaling pathway|WNT]]/[[beta-catenin]]<ref>{{Cite journal| last1 = Gutiérrez | first1 = N.| last2 = Ocio | first2 = E.| last3 = De Las Rivas | first3 = J.| last4 = Maiso | first4 = P.| last5 = Delgado | first5 = M.| last6 = Fermiñán | first6 = E.| last7 = Arcos | first7 = M.| last8 = Sánchez | first8 = M.| last9 = Hernández | first9 = J.| last10 = San Miguel | first10 = J. F.| title = 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| journal = Leukemia| volume = 21| issue = 3| pages = 541–549| year = 2007| pmid = 17252022| doi = 10.1038/sj.leu.2404520}}</ref>
| |
| *[[mTOR]]<ref>{{Cite journal| last1 = Burwick | first1 = N.| last2 = Roccaro | first2 = A.| last3 = Leleu | first3 = X.| last4 = Ghobrial | first4 = I.| title = Targeted therapies in Waldenström macroglobulinemia| journal = Current Opinion in Investigational Drugs| volume = 9| issue = 6| pages = 631–637| year = 2008| pmid = 18516762}}</ref>
| |
| *[[Extracellular signal-regulated kinases|ERK]]<ref name="PMID 18334673"/>
| |
| *[[MAPK]]<ref>{{Cite journal| last1 = Chng | first1 = W.| last2 = Schop | first2 = R.| last3 = Price-Troska | first3 = T.| last4 = Ghobrial | first4 = I.| last5 = Kay | first5 = N.| last6 = Jelinek | first6 = D.| last7 = Gertz | first7 = M.| last8 = Dispenzieri | first8 = A.| last9 = Lacy | first9 = M.| last10 = Kyle | first10 = R. A.| last11 = Greipp | first11 = P. R.| last12 = Tschumper | first12 = R. C.| last13 = Fonseca | first13 = R.| last14 = Bergsagel | first14 = P. L.| title = Gene-expression profiling of Waldenstrom macroglobulinemia reveals a phenotype more similar to chronic lymphocytic leukemia than multiple myeloma| journal = Blood| volume = 108| issue = 8| pages = 2755–2763| year = 2006| pmid = 16804116| pmc = 1895596| doi = 10.1182/blood-2006-02-005488}}</ref>
| |
| *[[Bcl-2]]<ref>{{Cite journal| last1 = Nichols | first1 = G.| last2 = Stein | first2 = C.| title = Modulation of the activity of Bcl-2 in Waldenstrom's macroglobulinemia using antisense oligonucleotides| journal = Seminars in Oncology| volume = 30| issue = 2| pages = 297–299| year = 2003| pmid = 12720156| doi = 10.1053/sonc.2003.50045}}</ref>
| |
| | |
| The protein [[Src (gene)|Src tyrosine kinase]] is overexpressed in Waldenström macroglobulinemia cells compared with control B cells.<ref>{{Cite journal| last1 = Ngo | first1 = H.| last2 = Azab | first2 = A.| last3 = Farag | first3 = M.| last4 = Jia | first4 = X.| last5 = Melhem | first5 = M.| last6 = Runnels | first6 = J.| last7 = Roccaro | first7 = A.| last8 = Azab | first8 = F.| last9 = Sacco | first9 = A.| last10 = Leleu | first10 = X.| last11 = Anderson | first11 = K. C.| last12 = Ghobrial | first12 = I. M.| title = Src tyrosine kinase regulates adhesion and chemotaxis in Waldenstrom macroglobulinemia| journal = Clinical Cancer Research| volume = 15| issue = 19| pages = 6035–6041| year = 2009| pmid = 19755386| pmc = 2990685| doi = 10.1158/1078-0432.CCR-09-0718}}</ref> Inhibition of Src arrests the [[cell cycle]] at phase G<sub>1</sub> and has little effect on the survival of WM or normal cells.
| |
| | |
| [[MicroRNA]]s involved in Waldenström's:<ref>{{Cite journal| last1 = Vacca | first1 = A.| last2 = Dammacco | first2 = F.| title = MicroRNAs to know in Waldenstrom macroglobulinemia| journal = Blood| volume = 113| issue = 18| pages = 4133–4134| year = 2009| pmid = 19406998| doi = 10.1182/blood-2009-01-199828| doi-access = free}}</ref><ref>{{Cite journal| last1 = Roccaro | first1 = A.| last2 = Sacco | first2 = A.| last3 = Chen | first3 = C.| last4 = Runnels | first4 = J.| last5 = Leleu | first5 = X.| last6 = Azab | first6 = F.| last7 = Azab | first7 = A.| last8 = Jia | first8 = X.| last9 = Ngo | first9 = H.| last10 = Melhem | first10 = M. R.| last11 = Burwick | first11 = N.| last12 = Varticovski | first12 = L.| last13 = Novina | first13 = C. D.| last14 = Rollins | first14 = B. J.| last15 = Anderson | first15 = K. C.| last16 = Ghobrial | first16 = I. M.| title = MicroRNA expression in the biology, prognosis, and therapy of Waldenström macroglobulinemia| journal = Blood| volume = 113| issue = 18| pages = 4391–4402| year = 2009| pmid = 19074725| pmc = 2943754| doi = 10.1182/blood-2008-09-178228}}</ref>
| |
| * increased expression of miRNAs-363*,<ref>{{Cite web | url=http://www.mirbase.org/cgi-bin/mirna_entry.pl?acc=MI0000764 | title=MiRNA Entry for MI0000764}}</ref> -206,<ref>{{Cite web | url=http://www.mirbase.org/cgi-bin/mirna_entry.pl?acc=MI0000490 | title=MiRNA Entry for MI0000490}}</ref> -494,<ref>{{Cite web | url=http://www.mirbase.org/cgi-bin/mirna_entry.pl?acc=MI0003134 | title=MiRNA Entry for MI0003134}}</ref> -155,<ref>{{Cite web | url=http://www.mirbase.org/cgi-bin/mirna_entry.pl?acc=MI0000681 | title=MiRNA Entry for MI0000681}}</ref> -184,<ref>{{Cite web | url=http://www.mirbase.org/cgi-bin/mirna_entry.pl?acc=MI0000481 | title=MiRNA Entry for MI0000481}}</ref> -542–3p.<ref>{{Cite web | url=http://www.mirbase.org/cgi-bin/mirna_entry.pl?acc=MI0003686 | title=MiRNA Entry for MI0003686}}</ref>
| |
| * decreased expression of miRNA-9*.<ref>{{Cite web | url=http://www.mirbase.org/cgi-bin/mirna_entry.pl?acc=MI0000466 | title=MiRNA Entry for MI0000466}}</ref>
| |
| 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 deacetylase]]s and histone-modifying genes are de-regulated.<ref>{{Cite journal| last1 = Roccaro | first1 = A.| last2 = Sacco | first2 = A.| last3 = Jia | first3 = X.| last4 = Azab | first4 = A.| last5 = Maiso | first5 = P.| last6 = Ngo | first6 = H.| last7 = Azab | first7 = F.| last8 = Runnels | first8 = J.| last9 = Quang | first9 = P.| last10 = Ghobrial | first10 = I. M.| title = microRNA-dependent modulation of histone acetylation in Waldenström macroglobulinemia| journal = Blood| volume = 116| issue = 9| pages = 1506–1514| year = 2010| pmid = 20519629| pmc = 2938840| doi = 10.1182/blood-2010-01-265686}}</ref>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%).<ref>{{Cite journal| last1 = Treon | first1 = S.| last2 = Kelliher | first2 = A.| last3 = Keele | first3 = B.| last4 = Frankel | first4 = S.| last5 = Emmanouilides | first5 = C.| last6 = Kimby | first6 = E.| last7 = Schlossman | first7 = R.| last8 = Mitsiades | first8 = N.| last9 = Mitsiades | first9 = C.| last10 = Preffer | first10 = F.| last11 = Anderson | first11 = K. C.| title = Expression of serotherapy target antigens in Waldenstrom's macroglobulinemia: therapeutic applications and considerations| journal = Seminars in Oncology| volume = 30| issue = 2| pages = 248–252| year = 2003| pmid = 12720146| doi = 10.1053/sonc.2003.50047}}</ref>
| |
| | |
| ==Pathophysiology==
| |
| 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.<ref name="Owen">{{cite journal | vauthors=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 | doi-access=free }}</ref><ref name="SanMiguel">{{cite journal |vauthors=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}}</ref><ref name="Ghobrial">{{cite journal |vauthors=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 | pmc=3133652}}</ref><ref name="Dimopoulos">{{cite journal |vauthors=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}}</ref> 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.<ref>[http://www.expertconsultbook.com/expertconsult/op/book.do?method=display&type=bookPage&decorator=none&eid=4-u1.0-B978-0-443-06715-0..50090-X--cesec8&isbn=978-0-443-06715-0 Morbidity Mediated By The Effects Of IgM] From Chapter 88 – Waldenström Macroglobulinemia/Lymphoplasmacytic Lymphoma. {{Cite book | last1 = Hoffman | first1 = Ronald | title = Hematology : basic principles and practic | year = 2009 | publisher = Churchill Livingstone/Elsevier | location = Philadelphia, PA | isbn = 978-0-443-06715-0 | pages = }}</ref>
| |
| | |
| ==Diagnosis==
| |
| 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.<ref name = workup>{{EMedicine|article|207097|Waldenstrom Macroglobulinemia|workup}}</ref> 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.<ref name = NCIfacts>National Cancer Institute. [http://www.cancer.gov/cancertopics/factsheet/Sites-Types/WM Waldenström Macroglobulinemia: Questions and Answers]. Retrieved on: 2011-08-14.</ref>
| |
| | |
| 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]].<ref name = NCIfacts/> [[Anemia]] is typically found in 80% of patients with WM. A [[Leukopenia|low white blood cell count]], and [[thrombocytopenia|low platelet count]] in the blood may be observed. A [[Neutropenia|low level of neutrophils]] (a specific type of white blood cell) may also be found in some individuals with WM.<ref name = workup/>
| |
| | |
| 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 [[Hyperuricemia|elevated]]. [[Creatinine]] is occasionally elevated and electrolytes are occasionally abnormal. A [[Hypercalcemia|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|date=July 2020}}
| |
|
| |
|
| Criteria for diagnosis of Waldenström macroglobulinemia include:
| | {{Redirect category shell| |
| | | {{R from move}} |
| 1. IgM monoclonal gammopathy that excludes [[chronic lymphocytic leukemia]] and [[Mantle cell lymphoma]]
| |
| | |
| 2. Evidence of anemia, constitutional symptoms, hyperviscosity, [[lymphadenopathy|swollen lymph nodes]], or [[hepatosplenomegaly|enlargement of the liver and spleen]] that can be attributed to an underlying lymphoproliferative disorder.<ref>Criteria for diagnosis of WM- IMWG 2009 guidelines</ref>
| |
| | |
| ==Treatment==
| |
| There is no single accepted treatment for WM.<ref>{{Cite journal| last1 = Leleu | first1 = X.| last2 = Gay | first2 = J.| last3 = Roccaro | first3 = A.| last4 = Moreau | first4 = A.| last5 = Poulain | first5 = S.| last6 = Dulery | first6 = R.| last7 = Champs | first7 = B.| last8 = Robu | first8 = D.| last9 = Ghobrial | first9 = I.| title = Update on therapeutic options in Waldenström macroglobulinemia| journal = European Journal of Haematology| volume = 82| issue = 1| pages = 1–12| year = 2009| pmid = 19087134| pmc = 3133624| doi = 10.1111/j.1600-0609.2008.01171.x}}</ref> There is marked variation in clinical outcome due to gaps in knowledge of the disease's molecular basis. Objective [[response rate (medicine)|response rates]] are high (> 80%) but complete response rates are low (0–15%).<ref name="cite pmid| 20040909"/> The medication [[ibrutinib]] targets the MYD88 L265P mutation induced activation of [[Bruton's tyrosine kinase]].<ref name="YangZhou2013">{{cite journal|last1=Yang|first1=G.|last2=Zhou|first2=Y.|last3=Liu|first3=X.|last4=Xu|first4=L.|last5=Cao|first5=Y.|last6=Manning|first6=R. J.|last7=Patterson|first7=C. J.|last8=Buhrlage|first8=S. J.|last9=Gray|first9=N.|last10=Tai|first10=Y.-T.|last11=Anderson|first11=K. C.|last12=Hunter|first12=Z. R.|last13=Treon|first13=S. P.|title=A mutation in MYD88 (L265P) supports the survival of lymphoplasmacytic cells by activation of Bruton tyrosine kinase in Waldenstrom macroglobulinemia|journal=Blood|volume=122|issue=7|year=2013|pages=1222–1232|issn=0006-4971|doi=10.1182/blood-2012-12-475111|pmid=23836557|doi-access=free}}</ref> 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.<ref name="TreonTripsas2015">{{cite journal|last1=Treon|first1=Steven P.|last2=Tripsas|first2=Christina K.|last3=Meid|first3=Kirsten|last4=Warren|first4=Diane|last5=Varma|first5=Gaurav|last6=Green|first6=Rebecca|last7=Argyropoulos|first7=Kimon V.|last8=Yang|first8=Guang|last9=Cao|first9=Yang|last10=Xu|first10=Lian|last11=Patterson|first11=Christopher J.|last12=Rodig|first12=Scott|last13=Zehnder|first13=James L.|last14=Aster|first14=Jon C.|last15=Harris|first15=Nancy Lee|last16=Kanan|first16=Sandra|last17=Ghobrial|first17=Irene|last18=Castillo|first18=Jorge J.|last19=Laubach|first19=Jacob P.|last20=Hunter|first20=Zachary R.|last21=Salman|first21=Zeena|last22=Li|first22=Jianling|last23=Cheng|first23=Mei|last24=Clow|first24=Fong|last25=Graef|first25=Thorsten|last26=Palomba|first26=M. Lia|last27=Advani|first27=Ranjana H.|title=Ibrutinib in Previously Treated Waldenström's Macroglobulinemia|journal=New England Journal of Medicine|volume=372|issue=15|year=2015|pages=1430–1440|issn=0028-4793|doi=10.1056/NEJMoa1501548|pmid=25853747}}</ref> Based on this study, the [[Food and Drug Administration]] approved ibrutinib for use in WM in 2015.<ref>{{cite web |url = https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm432123.htm?sf35886412=1 |date = 29 January 2015 |accessdate = 29 January 2015 |title = FDA expands approved use of Imbruvica for rare form of non-Hodgkin lymphoma |publisher = FDA |first = Tara |last = Goodin}}</ref>
| |
| | |
| There are different treatment flowcharts: Treon<ref>{{Cite journal| last1 = Treon | first1 = S. P.| title = How I treat Waldenström macroglobulinemia| journal = Blood| volume = 114| issue = 12| pages = 2375–2385| year = 2009| pmid = 19617573| doi = 10.1182/blood-2009-05-174359| doi-access = free}}</ref> and mSMART.<ref>{{Cite journal| last1 = Ansell | first1 = S. M.| last2 = Kyle | first2 = R. A.| last3 = Reeder | first3 = C. B.| last4 = Fonseca | first4 = R.| last5 = Mikhael | first5 = J. R.| last6 = Morice | first6 = W. G.| last7 = Bergsagel | first7 = P. L.| last8 = Buadi | first8 = F. K.| last9 = Colgan | first9 = J. P.| last10 = Dingli | first10 = D.| last11 = Dispenzieri | first11 = A.| last12 = Greipp | first12 = P. R.| last13 = Habermann | first13 = T. M.| last14 = Hayman | first14 = S. R.| last15 = Inwards | first15 = D. J.| last16 = Johnston | first16 = P. B.| last17 = Kumar | first17 = S. K.| last18 = Lacy | first18 = M. Q.| last19 = Lust | first19 = J. A.| last20 = Markovic | first20 = S. N.| last21 = Micallef | first21 = I. N. M.| last22 = Nowakowski | first22 = G. S.| last23 = Porrata | first23 = L. F.| last24 = Roy | first24 = V.| last25 = Russell | first25 = S. J.| last26 = Short | first26 = K. E. D.| last27 = Stewart | first27 = A. K.| last28 = Thompson | first28 = C. A.| last29 = Witzig | first29 = T. E.| last30 = Zeldenrust | first30 = S. R.| title = Diagnosis and Management of Waldenström Macroglobulinemia: Mayo Stratification of Macroglobulinemia and Risk-Adapted Therapy (mSMART) Guidelines| journal = Mayo Clinic Proceedings| volume = 85| issue = 9| pages = 824–833| year = 2010| pmid = 20702770| pmc = 2931618| doi = 10.4065/mcp.2010.0304}}</ref>
| |
| | |
| WM patients are at higher risk of developing second cancers than the general population, but it is not yet clear whether treatments are contributory.<ref>{{Cite journal | last1 = Varettoni | first1 = M. | last2 = Tedeschi | first2 = A. | last3 = Arcaini | first3 = L. | last4 = Pascutto | first4 = C. | last5 = Vismara | first5 = E. | last6 = Orlandi | first6 = E. | last7 = Ricci | first7 = F. | last8 = Corso | first8 = A. | last9 = Greco | first9 = A. | last10 = Mangiacavalli | first10 = S. | last11 = Lazzarino | first11 = M. | last12 = Morra | first12 = E. | title = Risk of second cancers in Waldenstrom macroglobulinemia | doi = 10.1093/annonc/mdr119 | journal = Annals of Oncology | year = 2011 | pmid = 21525403 | volume=23 | issue=2 | pages=411–415| doi-access = free }}</ref>
| |
| | |
| ===Watchful waiting===
| |
| In the absence of symptoms, many clinicians will recommend simply monitoring the patient;<ref>{{EMedicine|article|207097|Waldenstrom Macroglobulinemia|treatment}}</ref> Waldenström himself stated "let well do" for such patients. These asymptomatic cases are now classified as two successively more [[pre-malignant]] phases, [[Plasma cell dyscrasia#IgM MGUS|IgM monoclonal gammopathy of undetermined significance]] (i.e. IgM MGUS) and [[plasma cell dyscrasia#Smoldering Waldenström's macroglobulinemia|smoldering Waldenström's macroglobulinemia]].<ref name="pmid27161311"/><ref name="pmid28331368"/>
| |
| | |
| 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|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]].<ref>{{cite journal | author=Waldenström 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}}</ref>
| |
| | |
| ===First-line===
| |
| Should treatment be started it should address both the paraprotein level and the lymphocytic B-cells.<ref>{{Cite journal| last1 = Baehring | first1 = J.| last2 = Hochberg | first2 = E.| last3 = Raje | first3 = N.| last4 = Ulrickson | first4 = M.| last5 = Hochberg | first5 = F.| title = Neurological manifestations of Waldenström macroglobulinemia| journal = Nature Clinical Practice Neurology| volume = 4| issue = 10| pages = 547–556| year = 2008| pmid = 18813229| doi = 10.1038/ncpneuro0917}}</ref>
| |
| | |
| 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 (medical)|fatigue]] due to [[anemia]], [[weight loss]], progressive symptomatic [[lymphadenopathy]] or [[splenomegaly|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.<ref name="Kyel2003">{{cite journal |vauthors=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}}</ref>
| |
| | |
| Treatment includes the monoclonal antibody [[rituximab]], sometimes in combination with chemotherapeutic drugs such as [[chlorambucil]], [[cyclophosphamide]], or [[vincristine]] or with [[thalidomide]].<ref>{{Cite journal| last1 = Treon | first1 = S.| last2 = Soumerai | first2 = J.| last3 = Branagan | first3 = A.| last4 = Hunter | first4 = Z.| last5 = Patterson | first5 = C.| last6 = Ioakimidis | first6 = L.| last7 = Briccetti | first7 = F.| last8 = Pasmantier | first8 = M.| last9 = Zimbler | first9 = H.| last10 = Cooper | first10 = R. B.| last11 = Moore | first11 = M.| last12 = Hill j | first12 = J.| last13 = Rauch | first13 = A.| last14 = Garbo | first14 = L.| last15 = Chu | first15 = L.| last16 = Chua | first16 = C.| last17 = Nantel | first17 = S. H.| last18 = Lovett | first18 = D. R.| last19 = Boedeker | first19 = H.| last20 = Sonneborn | first20 = H.| last21 = Howard | first21 = J.| last22 = Musto | first22 = P.| last23 = Ciccarelli | first23 = B. T.| last24 = Hatjiharissi | first24 = E.| last25 = Anderson | first25 = K. C.| title = Thalidomide and rituximab in Waldenstrom macroglobulinemia| journal = Blood| volume = 112| issue = 12| pages = 4452–4457| year = 2008| pmid = 18713945| pmc = 2597120| doi = 10.1182/blood-2008-04-150854}}</ref> [[Corticosteroid]]s, 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.<ref name="Gertz">{{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}}</ref> [[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.<ref>{{cite journal |last1=Dimopoulos |first1=Meletios A. |last2=Tedeschi |first2=Alessandra |last3=Trotman |first3=Judith |last4=García-Sanz |first4=Ramón |last5=Macdonald |first5=David |last6=Leblond |first6=Veronique |last7=Mahe |first7=Beatrice |last8=Herbaux |first8=Charles |last9=Tam |first9=Constantine |last10=Orsucci |first10=Lorella |last11=Palomba |first11=M. Lia |last12=Matous |first12=Jeffrey V. |last13=Shustik |first13=Chaim |last14=Kastritis |first14=Efstathios |last15=Treon |first15=Steven P. |last16=Li |first16=Jianling |last17=Salman |first17=Zeena |last18=Graef |first18=Thorsten |last19=Buske |first19=Christian |title=Phase 3 Trial of Ibrutinib plus Rituximab in Waldenström’s Macroglobulinemia |journal=New England Journal of Medicine |date=21 June 2018 |volume=378 |issue=25 |pages=2399–2410 |doi=10.1056/NEJMoa1802917}}</ref>
| |
| | |
| Recently, autologous [[bone marrow transplantation]] has been added to the available treatment options.<ref name="Yang">{{cite journal |vauthors=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| doi-access=free }}</ref><ref name="Martino">{{cite journal |vauthors=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| doi-access=free }}</ref><ref name="Anagnostopoulos">{{cite journal |vauthors=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| doi-access=free }}</ref><ref name="Tournilhac">{{cite journal |vauthors=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}}</ref>
| |
| | |
| ===Salvage therapy===
| |
| When primary or secondary [[drug resistance|resistance]] invariably develops, [[salvage therapy]] is considered. [[Allogeneic stem cell transplantation]] can induce durable remissions for heavily pre-treated patients.<ref>{{Cite journal| last1 = Kyriakou | first1 = C.| last2 = Canals | first2 = C.| last3 = Cornelissen | first3 = J. J.| last4 = Socie | first4 = G.| last5 = Willemze | first5 = R.| last6 = Ifrah | first6 = N.| last7 = Greinix | first7 = H. T.| last8 = Blaise | first8 = D.| last9 = Deconinck | first9 = E.| last10 = Ferrant | first10 = A.| last11 = Schattenberg | first11 = A.| last12 = Harousseau | first12 = J. -L.| last13 = Sureda | first13 = A.| last14 = Schmitz | first14 = N.| title = 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 = Journal of Clinical Oncology| volume = 28| issue = 33| pages = 4926–4934| year = 2010| pmid = 20956626| doi = 10.1200/JCO.2009.27.3607}}</ref>
| |
| | |
| ===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.<ref>{{Cite journal| last1 = Rourke | first1 = M.| last2 = Anderson | first2 = K. C.| last3 = Ghobrial | first3 = I. M.| title = Review of clinical trials conducted in Waldenstrom macroglobulinemia and recommendations for reporting clinical trial responses in these patients| journal = Leukemia & Lymphoma| volume = 51| issue = 10| pages = 1779–1792| year = 2010| doi = 10.3109/10428194.2010.499977 | pmid=20795787}}</ref> A database of clinical trials investigating Waldenström's macroglobulinemia is maintained by the [[National Institutes of Health]] in the US.<ref>http://clinicaltrials.gov/ct2/results?term=Waldenstrom</ref>
| |
| | |
| ===Patient stratification===
| |
| Patients with [[polymorphism (biology)|polymorphic variants]] ([[alleles]]) [[FCGR3A]]-48 and -158 were associated with improved categorical responses to rituximab-based treatments.<ref>{{Cite journal | last1 = Treon | first1 = S. P. | last2 = Yang | first2 = G. | last3 = Hanzis | first3 = C. | last4 = Ioakimidis | first4 = L. | last5 = Verselis | first5 = S. J. | last6 = Fox | first6 = E. A. | last7 = Xu | first7 = L. | last8 = Hunter | first8 = Z. R. | last9 = Tseng | first9 = H. | last10 = Manning | first10 = R. J. | last11 = Patterson | first11 = C. J. | last12 = Sheehy | first12 = P. | last13 = Turnbull | first13 = B. | title = 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 | doi = 10.1111/j.1365-2141.2011.08726.x | journal = British Journal of Haematology | volume = 154 | issue = 2 | pages = 223–228 | year = 2011 | pmid = 21564078| pmc =}}</ref>
| |
| | |
| ==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.<ref name="Cheson" /> Currently, median survival is 6.5 years.<ref>{{EMedicine|article|207097|Waldenstrom Macroglobulinemia}}</ref> In rare instances, WM progresses to [[multiple myeloma]].<ref name="Johansson">{{cite journal |vauthors=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}}</ref>
| |
| | |
| The International Prognostic Scoring System for Waldenström’s Macroglobulinemia (IPSSWM) is a predictive model to characterise long-term outcomes.<ref>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.</ref><ref>{{Cite journal| last1 = Kastritis | first1 = E.| last2 = Kyrtsonis | first2 = M.| last3 = Hadjiharissi | first3 = E.| last4 = Symeonidis | first4 = A.| last5 = Michalis | first5 = E.| last6 = Repoussis | first6 = P.| last7 = Tsatalas | first7 = C.| last8 = Michael | first8 = M.| last9 = Sioni | first9 = A.| last10 = Kartasis | first10 = Z.| last11 = Stefanoudaki | first11 = E.| last12 = Voulgarelis | first12 = M.| last13 = Delimpasi | first13 = S.| last14 = Gavriatopoulou | first14 = M.| last15 = Koulieris | first15 = E.| last16 = Gika | first16 = D.| last17 = Zomas | first17 = A.| last18 = Roussou | first18 = P.| last19 = Anagnostopoulos | first19 = N.| last20 = Economopoulos | first20 = T.| last21 = Terpos | first21 = E.| last22 = Zervas | first22 = K.| last23 = Dimopoulos | first23 = M. A.| last24 = Greek Myeloma Study | first24 = G.| title = Validation of the International Prognostic Scoring System (IPSS) for Waldenstrom's macroglobulinemia (WM) and the importance of serum lactate dehydrogenase (LDH)| journal = Leukemia Research| volume = 34| issue = 10| pages = 1340–1343| year = 2010| pmid = 20447689| doi = 10.1016/j.leukres.2010.04.005}}</ref> According to the model, factors predicting reduced survival<ref>N.B. The article refers to them as "adverse covariates".</ref> are:
| |
| *Age > 65 years
| |
| *Hemoglobin ≤ 11.5 g/dL
| |
| *Platelet count ≤ 100×10<sup>9</sup>/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.<ref name="PMID 18641029">{{Cite journal| last1 = Dimopoulos | first1 = M.| last2 = Kastritis | first2 = E.| last3 = Delimpassi | first3 = S.| last4 = Zomas | first4 = A.| last5 = Kyrtsonis | first5 = M.| last6 = Zervas | first6 = K.| title = The International Prognostic Scoring System for Waldenstrom's macroglobulinemia is applicable in patients treated with rituximab-based regimens| journal = Haematologica| volume = 93| issue = 9| pages = 1420–1422| year = 2008| pmid = 18641029| doi = 10.3324/haematol.12846| doi-access = free}}</ref> The corresponding median survival rates are 12, 8, and 3.5 years.<ref>{{Cite web | url=http://www.cancer.org/cancer/waldenstrommacroglobulinemia/detailedguide/waldenstrom-macroglobulinemia-survival-rates | title=Survival Rates for Waldenstrom Macroglobulinemia}}</ref>
| |
| | |
| The IPSSWM has been shown to be reliable.<ref>{{Cite journal | doi = 10.3324/haematol.2010.029140 | pmid = 21393333 | last1 = Hivert | first1 = B. | last2 = Tamburini | first2 = J. | last3 = Vekhoff | first3 = A. | last4 = Tournilhac | first4 = O. | last5 = Leblond | first5 = V. | last6 = Morel | first6 = P. | title = Prognostic value of the International Scoring System and response in patients with advanced Waldenström macroglobulinemia | journal = [[Haematologica]] | volume = 96 | issue = 5 | pages = 785–788 | date = 2011-03-10 | pmc=3084930}}</ref> It is also applicable to patients on a rituximab-based treatment regimen.<ref name="PMID 18641029"/> An additional predictive factor is elevated serum lactate dehydrogenase (LDH).<ref>{{Cite journal| last1 = Dhodapkar | first1 = M.| last2 = Hoering | first2 = A.| last3 = Gertz | first3 = M.| last4 = Rivkin | first4 = S.| last5 = Szymonifka | first5 = J.| last6 = Crowley | first6 = J.| last7 = Barlogie | first7 = B.| title = Long-term survival in Waldenstrom macroglobulinemia: 10-year follow-up of Southwest Oncology Group-directed intergroup trial S9003| journal = Blood| volume = 113| issue = 4| pages = 793–796| year = 2009| pmid = 18931340| pmc = 2630265| doi = 10.1182/blood-2008-07-172080}}</ref>
| |
| | |
| ==Epidemiology==
| |
| Of all [[lymphoproliferative disorders|cancers involving the lymphocytes]], 1% of cases are WM.<ref name="isbn0-7817-5007-5">{{cite book|author=Turgeon, Mary Louise|title=Clinical hematology: theory and procedures|url=https://archive.org/details/clinicalhematolo0004turg|url-access=registration|publisher=Lippincott Williams & Wilkins|location=Hagerstown, MD|year=2005|isbn=978-0-7817-5007-3|quote=Frequency of lymphoid neoplasms. (Source: Modified from WHO Blue Book on Tumour of Hematopoietic and Lymphoid Tissues. 2001, p. 2001.)|page=[https://archive.org/details/clinicalhematolo0004turg/page/283 283]}}</ref>
| |
| | |
| WM is a rare disorder, with fewer than 1,500 cases occurring in the United States annually.<ref name="Cheson" /> The median age of onset of WM is between 60 and 65 years, with some cases occurring in late teens.<ref name="Cheson" /><ref name="Raje">{{cite book | vauthors = Raje N, Hideshima T, Anderson KC | year = 2003 | title = Holland-Frei Cancer Medicine | chapter = Plasma Cell Tumors | edition = 6th | veditors = Kufe DW, Pollock RE, Weichselbaum RR, Bast RC, Gansler TS | publisher = B.C. Decker | location = New York, NY | isbn = 978-1-55009-213-4 | url-access = registration | url = https://archive.org/details/cancermedicine60002unse }}</ref>
| |
| | |
| ==History ==
| |
| 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), [[lymphadenopathy|swollen lymph nodes]], neoplastic plasma cells in bone marrow, and [[Hyperviscosity syndrome|increased viscosity of the blood]] due to increased levels of a class of heavy proteins called [[macroglobulins]].<ref name="Waldenstrom1944">{{cite journal | doi= 10.1111/j.0954-6820.1944.tb03955.x | 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 | issue= 3–4}}</ref>
| |
| | |
| 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.<ref name="Harris">{{cite journal |vauthors=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}}</ref> In recent years, there have been significant advances in the understanding and treatment of WM.<ref name="cite pmid| 20040909">{{Cite journal| last1 = Neparidze | first1 = N.| last2 = Dhodapkar | first2 = M.| title = Waldenstrom's macroglobulinemia: Recent advances in biology and therapy| journal = Clinical Advances in Hematology & Oncology| volume = 7| issue = 10| pages = 677–681, 687–681| year = 2009| pmid = 20040909| pmc = 3612541}}</ref>
| |
| | |
| ==Research==
| |
| | |
| One recent investigation showed that a population of cells, lacking both B-cell and plasma cell markers, has characteristics of [[cancer stem cells|cancer-initiating cells]] in Waldenström's macroglobulinemia.<ref name=" pmid = 24189269">{{cite journal | author = Wada N | title = Characterization of subpopulation lacking both B-cell and plasma cell markers in Waldenstrom macroglobulinemia cell line | journal = Lab. Invest. | volume = 94 | issue = 1|date=Jan 2014 | pmid = 24189269 | pages = 79–88 | doi=10.1038/labinvest.2013.129| doi-access = free }}</ref>
| |
| | |
| == See also ==
| |
| * [[Waldenström hyperglobulinemic purpura]]
| |
| * [[List of hematologic conditions]]
| |
| | |
| == References ==
| |
| {{Reflist}}
| |
| | |
| == External links ==
| |
| {{Medical resources
| |
| | 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
| |
| }} | | }} |
|
| |
| {{Hematological malignancy histology}}
| |
| {{Immunoproliferative disorders}}
| |
|
| |
| {{DEFAULTSORT:Waldenstrom Macroglobulinemia}}
| |
| [[Category:Rare cancers]]
| |
| [[Category:Hematologic malignant neoplasms]]
| |
| [[Category:Vascular-related cutaneous conditions]]
| |
| [[Category:Lymphoma]]
| |
| {{stb}}
| |
