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Waldenstrom macroglobulinemia

Written2017-11Phillip Hsieh, Yu-Tzu Tai, Matthew Ho Zhi Guang, Giada Bianchi
LeBow Institute for Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, 02115. PH, YTT: these authors contribute equally.,,;

Abstract Waldenstrom's Macroglobulinemia (WM), also known as lymphoplasmacytic lymphoma (LPL), is lymphoproliferative disorder classified by the WHO as an indolent lymphoma. WM cells display characteristics of both lymphocytes and plasma cells with gene expression profiling revealing a phenotype more similar to chronic lymphocytic leukemia than multiple myeloma (MM). At its core, WM is a clonal disease of B-lymphocytes and is characterized by the presence of (1) a monoclonal IgM immunoglobulin (M-protein), (2) malignant lymphoplasmacytic cell infiltration in the bone marrow. WM patients can present with symptoms/signs consistent with hyperviscosity syndrome when the M protein is conspicuous. Clinically, WM presents similarly to MM except that organomegaly and lymphadenopathies are common in WM but not in MM, and lytic bone disease and renal disease are uncommon in WM but common in MM.

Keywords Waldenstrom Macroglobulinemia, plasma cell neoplasm, hyperviscosity, lymphoplasmacytic lymphoma

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ICD-Topo C420,C421,C424, C77.0, C42.2
ICD-Morpho 9761/3 Waldenstrom macroglobulinemia
Atlas_Id 2043

Clinics and Pathology

Disease WM is a cancer of lymphoplasmacytic origin that evolves from precursor IgM-Monoclonal Gammopathy of Undetermined Significance (MGUS). WM can remain indolent, not requiring any active treatment for many years, as patients with IgM-MGUS have 18% probability of progression to symptomatic WM, amyloidosis, or lymphoma at 10 years (Kyle R et al, 2012).
Phenotype / cell stem origin Stem cell origin: Post-germinal center, IgM-bearing, memory B-cell
Phenotype: CD19+; CD20+; CD22+; FMC7+; CD38+; cytoplasmic IgM bright+; CD5-; CD23-; CD10-
Etiology Etiology of WM is not known. No confirmed predisposing factors. Possible risk factors include:
  • Hereditary/genetic predisposition: Multiple studies have suggested a familiar pattern to WM with 20% of 181 WM patients having had close relatives with WM or other lymphoproliferative disease in one report (Adamia S et al, 2009), and in 26% of 924 patients in another (Hunter Z et al, 2017).
  • Autoimmune diseases such as Sjogren's syndrome have been associated with higher risk for WM.
    In 90% of cases, WM cells have an activating mutation in MYD88 (L265P) resulting in constitutive/dysregulated NF-kB signaling which promotes the proliferation and survival of WM cells (Treon SP et al, 2014).
  • Epidemiology Incidence: 3.4 per million in males, 1.7 per million in females (Hunter Z et al, 2017)
    Overall survival: 78% (5y) (Wang H et al, 2012)
    Median age at diagnosis: 65y (Wang H et al, 2012)
    Ethnicity: More common in Caucasians (90% of cases) than other ethnic groups; uncommon in Blacks (5% of cases) (Wang H et al, 2012). Those of Ashkenazi descent may be predisposed (Hanzis C et al, 2011)
    Clinics Signs
  • IgM M spike
  • Organomegaly involving liver, spleen, and/or lymph nodes
  • Anemia
  • Cytopenia
  • Peripheral Neuropathy
    Symptoms Resulting from Abnormal M-Protein/Light-Chain Secretion (Ansell SM et al, 2010)
  • Hyperviscosity Syndrome - this syndrome occurs secondary to increased viscosity of the blood in the setting of elevated levels of IgM protein. It presents with epistaxis, diplopia, headache, dyspnea and potentially macrovascular complications such as stroke
  • AL Amyloidosis - Results from the deposition of amyloidogenic light chains in fibrillary structures in organs such as the heart, liver and kidneys eventually leading to organ failure and death. Signs/symptoms are related to the organ involvement. For example, renal involvement typically presents with nephrotic syndrome; heart involvement with dyspnea and lower extremity edema in the setting of diastolic heart failure; etc..
  • Type I cryoglobulinemia - presenting as purpura, joint pain and fatigue in the setting of precipitation of IgM cryoglobulin.
  • Peripheral Neuropathy - Multifactorial in nature including cases of anti-myelin associated glycoprotein (MAG) neuropathy. Typically symmertric, distal, sensory or sensory-motor with progressive nature. EMG shows demyelinating pattern.
    Symptoms Secondary to LPL Infiltration (Ansell SM et al, 2010)
  • Weakness/Fatigue - Multifactorial, with a contribution from BM myelophtisis from WM infiltration, resulting in impaired normal hematopoiesis and cytopenias (e.g. anemia, neutropenia, thrombocytopenia)
  • Organomegaly - WM infiltration can cause enlargement of spleen, lymph node or liver, resulting in hepatosplenomegaly or lymphadenopathy which can cause mass effect symptoms.
  • Monoclonal IgM (M-Protein) < 3 g/dL
  • AND
  • LPL cells infiltration in BM <10%
  • Asymptomatic WM

  • LPL infiltration of BM >10%, AND/OR IgM M protein > 3g/dL
  • AND
  • No clinical symptoms
  • Symptomatic WM

  • LPL present in BM and any level of M-Protein
  • AND
  • Signs of organ damage and/or persistent symptoms related to WM
  • Pathology WM is a B cell neoplasm characterized by serum IgM and bone marrow involvement by clonal, plasmacytic infiltrate (Lin P et al, 2003).
    Bone marrow aspirate showing increased lymphoplasmacytoid lymphocytes Image taken from:
    Treatment (NCCN guidelines for WM)
    WM can remain indolent, thus not requiring treatment for many years. In the absence of clear symptoms/signs related to WM, watchful waiting approach with interim visit, laboratory evaluation and possibly imaging is appropriate.
    Once it becomes symptomatic, WM necessitate commencement of chemotherapy. As WM has features similar to lymphoma and MM, both lymphoma- and MM-based chemotherapy regimens are commonly used; the choice of regimen usually depends on whether the patient is being treated by a lymphoma or MM specialist.
    Types of agentsSingle AgentCombination Therapy

    CD20 mAb based therapies
    RituximabPreferred regimen: Dexamethasone, rituximab, cyclophosphamide (DRC)
    Other: Bendamustine, rituximab (BR); thalidomide, rituximab; lenalidomide, rituximab

    Proteasome inhibitor based therapies
    Bortezomib, rituximab, dexamethasone (BoRD)

    Used together in Rituximab based therapies

    (BTK tyrosine kinase inhibitor used in patients with MYD88 mutation),

    (anti-CD52 mAb)

    Purine nucleoside analogues:
    - Fludarabine
    - Cladribine

  • IgM MGUS or asymptomatic WM: No therapy; watch and wait
  • WM with minimal symptoms and modest disease burden: Single agent rituximab or bortezomib
  • Symptomatic WM: Combination therapy (DRC or BoRD) Note: Patients with signs/symptoms of hyperviscosity syndrome necessitate urgent plasmapheresis before/concomitantly with chemotherapy initiation
    Relapsed WM
  • If duration of response
  • ≥ 2 years: Repeat initial therapy used as frontline
  • < 2 years: Alternative first-line regimen or ibrutinib, carfilzomib, or immunomodulatory agents
  • Stem cell transplant (HCT) in selected patients
    Response Criteria (NCCN Guidelines for WM)
    Complete Response (CR)
    1. Normal IgM levels
    2. Disappearance of M protein
    3. No BM involvement
    4. No signs or symptoms
    5. Reconfirmation of CR status by repeated immunofixation studies
    Very Good Partial Response
    1. >90% reduction of IgM level in serum
    2. Decrease of adenopathy and organopathy
    3. No signs of active disease; no new symptoms
    Partial Response
    1. >50% reduction of IgM level in serum
    2. Decrease of adenopathy and organopathy
    3. No new signs of active disease; no new symptoms
    Minor Response
    1. 50%> x>25% reduction of IgM level in serum
    2. No signs of active disease; no new symptoms
    Stable Disease
    1. <25% increase or decrease of IgM levels in serum
    2. No progression of adenopathy or organopathy, cytopenias
    3. No progression of clinically important symptoms due to disease and/or signs of active WM
    Progressive Disease
    1. >25% increase of IgM levels in serum
    2. Progression of symptoms, addition of new symptoms
      1. Anemia
      2. Thrombocytopenia
      3. Leukopenia
      4. Bulky adenopathy and/or organopathy
      5. Fever >38.4 -C
      6. Night Sweats
      7. 10% Body Weight loss
      8. Hyperviscosity
      9. Neuropathy
      10. Symptomatic Cryoglobulinemia
      11. Amyloidosis
  • Evolution Transformation
    Of a group of 1,466 WM patients, 20 had WM transform into Diffuse Large B-Cell Lymphoma (DLBCL) (Castillo JJ et al, 2016).
  • The rates at which patients developed DLBCL were 1% at 5 years, 2.4% at 10 years, and 3.8% at 15 years, a cumulative increase over time
  • BCL6 and BCL2 were expressed in DLBCL cells, but not CD10
  • Median survival rate after transformation was 2.7 years; overall survival rate went down 7 years from 16 to 9.
  • ~50% patients were naïve to nucleoside analogues
  • 25% of patients were previously untreated for WM
  • >80% presented with extranodal movement
  • 65% had elevated international prognostic index (IPI) scores
  • Prognosis The median survival 78 months, but this varies greatly depending on:
  • Age
  • Clinical parameters such as:
  • Hyperviscosity symptoms
  • Constitutional symptoms
  • Bulky lymphadenopathy/splenomegaly
  • Presence of symptomatic or unresponsive neuropathy
  • Hemolytic anemia
  • Laboratory parameters
  • Hemoglobin
  • Platelet count
  • Bone marrow infiltration
  • Beta-2-microglobulin
  • Albumin
  • Genetics: Clinical presentation and survival are also dependent on somatic mutations in the genes MYD88 and CXCR4. CXCR4 mutations can lead to an increased BM disease burden, and patients with nonsense CXCR4 mutations can have higher M-protein levels and symptomatic hyperviscosity syndrome. Alone, MYD88 wild-type decreased BM disease burden along with lower M-protein levels, but the risk of death increased. Solitary CXCR4 wild-type was associated with higher response rates to the medication Ibrutinib. The mutation status of both MYD88 and CXCR4 can aid in guiding therapeutic decisions (Hunter Z et al, 2017). Advances in diagnostics and therapeutics have resulted in improved survival rates (Treon SP et al, 2014). Between the 1980's and the 21st century, 5- and 10-year survival rates have improved from 67% to 78% and 49% to 66%, respectively (Castillo JJ et al, 2014).
  • Cytogenetics

    Cytogenetics Morphological Abnormalities in chromosomes 9, 10, 11, 12, 18, and 21 have been reported, along with Trisomy 12 t(8;14), t(11;18), and t(14;18) were also observed (Mansoor A et al, 2001). In a separate study of 37 patients, 25 had normal diploid karyotype, while the other 12 presented with structural and/or numerical anomalies as shown below (Mansoor A et al, 2001).
  • pseudodiploid
  • hyperdiploid
  • hypodiploid
  • Trisomy 5 and 3 present in 3 and 2 cases, respectively
  • Monosomy of chromosome 8 occurred more frequently
    than monosomy of chromsomes 4, 7, 13, 19, 21, or 22
  • Deletion of chromosome 6q occurred in 50% of cases
  • 3q21 and 13q12 present in two patients
  • Gain of 12p11-13 detected in two patients

  • Genes involved and Proteins

    Note Mutations of these genes have been found in many cases of WM ((Hunter Z et al, 2017):
    Gene NameMYD88
    Location 3p22.2
    Protein Interacts with Toll like receptors and IL1; stimulates signaling molecules that activate NF kB.
    Gene NameCXCR4
    Location 2q22.1
    Protein Chemokine receptor for CXCL12, which is strongly chemotactic for lymphocytes.
    Gene NameARID1A
    Location 1p36.11
    Protein Part of the SWI/SNF family; regulates TP53
    Gene NameCD79B
    Location 17q23.3
    Protein Creates heterodimer with CD79A; CD79A/B interacts with IgH, an integral component to BCR surface expression and signalling.
    Gene NameLYN
    Location 8q12.1
    Protein B-cell receptor signaling regulator.
    Gene NameBCL2
    Location 18q21.33
    Protein Anti-apoptotic mediator.


    Genetic abnormalities in Waldenström's macroglobulinemia
    Adamia S, Pilarski PM, Belch AR, Pilarski LM
    Clin Lymphoma Myeloma 2009 Mar;9(1):30-2
    PMID 19362966
    Histological transformation to diffuse large B-cell lymphoma in patients with Waldenström macroglobulinemia
    Castillo JJ, Gustine J, Meid K, Dubeau T, Hunter ZR, Treon SP
    Am J Hematol 2016 Oct;91(10):1032-5
    PMID 27415417
    Associated malignancies in patients with Waldenström's macroglobulinemia and their kin
    Hanzis C, Ojha RP, Hunter Z, Manning R, Lewicki M, Brodsky P, Ioakimidis L, Tripsas C, Patterson CJ, Sheehy P, Treon SP
    Clin Lymphoma Myeloma Leuk 2011 Feb;11(1):88-92
    PMID 21454200
    Genomics, Signaling, and Treatment of Waldenström Macroglobulinemia
    Hunter ZR, Yang G, Xu L, Liu X, Castillo JJ, Treon SP
    J Clin Oncol 2017 Mar 20;35(9):994-1001
    PMID 28294689
    Diagnosis and Management of Waldenström Macroglobulinemia: Mayo Stratification of Macroglobulinemia and Risk-Adapted Therapy (mSMART) Guidelines 2016
    Kapoor P, Ansell SM, Fonseca R, Chanan-Khan A, Kyle RA, Kumar SK, Mikhael JR, Witzig TE, Mauermann M, Dispenzieri A, Ailawadhi S, Stewart AK, Lacy MQ, Thompson CA, Buadi FK, Dingli D, Morice WG, Go RS, Jevremovic D, Sher T, King RL, Braggio E, Novak A, Roy V, Ketterling RP, Greipp PT, Grogan M, Micallef IN, Bergsagel PL, Colgan JP, Leung N, Gonsalves WI, Lin Y, Inwards DJ, Hayman SR, Nowakowski GS, Johnston PB, Russell SJ, Markovic SN, Zeldenrust SR, Hwa YL, Lust JA, Porrata LF, Habermann TM, Rajkumar SV, Gertz MA, Reeder CB
    JAMA Oncol 2017 Sep 1;3(9):1257-1265
    PMID 28056114
    Progression in smoldering Waldenstrom macroglobulinemia: long-term results
    Kyle RA, Benson JT, Larson DR, Therneau TM, Dispenzieri A, Kumar S, Melton LJ 3rd, Rajkumar SV
    Blood 2012 May 10;119(19):4462-6
    PMID 22451426
    Waldenstrom macroglobulinemia involving extramedullary sites: morphologic and immunophenotypic findings in 44 patients
    Lin P, Bueso-Ramos C, Wilson CS, Mansoor A, Medeiros LJ
    Am J Surg Pathol 2003 Aug;27(8):1104-13
    PMID 12883242
    Cytogenetic findings in lymphoplasmacytic lymphoma/Waldenström macroglobulinemia
    Mansoor A, Medeiros LJ, Weber DM, Alexanian R, Hayes K, Jones D, Lai R, Glassman A, Bueso-Ramos CE
    Chromosomal abnormalities are associated with the polymorphous subtype and an aggressive clinical course Am J Clin Pathol
    PMID 11601139
    Waldenstrom's Macroglobulinemia
    NCCN Guidelines
    Somatic mutations in MYD88 and CXCR4 are determinants of clinical presentation and overall survival in Waldenstrom macroglobulinemia
    Treon SP, Cao Y, Xu L, Yang G, Liu X, Hunter ZR
    Blood 2014 May 1;123(18):2791-6
    PMID 24553177
    Temporal and geographic variations of Waldenstrom macroglobulinemia incidence: a large population-based study
    Wang H, Chen Y, Li F, Delasalle K, Wang J, Alexanian R, Kwak L, Rustveld L, Du XL, Wang M
    Cancer 2012 Aug 1;118(15):3793-800
    PMID 22139816


    This paper should be referenced as such :
    Hsieh P, Tai YT, Ho M, Bianchi G
    Waldenstrom macroglobulinemia;
    Atlas Genet Cytogenet Oncol Haematol. in press
    On line version :

    Other genes implicated (Data extracted from papers in the Atlas) [ 1 ]

    Genes GLI2

    External links

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