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Waldenstrom's Macroglobulinemia

This is a rare malignant condition, involving an excess of beta-lymphocytes (a type of cell in the immune system) which secrete immunoglobulins (a type of antibody). WM usually occurs in people over sixty, but has been detected in younger adults.

Information for Patients and the Public

Information for Health Professionals / Researchers

Latest Research Publications

Information Patients and the Public (17 links)

 Waldenstrom macroglobulinaemia

Macmillan Cancer Support
Content is developed by a team of information development nurses and content editors, and reviewed by health professionals. Further info.


 Waldenstrom's Macroglobulinemia

Cancer.Net
Content is peer reviewed and Cancer.Net has an Editorial Board of experts and advocates. Content is reviewed annually or as needed. Further info.


 Macroglobulinemia of Waldenstrom

MedlinePlus.gov
Produced by The National Library of Medicine with expert Advisory Board with representatives from the National Institutes of Health. Further info.
Detailed article covering causes, symptoms, tests, treatment and outlook.

  Waldenstrom's Macroglobulinemia Treatment Options


Lymphoma Research Foundation
Stephanie Gregory, MD, from Rush University gives an overview of WM and its treatment. (2012)

  Waldenstrom Macroglobulinemia

American Cancer Society

 Bing Center for Waldenstrom's Macroglobulinemia

Dana Farber Cancer Institute
The Waldenstrom's Macroglobulinemia program at Dana Farber Cancer Institute (DFCI) was founded in 1999 by Dr. Steve Treon with the help of patients, caregivers and DFCI scientists in an effort to advance understanding of the cause of WM, and to pursue novel therapies.

 European Waldenstrom's Macroglobulinemia Network

An umbrella organization of European Waldenstrom patient support groups

 International Waldenstrom's Macroglobulinemia Foundation

IWMF
Established in 1994 to offering educational information and caring support to Waldenstrom's macroglobulinemia (WM) patients. Since 2000 IWMF has funded research aimed at improving outcomes for WM.

 Waldenström France - Français - Translate to English

Established in 2009 to support French speaking WM patients and families.

 Waldenstrom Macroglobulinaemia

Leukaemia & Lymphoma Research
Short Factsheet (pdf)

 Waldenstrom Macroglobulinemia: Questions and Answers

National Cancer Institute
Detailed Q&A

 Waldenstrom's Macroglobulinaemia

Leukaemia Care
Information on WM covering signs and symptoms, diagnosis and treatment.

 WM UK

A not for profit organisation, developed jointly to bring WM patients and medical professionals closer together. It was originally set up to deliver an annual WMUK doctor/ patient seminar in London. We have a medical board of the leading doctors treating WM in the UK together with patient representatives.

 WSMG-NET@LISTSERV.ACOR.ORG

ACOR
Waldenstrom's Macroglobulinemia Cancer Online Discussion List

  Advances in the Genetics and Treatment of Waldenstrom's Macroglobulinemia


IWMF
A lecture by Dr. Steven Treon (Director of the Bing Center for Waldenstrom's) at the IWMF Patient Education Forum, which was held June 24-26, 2011 in Minneapolis, MN. This topic focuses on the increasing importance of genetics and the role it plays in the research of this disease.

Information for Health Professionals / Researchers (6 links)

• PubMed search for publications about Waldenstrom's Macroglobulinemia - Limit search to: [Reviews]

  PubMed Central search for free-access publications about Waldenstrom's Macroglobulinemia
  MeSH term: Waldenstrom Macroglobulinemia
  US National Library of Medicine
  PubMed has over 22 million citations for biomedical literature from MEDLINE, life science journals, and online books. Constantly updated.

 Waldenstrom's Macroglobulinaemia

Patient UK
PatientUK content is peer reviewed. Content is reviewed by a team led by a Clinical Editor to reflect new or updated guidance and publications. Further info.


 Case study: A forty-five year old famale with Waldenstroms's macroglobulinemia

Department of Pathology, University of Pittsburgh

 Waldenstrom Macroglobulinemia

Medscape
Detailed referenced article by Karen Seiter, MD, covering background, presentation, diagnosis, workup and treatment.

 Waldenstrom's Macroglobulinemia Clinical Trials Group

WA group comprised of over 20 major cancer centers around the world. The mission is to maintain active clinical trials year round in an effort to constantly improve our understanding and continue to offer patients the most effective treatments for Waldenstrom's macroglobulinemia.

 WM UK

A not for profit organisation, developed jointly to bring WM patients and medical professionals closer together. It was originally set up to deliver an annual WMUK doctor/ patient seminar in London. We have a medical board of the leading doctors treating WM in the UK together with patient representatives.

Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Canepa C
Waldenstrom-associated anti-MAG paraprotein polyneuropathy with neurogenic tremor.
BMJ Case Rep. 2019; 12(3) [PubMed] Related Publications

A 71-year-old female patient presented with a 14-year history of slowly progressive distal limb numbness, paraesthesia and reduced vibration perception, ataxic gait and intentional tremor. Examination revealed with a length-dependent sensory neuropathy. Nerve conduction studies showed a chronic sensorimotor inflammatory demyelinating polyneuropathy. Intravenous immunoglobulin treatment (on two occasions) proved ineffective. Serum electrophoresis showed increased monoclonal IgM with kappa light chains. Anti-myelin-associated glycoprotein (MAG) levels were extremely elevated, >70 000 BTU. Bone marrow biopsy revealed 15%-20% small B cells and positive MYD88 mutation, indicative of Waldenstrom macroglobulinaemia. A diagnosis of Waldenstrom-associated anti-MAG paraprotein neuropathy with intentional (neurogenic) tremor was made. Repeat nerve conduction study showed a severe sensory demyelinating neuropathy with no axonal lesion. Treatment with rituximab was given for 1 month with minimal improvement. Repeat anti-MAG levels dropped to 53 670 BTU, with minimal clinical improvement.

Related: Rituximab (Mabthera)

Stuhlmann-Laeisz C, Schönland SO, Hegenbart U, et al.
AL amyloidosis with a localized B cell neoplasia.
Virchows Arch. 2019; 474(3):353-363 [PubMed] Related Publications

Immunoglobulin light chain-derived (AL) amyloidosis may occur as a systemic disease usually with dismal prognosis and a localized variant with favorable outcome. We report 29 patients with AL amyloidosis and associated lymphoplasmacytic infiltrate spatially related to amyloid deposits. In 17 cases, the amyloid deposits were classified as ALλ and 12 as ALκ Histopathology in all cases showed relatively sparse plasma cells and B cells without tumor or sheet formation by the lymphoplasmacytic infiltrate. The B cells predominantly showed an immunophenotype of the marginal zone. In situ, hybridization revealed 17 cases with λ- and 10 with κ light chain restricted plasma cells, which was concordant with the AL subtype in each case. Clonal immunoglobulin heavy variable gene (IGHV) or κ light chain rearrangement was found in 23/29 interpretable cases. A single case harbored a MYD88

Related: MYD88

Durani U, Go RS, Kay NE
Immune-mediated hemolytic anemia and thrombocytopenia in clonal B-cell disorders: a review.
Clin Adv Hematol Oncol. 2018; 16(10):670-676 [PubMed] Related Publications

Autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia purpura (ITP) have been associated with B-cell lymphoproliferative disorders. Here, we review the epidemiology, pathogenesis, diagnosis, and treatment of these autoimmune disorders, specifically in the setting of B-cell malignancies. AIHA and ITP are classically associated with chronic lymphocytic leukemia (CLL) but have also been reported in plasmacytic and lymphoproliferative disorders. AIHA includes both warm AIHA and cold agglutinin disease, the latter of which is strongly associated with Waldenström macroglobulinemia. The pathogenesis of these cytopenias varies with the underlying disease, but malignant cells serving as antigen-presenting cells to T lymphocytes, with the generation of autoreactive lymphocytes, may be involved. The diagnosis requires the presence of hemolysis and a positive direct antiglobulin test result. In a minority of cases, the direct antiglobulin test result is negative, and more specialized testing may be required. Data on the prognostic effect of these comorbidities are conflicting, and the prognosis may vary depending on when in the B-cell malignant process the cytopenia(s) develops. The treatment of AIHA and ITP in the setting of B-cell lymphoproliferative disorders often involves treatment of the underlying disorder, although in some cases of CLL, treatment of the underlying disorder is not indicated, and management is similar to that for idiopathic AIHA or ITP.

Related: Chronic Lymphocytic Leukemia (CLL) CLL - Molecular Biology

Sekiguchi N, Nomoto J, Nagata A, et al.
Gene Expression Profile Signature of Aggressive Waldenström Macroglobulinemia with Chromosome 6q Deletion.
Biomed Res Int. 2018; 2018:6728128 [PubMed] Free Access to Full Article Related Publications

Background: Waldenström macroglobulinemia (WM) is a rare, indolent B-cell lymphoma. Clinically, chromosome 6q deletion (6q del) including loss of the B lymphocyte-induced maturation protein 1 gene (BLIMP-1) is reported to be associated with poor prognosis. However, it remains unclear how the underlying biological mechanism contributes to the aggressiveness of WM with 6q del.
Methods: Here, we conducted oligonucleotide microarray analysis to clarify the differences in gene expression between WM with and without 6q del. Gene ontology (GO) analysis was performed to identify the main pathways underlying differences in gene expression. Eight bone marrow formalin-fixed paraffin-embedded samples of WM were processed for interphase fluorescence in situ hybridization analysis, and three were shown to have 6q del.
Results: GO analysis revealed significant terms including "lymphocyte activation" (corrected p value=6.68E-11), which included 31 probes. Moreover,
Conclusion: The present study suggested that the BCR signaling pathway and

Related: Chromosome 6

Espinosa-Barberi G, Galván González FJ, Miranda Fernández S, et al.
Vasoproliferative retinopathy secondary to Waldenström's disease.
Arch Soc Esp Oftalmol. 2019; 94(2):85-89 [PubMed] Related Publications

A 66 year-old patient, monitored for diabetic retinopathy refractory to multiple treatment methods despite a good metabolic control, referred to progressive weight loss. For this reason, a systemic study was performed, detecting anaemia, elevation of the erythrocyte sedimentation rate, and hyperproteinaemia due to elevated serum levels of monoclonal IgM. Subsequently, by performing a bone marrow biopsy and genetic study, the diagnosis of Waldenström macroglobulinaemia was made. Waldenström's macroglobulinaemia is a low frequency lymphoproliferative disease, for which the main manifestation is a hyperviscosity syndrome that can produce ophthalmological signs detectable by funduscopy and imaging tests. A multimodal study is useful in the diagnosis and monitoring of retinal involvement. The incorporation of angiography by optical coherence tomography allows a more precise study of the microvascular disorders that may occur at the posterior pole level.

Related: Angiogenesis Inhibitors

McMaster ML, Berndt SI, Zhang J, et al.
Two high-risk susceptibility loci at 6p25.3 and 14q32.13 for Waldenström macroglobulinemia.
Nat Commun. 2018; 9(1):4182 [PubMed] Free Access to Full Article Related Publications

Waldenström macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) is a rare, chronic B-cell lymphoma with high heritability. We conduct a two-stage genome-wide association study of WM/LPL in 530 unrelated cases and 4362 controls of European ancestry and identify two high-risk loci associated with WM/LPL at 6p25.3 (rs116446171, near EXOC2 and IRF4; OR = 21.14, 95% CI: 14.40-31.03, P = 1.36 × 10

Related: Chromosome 14 Chromosome 6 MicroRNAs

Bouyssou JM, Liu CJ, Bustoros M, et al.
Profiling of circulating exosomal miRNAs in patients with Waldenström Macroglobulinemia.
PLoS One. 2018; 13(10):e0204589 [PubMed] Free Access to Full Article Related Publications

Waldenström Macroglobulinemia (WM) is a low-grade B-cell lymphoma characterized by disease progression from IgM MGUS to asymptomatic and then symptomatic disease states. We profiled exosomes from the peripheral blood of patients with WM at different stages (30 smoldering/asymptomatic WM, 44 symptomatic WM samples and 10 healthy controls) to define their role as potential biomarkers of disease progression. In this study, we showed that circulating exosomes and their miRNA content represent unique markers of the tumor and its microenvironment. We observed similar levels of miRNAs in exosomes from patients with asymptomatic (smoldering) and symptomatic WM, suggesting that environmental and clonal changes occur in patients at early stages of disease progression before symptoms occur. Moreover, we identified a small group of miRNAs whose expression correlated directly or inversely with the disease status of patients, notably the known tumor suppressor miRNAs let-7d and the oncogene miR-21 as well as miR-192 and miR-320b. The study of these miRNAs' specific effect in WM cells could help us gain further insights on the mechanisms underlying WM pathogenesis and reveal their potential as novel therapeutic targets for this disease.

Related: MicroRNAs

Gascue A, Merino J, Paiva B
Flow Cytometry.
Hematol Oncol Clin North Am. 2018; 32(5):765-775 [PubMed] Related Publications

Multiparameter flow cytometry (MFC) is valuable in the diagnosis and monitoring of most hematological malignancies. Although the assessment of cellular infiltrates in Waldenström macroglobulinemia (WM) relies on morphology and immunohistochemistry grounds, there is evidence pointing to the clinical significance of MFC in this disease. Herein, the authors review immunophenotypic patterns of B-cell development, the antigen profile of the WM clone and its normal B-cell counterpart, the clinical applicability of MFC in the differential diagnosis of immunoglobulin M-secreting lymphoproliferative disorders and monoclonal gammopathies, and its potential role in detecting minimal residual disease and monitoring treatment efficacy in WM.

Related: Haematological Malignancies & Realted Disorders

Magierowicz M, Tomowiak C, Leleu X, Poulain S
Working Toward a Genomic Prognostic Classification of Waldenström Macroglobulinemia: C-X-C Chemokine Receptor Type 4 Mutation and Beyond.
Hematol Oncol Clin North Am. 2018; 32(5):753-763 [PubMed] Related Publications

Waldenström macroglobulinemia is a rare indolent B-cell lymphoma. Whole-exome sequencing studies have improved our knowledge of the Waldenström macroglobulinemia mutational landscape. The MYD88 L265P mutation is present in nearly 90% of patients with Waldenström macroglobulinemia. CXCR4 mutations are identified in approximately 30% of MYD88L265P cases and have been associated with ibrutinib resistance in clinical trials. Mutations in CD79B, ARID1a, or TP53 were described at lower frequency. Deciphering the earliest initiating lesions and identifying the molecular alterations leading to disease progression currently represent important goals in the future to identify the most relevant targets for precision therapy in Waldenström macroglobulinemia.

Related: CXCR4 Signal Transduction

Treon SP, Xu L, Liu X, et al.
Genomic Landscape of Waldenström Macroglobulinemia.
Hematol Oncol Clin North Am. 2018; 32(5):745-752 [PubMed] Related Publications

Next-generation sequencing has revealed recurring somatic mutations in Waldenström macroglobulinemia (WM). Common mutations include MYD88 (95%-97%), as well as CXCR4 (30%-40%), ARID1A (17%), and CD79B (8%-15%), which are typically found in MYD88-mutated patients. The genomic findings provide important insights into the pathogenesis, prognostication, and treatment outcome in WM. We discuss the genomic landscape of WM, and the impact of underlying genomics on disease presentation, transcriptional changes, treatment outcome, and overall survival impact.

Related: Signal Transduction

Wada N, Nojima S, Tahara SI, et al.
Effect of glutamine on lymphoplasmacytic lymphoma, especially on the viewpoint of the differentiation into vulnerable subpopulation.
Pathol Res Pract. 2018; 214(10):1667-1674 [PubMed] Related Publications

Glutamine (Gln) is important not only for cell proliferation but also for differentiation. Although Gln is essential for plasmacytic differentiation of lymphocytes, no study has been done on the effect of Gln on differentiation of tumor cells, such as lymphoma. Here we examined the effect of Gln on plasmacytic differentiation of lymphoplasmacytic lymphoma (LPL) with its cell lines, MWCL-1 and RPCI-WM1. Gln promoted plasmacytic differentiation of LPL, and p38 MAPK signaling pathway mediated such differentiation. We previously reported that the subpopulation with plasmacytic differentiation was vulnerable to apoptosis in LPL. Although it is difficult to lead these findings to the radical therapy, they might help the treatment of LPL, in which stimulation of p38 MAPK by Gln induced differentiation of LPL into vulnerable subpopulation.

Related: Apoptosis

Vaxman I, Shepshelovich D, Hayman L, et al.
Agranulocytosis Associated with Waldenström Macroglobulinemia.
Acta Haematol. 2018; 140(1):42-45 [PubMed] Related Publications

Currently, there are only 2 case reports of Waldenström macroglobulinemia (WM) associated with severe neutropenia. This is a case report of a woman with a past medical history of WM who presented with neutropenic fever. The patient's febrile neutropenia resolved after RCD chemotherapy (cyclophosphamide 750 mg/m2, dexamethasone 20 mg, and rituximab 375 mg/m2). Fourteen days after administration, the neutrophil level had started to rise and normalized after 6 days. To the best of our knowledge, this is the 3rd reported case of agranulocytosis due to WM.

Related: Cyclophosphamide Rituximab (Mabthera)

Jalali S, Price-Troska T, Paludo J, et al.
Soluble PD-1 ligands regulate T-cell function in Waldenstrom macroglobulinemia.
Blood Adv. 2018; 2(15):1985-1997 [PubMed] Free Access to Full Article Related Publications

Although immune checkpoint molecules regulate the progression of certain cancers, their significance in malignant development of Waldenstrom macroglobulinemia (WM), an incurable low-grade B-cell lymphoma, remains unknown. Recently, cytokines in the bone marrow (BM) microenvironment are shown to contribute to the pathobiology of WM. Here, we investigated the impact of cytokines, including interleukin-6 (IL-6) and IL-21, on immune regulation and particularly on the programmed death-1 (PD-1) and its ligands PD-L1 and PD-L2. We showed that IL-21, interferon γ, and IL-6 significantly induced PD-L1 and PD-L2 gene expression in WM cell lines. Increased PD-L1 and PD-L2 messenger RNA was also detected in patients' BM cells. Patients' nonmalignant BM cells, including T cells and monocytes, showed increased PD-L1, but minimal or undetectable PD-L2 surface expression. There was also very modest PD-L1 and PD-L2 surface expression by malignant WM cells, suggesting that ligands are cleaved from the cell surface. Levels of soluble ligands were higher in patients' BM plasma and blood serum than controls. Furthermore, IL-21 and IL-6 increased secreted PD-L1 in the culture media of WM cell lines, implying that elevated levels of soluble PD-1 ligands are cytokine mediated. Soluble PD-1 ligands reduced T-cell proliferation, phosphorylated extracellular signal-regulated kinase and cyclin A levels, mitochondrial adenosine triphosphate production, and spare respiratory capacity. In conclusion, we identify that soluble PD-1 ligands are elevated in WM patients and, in addition to surface-bound ligands in WM BM, could regulate T-cell function. Given the capability of secreted forms to be bioactive at distant sites, soluble PD-1 ligands have the potential to promote disease progression in WM.

Related: Cytokines