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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.

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Latest Research Publications

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

Trianto HB, Wardhani SO
A 44-Year-Old Man with Waldenstrom Macroglobulinemia and Bilateral Maxillary Sinusitis.
Acta Med Indones. 2016; 48(3):221-227 [PubMed] Related Publications
Waldenstrom macroglobulinemia is a chronic, indolent, lymphoproliferative disorder, which is characterized by the presence of a high macroglobulin (IgM) level, elevated serum viscosity, and the presence of a lymphoplasmacytic infiltrate in the bone marrow. Clinical manifestations may be found due to the presence of IgM paraprotein and malignant lymphoplasmacytic cell infiltration of the bone marrow and other tissues. We reported a case of male patient with Waldenstrom macroglobulinemia and bilateral maxillary sinusitis. He had received symptomatic and antibiotic treatment for his sinusitis, FFP and PRC transfusion to improve his general condition and chemotherapy with CHOP regimen as definitive treatment.

Yan C, Kong X, Yang L, Ma W
An uncommon case of lymphoplasmacytic lymphoma in cerebellopontine angle region: Case report with a literature review.
Medicine (Baltimore). 2016; 95(34):e4627 [PubMed] Related Publications
In the central nervous system, cerebellopontine angle (CPA) lymphomas are rare; few cases have been reported. Lymphoplasmacytic lymphoma (LPL) in the CPA is rarer still, and often misdiagnosed as acoustic neuroma.We report a rare case of CPA LPL-a challenging diagnosis guided by clinical presentations, radiological signs, and postoperative pathological test.A 43-year-old woman presented with headaches. Her magnetic resonance imaging revealed an abnormal homogeneously enhancing mass in the left CPA. We present detailed analysis of her disease and review relevant literature.When surgically treated, her specimen showed a typical LPL histopathology pattern. After surgery, the patient's symptoms improved greatly, and she received chemotherapy.Despite its rarity, LPL should be considered in differential diagnoses of CPA lesions that mimic acoustic neuromas.

Santos-Lozano A, Morales-Gonzalez A, Sanchis-Gomar F, et al.
Response rate to the treatment of Waldenström macroglobulinemia: A meta-analysis of the results of clinical trials.
Crit Rev Oncol Hematol. 2016; 105:118-26 [PubMed] Related Publications
Waldenström macroglobulinemia (WM) is a malignant lymphoproliferative disorder characterized by the presence of a high level of serum monoclonal IgM and a lymphoplasmacytic infiltrate in the bone marrow. This meta-analysis sought to assess the effectiveness of the different treatments for WM tested in published trials using the response rate (RR) as the main outcome measure. Forty-six articles (1409 patients) identified were entered in a variable effects model meta-analysis of proportions (rates and sample sizes). A greater response to treatment was produced in patients treated with a combination of 2+ drugs (RR=73%; 95%CI: 62, 83; p<0.01) than in those receiving monotherapy with rituximab (RR=44%; 95%CI: 34, 55; p<0.01) or a purine analogue [61% (95%CI: 43, 78; p<0.01) for cladribine and 53% (95%CI: 34, 72; p<0.01) for fludarabine]. The combination rituximab+cladribine emerged as particularly effective (RR=87%; 95%CI: 78, 94; p<0.01), slightly more effective than rituximab+bortezomib/dexamethasone (RR=84%; 95%CI: 79, 88; p<0.01) and rituximab+cyclophosphamide/dexamethasone [RR=81% (95%CI: 72, 88; p<0.01)]. Our results are in overall agreement with treatment recommendations from the seventh International Workshops on WM. Our findings are limited by the fact that we could not analyze progression-free survival (PFS). More phase II/III trials are needed to corroborate promising recent findings with bendamustine and carfilzomib and further research are needed to standardize recommendations based on maximum treatment efficacy combined with lowest toxicity, differentiation between first vs second line treatment, or long-term follow up after treatment.

King RL, Gonsalves WI, Ansell SM, et al.
Lymphoplasmacytic Lymphoma With a Non-IgM Paraprotein Shows Clinical and Pathologic Heterogeneity and May Harbor MYD88 L265P Mutations.
Am J Clin Pathol. 2016; 145(6):843-51 [PubMed] Related Publications
OBJECTIVES: Lymphoplasmacytic lymphoma (LPL) with non-immunoglobulin M (IgM) paraproteinemia remains poorly understood. The goal of this study was to investigate the clinicopathologic features of LPL in the bone marrow in patients with immunoglobulin G (IgG) or immunoglobulin A (IgA) paraproteins and evaluate MYD88 L265P mutation status to determine the relationship of these cases to Waldenström macroglobulinemia (WM).
METHODS: Bone marrows from LPL cases with IgG or IgA paraproteins diagnosed between January 1, 2007, and June 30, 2014, were retrieved from the clinical archive. Clinicopathologic features were retrospectively reviewed. MYD88 L265P mutation status was assessed by allele-specific polymerase chain reaction prospectively on all cases.
RESULTS: Of 27 cases, four were reclassified as multiple myeloma, all MYD88 mutation negative. MYD88 L265P mutations were present in 10 (43%) of 23 remaining cases. No association between MYD88 status and bone marrow morphologic or phenotypic features, including the presence of Dutcher bodies, mast cells, expression of CD19 by plasma cells, or hemosiderin, was identified, although these features were present in a subset of cases, similar to WM. Clinical features of WM such as hyperviscosity were uncommon in this group and did not correlate with MYD88 status.
CONCLUSIONS: Non-IgM LPLs are a clinically and pathologically heterogeneous group and often harbor MYD88 L265P mutation, albeit at a lower rate than classic WM. MYD88 status does not correlate with any specific pathologic or clinical manifestations.

Humeau C, Monjanel H, Schellenberg F
Discovery of a gamma heavy chain disease in a patient followed-up for a lymphoplasma cell proliferative disorder.
Ann Biol Clin (Paris). 2016; 74(3):338-40 [PubMed] Related Publications
Gamma-heavy chains disease is a rare disease, with very few cases described in the literature. It is characterized by the presence of a monoclonal gamma-heavy chain without associated light chain. Its prevalence and prognosis are unknown. We report here the accidental discovery of a case of gamma-heavy chain disease during a pancytopenia exploration, performed in the hospital, in a patient known since 2002 for a lymphoplasmacytic type lymphoma first localized in bone marrow.

Kapoor P, Paludo J, Ansell SM
Waldenstrom Macroglobulinemia: Familial Predisposition and the Role of Genomics in Prognosis and Treatment Selection.
Curr Treat Options Oncol. 2016; 17(3):16 [PubMed] Related Publications
OPINION STATEMENT: Waldenstrom macroglobulinemia (WM) is a non-Hodgkin lymphoma (NHL) characterized by the presence of a CD20 + lymphoplasmacytic bone marrow (BM) infiltrate and serum immunoglobulin M monoclonal protein. Both sporadic and familial forms exist. A remarkable improvement in outcome of nearly all age groups of WM patients may be primarily a consequence of successful integration of anti-CD20 monoclonal antibody, rituximab, to the conventional chemotherapy. However, the seminal discoveries of MYD88 (L265P) mutation, present in the vast majority (85-100 %), and CXCR4 (WHIM) mutations, identified in nearly a third of patients (who almost exclusively harbor the MYD88 (L265P) variant), have laid a solid foundation for a paradigm shift in our diagnostic and therapeutic approaches towards this rare hematologic malignancy. Given that 20-25 % of patients are asymptomatic at diagnosis and early intervention does not translate into survival benefit, we follow a risk-adapted approach and actively monitor this subset of "smoldering" patients. Those with low-grade cytopenias can generally be managed with an abbreviated course of rituximab monotherapy, while those with B symptoms, bulky lymphadenopathy, or profound disease-related cytopenias require more aggressive strategies, incorporating several courses of chemoimmunotherapy. For symptoms associated with hyperviscosity, prompt plasma exchange is warranted prior to initiation of cytoreductive therapy. Prospective data are unavailable to a support a unique approach in familial WM or initiation of rituximab maintenance post-induction. A multitude of potentially effective therapies targeting cell-survival pathways are in development and offer a more precise approach for WM patients. One such agent, ibrutinib, a Bruton's tyrosine kinase inhibitor, was recently granted approval. Off-study, we limit the use of ibrutinib to relapsed-refractory WM patients who harbor MYD88 mutations. Autologous stem-cell transplantation (ASCT) is another viable option in the relapsed setting for chemosensitive transplant-eligible patients. Unfortunately, despite substantial progress, achieving a minimal residual disease-negative state-a prerequisite for cure-is rare in WM.

Harmon CM, Smith LB
B-cell Non-Hodgkin Lymphomas with Plasmacytic Differentiation.
Surg Pathol Clin. 2016; 9(1):11-28 [PubMed] Related Publications
B-cell non-Hodgkin lymphomas with plasmacytic differentiation are a diverse group of entities with extremely variable morphologic features. Diagnostic challenges can arise in differentiating lymphoplasmacytic lymphoma from marginal zone lymphoma and other low-grade B-cell lymphomas. In addition, plasmablastic lymphomas can be difficult to distinguish from diffuse large B-cell lymphoma or other high-grade lymphomas. Judicious use of immunohistochemical studies and molecular testing can assist in appropriate classification.

Karlsson J, Roalfe L, Hogevik H, et al.
Poor Correlation between Pneumococcal IgG and IgM Titers and Opsonophagocytic Activity in Vaccinated Patients with Multiple Myeloma and Waldenstrom's Macroglobulinemia.
Clin Vaccine Immunol. 2016; 23(4):379-85 [PubMed] Free Access to Full Article Related Publications
Patients with multiple myeloma and other B cell disorders respond poorly to pneumococcal vaccination. Vaccine responsiveness is commonly determined by measuring pneumococcal serotype-specific antibodies by enzyme-linked immunosorbent assay (ELISA), by a functional opsonophagocytosis assay (OPA), or by both assays. We compared the two methods in vaccinated elderly patients with multiple myeloma, Waldenstrom's macroglobulinemia, and monoclonal gammopathy of undetermined significance (MGUS). Postvaccination sera from 45 patients (n= 15 from each patient group) and 15 control subjects were analyzed by multiplexed OPA for pneumococcal serotypes 4, 6B, 14, and 23F, and the results were compared to IgG and IgM antibody titers measured by ELISA. While there were significant correlations between pneumococcal OPA and IgG titers for all serotypes among the control subjects (correlation coefficients [r] between 0.51 and 0.85), no significant correlations were seen for any of the investigated serotypes in the myeloma group (r= -0.18 to 0.21) or in the group with Waldenstrom's macroglobulinemia (borderline significant correlations for 2 of 4 serotypes). The MGUS group resembled the control group by having good agreement between the two test methods for 3 of 4 serotypes (r= 0.53 to 0.80). Pneumococcal postvaccination IgM titers were very low in the myeloma patients compared to the other groups and did not correlate with the OPA results. To summarize, our data indicate that ELISA measurements may overestimate antipneumococcal immunity in elderly subjects with B cell malignancies and that a functional antibody test should be used specifically for myeloma and Waldenstrom's macroglobulinemia patients.

Ghobrial IM, Siegel DS, Vij R, et al.
TAK-228 (formerly MLN0128), an investigational oral dual TORC1/2 inhibitor: A phase I dose escalation study in patients with relapsed or refractory multiple myeloma, non-Hodgkin lymphoma, or Waldenström's macroglobulinemia.
Am J Hematol. 2016; 91(4):400-5 [PubMed] Related Publications
The PI3K/AKT/mTOR signaling pathways are frequently dysregulated in multiple human cancers, including multiple myeloma (MM), non-Hodgkin lymphoma (NHL), and Waldenström's macroglobulinemia (WM). This was the first clinical study to evaluate the safety, tolerability, maximal-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics, and preliminary clinical activity of TAK-228, an oral TORC1/2 inhibitor, in patients with MM, NHL, or WM. Thirty-nine patients received TAK-228 once daily (QD) at 2, 4, 6, or 7 mg, or QD for 3 days on and 4 days off each week (QDx3d QW) at 9 or 12 mg, in 28-day cycles. The overall median age was 61.0 years (range 46-85); 31 patients had MM, four NHL, and four WM. Cycle 1 DLTs occurred in five QD patients (stomatitis, urticaria, blood creatinine elevation, fatigue, and nausea and vomiting) and four QDx3d QW patients (erythematous rash, fatigue, asthenia, mucosal inflammation, and thrombocytopenia). The MTDs were determined to be 4 mg QD and 9 mg QDx3d QW. Thirty-six patients (92%) reported at least one drug-related toxicity; the most common grade ≥3 drug-related toxicities were thrombocytopenia (15%), fatigue (10%), and neutropenia (5%). TAK-228 exhibited a dose-dependent increase in plasma exposure and no appreciable accumulation with repeat dosing; mean plasma elimination half-life was 6-8 hr. Of the 33 response-evaluable patients, one MM patient had a minimal response, one WM patient achieved partial response, one WM patient had a minor response, and 18 patients (14 MM, two NHL, and two WM) had stable disease. These findings encourage further studies including combination strategies.

Albitar A, Ma W, DeDios I, et al.
Positive selection and high sensitivity test for MYD88 mutations using locked nucleic acid.
Int J Lab Hematol. 2016; 38(2):133-40 [PubMed] Related Publications
INTRODUCTION: Detection of mutations in the myeloid differentiation primary response gene 88 (MYD88) has clinical implications on diagnosis and therapy, especially in patients with Waldenström's macroglobulinemia (WM) and IgM monoclonal gammopathy of unknown significance (IgM-MGUS). We describe a method that provides greatly increased sensitivity for detecting minority mutations in MYD88.
METHODS: We used a locked nucleic acid oligonucleotide to block amplification of wild-type DNA during polymerase chain reaction (PCR). Sanger sequencing of amplified DNA was used for detecting mutations in MYD88 gene. This approach was used to test samples from patients with WM and IgM-MGUS.
RESULTS: When compared to traditional PCR followed by Sanger sequencing, our methodology was significantly more sensitive (one mutant allele in a background of 200 wild-type alleles). Using sequencing allowed us to visualize the PCR product, giving advantages over other methodologies such as allele-specific PCR. Based on analyzing 36 randomly selected, MYD88 mutated, clinically tested samples, we demonstrate that traditional PCR failed to detect MYD88 mutations in 64% of the samples that were clearly positive by wild-type blocking PCR.
CONCLUSION: The new methodology is essential for attaining accurate results in clinical testing.

Castillo JJ, D'Sa S, Lunn MP, et al.
Central nervous system involvement by Waldenström macroglobulinaemia (Bing-Neel syndrome): a multi-institutional retrospective study.
Br J Haematol. 2016; 172(5):709-15 [PubMed] Related Publications
Bing-Neel syndrome (BNS) is a rare complication seen in patients with Waldenström macroglobulinaemia (WM), in which lymphoplasmacytic lymphoma cells colonize the central nervous system. In this retrospective multi-centre study, we present the clinicopathological features, imaging findings, therapy, response and outcomes of 34 patients with BNS. The median time from WM diagnosis to BNS diagnosis was 3 years, 15% of patients were diagnosed with BNS at the time of WM diagnosis, and 22% of patients developed BNS when responding to active treatment for WM. Patients with BNS presented with variable clinical features including limb motor deficits, change in mental status and cranial nerve palsies. The diagnosis was made using a combination of cerebrospinal fluid cytology, flow cytometry and detection of the MYD88 L265 mutation, and magnetic resonance imaging. The estimated 3-year overall survival rate was 59%. Of the survivors, 40% have evidence of pathological and/or radiological persistence of disease. Age older than 65 years, platelet count lower than 100 × 10(9) /l, and treatment for WM prior to BNS diagnosis were associated with worse outcome. Exposure to rituximab for treatment of BNS was associated with a better outcome. Multi-institutional collaboration is warranted to improve treatment and outcomes in patients with BNS.

Xu L, Hunter ZR, Tsakmaklis N, et al.
Clonal architecture of CXCR4 WHIM-like mutations in Waldenström Macroglobulinaemia.
Br J Haematol. 2016; 172(5):735-44 [PubMed] Related Publications
CXCR4(WHIM) somatic mutations are distinctive to Waldenström Macroglobulinaemia (WM), and impact disease presentation and treatment outcome. The clonal architecture of CXCR4(WHIM) mutations remains to be delineated. We developed highly sensitive allele-specific polymerase chain reaction (AS-PCR) assays for detecting the most common CXCR4(WHIM) mutations (CXCR4(S338X C>A and C>G) ) in WM. The AS-PCR assays detected CXCR4(S338X) mutations in WM and IgM monoclonal gammopathy of unknown significance (MGUS) patients not revealed by Sanger sequencing. By combined AS-PCR and Sanger sequencing, CXCR4(WHIM) mutations were identified in 44/102 (43%), 21/62 (34%), 2/12 (17%) and 1/20 (5%) untreated WM, previously treated WM, IgM MGUS and marginal zone lymphoma patients, respectively, but no chronic lymphocytic leukaemia, multiple myeloma, non-IgM MGUS patients or healthy donors. Cancer cell fraction analysis in WM and IgM MGUS patients showed CXCR4(S338X) mutations were primarily subclonal, with highly variable clonal distribution (median 35·1%, range 1·2-97·5%). Combined AS-PCR and Sanger sequencing revealed multiple CXCR4(WHIM) mutations in many individual WM patients, including homozygous and compound heterozygous mutations validated by deep RNA sequencing. The findings show that CXCR4(WHIM) mutations are more common in WM than previously revealed, and are primarily subclonal, supporting their acquisition after MYD88(L265P) in WM oncogenesis. The presence of multiple CXCR4(WHIM) mutations within individual WM patients may be indicative of targeted CXCR4 genomic instability.

Quest GR, Johnston JB
Clinical features and diagnosis of hairy cell leukemia.
Best Pract Res Clin Haematol. 2015; 28(4):180-92 [PubMed] Related Publications
Significant advances in the diagnosis and treatment of hairy cell leukemia (HCL) have recently been made. Improved distinction of HCL from its mimics though clinical presentations, morphologic and immunophenotypic features, and more recently molecular biology, has highlighted marked differences in treatment response and overall prognosis between these disorders. As our understanding of the unique pathobiology of HCL has grown, exciting new avenues of treatment as well as insight into immune function have been obtained. This review provides an overview of the clinical features and diagnostic attributes of HCL, with contrast to other mature B cell lymphoproliferative disorders with overlapping features.

Dimopoulos MA, Kastritis E, Ghobrial IM
Waldenström's macroglobulinemia: a clinical perspective in the era of novel therapeutics.
Ann Oncol. 2016; 27(2):233-40 [PubMed] Free Access to Full Article Related Publications
Waldenström's macroglobulinemia (WM) is a rare, low-grade malignancy with no established standard of care. Rituximab regimens are most commonly used, supported by their efficacy in hematologic malignancies, including WM. A growing number of investigational regimens for WM have been evaluated in phase II clinical trials, including single-agent and combination strategies that include newer-generation monoclonal antibodies (ofatumumab and alemtuzumab), proteasome inhibitors (bortezomib and carfilzomib), immunomodulatory agents (thalidomide and lenalidomide), phosphoinositide 3-kinase/protein kinase B (Akt)/mammalian target of rapamycin pathway inhibitors (everolimus and perifosene), a Bruton's tyrosine kinase inhibitor (ibrutinib), and a histone deacetylase inhibitor (panobinostat). Other novel agents are in early-stage development for WM. International treatment guidelines for WM suggest suitable regimens in the newly diagnosed and relapsed/refractory settings, in accordance with patient age, disease presentation, and efficacy and safety profiles of particular drugs. These factors must be considered when choosing appropriate therapy for individual patients with WM, to maximize response and prolong survival, while minimizing the risk of adverse events. This review article provides a clinical perspective of the modern management of patients with WM, in the context of available trial data for novel regimens and recently updated treatment guidelines.

Kim HJ, Hur M, Kim H, et al.
A Rare Case of Waldenström Macroglobulinemia/Lymphoplasmacytic Lymphoma with Light Chain Discrepancy between B Lymphocyte Population and Serum Paraprotein.
Ann Clin Lab Sci. 2015; 45(5):593-7 [PubMed] Related Publications
Waldenström macroglobulinemia (WM) is a subset of lymphoplasmacytic lymphoma with bone marrow involvement, monotypic immunoglobulin (Ig) M and a light chain of neoplastic cells. A 68-year-old woman presented with fever, nausea, vomiting, and pancytopenia. Her serum albumin/globulin ratio was reversed, and monoclonal gammopathy of IgM, lambda type (23.20%, 1.58 g/dL) was detected. In her bone marrow, increased small lymphocytes were admixed with plasmacytoid lymphocytes and plasma cells. She was diagnosed as having lymphoplasmacytic variant of WM. Immunohistochemical stains and flow cytometic analysis revealed two distinct populations; monoclonal B cells (kappa+) and abnormal plasma cells (CD19-/CD56+/lambda+). She expired 19 days after admission due to septic shock. This is a rare case of WM exhibiting a light chain discrepancy between monoclonal B lymphocytes and paraprotein-secreting plasma cells. Light chain restriction may occur distinctly between lymphocyte and plasma cell populations in WM.

Brandefors L, Kimby E, Lundqvist K, et al.
Familial Waldenstrom's macroglobulinemia and relation to immune defects, autoimmune diseases, and haematological malignancies--A population-based study from northern Sweden.
Acta Oncol. 2016; 55(1):91-8 [PubMed] Related Publications
BACKGROUND: Waldenstrom's macroglobulinemia (WM) is a rare lymphoprolipherative disorder with geographic and ethnic disparities in incidence. The cause of WM remains mostly unknown although a role for genetic, immune-related, and environmental factors has been suggested. Most cases of WM are sporadic although familial cases occur.
AIM: This study estimated the incidence of WM in northern Sweden and identified and described patients with familial WM in this area.
PATIENTS AND METHODS: The Swedish and Northern Lymphoma Registry, the Swedish Cancer Registry (1997-2011), and medical records were used to identify patients with WM in two counties (Norrbotten and Västerbotten) in northern Sweden and to calculate the overall age-adjusted incidence (2000-2012). We identified 12 families with a family history of WM, IgM monoclonal gammophathy (MGUS), and/or multiple myeloma (MM).
RESULTS: In Norrbotten and Västerbotten, the age-adjusted incidence of WM/LPL is 1.75 and 1.48 per 100,000 persons per year, respectively (2000-2012), rates that are higher than the overall incidence of WM/LPL in Sweden (1.05 per 100,000 persons per year; 2000-2012). Autoimmune diseases and other haematological malignancies in the medical history (their own or in relatives) were reported in 9/12 and 5/12 families, respectively. A high proportion of abnormal serum protein electrophoresis was found in the relatives; 12/56 (21%) had a MGUS and 13/56 (25%) showed abnormalities in the immunoglobulin levels (i.e. subnormal levels and poly/oligoclonality).
CONCLUSION: The incidence of WM in Norrbotten and Västerbotten counties was higher than expected. We found a strong correlation between autoimmune/inflammatory diseases, other haematological malignancies, and familial WM and a high frequency of serum immunoglobulin abnormalities in the relatives of the WM patients, findings that strengthen the hypothesis that the aetiology of WM depends on both immune-related and genetic factors.

Lemal R, Bard-Sorel S, Montrieul L, et al.
TCL1 expression patterns in Waldenström macroglobulinemia.
Mod Pathol. 2016; 29(1):83-8 [PubMed] Related Publications
The oncogenic role of TCL1 in chronic lymphocytic leukemia is well established in transgenic mice. TCL1 expression in other B-cell malignancies has been also described: post-germinal center-derived malignancies, such as multiple myeloma, classically do not express TCL1. Waldenström macroglobulinemia is a post-germinal center malignancy that is known to be similar to chronic lymphocytic leukemia in terms of its gene expression profile. TCL1 expression has not been so far assessed in Waldenström macroglobulinemia. Transcriptomic explorations show that TCL1A expression is linked to signaling pathways and biological functions that are known to be involved in Waldenström macroglobulinemia as well as to gene signatures of interest in B-cell malignancies. We investigated TCL1 expression at the protein level in the bone marrow of a series of 59 patients with Waldenström macroglobulinemia: 76% of patients expressed TCL1, which appeared to be associated with a pejorative prognostic impact. TCL1 could have an oncogenic role in Waldenström macroglobulinemia, and deserves further exploration.

Kikukawa Y, Yamamura-Fujimoto A, Endo S, et al.
Successful Treatment of Bing-Neel Syndrome Accompanying Waldenström's Macroglobulinemia with R-MPV: A Case Report.
J Clin Exp Hematop. 2015; 55(2):113-9 [PubMed] Related Publications
Waldenström's macroglobulinemia (WM) is a neoplasm of lymphoplasmacytic cells that produces monoclonal IgM protein. Although hyperviscosity syndrome is a common feature of WM, central nervous system (CNS) involvement in WM is rare and is known as Bing-Neel syndrome. A 60-year-old woman was referred to our hospital with bed-bound polyneuropathy, edema, splenomegaly, IgM-λ-type monoclonal protein and CD20-positive lymphocyte infiltration in the bone marrow. She was diagnosed with WM accompanying POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes) and was treated with rituximab and thalidomide. She achieved partial remission of WM, and thalidomide was continued for POEMS syndrome. She visited our outpatient clinic 6 years later with sudden onset of vertigo and nausea. Magnetic resonance imaging (MRI) revealed a low-density area 4 cm in diameter in her right cerebrum and right mid-brain and she was referred to our hospital. Pathological analysis of brain biopsy samples revealed diffuse large B-cell lymphoma (DLBCL) in the CNS. Nucleic acid sequence analysis of the VDJ region using DNA obtained from the original WM tumor cells and brain tissue revealed that the DLBCL cells were derived from the original WM malignant lymphoma cells. She received five cycles of rituximab, methotrexate, procarbazine, and vincristine (R-MPV) therapy and 23.4 Gy of whole-brain irradiation followed by two cycles of high-dose cytarabine, which resolved her neurological symptoms in association with reduction of IgM levels to 367 mg/dL. MRI and computed tomography of the brain demonstrated complete remission of her CNS lymphoma.

Poulain S, Roumier C, Venet-Caillault A, et al.
Genomic Landscape of CXCR4 Mutations in Waldenström Macroglobulinemia.
Clin Cancer Res. 2016; 22(6):1480-8 [PubMed] Related Publications
PURPOSE: Whole-genome sequencing has revealed MYD88 L265P and CXCR4 mutations (CXCR4(mut)) as the most prevalent somatic mutations in Waldenström macroglobulinemia. CXCR4 mutation has proved to be of critical importance in Waldenström macroglobulinemia, in part due to its role as a mechanism of resistance to several agents. We have therefore sought to unravel the different aspects of CXCR4 mutations in Waldenström macroglobulinemia.
EXPERIMENTAL DESIGN: We have scanned the two coding exons of CXCR4 in Waldenström macroglobulinemia using deep next-generation sequencing and Sanger sequencing in 98 patients with Waldenström macroglobulinemia and correlated with SNP array landscape and mutational spectrum of eight candidate genes involved in TLR, RAS, and BCR pathway in an integrative study.
RESULTS: We found all mutations to be heterozygous, somatic, and located in the C-terminal domain of CXCR4 in 25% of the Waldenström macroglobulinemia. CXCR4 mutations led to a truncated receptor protein associated with a higher expression of CXCR4. CXCR4 mutations pertain to the same clone as to MYD88 L265P mutations but were mutually exclusive to CD79A/CD79B mutations (BCR pathway). We identified a genomic signature in CXCR4(mut) Waldenström macroglobulinemia traducing a more complex genome. CXCR4 mutations were also associated with gain of chromosome 4, gain of Xq, and deletion 6q.
CONCLUSIONS: Our study panned out new CXCR4 mutations in Waldenström macroglobulinemia and identified a specific signature associated to CXCR4(mut), characterized with complex genomic aberrations among MYD88L265P Waldenström macroglobulinemia. Our results suggest the existence of various genomic subgroups in Waldenström macroglobulinemia.

Zegers IH, Aaldering KN, Nieuwhof CM, Schouten HC
Non-myeloablative allogeneic stem cell transplantation: a new treatment option for acquired angioedema?
Neth J Med. 2015; 73(8):383-5 [PubMed] Related Publications
INTRODUCTION: Acquired angioedema is a rare disorder causing recurrent life-threatening angioedema, due to decreased activity of C1 esterase inhibitor.
CASE REPORT: A 57-year-old man presented to our hospital with recurrent swelling of the hands, lips, tongue, scrotum and throat. Lab examination showed the presence of an IgM kappa monoclonal antibody. Additional analysis showed that in the IgM fraction autoantibody activity against C1 esterase inhibitor was present. This confirmed the diagnosis of acquired angioedema in the presence of lymphoplasmacytic lymphoma. Despite standard therapy, there was an increase in the episodes of laryngeal oedema. Therefore it was decided to perform a non-myeloablative allogeneic haematopoietic stem cell transplantation, with his HLA-identical brother as donor. The post-transplantation course was without complications. Five years following alloSCT he is in complete remission without symptoms and with increased C1 esterase inhibitor activity.
DISCUSSION: In this case all other known treatment options for severe acquired angioedema failed. This is the first case describing treatment of severe acquired angioedema, caused by lymphoplasmacytic lymphoma, with an alloSCT.

Pace AA, Lownes SE, Shivane A, et al.
A tale of the unexpected: Amyloidoma associated with intracerebral lymphoplasmacytic lymphoma.
J Neurol Sci. 2015; 359(1-2):404-8 [PubMed] Related Publications
Amyloidoma is a rare cause for intracranial space-occupying lesions diagnosed on brain imaging. Histology of excised tissue usually reveals the presence of a discrete, λ-light chain secreting plasmacytoma adjacent to an amyloid mass comprising aggregated monoclonal immunoglobulin light chains. We described a patient with intracerebral amyloidoma associated with a localised lymphoplasmacytic lymphoma and no systemic paraproteinaemia, tumour or amyloid deposits.

Swerdlow SH, Kuzu I, Dogan A, et al.
The many faces of small B cell lymphomas with plasmacytic differentiation and the contribution of MYD88 testing.
Virchows Arch. 2016; 468(3):259-75 [PubMed] Free Access to Full Article Related Publications
Plasmacytic differentiation may occur in almost all small B cell lymphomas (SBLs), although it varies from being uniformly present (as in lymphoplasmacytic lymphoma (LPL)) to very uncommon (as in mantle cell lymphomas (MCLs)). The discovery of MYD88 L265P mutations in the vast majority of LPLs has had a major impact on the study of these lymphomas. Review of the cases contributed to the 2014 European Association for Haematopathology/Society for Hematopathology slide workshop illustrated how mutational testing has helped refine the diagnostic criteria for LPL, emphasizing the importance of identifying a clonal monotonous lymphoplasmacytic population and highlighting how LPL can still be diagnosed with extensive nodal architectural effacement, very subtle plasmacytic differentiation, follicular colonization, or uncommon phenotypes such as CD5 or CD10 expression. MYD88 L265P mutations were found in 11/11 LPL cases versus only 2 of 28 other SBLs included in its differential diagnosis. Mutational testing also helped to exclude other cases that would have been considered LPL in the past. The workshop also highlighted how plasmacytic differentiation can occur in chronic lymphocytic leukemia/small lymphocytic lymphoma, follicular lymphoma, SOX11 negative MCL, and particularly in marginal zone lymphomas, all of which can cause diagnostic confusion with LPL. The cases also highlighted the difficulty in distinguishing lymphomas with marked plasmacytic differentiation from plasma cell neoplasms. Some SBLs with plasmacytic differentiation can be associated with amyloid, other immunoglobulin deposition, or crystal-storing histiocytosis, which may obscure the underlying neoplasm. Finally, although generally indolent, LPL may transform, with the workshop cases suggesting a role for TP53 abnormalities.

Frank C, Fallah M, Chen T, et al.
Search for familial clustering of multiple myeloma with any cancer.
Leukemia. 2016; 30(3):627-32 [PubMed] Related Publications
Multiple myeloma (MM) is a disease of immunoglobulin-producing plasma cells, which reside mainly in the bone marrow. Family members of MM patients are at a risk of MM, but whether other malignancies are in excess in family members is not established and is the aim of this study. MM patients (24 137) were identified from the Swedish Cancer Registry from years 1958 to 2012. Relative risks (RRs) were calculated for MM defined by any cancer diagnosed in first-degree relatives and compared with individuals whose relatives had no cancer. MM was reliably associated with relative's colorectal, breast and prostate cancers, non-thyroid endocrine tumors, leukemia and cancer of unknown primary; in addition, MM was associated with subsites of bone and connective tissue tumors and of non-Hodgkin lymphoma, including lymphoplasmacytic lymphoma/Waldenström macroglobulinema (RR 3.47). MM showed a strong association (RR 1.91) in colorectal cancer families, possibly as part of an unidentified syndrome. All the associations of MM with discordant cancers are novel suggesting that MM shares genetic susceptibility with many cancers. The associations of MM bone and connective tissue tumors were supported by at least two independent results. Whether the results signal bone-related biology shared by MM and these tumors deserves further study.

Santos T, Machado S, Sousa V, Campos M
Cast nephropathy: an extremely rare renal presentation of Waldenström's macroglobulinaemia.
BMJ Case Rep. 2015; 2015 [PubMed] Related Publications
Renal involvement in Waldenström's macroglobulinaemia (WM) is very unusual when compared to multiple myeloma. We report a case of a patient who developed anuric acute kidney injury secondary to cast nephropathy, dependent on high-flux haemodialysis. Complementary study revealed the presence of blood IgM monoclonal gammopathy and a massive bone marrow lymphoplasmacytic infiltration. There were no osteolytic lesions and no clinical signs/symptoms of hyperviscosity syndrome. The diagnosis of WM was established and a dexamethasone plus cyclophosphamide regime was started, in addition to plasmapheresis. The patient partially recovered renal function allowing haemodialysis and plasmapheresis withdrawal. He remained asymptomatic with a good response to chemotherapy and 12 months after his renal function remained stable. This is a rare clinical case in which WM presented as an IgM cast nephropathy, which in turn is an extremely rare renal presentation of this equally rare haematological disorder.

Bhattarai M, Woytowitz DV, Kaldash H, et al.
Recurrent Mixed Cryoglobulinemia (MCS): A Case Report and Literature Review.
R I Med J (2013). 2015; 98(10):33-7 [PubMed] Related Publications
We report a case of recurrent mixed type II cryoglobulinemia with difficult diagnosis and treatment dilemma and uncertain prognosis in view of limited studies. A 60-year-old male with history of essential mixed cryoglobulinemia 12 years ago treated successfully with six months of cyclophosphamide and prednisone presented with bilateral lower extremity pupuric rash and swelling. He was found to have proteinuria, hematuria, RBC casts, low serum complement levels, and acute kidney injury (AKI). Initial therapy with methylprednisone and oral cyclophosphamide was ineffective (patient developed respiratory failure due to alveolar hemorrhage). Additional labs revealed positive type II cryoglobulins, high free Kappa/Lambda, UPEP with minimal urine protein, SPEP with marked hypogammaglobulinemia, and negative tests for HIV, HCV, ANA, and ANCA. More aggressive therapy with daily plasmapheresis and rituximab was instituted with very good clinical response. He achieved clinical remission but developed another flare 8 months later. Kidney biopsy showed membranoproliferatve glomerulonephritis with cryoglobulin deposits. Flow cytometry and biopsy of bone marrow was consistent with lymphoplasmacytic lymphoma. His diagnosis was eventually confirmed and responded clinically to another course of rituximab and plasmapheresis, but prognosis is yet to be seen.

Cao X, Medeiros LJ, Xia Y, et al.
Clinicopathologic features and outcomes of lymphoplasmacytic lymphoma patients with monoclonal IgG or IgA paraprotein expression.
Leuk Lymphoma. 2016; 57(5):1104-13 [PubMed] Related Publications
Lymphoplasmacytic lymphoma secreting IgG or IgA (non-IgM LPL) is rarely seen. Systematic studies of the clinical features and treatment outcomes are lacking in these patients. This study evaluated 17 patients with non-IgM LPL. The paraprotein secreted by these tumors was IgA (n=8; 47%) and IgG (n=9; 53%). The median serum level of paraprotein was 2,475 mg/dl (range=747-5260) for IgA and 2580 mg/dl (range=1900-7100) for IgG. The IgA-LPL group was more likely to present with B symptoms, a high beta2-microglobulin level and extramedullary involvement. Compared with patients with Waldenström macroglobulinemia (WM), patients with non-IgM LPL showed similar clinical and pathologic features, but a higher mortality within the first year after diagnosis (p<0.001) and worse overall survival (p=0.024), with no difference in progression-free survival and disease-specific survival. Rituximab alone or rituximab-based therapy was used frequently and was effective as either first-line or salvage therapy.

Simon L, Fitsiori A, Lemal R, et al.
Bing-Neel syndrome, a rare complication of Waldenström macroglobulinemia: analysis of 44 cases and review of the literature. A study on behalf of the French Innovative Leukemia Organization (FILO).
Haematologica. 2015; 100(12):1587-94 [PubMed] Free Access to Full Article Related Publications
Central nervous system involvement by malignant cells is a rare complication of Waldenström macroglobulinemia, and this clinicopathological entity is referred to as the Bing-Neel syndrome. There is currently no consensus on the diagnostic criteria, therapeutic approaches and response evaluation for this syndrome. In this series, we retrospectively analyzed 44 French patients with Bing-Neel syndrome. Bing-Neel syndrome was the first manifestation of Waldenström macroglobulinemia in 36% of patients. When Waldenström macroglobulinemia was diagnosed prior to Bing-Neel syndrome, the median time interval between this diagnosis and the onset of Bing-Neel syndrome was 8.9 years. This study highlights the possibility of the occurrence of Bing-Neel syndrome without any other evidence of progression of Waldenström macroglobulinemia. The clinical presentation was heterogeneous without any specific signs or symptoms. Biologically, the median lymphocyte count in the cerebrospinal fluid was 31/mm(3). Magnetic resonance imaging revealed abnormalities in 78% of the cases. The overall response rate after first-line treatment was 70%, and the overall survival rate after the diagnosis of Bing-Neel syndrome was 71% at 5 years. Altogether, these results suggest that Bing-Neel syndrome should be considered in the context of any unexplained neurological symptoms associated with Waldenström macroglobulinemia. The diagnostic approach should be based on cerebrospinal fluid analysis and magnetic resonance imaging of the brain and spinal axis. It still remains difficult to establish treatment recommendations or prognostic factors in the absence of large-scale, prospective, observational studies.

Pertesi M, Galia P, Nazaret N, et al.
Rare Circulating Cells in Familial Waldenström Macroglobulinemia Displaying the MYD88 L265P Mutation Are Enriched by Epstein-Barr Virus Immortalization.
PLoS One. 2015; 10(9):e0136505 [PubMed] Free Access to Full Article Related Publications
The MYD88 L265P is a recurrent somatic mutation in neoplastic cells from patients with Waldenström Macroglobulinemia (WM). We identified the MYD88 L265P mutation in three individuals from unrelated families, but its presence did not explain the disease segregation within these WM pedigrees. We observed the mutation in these three individuals at high allele fractions in DNA extracted from EBV-immortalized Lymphoblastoid cell lines established from peripheral blood (LCL), but at much lower allele fractions in DNA extracted directly from peripheral blood, suggesting that this mutation is present in a clonal cell subpopulation rather than of germ-line origin. Furthermore, we observed that the MYD88 L265P mutation is enriched in WM families, detected in 40.5% of patients with familial WM or MGUS (10/22 WM, 5/15 MGUS), compared to 3.5% of patients with familial MM or MGUS (0/72 MM, 4/41 MGUS) (p = 10-7). The mutant allele frequency increased with passages in vitro after immortalization with Epstein-Barr virus (EBV) consistent with the MYD88 L265P described gain-of-function proposed for this mutation. The MYD88 L265P mutation appears to be frequently present in circulating cells in patients with WM, and MGUS, and these cells are amenable to immortalization by EBV.

Fouquet G, Guidez S, Petillon MO, et al.
Lenalidomide is safe and active in Waldenström macroglobulinemia.
Am J Hematol. 2015; 90(11):1055-9 [PubMed] Related Publications
Lenalidomide is manageable and effective in multiple myeloma, particularly in elderly patients. Surprisingly, the combination of lenalidomide with rituximab produced clinically significant anemia at 25 mg/day for 21/28 days, the highest possible dose, in Waldenström's Macroglobulinemia (WM). We aimed to determine the maximum tolerated dose (MTD) of single agent lenalidomide and determine its impact on WM. RV-WM-0426 is a multicenter dose escalation open label phase 1/2 study of lenalidomide in relapsed/refractory WM (RRWM). Lenalidomide was given orally 21/28 days per cycle for 1 year, at escalated dose of 15 to 20 mg during phase 1 to determine the MTD; the phase 2 part was conducted at the MTD. Seventeen RRWM patients were included. The MTD was established at 15 mg/day 21/28. By ITT analysis, the overall response rate was 29%. With a median follow-up of 36 months, median TTP was 16 months (95% CI 5.5-26), the 5-year OS was 91%. The most frequent adverse events ≥ grade 3 at 15 mg were 14% anemia and 43% neutropenia. The MTD of lenalidomide is 15 mg/day 21/28 days in RRWM. Lenalidomide is active in the treatment of RRWM and the safety profile appears manageable. Future studies may look into combinations of lenalidomide and continuous dosing.

Min C, Higuchi T, Koyamada R, et al.
Pulmonary Extranodal Marginal Zone Lymphoma with Macroglobulinemia and Mixed Cryoglobulinemia Developed in a Patient with Chronic Hepatitis C.
Intern Med. 2015; 54(16):2061-4 [PubMed] Related Publications
We report a 65-year-old woman with a chronic hepatitis C virus infection who developed pulmonary extranodal marginal zone lymphoma (EMZL) of mucosa-associated lymphoid tissues complicated with macroglobulinemia and mixed cryoglobulinemia. She was treated with immunochemotherapy which resulted in the reduction of both the tumors and the serum immunoglobulin (Ig) M level. This case exemplifies an extensive stimulation upon immune system with derangement in the production of immunoglobulines associated with EMZL, and suggests that it is necessary to consider the possibility of B-cell lymphoma when IgM paraprotein is detected.

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