Waldenstrom's Macroglobulinemia
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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

Information Patients and the Public (17 links)


Information for Health Professionals / Researchers (6 links)

Latest Research Publications

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

Roberts MJ, Chadburn A, Ma S, et al.
Nuclear protein dysregulation in lymphoplasmacytic lymphoma/waldenstrom macroglobulinemia.
Am J Clin Pathol. 2013; 139(2):210-9 [PubMed]
Waldenström macroglobulinemia (WM) is characterized by monoclonal gammopathy, usually IgM, in association with lymphoplasmacytic lymphoma (LPL). Little is known of the expression of nuclear proteins involved in B-cell development in LPL/WM. In this study, the expression patterns of PAX5/BSAP, MUM1/IRF4, and PRDM1/BLIMP1 were analyzed in plasma cells and lymphocytes in 29 cases of newly diagnosed LPL/WM by double immunohistochemical staining with CD138 and CD22. These patterns were compared with the expression profiles seen in normal bone marrow samples, reactive tonsils, and cases of plasma cell myeloma and marginal zone lymphoma. The median percentage of plasma cells coexpressing CD138 and PAX5 was significantly higher in LPL/WM compared with benign tissues (P = .001), marginal zone lymphoma (P = .002), and plasma cell myeloma (P < .0001), whereas the median percentage of plasma cells coexpressing CD138 and MUM1 was lower in LPL/WM than plasma cells in benign tissues (P = .02), marginal zone lymphoma (P = .001), and plasma cell myeloma (P = .0002). These findings show that a subset of plasma cells in LPL/WM demonstrates a nuclear protein expression pattern characteristic of the B-cell developmental program. Thus, the results better define the immunophenotypic profile of the neoplastic cells in LPL/WM.


Xu L, Hunter ZR, Yang G, et al.
MYD88 L265P in Waldenström macroglobulinemia, immunoglobulin M monoclonal gammopathy, and other B-cell lymphoproliferative disorders using conventional and quantitative allele-specific polymerase chain reaction.
Blood. 2013; 121(11):2051-8 [PubMed] Article available free on PMC after 14/03/2014
By whole-genome and/or Sanger sequencing, we recently identified a somatic mutation (MYD88 L265P) that stimulates nuclear factor κB activity and is present in >90% of Waldenström macroglobulinemia (WM) patients. MYD88 L265P was absent in 90% of immunoglobulin M (IgM) monoclonal gammopathy of undetermined significance (MGUS) patients. We therefore developed conventional and real-time allele-specific polymerase chain reaction (AS-PCR) assays for more sensitive detection and quantification of MYD88 L265P. Using either assay, MYD88 L265P was detected in 97 of 104 (93%) WM and 13 of 24 (54%) IgM MGUS patients and was either absent or rarely expressed in samples from splenic marginal zone lymphoma (2/20; 10%), CLL (1/26; 4%), multiple myeloma (including IgM cases, 0/14), and immunoglobulin G MGUS (0/9) patients as well as healthy donors (0/40; P < 1.5 × 10(-5) for WM vs other cohorts). Real-time AS-PCR identified IgM MGUS patients progressing to WM and showed a high rate of concordance between MYD88 L265P ΔCT and BM disease involvement (r = 0.89, P = .008) in WM patients undergoing treatment. These studies identify MYD88 L265P as a widely present mutation in WM and IgM MGUS patients using highly sensitive and specific AS-PCR assays with potential use in diagnostic discrimination and/or response assessment. The finding of this mutation in many IgM MGUS patients suggests that MYD88 L265P may be an early oncogenic event in WM pathogenesis.


Ghobrial IM, Campigotto F, Murphy TJ, et al.
Results of a phase 2 trial of the single-agent histone deacetylase inhibitor panobinostat in patients with relapsed/refractory Waldenström macroglobulinemia.
Blood. 2013; 121(8):1296-303 [PubMed] Article available free on PMC after 21/02/2014
The present study aimed to determine the safety and activity of the histone deacetylase inhibitor panobinostat in patients with relapsed/refractory Waldenström macroglobulinemia (WM). Eligibility criteria included patients with relapsed/refractory WM with any number of prior therapies. Patients received panobinostat at 30 mg 3 times a week; 12 of 36 (33%) patients were enrolled at 25 mg dose. A total of 36 patients received therapy. The median age was 62 years (range, 47-80) and the median number of prior therapies was 3 (range, 1-8). All of the patients had received prior rituximab. Minimal response (MR) or better was achieved in 47% of patients (90% confidence interval [CI], 33-62), with 22% partial remissions and 25% MR. In addition, 18 (50%) patients achieved stable disease and none showed progression while on therapy. The median time to first response was 1.8 months (range, 1.7-3.2). The median progression-free survival was 6.6 months(90% CI, 5.5-14.8). Grade 3 and 4 toxicities included thrombocytopenia (67%), neutropenia (36%), anemia (28%), leukopenia (22%), and fatigue (11%). We conclude that panobinostat is an active therapeutic agent in patients with relapsed/ refractory WM. This study (www.clinicaltrials.gov identifier: NCT00936611) establishes a role for histone deacetylase inhibitors as an active class of therapeutic agents in WM.


Peker D, Quigley B, Qin D, et al.
Burkitt lymphoma arising from lymphoplasmacytic lymphoma following acquisition of MYC translocation and loss of the ETV6 tumor suppressor gene.
Arch Pathol Lab Med. 2013; 137(1):130-3 [PubMed]
Lymphoplasmacytic lymphoma is a mature B-cell lymphoma with variable plasmacytic differentiation that displays an indolent clinical course. Its transformation to a high-grade B-cell lymphoma may occur uncommonly. Although acquisition of a MYC translocation could result in transformation of a low-grade lymphoma into diffuse large B-cell lymphoma, Burkitt lymphoma, or B-lymphoblastic leukemia, to our knowledge the latter 2 transformations have not been well documented in lymphoplasmacytic lymphoma. We report the case of a 70-year-old woman with a 9-year history of lymphoplasmacytic lymphoma/Waldenström macroglobulinemia who presented with rapid enlargement of a left neck mass and pancytopenia, which was diagnosed as Burkitt lymphoma with extensive bone marrow involvement. A series of histopathologic, molecular, and cytogenetic evaluations proved a cytogenetic evolution including t(8;14)(q24;q32)/MYC-IgH and identical clonal B-cell gene rearrangements from the 2 distinct lymphomas, confirming stage 4 aggressive Burkitt lymphoma arising from lymphoplasmacytic lymphoma.


Leblond V, Johnson S, Chevret S, et al.
Results of a randomized trial of chlorambucil versus fludarabine for patients with untreated Waldenström macroglobulinemia, marginal zone lymphoma, or lymphoplasmacytic lymphoma.
J Clin Oncol. 2013; 31(3):301-7 [PubMed]
PURPOSE: Treatment options for patients with Waldenström macroglobulinemia (WM) and closely related disorders include alkylating agents, purine analogs, and monoclonal antibodies. No large randomized studies have yet been reported comparing any of these approaches.
PATIENTS AND METHODS: The randomized WM1 study (Trial Comparing Chlorambucil to Fludarabine in Patients With Advanced Waldenström Macroglobulinemia) was undertaken in 101 centers in five countries enrolling 414 eligible patients (339 with WM, 37 with non-mucosa-associated lymphoid tissue marginal zone lymphoma, and 38 with lymphoplasmacytic lymphoma) who were randomly assigned to receive chlorambucil or fludarabine. The primary end point was the overall response rate (ORR).
RESULTS: On the basis of intent-to-treat analysis, the ORR was 47.8% (95% CI, 40.9% to 54.8%) in the fludarabine arm versus 38.6% (95% CI, 32.0% to 45.7%) in the chlorambucil arm (P = .07). With a median follow-up of 36 months (interquartile range, 18 to 58 months), median progression-free survival (PFS), and duration of response (DR) were significantly improved in the fludarabine arm compared with the chlorambucil arm: PFS, 36.3 versus 27.1 months (P = .012) and DR, 38.3 versus 19.9 months (P < .001). In patients with WM, median overall survival (OS) was not reached in the fludarabine arm versus 69.8 months in the chlorambucil arm (95% CI, 61.6 to 79.8 months; P = .014). Grade 3 to 4 neutropenia was significantly higher among patients treated with fludarabine (36%) compared with patients treated with chlorambucil (17.8%; P < .001). Second malignancies were significantly more frequent in the chlorambucil arm with 6-year cumulative incidence rate of 20.6% versus 3.7% in the fludarabine arm (P = .001).
CONCLUSION: In the complete intent-to-treat study population, fludarabine significantly improved PFS compared with chlorambucil, and in patients with WM, it improved OS.


Baker PS, Garg SJ, Fineman MS, et al.
Serous macular detachment in Waldenström macroglobulinemia: a report of four cases.
Am J Ophthalmol. 2013; 155(3):448-55 [PubMed]
PURPOSE: To describe a series of 4 patients with Waldenström macroglobulinemia and serous macular detachment, and propose a mechanism for development of subretinal fluid based on optical coherence tomography (OCT) findings.
DESIGN: Retrospective observational case series.
METHODS: The records of patients with Waldenström macroglobulinemia and OCT documentation of serous macular detachment at Wills Eye Institute were reviewed. Data collection included clinical examination, as well as findings on fluorescein angiography (FA) and OCT.
RESULTS: Four patients (8 eyes) with Waldenström macroglobulinemia and serous retinal detachment were identified. All eyes had varying degrees of venous stasis retinopathy and intraretinal edema overlying the macular detachment. Three patients had no FA leakage, while 1 patient had macular leakage in a petaloid pattern. Focal outer retinal defects within the detached retina were seen in 4 eyes on OCT imaging. In one eye, development of cystoid macular edema was observed before the outer retinal defect and serous macular detachment. All patients with serous macular detachment had some degree of outer retinal disruption.
CONCLUSION: Discontinuity of the outer retina within the macular detachment may enable immunoglobulins along with accumulated intraretinal fluid to flow into the subretinal space, creating a serous retinal detachment. Even with systemic treatment of the underlying Waldenström macroglobulinemia, the visual prognosis was guarded.


Kristinsson SY, Eloranta S, Dickman PW, et al.
Patterns of survival in lymphoplasmacytic lymphoma/Waldenström macroglobulinemia: a population-based study of 1,555 patients diagnosed in Sweden from 1980 to 2005.
Am J Hematol. 2013; 88(1):60-5 [PubMed]
Clinical management of lymphoplasmacytic lymphoma (LPL)/Waldenström macroglobulinemia (WM) has changed considerably over recent years, reflected in the use of new therapeutic agents (purine analogs, monoclonal antibodies, thalidomide- and bortezomib-based therapies). No population-based studies and few randomized trials have been performed to assess survival in newly diagnosed LPL/WM. We performed a large population-based study in Sweden including 1,555 LPL/WM patients diagnosed from 1980 to 2005. Relative survival ratios (RSRs) and excess mortality rate ratios (EMRR) were computed as measures of survival. Survival of LPL/WM patients has improved significantly (P = 0.007) over time with 5-year RSR = 0.57 (95% confidence interval [CI] 0.46-0.68), 0.65 (0.57-0.73), 0.74 (0.68-0.80), 0.72 (0.66-0.77), and 0.78 (0.71-0.85) for patients diagnosed during the calendar periods 1980-1985, 1986-1990, 1991-1995, 1996-2000, and 2001-2005, respectively. Improvement in 1- and 5-year relative survival was found in all age groups and for LPL and WM separately. Patients with WM had lower excess mortality compared to LPL (EMRR = 0.38; 95% CI 0.30-0.48). Older age at diagnosis was associated with a poorer survival (P < 0.001). Taken together, we found a significant improvement in survival in LPL/WM over time. Despite this progress, new effective agents with a more favourable toxicity profile are needed to further improve survival in LPL/WM, especially in the elderly.


Owen RG, Kyle RA, Stone MJ, et al.
Response assessment in Waldenström macroglobulinaemia: update from the VIth International Workshop.
Br J Haematol. 2013; 160(2):171-6 [PubMed]
This report represents a further update of the consensus panel criteria for the assessment of clinical response in patients with Waldenström macroglobulinaemia (WM). These criteria have been updated in light of further data demonstrating an improvement in categorical responses with new drug regimens as well as acknowledgement of the fact that such responses are predictive of overall outcome. A number of key changes are proposed but challenges do however remain and these include the variability in kinetics of immunoglobulin M (IgM) reduction with different treatment modalities and the apparent discrepancy between IgM and bone marrow/tissue response noted with some regimens. Planned sequential bone marrow assessments are encouraged in clinical trials.


Anderson KC, Alsina M, Bensinger W, et al.
Waldenström's macroglobulinemia/lymphoplasmacytic lymphoma, version 2.2013.
J Natl Compr Canc Netw. 2012; 10(10):1211-9 [PubMed]
These NCCN Guidelines Insights highlight the important updates/changes specific to the management of Waldenström's Macroglobulinemia/Lymphoplasmacytic Lymphoma. These include the addition of regimens containing novel agents as primary and salvage therapy options, inclusion of the updated summary of response categories and criteria from the sixth international workshop on Waldenström's Macroglobulinemia, and a section on management of peripheral neuropathy in the accompanying discussion.


Hodge LS, Ziesmer SC, Yang ZZ, et al.
IL-21 in the bone marrow microenvironment contributes to IgM secretion and proliferation of malignant cells in Waldenstrom macroglobulinemia.
Blood. 2012; 120(18):3774-82 [PubMed]
Cytokines within the tumor microenvironment play an important role in supporting the growth and survival of B-cell malignancies. One such cytokine, IL-21, promotes the growth of myeloma and Hodgkin lymphoma cells while inducing apoptosis in chronic lymphocytic leukemia. However, the biologic significance of IL-21 has not been examined in Waldenstrom macroglobulinemia (WM), a B-cell lymphoma characterized by elevated serum IgM and a lymphoplasmacytic bone marrow infiltrate. We report here on the presence of IL-21 in the bone marrow of patients with WM and have identified activated T cells as the source of this cytokine. We readily detected the IL-21 receptor on malignant WM B cells and show that IL-21 significantly increases both IgM secretion and cellular proliferation of these cells with no effect on viability. IL-21 rapidly induces phosphorylation of STAT3 in WM cells, and treatment of the WM cell line MWCL-1 with a STAT3 inhibitor abolished the IL-21-mediated increases in cellular proliferation and IgM secretion. IL-21 also increased the expression of known STAT3 targets involved in B-cell differentiation, including BLIMP-1, XBP-1, IL-6, and IL-10. Overall, our data indicate that IL-21 in the bone marrow microenvironment significantly affects the biology of WM tumor cells through a STAT3-dependent mechanism.


Chung YY, Wang CC, Lai KJ, Chang CC
Waldenström's macroglobulinemia-associated renal amyloidosis presenting as a solitary lung mass.
Ren Fail. 2012; 34(9):1173-6 [PubMed]
A single nodular lesion can be observed in various pulmonary diseases, including cancer, tuberculosis, and fungal infection. Waldenström's macroglobulinemia (WM) usually occurs in older adults and involves the lymph nodes, bone marrow, and spleen. Respiratory tract involvement is very rare. We reported a case of WM-associated renal amyloidosis. The patient was admitted with the initial presentation as a single mass in the lung and progression to renal involvement.


Gachard N, Parrens M, Soubeyran I, et al.
IGHV gene features and MYD88 L265P mutation separate the three marginal zone lymphoma entities and Waldenström macroglobulinemia/lymphoplasmacytic lymphomas.
Leukemia. 2013; 27(1):183-9 [PubMed]
To clarify the relationships between marginal zone lymphomas (MZLs) and Waldenström macroglobulinemia/lymphoplasmacytic lymphomas (WM/LPLs), immunoglobulin heavy chain variable gene (IGHV) features were analyzed and the occurrence of MYD88 L265P mutations was identified in a series of 123 patients: 53 MZLs from the spleen (SMZLs), 11 from lymph nodes (NMZLs), 28 mucosa-associated lymphatic tissue (MALT) lymphomas and 31 WM/LPLs. SMZLs were characterized by overrepresentation of IGHV1-2 gene rearrangements with a canonical motif, without selection pressure and with long CDR3 segments. NMZLs had increased frequencies of IGHV3 genes. The IGHV gene was unmutated in most cases, often with long CDR3 segments. MALT lymphomas were usually associated with a mutated IGHV gene, but with the absence of selection pressure. WM/LPLs were associated with an IGHV3-23 overrepresentation and high IGHV mutation rate, with features of selection pressure and short CDR3 segments. MYD88 L265P mutations were almost restricted exclusively to WM/LPL patients. Taken all diagnoses together, all patients with MYD88 L265P mutations had an immunoglobulin M peak and almost all patients except one had bone marrow infiltration. These results demonstrate that the history of antigen exposure of the four entities studied was different and MYD88 L265P was specifically associated with WM/LPLs. WM/LPL may thus be functionally associated with constitutive nuclear factor-κB activation.


Treon SP, Xu L, Yang G, et al.
MYD88 L265P somatic mutation in Waldenström's macroglobulinemia.
N Engl J Med. 2012; 367(9):826-33 [PubMed]
BACKGROUND: Waldenström's macroglobulinemia is an incurable, IgM-secreting lymphoplasmacytic lymphoma (LPL). The underlying mutation in this disorder has not been delineated.
METHODS: We performed whole-genome sequencing of bone marrow LPL cells in 30 patients with Waldenström's macroglobulinemia, with paired normal-tissue and tumor-tissue sequencing in 10 patients. Sanger sequencing was used to validate the findings in samples from an expanded cohort of patients with LPL, those with other B-cell disorders that have some of the same features as LPL, and healthy donors.
RESULTS: Among the patients with Waldenström's macroglobulinemia, a somatic variant (T→C) in LPL cells was identified at position 38182641 at 3p22.2 in the samples from all 10 patients with paired tissue samples and in 17 of 20 samples from patients with unpaired samples. This variant predicted an amino acid change (L265P) in MYD88, a mutation that triggers IRAK-mediated NF-κB signaling. Sanger sequencing identified MYD88 L265P in tumor samples from 49 of 54 patients with Waldenström's macroglobulinemia and in 3 of 3 patients with non-IgM-secreting LPL (91% of all patients with LPL). MYD88 L265P was absent in paired normal tissue samples from patients with Waldenström's macroglobulinemia or non-IgM LPL and in B cells from healthy donors and was absent or rarely expressed in samples from patients with multiple myeloma, marginal-zone lymphoma, or IgM monoclonal gammopathy of unknown significance. Inhibition of MYD88 signaling reduced IκBα and NF-κB p65 phosphorylation, as well as NF-κB nuclear staining, in Waldenström's macroglobulinemia cells expressing MYD88 L265P. Somatic variants in ARID1A in 5 of 30 patients (17%), leading to a premature stop or frameshift, were also identified and were associated with an increased disease burden. In addition, 2 of 3 patients with Waldenström's macroglobulinemia who had wild-type MYD88 had somatic variants in MLL2.
CONCLUSIONS: MYD88 L265P is a commonly recurring mutation in patients with Waldenström's macroglobulinemia that can be useful in differentiating Waldenström's macroglobulinemia and non-IgM LPL from B-cell disorders that have some of the same features. (Funded by the Peter and Helen Bing Foundation and others.).


Hivert B, Caron C, Petit S, et al.
Clinical and prognostic implications of low or high level of von Willebrand factor in patients with Waldenstrom macroglobulinemia.
Blood. 2012; 120(16):3214-21 [PubMed]
Acquired von Willebrand syndrome is described in patients with Waldenström macroglobulinemia (WM). Assessment of ristocetin cofactor activity (VWF:RCo) and von Willebrand factor (VWF) antigen (VWF:Ag) in 72 consecutive patients with WM showed a negative relation between VWF levels < 130 U/dL and both monoclonal immunoglobulin M concentration (mIgMC) and viscosity. Ten patients with VWF:RCo < 50 U/dL (< 40 for patients with blood group O) fulfilled the acquired von Willebrand syndrome criteria. They had higher mIgMC and viscosity. Reduction in mIgMC was associated with increase in VWF levels. The low VWF:RCo/VWF:Ag ratio suggested that high viscosity might be associated with increased shear force and cleavage of multimers. Surprisingly, 43 patients (59%) presented with high VWF:Ag (> 110 U/dL). They had higher bone marrow microvessel density and vascular endothelial growth factor expression on bone marrow mast cells. Five-year survival rates of patients with VWF:Ag < 110, between 110 and 250, and more than 250 U/dL were 96%, 71%, and 44%, respectively (P < .0001). High VWF:Ag was also a significant adverse prognostic factor for survival after first-line therapy (P < .0001), independently of the international scoring system. These results support systematic assessment of VWF in patients with WM. The adverse prognostic value of high VWF levels raises issues on interactions between lymphoplasmacytic cells, mast cells, and endothelial cells in WM.


Hensel M, Brust J, Plöger C, et al.
Excellent long-term survival of 170 patients with Waldenström's macroglobulinemia treated in private oncology practices and a university hospital.
Ann Hematol. 2012; 91(12):1923-8 [PubMed]
The purpose of this study was to compare treatment and outcome of patients with Waldenström's macroglobulinemia (WM) in four private oncology practices (PP) and a university hospital (UH) in southwest Germany. We retrospectively reviewed the charts of all patients with WM of the last two decades of four PP in Mannheim, Heidelberg, Karlsruhe, and Speyer and the Department of Hematology of the University of Heidelberg. One hundred seventy patients could be identified, 74 from PP, 96 from the UH. Median age was 63.3 years. Patients from PP were older (median 65.3 vs. 62.5 years, p = 0.01). Only 54 % of patients from PP have received treatment during the observation time, as compared to 78.1 % of the UH (p < 0.001). In PP, 35 % of treated patients have received rituximab, as compared to 62.6 % of the patients of the UH (p < 0.001). Sixty percent of treated patients of PP have received bendamustine, as compared to only 8 % of the patients of the UH (p < 0.001). Time to first treatment was significantly shorter in patients from the UH compared to PP (median 13.7 vs. 52.9 months, p = 0.05). A trend towards a better overall survival was observed for patients treated with a rituximab-containing first-line regimen. The International Prognostic Scoring System for WM had significant prognostic value. Median overall survival was 25.0 years and did not differ between PP and UH. Despite different treatment strategies between PP and UH today overall survival of patients with WM is excellent, and better than previously reported.


Inoue D, Matsushita A, Kiuchi M, et al.
Successful treatment of γ-heavy-chain disease with rituximab and fludarabine.
Acta Haematol. 2012; 128(3):139-43 [PubMed]
An 84-year-old Japanese man was admitted because of pancytopenia. The bone marrow was hypoplastic with a predominance of abnormal small lymphocytes and grape cells, which were positive for CD19 and CD20, and partially for the surface ĸ-light chain. Systemic CT scanning showed neither lymph node swelling nor hepatosplenomegaly. Serum immunoelectrophoresis and rocket immunoselection assays showed the presence of monoclonal IgG protein without a corresponding light chain and faint IgMĸ monoclonal protein. Histologic analysis of the clot preparation of the bone marrow aspirate facilitated a diagnosis of lymphoplasmacytic lymphoma (LPL). PCR analysis of the marrow cells demonstrated a clonal rearrangement of the immunoglobulin heavy-chain gene. From these results, we made a final diagnosis of γ-heavy-chain disease (γ-HCD) with underlying LPL localized in the bone marrow. We performed only a single course of immunochemotherapy (rituximab and fludarabine) in view of severely impaired hematopoiesis, which resulted in marked reduction of lymphoma cells and improvement of hematopoiesis. This report suggests the efficacy of rituximab plus fludarabine therapy for LPL-associated γ-HCD.


Hirota-Kawadobora M, Matsuda K, Yamauchi K, et al.
Waldenström macroglobulinemia transforming from t (11;18) (q21;q21) -negative gastric MALT lymphoma after systemic dissemination.
Rinsho Byori. 2012; 60(6):528-35 [PubMed]
AIM: We here describe the clinical course of a 70-year-old male patient with Waldenström macroglobulinemia (WM) putatively transformed from refractory mucosa-associated lymphoid tissue lymphoma (MALTL).
METHODS: Immunological staining was performed on formalin-fixed, paraffin-embedded tissue sections, and M-protein and cryoglobulin were identified by immunofixation electrophoresis and the cold precipitation method. Chromosome translocation was analyzed by the G-banded karyotype, and API2/MALT1 fusion gene underwent fluorescent in situ hybridization. Multiplex polymerase chain reaction was performed to analyze the VH-JH or DH-JH rearrangements of the IGH gene.
RESULTS: At diagnosis, the WM patient had monoclonal IgM with cryoglobulinemia and hyperviscosity syndrome. Eight years before developing WM, the patient experienced the onset of typical gastric MALT-L with H. pylori infection, but in spite of negative for chromosome translocation, t (11;18) and the successful eradication of H. pylori, the MALT-L relapsed repeatedly, and finally led to systemic metastasis. The lymphoma cells also infiltrated the large intestine and spleen. Immunoglobulin gene analyses of cellular clonality revealed that the same clone had been present in the stomach, bone marrow (BM) at the onset of MALT L, and in the BM at the diagnosis of WM.
CONCLUSIONS: In this case, lymphoma developed as H. pylori-associated gastric MALT-L with negative for t (11;18), and might be transformed into MW during the systemic metastasis.


Ghobrial IM, Moreau P, Harris B, et al.
A multicenter phase II study of single-agent enzastaurin in previously treated Waldenstrom macroglobulinemia.
Clin Cancer Res. 2012; 18(18):5043-50 [PubMed]
PURPOSE: Enzastaurin is a serine/threonine kinase inhibitor that showed antiangiogenic, antiproliferative, and proapoptotic properties in vitro and antitumor activity in vivo in a xenograft Waldenström macroglobulinemia (WM) model. These findings provided the rationale for a multicenter phase II trial of oral enzastaurin in previously treated patients with WM. Experimental design: Patients who were treated with 1 to 5 prior regimens and who had a baseline immunoglobulin M level 2 times or more the upper limit of normal received oral enzastaurin 250 mg twice daily (500 mg total) after a single loading dose (day 1, cycle 1) of 375 mg 3 times daily (1,125 mg total) for 8 cycles of 28 days each or until progressive disease. Six patients who progressed during treatment with enzastaurin had dexamethasone added per protocol.
RESULTS: From July 2008 to December 2010, 42 patients were enrolled. The objective response rate (RR) was 38.1% (2 partial and 14 minor responses). One patient had grade 3 leukopenia and one patient died during the study from septic shock; both events were considered drug related. A statistically significant association between RR and interleukin 15 (IL-15) was observed, suggesting that higher concentration levels of IL-15 may be associated with better response.
CONCLUSION: Enzastaurin was active and well tolerated in previously treated patients with WM. Because of the small sample size of this uncontrolled study, further assessment of the relationship between IL-15 and response to enzastaurin in patients with WM is required. These results warrant further investigation of enzastaurin for the treatment of WM.


Tanaka H, Hashimoto S, Sugita Y, et al.
Occurrence of lymphoplasmacytic lymphoma 6 years after amelioration of primary cold agglutinin disease by rituximab therapy.
Int J Hematol. 2012; 96(4):501-5 [PubMed]
Cold agglutinin disease (CAD) is a rare autoimmune hemolytic anemia, classified into primary and secondary types. Secondary CAD accompanies infection or malignant disease, most often lymphoma, whereas primary CAD frequently represents a lymphoproliferative bone marrow disorder characterized by clonal expansion of B cells. Here, I describe a case of lymphoplasmacytic lymphoma (LPL) developed 6 years after amelioration of primary CAD by rituximab monotherapy. A 54-year-old Japanese woman was diagnosed with primary CAD characterized by a small fraction of B lymphocytes and kappa laterality in the peripheral blood. M-protein was not detected by immuno-electrophoresis. The patient achieved remission following two courses of rituximab monotherapy. The level of IgM was specifically decreased, although levels of IgG and IgA were slightly increased. Six years after rituximab monotherapy, she developed LPL without CAD recurrence. Flow cytometry performed on bone marrow specimens revealed that lymphoma cells were positive for CD19 and CD20 with kappa laterality. The lymphoma may have transformed from clonal B lymphocytes at presentation of CAD. Rituximab monotherapy induced remission of CAD by specific decrease of IgM level, but did not eliminate the clonal B lymphocytes that may have progressed to LPL. This experience may provide clues toward the understanding of the pathophysiology of primary CAD with clonal lymphoproliferative disease of the bone marrow.


Zhang Y, Roccaro AM, Rombaoa C, et al.
LNA-mediated anti-miR-155 silencing in low-grade B-cell lymphomas.
Blood. 2012; 120(8):1678-86 [PubMed]
miR-155 acts as an oncogenic miR in B-cell lymphoproliferative disorders, including Waldenstrom macroglobulinemia (WM) and chronic lymphocytic leukemia, and is therefore a potential target for therapeutic intervention. However, efficient targeting of miRs in tumor cells in vivo remains a significant challenge for the development of miR-155-based therapeutics for the treatment of B-cell malignancies. In the present study, we show that an 8-mer locked nucleic acid anti-miR-155 oligonucleotide targeting the seed region of miR-155 inhibits WM and chronic lymphocytic leukemia cell proliferation in vitro. Moreover, anti-miR-155 delivered systemically showed uptake in the BM CD19(+) cells of WM-engrafted mice, resulting in the up-regulation of several miR-155 target mRNAs in these cells, and decreased tumor growth significantly in vivo. We also found miR-155 levels to be elevated in stromal cells from WM patients compared with control samples. Interestingly, stromal cells from miR-155-knockout mice led to significant inhibition of WM tumor growth, indicating that miR-155 may also contribute to WM proliferation through BM microenvironmental cells. The results of the present study highlight the therapeutic potential of anti-miR-155-mediated inhibition of miR-155 in the treatment of WM.


Miwa M, Sakao Y, Ishigaki S, et al.
Recovery of kidney function by rituximab-based therapy in a patient with Waldenström's macroglobulinemia-related nephropathy presenting cast nephropathy and interstitial lymphocytic infiltration.
Intern Med. 2012; 51(13):1725-30 [PubMed]
A 60-year-old man with Waldenström's macroglobulinemia (WM) was admitted to our hospital for evaluation of rapid progressive renal deterioration despite 3 cycles of oral melphalan and prednisolone (MP) therapy. Renal biopsy just before introducing hemodialysis revealed cast nephropathy and severe tubulo-interstitial infiltration of B lymphocytes. After 6 cycles of rituximab, cyclophosphamide, vincristine and prednisolone (R-COP) therapy, his renal function improved enough to discontinue hemodialysis. This is a rare case of WM-related renal involvement caused by both monoclonal protein and tumor infiltration and, to our knowledge, the second report on improved renal function by rituximab-based therapy.


Pyatt N, Mitra S
Cytomegalovirus oesophagitis following treatment with fludarabine for refractory lymphoplasmacytic lymphoma.
BMJ Case Rep. 2012; 2012 [PubMed]
A 64-year-old man with a 2-week history of fatigue and fever presented to the medical admissions unit. He had a background of lymphoplasmacytic lymphoma and had recently completed a course of fludarabine-based chemotherapy. CT of the abdomen demonstrated an increase in spleen size and it was thought that his fevers were most likely due to disease recurrence or high-grade transformation. A bone marrow trephine was organised, which showed no evidence of lymphoma and positron emission tomography-CT demonstrated an area of increased avidity at the gastro-oesophageal junction. An oesophagogastroduodenoscopy was recommended, which revealed ulceration within the oesophagus and stomach. Biopsy of the lesions and immunohistochemistry confirmed a diagnosis of cytomegalovirus oesophagitis. He was treated with intravenous ganciclovir followed by oral valganciclovir for a total of 3 weeks. His fever resolved and he was discharged home approximately 8 weeks after he first presented.


Gnemmi V, Leleu X, Provot F, et al.
Cast nephropathy and light-chain deposition disease in Waldenström macroglobulinemia.
Am J Kidney Dis. 2012; 60(3):487-91 [PubMed]
Waldenström macroglobulinemia is a rare low-grade hematologic malignancy due to clonal proliferation of B lymphocytes responsible for immunoglobulin M (IgM) monoclonal gammopathy secreted in serum. This disease is characterized by lymphoplasmacytic tumoral infiltration of bone marrow and various organs, especially the liver and spleen. Kidney involvement in Waldenström macroglobulinemia has been described previously with reports of various forms of glomerular injury: large intracapillary IgM pseudothrombi, cryoglobulinemia-associated membranoproliferative glomerulonephritis, or amyloidosis. Interstitial infiltration by tumoral B lymphocytes is another classic pattern. Conversely, tubular involvement in the form of myeloma-like casts or basement membrane deposition of monoclonal light chain (light-chain deposition disease) is unusual. We report the occurrence of cast nephropathy associated with light-chain deposition disease in 2 patients with Waldenström macroglobulinemia, which resulted in severe and prolonged kidney failure.


Brown R, Kabani K, Favaloro J, et al.
CD86+ or HLA-G+ can be transferred via trogocytosis from myeloma cells to T cells and are associated with poor prognosis.
Blood. 2012; 120(10):2055-63 [PubMed]
The transfer of membrane proteins between cells during contact, known as trogocytosis, can create novel cells with a unique phenotype and altered function. We demonstrate that trogocytosis is more common in multiple myeloma (MM) than chronic lymphocytic leukemia and Waldenstrom macroglobulinaemia; that T cells are more probable to be recipients than B or natural killer cells; that trogocytosis occurs independently of either the T-cell receptor or HLA compatibility; and that after trogocytosis, T cells with acquired antigens can become novel regulators of T-cell proliferation. We screened 168 patients with MM and found that CD86 and human leukocyte antigen G (HLA-G) were antigens commonly acquired by T cells from malignant plasma cells. CD3+ CD86acq+ and CD3+ HLA-Gacq+ cells were more prevalent in bone marrow than peripheral blood samples. The presence of either CD86 or HLA-G on malignant plasma cells was associated with a poor prognosis. CD38++ side population cells expressed HLA-G, suggesting that these putative myeloma stem cells could generate immune tolerance. HLA-G+ T cells had a regulatory potency similar to natural Tregs, thus providing another novel mechanism for MM to avoid effective immune surveillance.


Wang E, Stoecker M, Burchette J, Rehder C
Follicular lymphoma with prominent Dutcher body formation: a pathologic study of 3 cases in comparison with nodal or splenic lymphoplasmacytic lymphoma and marginal zone lymphoma.
Hum Pathol. 2012; 43(11):2001-11 [PubMed]
Dutcher bodies have been described in lymphoid neoplasms with plasmacytic differentiation, including plasma cell myeloma, lymphoplasmacytic lymphoma, and marginal zone lymphoma. We report a pathologic study of 3 cases of follicular lymphoma with extensive Dutcher body formation in comparison with lymphoplasmacytic lymphoma and marginal zone lymphoma. Of 3 cases, 1 showed a follicular growth pattern, whereas the other 2 cases demonstrated only a vague nodular appearance highlighted by immunohistochemical analysis. Cells containing Dutcher bodies were counted at 25, 90, or 110 per high-power field in each case, respectively. In 2 cases, cells with Dutcher bodies were clustered in an intrafollicular distribution, a possible histopathologic clue for follicular lymphoma. Immunoglobulin M κ was identified as the component of Dutcher bodies in all 3 cases, implying a possible molecular basis for the formation of Dutcher bodies in B-cell lymphomas. All 3 cases had cytogenetic changes supporting the diagnosis of follicular lymphoma, including dual rearrangement of BCL2 and BCL6, rearrangement of BCL2 with trisomy 3 (BCL6), and isolated BCL6 rearrangement. We emphasize immunohistochemical analyses with anti-κ/λ and anti-immunoglobulin heavy-chain isotypes to characterize Dutcher bodies and document clonality in addition to the routine lymphoma workup and indicated cytogenetic studies in B-cell lymphomas with prominent Dutcher bodies.


Tan JN, Kroll MH, O'Hara CJ, et al.
Gamma heavy chain disease in a patient with underlying lymphoplasmacytic lymphoma of the thyroid. Report of a case and comparison with other reported cases with thyroid involvement.
Clin Chim Acta. 2012; 413(19-20):1696-9 [PubMed]
BACKGROUND: Gamma heavy chain disease with underlying thyroid pathology is rare. There are 5 reported cases in the English literature, including the present case of an elderly female with γ heavy chain disease with underlying lymphoplasmacytic lymphoma of the thyroid who initially presented with long-standing goiter and chronic thyroiditis.
METHODS: The protein studies and histopathologic findings in her thyroid are described. Her case is compared with reported cases of γ heavy chain disease with thyroid involvement.
RESULTS: Initial impression on most cases was chronic thyroiditis; however pathology showed 3 cases with plasmacytoma and 2 with lymphoplasmacytic infiltrate. All were diagnosed and followed up using serum and urine electrophoresis.
CONCLUSION: Gamma heavy chain disease has a protean manifestation; however there appears to be a more uniform pattern of the disease when it is associated with the thyroid. The inclusion of protein studies in cases diagnosed with chronic thyroiditis by FNA may aid in establishing γ heavy chain disease with underlying thyroid involvement. In this case serum and urine electrophoresis, and immunofixation studies which are simple and affordable tests facilitated the hematologic workup and follow up.


Takeuchi M, Ogawa F, Onishi T, Moriyama Y
Plasmablastic lymphoma in an elderly immunocompetent patient.
Pathol Int. 2012; 62(5):347-50 [PubMed]
Plasmablastic lymphoma (PBL) is a distinct type of diffuse B cell lymphoma that typically occurs in the oral cavity of patients with HIV infection or immunodeficiency status. PBL is characterized by its plasmablastic morphology and an immunophenotype indicative of a plasma cell differentiation. We present a case of a 75-year-old HIV-negative and Epstein-Barr virus (EBV)-negative patient presenting with an isolated oral cavity mass. The tumor consisted of a monotonous proliferation of undifferentiated large cells with relatively abundant cytoplasm, eccentrically located round nuclei with prominent nucleoli and numerous mitoses. Immunohistochemically, these cells were negative for CD45 and B cell antigens, while they showed diffuse positivity of CD138 and focal staining for epithelial membrane antigen (EMA), indicating plasma cell differentiation. Based on these histopathological and immunohistochemical characteristics, we diagnosed it as PBL. The patient received chemotherapy and is alive with locally persistent disease 3 years after diagnosis. To date, only several cases of oral PBL have been reported in HIV-negative, EBV-negative and immunocompetent patients. PBL should be included in the differential diagnosis of oral mass lesions and careful evaluation of the morphology and awareness of the existence of this uncommon type of lymphoma can lead to a correct diagnosis.


Gertz MA
Waldenström macroglobulinemia.
Hematology. 2012; 17 Suppl 1:S112-6 [PubMed]
Waldenström macroglobulinemia is a lymphoplasmacytic lymphoma. A serum monoclonal IgM protein is required to establish this diagnosis. The clinical features patients develop include normochromic normocytic anemia, thrombocytopenia, hepatosplenomegaly, lymphadenopathy and signs of hyperviscosity. The International Staging System for Waldenström macroglobulinemia divides patients prognostically based on age, hemoglobin, platelet count, IgM level, and beta2 microglobulin. Some patients with Waldenström macroglobulinemia have a smoldering form and can be observed without intervention. Active agents in the treatment of Waldenström macroglobulinemia include rituximab, chlorambucil, cyclophosphamide, fludarabine, bortezomib, lenalidomide, bendamustine, everolimus, and alemtuzumab. The current preferred Mayo Clinic non-study treatment is rituximab, cyclophosphamide, and dexamethasone. The median survival associated with this disease is now over 10 years.


Gertz MA
Waldenström macroglobulinemia: 2012 update on diagnosis, risk stratification, and management.
Am J Hematol. 2012; 87(5):503-10 [PubMed]
UNLABELLED: DISEASE OVERVIEW: Waldenström macroglobulinemia (WM) is a lymphoplasmacytic lymphoma with immunoglobulin M (IgM) monoclonal protein. Clinical features include anemia, thrombocytopenia, hepatosplenomegaly, and lymphadenopathy.
DIAGNOSIS: Presence of IgM monoclonal protein associated with ≥10% clonal lymphoplasmacytic cells in bone marrow confirms the diagnosis. RISK STRATIFICATION: Age, hemoglobin level, platelet count, β(2) microglobulin, and monoclonal IgM concentrations are characteristics required for prognosis. RISK-ADAPTED THERAPY: Not all patients who fulfill WM criteria require therapy; these patients can be observed until symptoms develop. Rituximab-based therapy is used in virtually all US patients with WM and can be combined with alkylating agent or purine nucleoside analog (or both). The preferred Mayo Clinic nonstudy therapeutic induction is rituximab, cyclophosphamide, and dexamethasone. Future stem-cell transplantation should be considered in induction therapy selection. MANAGEMENT OF REFRACTORY DISEASE: Bortezomib, thalidomide, lenalidomide, and bendamustine have all been shown to have activity in WM. Given WM's natural history, reduction of complications will be a priority for future treatment trials.


Wei Z, Yanxia Y, Ying X, et al.
Splenic re-irradiation for waldenstrőm's macroglobulinemia.
Radiat Oncol. 2012; 7:58 [PubMed] Article available free on PMC after 21/02/2014
We report on a case of Waldenström's macroglobulinemia (WM) treated with splenic re-irradiation. To the best of our knowledge this has not been reported before. A 69-year-old Asian female patient with WM received a three-dimensional conformal radiotherapy, with 24 Gy in 12 treatment fractions in the first stage. She tolerated the treatment well, with a 37% reduction of the monoclonal immunoglobulin, an impalpable spleen, and improved hematological laboratory tests for 4 months. She was then treated with splenic re-irradiation up to 24 Gy for tumor progression. She showed no evidence of progression one year after re-irradiation, with a 55% reduction of the monoclonal immunoglobulin. Our experience demonstrates that splenic irradiation is an effective treatment to control the progression of WM.


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