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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).

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.

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

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.

Zou H, Yang R, Liao ZX, et al.
Serum markers in the differential diagnosis of Waldenstrom macroglobulinemia and other IgM monoclonal gammopathies.
J Clin Lab Anal. 2019; 33(3):e22827 [PubMed] Related Publications
BACKGROUND: IgM monoclonal gammopathy can be present in a broad spectrum of diseases. We evaluated the value of serum markers in the differential diagnosis of Waldenstrom macroglobulinemia (WM) and other types of IgM monoclonal gammopathies.
METHODS: We included patients who were first admitted to hospital and identified as having IgM monoclonal gammopathy by serum immunofixation electrophoresis (sIFE). We evaluated basic clinical features, sIFE, diagnosis, and serum markers. Furthermore, we applied the receiver operating characteristic (ROC) curve to analyze the differential diagnosis value of serum markers for WM. Finally, we used logistic regression and ROC curve to analyze the differential diagnosis value of multimarker combinations to identify WM.
RESULTS: IgM monoclonal gammopathy was most frequently found in patients with Waldenstrom macroglobulinemia, followed by monoclonal gammopathy of undetermined significance (MGUS), B-cell non-Hodgkin Lymphoma (B-NHL), and multiple myeloma (MM). Serum markers showed significant differences among the four diseases. The diagnostic markers LDH, IgM, IgG, IgA, and serum light chain К had higher diagnostic efficiency. Among these markers, serum IgM provided the highest diagnostic efficiency. Additionally, the combined use of all five serum markers provided the most effective diagnosis.
CONCLUSIONS: The five serum markers, LDH, IgM, IgG, IgA, and К, each yielded a specific efficacy in differential diagnosis of WM. The single marker with the highest diagnostic efficiency was the serum IgM level. However, a combination of multiple serum markers was better than the use of a single marker in diagnosing WM. The combined use of all five serum markers provided the most effective diagnosis, with an AUC of .952 and sensitivity and specificity of 87.8% and 86.9%, respectively.

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

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.

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

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.

Tallant A, Selig D, Wanko SO, Roswarski J
First-line ibrutinib for Bing-Neel syndrome.
BMJ Case Rep. 2018; 2018 [PubMed] Related Publications
The authors present a case of an elderly man with a history of Waldenstrom macroglobulinaemia in remission who presented with progressively worsening gait abnormalities and falls for several months. His examination was notable for bilateral lower extremity weakness and an unsteady gait. Brain and spinal MRI showed focal leptomeningeal enhancement in the brain and spinal column. Lumbar puncture was performed and cerebrospinal fluid flow cytometry demonstrated a monoclonal CD5/CD10-negative, CD20-positive B-cell lymphocyte population consistent with a diagnosis of Bing-Neel syndrome. He was started on ibrutinib, an oral Bruton's tyrosine kinase inhibitor, and had marked improvement in his weakness and gait. Repeat imaging 2 months after starting ibrutinib showed improvement in his leptomeningeal enhancement. During subsequent follow-up, he continued to tolerate ibrutinib and had a sustained clinical response.

Vergnolle I, Sigur N, Corre J
IgG lymphoplasmacytic lymphoma: a case report.
Ann Biol Clin (Paris). 2018; 76(6):665-668 [PubMed] Related Publications
Lymphoplasmacytic lymphoma is rare. Although most cases of LPL are Waldenström macroglobulinemia associated with an immunoglobulin M, there are exceptions. Indeed, few cases are immunoglobulin A-secreting or immunoglobulin G-secreting. These cases are poorly described and raise diagnostic difficulties. The purpose of this article is to describe an IgG lymphoplamacytic lymphoma case diagnosed recently in the hematology laboratory University Hospital of Toulouse.

Xu H, Yao F
Microarray-Based Gene Expression Analysis Identifies Potential Diagnostic and Prognostic Biomarkers for Waldenström Macroglobulinemia.
Acta Haematol. 2018; 140(2):87-96 [PubMed] Related Publications
Waldenström macroglobulinemia (WM), also known as lymphoplasmacytic lymphoma, is rare but a clinicopathologically distinct B-cell malignancy. This study assessed differentially expressed genes (DEGs) to identify potential WM biomarkers and uncover the underlying the molecular mechanisms of WM progression using gene expression profiles from the Gene Expression Omnibus database. DEGs were identified using the LIMMA package and their potential functions were then analyzed by using the gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses and the protein-protein interaction (PPI) network analysis by using the Search Tool for the Retrieval of Interacting Genes/Proteins database. Data showed that among 1,756 DEGs, 926 were upregulated and 830 were downregulated by comparing WM BM CD19+ with normal PB CD19+ B cell samples, whereas 241 DEGs (95 upregulated and 146 downregulated) were identified by comparing WM BM CD138+ with normal BM CD138+ plasma cell samples. The DEGs were enriched in different GO terms and pathways, including the apoptotic process, cell cycle arrest, immune response, cell adhesion, mitogen-activated protein kinase signaling pathway, toll-like receptor signaling pathway, and the gonadotropin-releasing hormone signaling pathway. Hub nodes in the PPI network included CDK1, JUN, CREBBP, EP300, CAD, CDK2, and MAPK14. Bioinformatics analysis of the GSE9656 dataset identified 7 hub genes that might play an important role in WM development and progression. Some of the candidate genes and pathways may serve as promising therapeutic targets for WM.

Brandefors L, Melin B, Lindh J, et al.
Prognostic factors and primary treatment for Waldenström macroglobulinemia - a Swedish Lymphoma Registry study.
Br J Haematol. 2018; 183(4):564-577 [PubMed] Related Publications
We present a nationwide prospective Swedish registry-based study of Waldenström macroglobulinaemia (WM), that focuses on incidence and survival in relation to clinical prognostic factors and primary systemic therapies. A total of 1511 patients with WM and lymphoplasmocytic lymphoma (LPL) were registered in the Swedish Lymphoma Registry (SLR) between 1 January 2000 and 31 December 2014. The age-adjusted incidence of WM/LPL was 11·5 per million persons per year, three times higher than the reported incidence worldwide. Medical records were retrieved for 1135 patients (75%). A retrospective review showed that 981 (86·1%) of these patients fulfilled the World Health Organization diagnostic criteria for WM and these patients were analysed further. The overall survival (OS) improved between two periods - 2000-2006 and 2007-2014 - with a five-year OS of 61% and 70%, respectively. Significant prognostic factors for OS, evaluated at the time of diagnosis, were age, elevated lactate dehydrogenase level and haemoglobin ≤115 g/l for patients receiving therapy 0-3 months after diagnosis, and age, poor performance status, haemoglobin ≤115 g/l, and female sex in "watch and wait" patients (multivariable analysis). The level of the IgM monoclonal immunoglobulin had no significant prognostic value. Rituximab included in first-line therapy was associated with improved survival.

Tedeschi A, Conticello C, Rizzi R, et al.
Diagnostic framing of IgM monoclonal gammopathy: Focus on Waldenström macroglobulinemia.
Hematol Oncol. 2019; 37(2):117-128 [PubMed] Related Publications
The finding of an IgM monoclonal gammopathy often represents a diagnostic challenge. In fact, there are many pathological disorders associated with this condition, each of which has distinctive characteristics and requires specific clinical, instrumental, and laboratory assessments to set the appropriate treatment. This review has two aims. Firstly, to provide a framework of the broad spectrum of IgM-associated disorders: (1) monoclonal gammopathy of undetermined significance (MGUS); (2) Waldenström macroglobulinemia (WM); (3) IgM-related disorders (among which hyperviscosity syndrome, light chain amyloidosis, cold agglutinin disease, cryoglobulinaemia, IgM neuropathy, Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes (POEMS) syndrome, Castleman disease); (4) IgM-secreting multiple myeloma (IgM-MM); and (5) other lymphoproliferative disorders which may be associated with IgM (such as chronic lymphocytic leukemia, small lymphocytic lymphoma, and B-cell non Hodgkin lymphoma). Secondly, to give a detailed insight regarding diagnosis and treatment of WM.

Spinner MA, Varma G, Advani RH
Novel Approaches in Waldenström Macroglobulinemia.
Hematol Oncol Clin North Am. 2018; 32(5):875-890 [PubMed] Related Publications
Recent advances in the understanding of Waldenström macroglobulinemia (WM) biology have paved the way for development of a plethora of novel therapeutic strategies. The success of ibrutinib in WM has shifted treatment paradigms away from conventional chemoimmunotherapy approaches. Recognition of high-risk genomic subgroups as well as mechanisms of acquired resistance to ibrutinib have led to targeting of additional pathways. In this article, the authors review ongoing and emerging trials of novel therapies in WM that target the B-cell receptor pathway beyond ibrutinib, toll-like receptor pathway, chemokine signaling, apoptotic pathway, chromatin remodeling, protein transport, the immune microenvironment, and CD19-directed immunotherapy.

Kyriakou C
High-Dose Therapy and Hematopoietic Stem Cell Transplantation in Waldenström Macroglobulinemia.
Hematol Oncol Clin North Am. 2018; 32(5):865-874 [PubMed] Related Publications
Waldenström macroglobulinemia (WM) is an indolent low-grade non-Hodgkin lymphoma characterized by bone marrow infiltration by lymphoplasmacytic cells and associated clonal IgM paraproteinemia. Recent insights into the biology and genomic characteristics of WM have provided a further platform for more targeted therapies. Despite the high response rates and better depth and duration of responses, the disease remains incurable. This review focuses on use of the high-dose therapy with either autologous or allogeneic hematopoietic stem cell transplantation.

Argyropoulos KV, Palomba ML
First-Generation and Second-Generation Bruton Tyrosine Kinase Inhibitors in Waldenström Macroglobulinemia.
Hematol Oncol Clin North Am. 2018; 32(5):853-864 [PubMed] Related Publications
Waldenström macroglobulinemia (WM) is an indolent B-cell lymphoma that is heavily dependent on Bruton tyrosine kinase (BTK) hyperactivation. Ibrutinib is a first-generation BTK inhibitor that has shown high activity and durable responses in patients with relapsed/refractory WM. Newer and more selective BTK inhibitors are currently being tested in several clinical trials and are expected to address the toxicity and the acquired resistance observed in patients receiving ibrutinib. Updates on ibrutinib and second-generation BTK inhibitors are summarized in this review.

Dominguez A, Kastritis E, Castillo JJ
Monoclonal Antibodies for Waldenström Macroglobulinemia.
Hematol Oncol Clin North Am. 2018; 32(5):841-852 [PubMed] Related Publications
For the last 2 decades, anti-CD20 monoclonal antibodies have revolutionized the treatment of patients with B-cell lymphomas. These agents have shown efficacy when used as single agents and also have improved response and survival rates when added to chemotherapy. Monoclonal antibodies are safe and effective as well in patients with Waldenström macroglobulinemia (WM). The purpose of this article is to review the mechanism of action of monoclonal antibodies and to discuss current clinical data supporting their use in patients with WM. This review focuses on retrospective and prospective studies and clinical trials on anti-CD20 antibodies, anti-CD38 antibody, and anti-CXCR4 antibody.

Kastritis E, Dimopoulos MA
Proteasome Inhibitors in Waldenström Macroglobulinemia.
Hematol Oncol Clin North Am. 2018; 32(5):829-840 [PubMed] Related Publications
Waldenström macroglobulinemia (WM) remains an incurable B-cell lymphoproliferative disorder, yet therapy is only considered for patients with symptomatic disease. Primary therapy options for WM include combinations based on anti-CD20 monoclonal antibodies, mainly rituximab. However, proteasome inhibitors have become an important part of WM therapy both as primary therapy and as salvage option. Bortezomib is the proteasome inhibitor most studied and with extensive clinical experience, but new proteasome inhibitors (carfilzomib, ixazomib, oprozomib), with different toxicity profiles, routes of administration, and probably with preserved or improved activity, have become available and may also find their way into WM therapy.

Castillo JJ, Treon SP
Initial Evaluation of the Patient with Waldenström Macroglobulinemia.
Hematol Oncol Clin North Am. 2018; 32(5):811-820 [PubMed] Related Publications
The initial evaluation of the patient with Waldenström macroglobulinemia can be challenging. Not only is it a rare disease, but the clinical features can vary greatly from patient to patient. In this article, we aim at providing concise and practical recommendations for the initial evaluation of patients with Waldenström macroglobulinemia, specifically regarding history taking, physical examination, laboratory testing, bone marrow aspiration, and biopsy evaluation and imaging studies. We then review the most common special clinical situations seen in patients with Waldenström macroglobulinemia, especially anemia, hyperviscosity, cryoglobulinemia, peripheral neuropathy, extramedullary disease, Bing-Neel syndrome, and amyloidosis.

McMaster ML
Familial Waldenström Macroglobulinemia: Families Informing Populations.
Hematol Oncol Clin North Am. 2018; 32(5):787-809 [PubMed] Related Publications
Familial clustering of Waldenström macroglobulinemia (WM) has been observed for nearly 6 decades. Family studies have provided seminal observations in delineating the phenotypic spectrum of WM susceptibility and confirming the importance of immunoglobulin M (IgM) monoclonal gammopathy of undetermined significance (IgM MGUS) as a precursor condition for WM, providing the rationale for large population-based epidemiologic studies of IgM MGUS and WM, and providing both the basis and the material for ongoing genetic studies aimed at identifying WM predisposition genes. Together, these investigations may help elucidate the host factors underlying WM development.

Jalali S, Ansell SM
The Bone Marrow Microenvironment in Waldenström Macroglobulinemia.
Hematol Oncol Clin North Am. 2018; 32(5):777-786 [PubMed] Related Publications
Waldenström macroglobulinemia (WM) is an indolent B-cell lymphoma defined predominantly by infiltration of lymphoplasmacytic cells into the bone marrow (BM) and increased production of monoclonal immunoglobulin M (IgM) by lymphoplasmacytic cells, and the secretion of IgM is enhanced by cytokines in the bone marrow microenvironment. This article highlights the available data regarding the interaction of WM cells with both the cellular and noncellular compartments of the BM microenvironment and discusses how the BM promotes malignant cell growth and increases IgM production in this disease.

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.

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.

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.

Miyamoto Y, Hamasaki Y, Matsumoto A, et al.
Prediction of immunoglobulin M reduction via therapeutic dose of simple plasma exchange and double filtration plasmapheresis using membrane separation in patients with hyperviscosity syndrome caused by Waldenstrom macroglobulinemia.
J Clin Apher. 2018; 33(5):611-615 [PubMed] Related Publications
BACKGROUND: Plasma exchange (PE) and double filtration plasmapheresis (DFPP) are known as effective treatment options for hyperviscosity syndrome (HVS) caused by Waldenstrom macroglobulinemia. Nonetheless, few data are available for the relation between the prescribed dose of apheresis and the reduction rate of target molecule immunoglobulin M (IgM), especially in the modality using membrane separation.
OBJECTIVES: This study was conducted to establish a model to predict the IgM reduction rate by the dose of simple PE and DFPP using membrane separation in patients with HVS and to compare the consumption of albumin between PE and DFPP.
METHODS: We retrospectively analyzed data of total 17 sessions of PE and DFPP with various therapeutic doses performed for five patients at our institution. We used linear regression analysis to examine the relation between the ratio of processed plasma volume to estimated circulating plasma volume (X) and the reduction rate of IgM (Y).
RESULTS: Regression analysis revealed that Y is expressed by X as the following equation: Y = 0.35X + 0.095. The total usage of albumin for replacement fluid was lower in DFPP than in PE (21.5 g vs 150 g per session), although the treatment efficacies of both modalities are similar.
CONCLUSION: The dose of PE and DFPP using membrane separation can predict IgM reduction rate in the HVS patients. Predicted IgM reduction rates based on our model are lower than those calculated using a known theoretical model. In terms of the amount of use of albumin, DFPP is preferred to PE.

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.

Suzuki Y, Aizawa H, Sakashita K, et al.
Autopsy-proven case of paraneoplastic lower motor neuron disease with sensorimotor neuropathy due to Waldenström's macroglobulinemia.
Neuropathology. 2018; 38(5):568-573 [PubMed] Related Publications
We report a case of a male patient with a 19-year history of monoclonal and later polyclonal gammopathy who subsequently developed tetraparesis, bulbar palsy, and respiratory failure. Autopsy findings showed degeneration of the hypoglossal nuclei, prominent neuronal loss and atrophy in the anterior horn of the whole spinal cord despite the presence of mild astrocytosis, degeneration of the gracilis on one side, and infiltration of inflammatory cells, which included B cells and plasma cells in the anterior and posterior roots of the lumbar spinal cord, iliopsoas muscle, and perivascular area of the cervical cord. On immunostaining, cytoplasmic inclusions of phosphorylated transactivation response DNA-binding protein of 43 kDa were observed in the motor neurons and astrocytes of the hypoglossal nuclei and whole spinal cord. The final diagnosis was paraneoplastic lower motor neuron disease with sensorimotor neuropathy due to Waldenström's macroglobulinemia.

Abeykoon JP, Zanwar S, Ansell SM, et al.
Predictors of symptomatic hyperviscosity in Waldenström macroglobulinemia.
Am J Hematol. 2018; 93(11):1384-1393 [PubMed] Related Publications
Symptomatic hyperviscosity is a well-established phenomenon in Waldenström macroglobulinemia (WM). Monoclonal IgM can variably impact intrinsic serum viscosity, leading to widely disparate symptomatic thresholds for development of hyperviscosity-related symptoms. Data regarding the predictors of symptomatic hyperviscosity and outcomes related to this complication remain scarce and a recent study proposed that IgM >6000 mg/dL be considered a new criterion for initiating therapy in otherwise asymptomatic (smoldering) WM to pre-empt hyperviscosity-related injury. Herein, we attempt to identify predictors of the development of symptomatic hyperviscosity and its impact in patients with WM. Of 997 WM patients evaluated from January, 1996 through June, 2017, symptomatic hyperviscosity was observed in 130 (13%) patients. Overall survival (OS) of these 130 patients was similar to that of patients without symptomatic hyperviscosity (median: 11.5 vs 11.6 years; P = 0.63). On multivariate-analysis, only viscosity >1.8 cp (risk ratio: 4.0, P = 0.02) assessed at the time of WM diagnosis was an independent predictor for the development of subsequent symptomatic hyperviscosity. Among patients with smoldering WM and IgM >6000 mg/dL at diagnosis (n = 13) who were managed expectantly, the median time-to-initial therapy was 6.9 years and only 15% developed hyperviscosity-related symptoms subsequently. In summary, the occurrence of symptomatic hyperviscosity does not impact OS. Serum viscosity at diagnosis of WM, and not IgM concentration, represents the single most important independent predictor for development of subsequent hyperviscosity-related symptoms. Patients with smoldering WM and high serum IgM can be safely observed in the absence of any indications per the Consensus recommendations to initiate WM-directed therapy.

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.

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.

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