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Background: Anti-myelin-associated-glycoprotein (MAG) neuropathy is a distal, predominantly demyelinating, sensory or sensory-motor polyneuropathy most often developing in the context of an IgM-type monoclonal gammopathy due to monoclonal gammopathy of undetermined significance or lymphoplasmacytic lymphoma. Rituximab is considered standard therapy for treatment naïve patients, but optimal treatment methods for relapsed/refractory patients have not been established. Case presentation: We demonstrate that tirabrutinib, a second-generation Burton kinase inhibitor, led to drastic improvements of polyneuropathy that were affirmed by nerve conduction studies in a rituximab-refractory anti-MAG neuropathy patient. Tirabrutinib continues to give excellent disease control with no apparent adverse events at 11 months since initiation, and the patient remains free of plasmapheresis sessions which were originally mandatory. Conclusion: Tirabrutinib is an extremely promising treatment option for anti-MAG neuropathy.

Waldenstrӧm Macroglobulinemia (WM) is a rare B-cell malignancy characterized by lymphoplasmacytic lymphoma (LPL) involvement of the bone marrow with an IgM monoclonal gammopathy. We present a case of Parkinson-like symptoms, in which diagnostic workup including imaging, biopsy, and lumbar puncture revealed both an LPL manifesting as a cervical spine mass and central nervous system involvement of LPL (termed Bing Neel syndrome) as the etiologies of the patient's presenting symptoms. Ibrutinib was administered, at a lower dose of 280 mg, due to the patient's history of arrhythmias, in combination with radiation to the cervical spine mass and steroids. Four weeks later, the patient's symptoms had completely resolved. This case highlights a rare presentation of LPL as well as the efficacy of ibrutinib.

A 60-year-old man was admitted for ground glass opacity in the lower lung field and mediastinal lymphadenopathy. Blood tests revealed elevated serum IgM levels, and the urine test detected Bence-Jones protein. Surgical biopsy from the mediastinal lymph node and lung showed small lymphocytes and plasma cells between follicles, and AL kappa amyloid deposition. Genetic examination detected MYD88 L265P mutation. Our diagnosis was lymphoplasmacytic lymphoma (LPL), involving the mediastinum and the lung, followed by amyloidosis. Mutation analysis, in addition to conventional histological evaluation, was useful for a precise diagnosis.

Waldenström macroglobulinemia (WM) is a unique CD20+, B-cell non-Hodgkin lymphoma, characterized by lymphoplasmacytic infiltration of the bone marrow and circulating monoclonal immunoglobulin M. The clinical manifestations and outcomes of patients are highly variable. High-level evidence supports integration of monoclonal anti-CD20 antibody, rituximab, to the chemotherapy backbone to treat WM. However, its contemporary management has become more nuanced, with deeper understanding of the pathophysiology and incorporation of Bruton's tyrosine kinase (BTK) inhibitors to the treatment paradigm. Prior knowledge of the patients' MYD88 L265P and CXCR4 mutation status may aid in the treatment decision-making. Currently, the two frequently utilized approaches include fixed-duration chemoimmunotherapy and BTK inhibitor-based continuous treatment until progression. Randomized trials comparing these two vastly divergent approaches are lacking. Recent studies demonstrating efficacy of B cell lymphoma-2 (BCL2) inhibitors and non-covalent BTK inhibitors in patients, previously exposed to a covalent BTK inhibitor, are a testament to the rapidly expanding options against WM., Competing Interests: Declaration of Competing Interest Prashant Kapoor, MD is the principal investigator of trials for which Mayo Clinic has received research funding from Amgen, Regeneron, Bristol Myers Squibb, Loxo Pharmaceuticals, Ichnos, Karyopharm, Sanofi, AbbVie and GlaxoSmithKline. Prashant Kapoor has served on the Advisory Boards of BeiGene, Pharmacyclics, X4 Pharmaceuticals, Kite, Oncopeptides, Angitia Bio, GlaxoSmithKline, AbbVie and Sanofi. S. Vincent Rajkumar, MD has no conflict of interest to declare., (Copyright © 2023. Published by Elsevier Ltd.)

As doenças linfoproliferativas com diferenciação plasmocitária e pico monoclonal são causas de dificuldade diagnóstica no estudo de espécimes de medula óssea. Conhecer os aspectos clínicos, morfológicos, imunofenotípicos e citogenéticos é fundamental para o diagnóstico correto. Descrevemos os aspectos práticos mais relevantes para a interpretação de biópsias de medula óssea frente às situações mais frequentes.Some lymphoproliferative diseases with plasma cell differentiation and monoclonal gammopathy are challenging to diagnose when dealing with bone marrow biopsies. Knowledge of clinical, morphological, phenotypic and cytogenetic aspects is crucial to establish the correct diagnosis. We describe practical relevant aspects that help in the interpretation of bone marrow biopsies in these situations.

Waldenström Macroglobulinemia (WM) is a rare hematologic malignancy characterized by the presence of lymphoplasmacytic lymphoma cells involving the bone marrow and production of a monoclonal IgM paraprotein. Recurrent somatic mutations in MYD88 L265P and CXCR4 have been reported in 90% to 95% and 30% to 40% of patients with WM, respectively. Standard treatment regimens combine the anti-CD20 antibody rituximab with alkylating agents (eg, bendamustine, cyclophosphamide), nucleoside analogs (eg, fludarabine, cladribine), or proteasome inhibitors (eg, bortezomib, carfilzomib, and ixazomib). Covalent BTK inhibitors (eg, ibrutinib, acalabrutinib, zanubrutinib) have shown to be safe and highly effective in patients with WM. Novel and promising agents in this disease include next-generation covalent BTK inhibitors (eg, tirabrutinib, orelabrutinib), non-covalent BTK inhibitors (eg, pirtobrutinib, ARQ531), BCL-2 antagonists (eg, venetoclax), and CXCR4-targeted agents (eg, mavorixafor, ulocuplumab), among others. Future studies will focus on developing fixed-duration combinations regimens with these novel agents aimed at increasing durable responses while minimizing toxicity and cost., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Waldenstrom macroglobulinemia (WM) is a low-grade B-cell lymphoproliferative disorder. It is defined by having ≥ 10% bone marrow infiltration with lymphoplasmacytic cells and/or an immunoglobulin M (IgM) monoclonal gammopathy of ≥3g/dL. Risk factors include a personal history of IgM MGUS, and a family history of WM or a related disorder. Race, sex, and chronic antigen stimulation also appear to influence risk. Between 93 to 97% of patients with WM have a somatic mutation of the MYD88 gene. Of these, approximately 30% also have a mutation of CXCR4. The presence of a MYD88 mutation is associated with higher 10-year overall survival (90% vs. 73%; P < .001), while CXCR4 mutation status does not appear to have a similar effect. Based on consensus guidelines, WM patients with a disease-related hemoglobin level of less than 10g/dL, a platelet count of less than 100×10 9/L, bulky adenopathy or organomegaly, symptomatic hyperviscosity, severe neuropathy, amyloidosis, cryoglobulinemia, cold agglutinin disease, or evidence of disease transformation, should be considered for immediate therapy. Patients not meeting these criteria may be observed, with monitoring at 3 to 6 month intervals. When treatment is warranted, combinations of rituximab with alkylating agents and proteasome inhibitors are often effective, as are Bruton's tyrosine kinase (BTK) inhibitors and BCL-2 inhibitors. Selection among available regimens should take patients' gene mutation profile, disease-related features, and co-morbid conditions into account. Promising novel therapies in development include non-covalent BTK inhibitors, CXCR4 antagonists, BCL 2 inhibitors, bi-specific antibodies, radioimmunoconjugates, and CD19- and CD20-Targeted Chimeric Antigen Receptor T cells., (Copyright © 2021. Published by Elsevier Inc.)

Toxoplasma gondii can develop toxoplasmic encephalitis (TE) in immunodeficient conditions such as AIDS and after organ transplantation. While some cases of TE with malignant lymphoma were reported, these cases occurred immediately after chemotherapy or when their diseases were active. Here we report the first Case of TE that occurred in patient who was in partial remission (PR) of lymphoplasmacytic lymphoma (LPL) for two years. A 76-year-old man was referred to our institute because of disturbance of consciousness, right arm weakness and paresthesia. A computed tomography (CT) scan detected multiple nodules in his brain. Magnetic resonance imaging (MRI) of the head detected multiple gadolinium-enhancing parenchymal lesions with hyperintense signals on T2-and diffusion-weighted images, located in both cerebral and cerebellar hemispheres. Blood test and cerebrospinal fluid (CSF) findings were unremarkable. His rapidly deteriorating consciousness precluded a chance of brain biopsy. Considering the limited efficacy of antimicrobials and the imaging findings that could be compatible with the diagnosis of malignant lymphoma, we suspected central nerve system (CNS) recurrence of LPL. Although chemotherapy was initiated, he died of respiratory failure just after chemotherapy. A pathological autopsy showed his cause of death was TE. To our knowledge, this is the first case of TE in long-term PR of malignant lymphoma. TE should be suspected when patients with malignant lymphoma present unexplained neurologic symptoms regardless of their treatment efficacy of lymphoma. (226/250 words)., (Copyright © 2021 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Waldenström macroglobulinemia (WM) is a low-grade B-cell clonal disorder characterized by lymphoplasmacytic bone marrow involvement associated with monoclonal immunoglobulin M. Although WM remains to be an incurable disease with a heterogeneous clinical course, the recent discovery of mutations in the MYD88 and CXCR4 genes further enhanced our understanding of its pathogenesis. Development of new therapies including monoclonal antibodies, proteasome inhibitors, and Bruton tyrosine kinase inhibitors have made the management of WM increasingly complex. Treatment should be tailored to the individual patient while considering many clinical factors. The clinical outcomes are expected to continue to improve, given the emergence of novel therapeutics and better understanding of the underlying pathogenesis., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objectives: Waldenstrom macroglobulinemia (WM) is a B-cell lymphoma characterized by the accumulation of lymphocytes and plasmacytic cells in the bone marrow and by excess production of immunoglobulin M in serum. WM has been closely linked with the MYD88(L265P) mutation. Whole genome sequencing has identified somatic mutations in the CXCR4 gene in ∼29% of WM cases with MYD88(L265P). CXCR4 mutations may interfere with treatment response to ibrutinib. The goal of this study was to design and validate a clinical assay to detect CXCR4 mutations., Methods: Thirty-three low-grade B-cell lymphomas with plasmacytic differentiation (23 MYD88(L265P) and 10 MYD88(WT)) involving various samples types (fresh and formalin-fixed tissues) formed the study group. We designed and validated Sanger sequencing and pyrosequencing assays to detect mutations in CXCR4 in a Clinical Laboratory Improvement Amendments-approved clinical laboratory., Results: We identified 8 cases with CXCR4 mutations, including 5 single nucleotide substitutions (3 resulting in p.S338* and 1 in p.R334*), and 3 insertion/deletions. Seven of 8 CXCR4 mutated cases were also MYD88(L265P) mutant. Among the single nucleotide substitutions, we identified a novel missense variant (p.L326P) and a previously reported variant (G335S) of uncertain clinical significance., Conclusions: We successfully validated a set of clinical assays to detect mutations in CXCR4 mutations in a clinical laboratory., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Waldenström's Macroglobulinemia (WM) is characterized by the presence of an IgM monoclonal protein regardless of its size, 10% or more bone marrow infiltration by small lymphocytes with a plasmacytoid or plasma cell differentiation. These cells usually have the following markers: IgM+, CD5 - , CD10 - , CD19 + , CD20 + and CD23 - . Chronic lymphocytic leukemia as well as other lymphoproliferative disorders such as mantle cell, marginal zone and mucosa-associated lymphoid tissue (MALT) lymphoma must be excluded. Weakness or fatigue from anemia, fever, night sweats, or weight loss represent the most common symptoms. Hepatosplenomegaly may be a major feature. Anemia, thrombocytopenia, hyperviscosity or peripheral neuropathy may be prominent features. Systemic amyloidosis, renal insufficiency and cryoglobulinemia may also be seen. WM must be differentiated from smoldering Waldenström's Macroglobulinemia (SWM) which is an intermediate disease state characterized by an IgM protein ≥3 g/dL and/or a bone marrow containing ≥10% bone marrow lymphoplasmacytic infiltration but no end-organ damage such as symptomatic anemia, constitutional symptoms, hyperviscosity, symptomatic hepatosplenomegaly or lymphadenopathy., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Waldenström macroglobulinemia (WM) is a lymphoplasmacytic lymphoma characterized by the proliferation of small B-lymphocytes in the bone marrow that produce monoclonal immunoglobulin M (IgM). We describe two patients with WM who presented with neurological symptoms due to infiltration of lymphoplasmacytoid tumor cells in the central nervous system, a condition known as Bing-Neel syndrome. A literature review revealed that this syndrome is rare and commonly missed in clinical practice due to its variable presentation and a lack of awareness or knowledge. Brain and spinal magnetic resonance imaging may show a focal mass or diffuse infiltration. The diagnosis of Bing-Neel syndrome requires proof of IgM or lymphoplasmacytoid cells in cerebrospinal fluid or in a brain biopsy. Treatment with intravenous and/or intrathecal chemotherapy and cranial radiotherapy is described in literature with generally poor outcome, although a combination of these therapies seems to improve outcome. Nevertheless, insufficient data are currently available to make general treatment recommendations., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Waldenström macroglobulinemia (WM) is a distinct hematologic malignancy characterized by a lymphoplasmacytic bone marrow infiltration and the presence of immunoglobulin (Ig)M monoclonal protein. Patients typically present at an advanced age, and a substantial proportion are asymptomatic at diagnosis. A unifying diagnosis of WM may be missed by an unsuspecting hematologist, as symptomatic patients present with a multitude of non-specific manifestations. Although constitutional and neuropathy-related symptoms predominate, concomitant IgM-induced hyperviscosity-associated features can provide useful diagnostic clues. There are specific indications for initiation of therapy. This review focuses on the most up-to-date management strategies of WM, in addition to highlighting the recent discoveries of MYD88 and CXCR4 mutations that have shed unprecedented light on the complex signaling pathways, and opened avenues for novel therapeutic targeting. Although WM remains incurable, with the rapid emergence and integration of effective novel therapies, its clinical course appears poised to improve in the foreseeable future., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Clinical guidelines have recommended annual follow-up examinations of most patients with monoclonal gammopathy of undetermined significance (MGUS); however, evidence supporting this practice is lacking. We performed a population-based study to examine the patterns of disease presentation and outcomes of patients with multiple myeloma, Waldenström macroglobulinemia, and lymphoplasmacytic lymphoma (monoclonal gammopathy-associated malignancies) comparing those with or without a previous MGUS follow-up examination., Materials and Methods: Patients with monoclonal gammopathy-associated malignancy from 1994 through 2007 were identified using the Surveillance, Epidemiology, and End Results-Medicare linked database and divided into 2 cohorts: those with follow-up (MGUS follow-up examination preceding the diagnosis) and those with no follow-up (no such follow-up examination). We compared the outcomes, including the rates of major complications at cancer diagnosis (acute kidney injury, cord compression, dialysis use, fracture, and hypercalcemia) and survival using propensity score adjustment and Cox proportional hazard models. All statistical tests were 2-sided., Results: Of the 17,457 study patients, 6% had undergone MGUS follow-up. After multivariable modeling, the follow-up group had significantly fewer major complications at diagnosis (odds ratio 0.68; 95% confidence interval [CI], 0.57-0.80) and better disease-specific (median, 38 vs. 29 months, P < .001; hazard ratio [HR] 0.85; 95% CI, 0.76-0.94) and overall (median, 23 vs. 19 months, P < .001; HR 0.87; 95% CI, 0.80-0.95) survival., Conclusion: Patients with MGUS follow-up preceding the diagnosis of a monoclonal gammopathy-associated malignancy can experience fewer major complications and have longer survival than those without such follow-up examinations. Future studies replicating our findings in the non-Medicare population and determining the optimal schedule and cost-effectiveness of MGUS follow-up are warranted., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Waldenström macroglobulinemia represents a lymphoplasmacytic lymphoma with an indolent clinical course. The existing literature associates this hematologic malignancy with various autoimmune disorders. Notwithstanding, these autoimmune conditions have not been comprehensively characterized or systematized to date. As a result, their clinical implications remain largely unknown. The authors offer a comprehensive review of the existing literature on various hematologic and nonhematologic autoimmune disorders documented in the course of Waldenström macroglobulinemia. Whereas some of them are thought to be secondary to a dysfunctional immune response associated with an underlying malignant process, others might be primary and might even play a role in its pathogenesis. Moreover, the observations that personal history and family history of certain autoimmune diseases were associated with an increased risk of subsequent Waldenström macroglobulinemia strengthen further the hypothesis that shared susceptibility genes and chronic antigenic stimulation might predispose individuals to both conditions., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The diagnosis of bone marrow (BM) infiltration by Waldenström macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) poses a diagnostic challenge in hematopathology. No definitive morphology or immunophenotype is able to distinguish between infiltration of paraffin-embedded BM sections by WM/LPL and other indolent lymphomas, in particular those of the splenic marginal zone (SMZL) which may also show plasmacytic maturation. An oncogenic gain-of-function mutation (L265P) in the human MYD88 gene has been found to be present in most cases of WM/LPL, yet is absent in most other cases of B-cell chronic lymphoproliferative disorders (LPD), including SMZL. Here, we compare two newly developed diagnostic protocols for detection of this mutation in paraffin-embedded archival tissues which are particularly applicable to decalcified BM biopsies. Sanger sequencing can easily detect levels of BM infiltration above 15% by WM lymphoplasmacytic cells, while the allele-specific PCR can detect the L265P mutation in BM infiltrations below 1% of lymphoma cells. We show that these methods are easily applicable to archival BM specimens and markedly improve diagnostic accuracy of BM infiltrations by indolent B-cell lymphomas., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Waldenström macroglobulinemia (WM), first described by Jan Waldenström in 1944, is a lymphoplasmacytic lymphoma characterized by the presence of an immunoglobulin M monoclonal gammopathy in the blood and monoclonal small lymphocytes and lymphoplasmacytoid cells in the bone marrow. WM is a rare and indolent disease but remains incurable. In this review we discuss the pathogenesis of WM and focus on novel treatment options that target pathways deregulated in this disease. Recent studies have helped us identify specific genetic mutations that are commonly seen in WM and might prove to be important therapeutic targets in the future. We discuss the role of epigenetics and the changes in the bone marrow microenvironment that are important in the pathogenesis of WM. The commonly used drugs are discussed with a focus on novel agents that are currently being used as single agents or in combination to treat WM. We finally focus on some agents that have shown preclinical efficacy and might be available in the near future., (Copyright © 2013 Elsevier Inc. All rights reserved.)