High frequency of central nervous system involvement in transformed Waldenstrom macroglobulinemia

Histologicaltransformation (HT) to diffuse large B-cell lymphoma (DLBCL) is a rare event in Waldenström macroglobulinemia (WM) and is associated with a poor prognosis.1-4 It confers an inferior outcome compared with WM patients without HT.2,3 Most transformed WM patients present with elevated serum lactate dehydrogenase (LDH) levels and extranodal disease.1 Among extranodal sites, the central nervous system (CNS) is one of the most frequently involved sites identified at diagnosis of transformed WM (ranging from 13% to 18%).1,3 However, the prognostic value of CNS involvement is unknown, and the rate of CNS involvement at relapse has not been previously reported in this setting.This work was supported by Cancer Research UK [C355/A26819], FC AECC, and AIRC under the “Accelerator Award Program” [EDITOR] to M.A. and R.G.-S

IgM-Associated Cryoglobulinaemia

Cryoglobulinaemia is characterised by serum immunoglobulins that precipitate at temperatures below 37 °C and redissolve on warming. Monoclonal IgM immunoglobulin can be associated with type I and II cryoglobulinaemia with underlying Waldenström macroglobulinemia, monoclonal gammopathy of undetermined significance, or another non-Hodgkin lymphoma. In this research, we review the clinical characteristics of monoclonal IgM-associated cryoglobulinaemia and suggest a management approach for addressing them. Laboratory testing is critical as even a minimal amount of measurable cryoglobulin may result in symptoms. Accurate detection of cryoglobulins may be challenging, care must be taken with preanalytical variables, and repeated testing of monoclonal protein and cryoglobulins is indicated if clinical suspicion is high. Presentations range from asymptomatic to showing multisystem involvement, meaning that careful evaluation of the features and a thorough interrogation of organ systems and the underlying clone are critical. Immediate management is required for clinical red-flag features. Due to their rarity, data to inform treatment decisions are scant and collaborative research is imperative must be conducted to aid researchers in efforts to define optimal treatment strategies

Cold Agglutinin Disease: Improved Understanding of Pathogenesis Helps Define Targets for Therapy

The last 2 decades have seen great progress in understanding the pathogenesis of cold agglutinin disease (CAD) and development of effective therapies. Cold agglutinins can cause hemolytic anemia as well as peripheral circulatory symptoms such as acrocyanosis. We distinguish CAD, a well-defined clinicopathologic entity, from secondary cold agglutinin syndrome. This review addresses the histopathologic, immune phenotypic, and molecular features that allow CAD to be classified as a distinct clonal lymphoproliferative disorder of the bone marrow, recently recognized in the WHO classification. We discuss recent data on the possible overlap or distinction between CAD and Waldenström’s macroglobulinemia. Two major steps in the pathogenesis of CAD are identified: clonal B-cell lymphoproliferation (leading to monoclonal IgM production) and complement-mediated hemolysis. Each of these steps constitutes a target for treatment. Established as well as novel and experimental therapies are reviewed

Cold Agglutinin Disease: Improved Understanding of Pathogenesis Helps Define Targets for Therapy

The last 2 decades have seen great progress in understanding the pathogenesis of cold agglutinin disease (CAD) and development of effective therapies. Cold agglutinins can cause hemolytic anemia as well as peripheral circulatory symptoms such as acrocyanosis. We distinguish CAD, a well-defined clinicopathologic entity, from secondary cold agglutinin syndrome. This review addresses the histopathologic, immune phenotypic, and molecular features that allow CAD to be classified as a distinct clonal lymphoproliferative disorder of the bone marrow, recently recognized in the WHO classification. We discuss recent data on the possible overlap or distinction between CAD and Waldenström’s macroglobulinemia. Two major steps in the pathogenesis of CAD are identified: clonal B-cell lymphoproliferation (leading to monoclonal IgM production) and complement-mediated hemolysis. Each of these steps constitutes a target for treatment. Established as well as novel and experimental therapies are reviewed

Bing–Neel Syndrome: Update on Diagnosis and Treatment

Bing–Neel syndrome (BNS) is a rare neurological complication of Waldenström macroglobulinaemia. We highlight key issues in clinical presentation, diagnosis, and treatment while focusing on new and emerging therapies available for patients diagnosed with BNS. It is anticipated that further development of Bruton Tyrosine Kinase (BTK) inhibitors and less toxic chemoimmunotherapies will improve treatment delivery and response

Bing–Neel Syndrome: Update on Diagnosis and Treatment

Bing–Neel syndrome (BNS) is a rare neurological complication of Waldenström macroglobulinaemia. We highlight key issues in clinical presentation, diagnosis, and treatment while focusing on new and emerging therapies available for patients diagnosed with BNS. It is anticipated that further development of Bruton Tyrosine Kinase (BTK) inhibitors and less toxic chemoimmunotherapies will improve treatment delivery and response

IgM monoclonal gammopathies of clinical significance: diagnosis and management

IgM monoclonal gammopathy of undetermined significance is a pre-malignant condition for Waldenström macroglobulinemia and other B-cell malignancies, defined by asymptomatic circulating IgM monoclonal protein below 30 g/L with a lymphoplasmacytic bone marrow infiltration of less than 10%. A significant proportion, however, develop unique immunological and biochemical manifestations related to the monoclonal protein itself in the absence of overt malignancy and are termed IgM-related disorders or, more recently, monoclonal gammopathy of clinical significance. The indication for treatment in affected patients is dictated by the pathological characteristics of the circulating IgM rather than the tumor itself. The clinical workup and treatment options vary widely and differ from those for Waldenström macroglobulinemia. The aim of this review is to alert clinicians to IgM monoclonal gammopathy of clinical significance and to provide practical guidance on when to screen for these phenotypes. We discuss clinical characteristics, the underlying clonal profile, diagnostic workup and treatment considerations for five important subtypes: cold agglutinin disease, type I and II cryoglobulinemia, IgM-associated peripheral neuropathy, Schnitzler syndrome and IgM-associated AL amyloidosis. The inhibition of the pathogenic effects of the IgM has led to great success in cold agglutinin disease and Schnitzler syndrome, whereas the other treatments are centered on eradicating the underlying clone. Treatment approaches in cryoglobulinemia and IgM-associated peripheral neuropathy are the least well developed. A multidisciplinary approach is required, particularly for IgM-related neuropathies and Schnitzler syndrome. Future work exploring novel, clone-directed agents and pathogenic IgM-directed therapies is welcomed