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Monoclonal gammopathy has been reported to interfere with several laboratory measurement results. We investigated potential interference in monoclonal gammopathy on immunoglobulin A (IgA), immunoglobulin G (IgG), and immunoglobulin M (IgM) concentrations using three different routine chemistry instruments: Alinity (Abbott Laboratories), Cobas 8000 (Roche Diagnostics) and Optilite (Binding Site) at the Department of Clinical Biochemistry, Aalborg University Hospital, Denmark. Blood samples collected from 216 patients with known monoclonal gammopathy were analyzed on Alinity, Cobas and Optilite. Diagnoses were ascertained from clinical records. Scatter plots with Passing-Bablok regression were used to investigate associations between concentrations of IgA, IgG and IgM measured with each of the different instruments. Furthermore, comparison of IgG analyses on Alinity, Optilite and Cobas according to monoclonal IgM concentration was explored with Bland-Altman plots. A total of 81 patients were identified with IgM type monoclonal gammopathy and 8 of these patients (10%) had analytical interference as reflected by more than 25% decrease in the level of IgG measured on Alinity as compared to Optilite and Cobas. All blood samples with interference on IgG measurement using Alinity were from patients with lymphoplasmacytic lymphoma/Waldenströms macroglobulinemia and all of them had monoclonal IgM concentrations above 10 g/L. This study identified a source of interference from IgM monoclonal gammopathy on IgG measurement performed using Alinity. The interferences caused falsely low results of IgG which is important to recognize to ensure proper patient management.

Waldenström macroglobulinaemia (WM) is a unique, cluster of differentiation (CD) 20+ B-cell malignancy, with a characteristic immunoglobulin M-secreting lymphoplasmacytic bone marrow infiltrate that is bolstered by a highly supportive microenvironment, including upregulated programmed death 1 expression. However, the impact of checkpoint inhibition in WM is unclear. Commentary on: Kothari et al. PembroWM: A phase II trial to investigate the safety and efficacy of rituximab and pembrolizumab in relapsed/refractory Waldenström's macroglobulinaemia. Br J Haematol 2024 (Online ahead of print). doi: 10.1111/bjh.19706., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

Lymphoplasmacytic lymphoma (LPL) is a relatively rare form of indolent B-cell non-Hodgkin's lymphoma, termed Waldenström's macroglobulinaemia (WM) in the presence of an IgM paraprotein. Although traditionally treated with combination chemoimmunotherapy, the management is evolving in the era of targeted molecular therapies including Bruton's tyrosine kinase inhibitors (BTKi). However, intolerance and refractoriness to BTKi mean newer agents are required, and the prognosis of so-called quadruple-refractory patients is poor. BCL2 is an anti-apoptotic, pro-survival protein that promotes lymphoma cell survival. Inhibition of BCL2 using first-in-class agent venetoclax has already altered the treatment paradigm in other conditions, including chronic lymphocytic leukaemia (CLL). In-vivo inhibition of BCL2 has been shown to lead to apoptosis of LPL/WM cells. Five studies have published results on the use of BCL2 inhibitors in WM to date, including oblimersen sodium, venetoclax, and sonrotoclax. Fixed-duration venetoclax resulted in high response rates, but many patients relapsed following the completion of therapy. The combination of venetoclax with ibrutinib resulted in higher and relatively deep response rates, but unexpected deaths due to ventricular events mean this combination cannot be explored. Two pivotal trials are currently evaluating the use of fixed-duration venetoclax, either in combination with rituximab or pirtobrutinib, whereas another multi-arm study is studying the use of continuous sonrotoclax monotherapy for R/R WM or in fixed-duration combination with Zanubrutinib for treatment-naïve patients. The potential role of BCL2 inhibitors in WM/LPL remains under study, with many hopeful that they may provide an additional chemotherapy-free oral alternative for patients requiring treatment. In an indolent condition with existing effective treatment regimens, including CIT and cBTKi, cost-effectiveness and toxicity profile will be key, although an additional treatment modality for quadruple-refractory patients with limited treatment options is urgently required., Competing Interests: SD’S has received research support from Janssen and BeiGene, and advisory board honoraria from Janssen, BeiGene, HillStarBio, Kite and Sanofi. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Tomkins and D’Sa.)

Composite lymphoma, defined as two or more distinct well-defined entities involving the same anatomic site, is rare. Here we report a 79-year-old woman with composite mantle cell lymphoma (MCL) and lymphoplasmacytic lymphoma (LPL) involving bone marrow at the time of initial diagnosis. The patient presented with splenomegaly and lymphadenopathy and laboratory studies showed an elevated serum IgM level and IgM kappa paraprotein. Bone marrow evaluation showed concurrent involvement by MCL and LPL, supported by immunophenotypic studies that revealed two distinct aberrant B-cell populations. Next-generation sequencing analysis identified concurrent MYD88 and CXCR4 mutations and fluorescence in-situ hybridization showed CCND1 translocation, supporting the diagnosis of concomitant MCL and LPL. In conclusion, composite lymphoma can present in the bone marrow. The use of ancillary studies was essential in reaching the diagnosis in this case, as the results excluded the possibility of MCL lymphoma with plasmacytic differentiation, as well as other CD5- and CD10-negative small B-cell lymphomas., Competing Interests: Declaration of competing interest The authors declare no conflict of interest associated with this publication., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose of Review: Waldenström macroglobulinemia is a rare non-Hodgkin lymphoma (NHL) characterized by lymphoplasmacytic bone marrow infiltration associated with an immunoglobulin M (IgM) monoclonal gammopathy. Over the past two decades, a number of important novel therapies have emerged for the treatment of relapsed and refractory (R/R) WM. The purpose of this review is to discuss these novel agents., Recent Findings: Chemoimmunotherapy which formed the basis treatment for R/R WM is slowly being replaced by novel targeted agents. These therapies, including Bruton's tyrosine kinase inhibitors, proteasome inhibitors, and B-cell lymphoma 2 inhibitors, have widened the landscape of management. Emerging therapies currently under investigation, such as bispecific T-cell engagers, chimeric antigen T-cell receptor therapy, and novel small molecule inhibitors, have additionally shown the potential to improve response and survival. The treatment of R/R WM has greatly evolved, in large part due to a greater understanding of the biology of WM, and the evaluation of novel targeted agents in the basket trials of NHL, showing early activity in the small WM cohorts. Combination regimens with these established and emerging novel therapies have the potential to further improve disease control and induce higher rates of deep responses. Strategies aimed at altering the disease trajectory would require randomized controlled trials to provide relevant data on optimal integration and sequencing of more effective and tolerable regimens earlier in the disease course., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Immune-related neurological syndromes (affecting both the central and peripheral nervous system, as well as the neuromuscular junction) can associate with low-grade B-cell lymphomas., Methods: We conducted a retrospective study on the records of patients with miscellaneous immune-related neuropathies followed by the "Referral Centre for Neuromuscular Diseases and ALS" in collaboration with the Services of Internal Medicine and Hematology (La Timone Hospital, and the Paoli Calmettes-Insitute, Marseille, France; Geneva University Hospitals, Geneva, Switzerland). Clinical, biological, immunological and histological work-up was carried out and data collected., Results: We identified 12 patients with neurological syndromes and atypical presentation/course. In all these patients multiple autoantibodies were found. This prompted us to perform thorough hematologic investigations, that led to the diagnosis of different type of Low-Grade B-Cell lymphomas [i.e. marginal zone lymphomas with lymphoplasmacytic differentiation (n=3), splenic marginal area lymphoma with secondary lymph node invasion (n=1), unclassified marginal area lymphomas (n=8)]. Treatment of the underling lymphoma resulted in an improvement (n=8) or stabilization (n=4) of neurological disease., Conclusion: Atypical presentation of immune-related neurological syndromes, as well as the presence of antibodies with different antigenic targets should be regarded as "warning signs" and raise the suspicion of a paraneoplastic origin sustained by an underlying low-grade B-cell lymphoma that should be actively sought and treated. Close collaboration between internists, neurologists and hematologists allows for the appropriate management of each case., Competing Interests: Declaration of Competing Interest There is no conflict of interest., (Copyright © 2024. Published by Elsevier GmbH.)

Waldenström's macroglobulinemia (WM) is a B-cell non-Hodgkin's lymphoma characterized by clonal IgM-secreting lymphoplasmacytic cell proliferation. Bing-Neel syndrome (BNS) is a rare complication of WM that results in the infiltration of the central nervous system (CNS) with IgM-secreting lymphoplasmacytic cells. This case study presents a 75-year-old Caucasian male with a history of WM and Agent Orange exposure who ultimately was diagnosed with BNS. This patient posed unique diagnostic challenges as the patient experienced clinical symptoms despite the absence of MRI abnormalities and therapeutic challenges., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Kotlarz et al.)

Waldenström macroglobulinemia (WM) is an infrequent variant of lymphoma, classified as a B-cell malignancy identified by the presence of IgM paraprotein, infiltration of clonal, small lymphoplasmacytic B cells in the bone marrow, and the MYD88 L265P mutation, which is observed in over 90% of cases. The direct invasion of the malignant cells into tissues like lymph nodes and spleen, along with the immune response related to IgM, can also lead to various health complications, such as cytopenias, hyperviscosity, peripheral neuropathy, amyloidosis, and Bing-Neel syndrome. Chemoimmunotherapy has historically been considered the preferred treatment for WM, wherein the combination of rituximab and nucleoside analogs, alkylating drugs, or proteasome inhibitors has exhibited notable efficacy in inhibiting tumor growth. Recent studies have provided evidence that Bruton Tyrosine Kinase inhibitors (BTKI), either used independently or in conjunction with other drugs, have been shown to be effective and safe in the treatment of WM. The disease is considered to be non-curable, with a median life expectancy of 10 to 12 years., Competing Interests: Competing interests: Michele Bibas declares no conflict of interest. Shayna Sarosiek: Research funds or honoraria from ADC Therapeutics, Beigene, and Cellectar. J.J. Castillo: Research funds and/or consulting fees from Abbvie, AstraZeneca, Beigene, Cellectar, Janssen, Loxo, Mustang Bio, and Pharmacyclics.

Waldenström macroglobulinemia (WM) is a chronic B-cell lymphoproliferative disorder characterized by lymphoplasmacytic cell overgrowth in the bone marrow and increased secretion of IgM immunoglobulins into the serum. Patients with WM have a variety of clinical outcomes, including long-term survival but inevitable recurrence. Recent advances in disease knowledge, including molecular and genetic principles with the discovery of MYD88 and CXCR4 mutations, have rapidly increased patient-tolerable treatment options. WM patients may benefit from chemotherapy regimens that include rituximab-based regimens, alkylating drugs, proteasome inhibitors, monoclonal antibodies, and drugs targeting Bruton tyrosine kinase inhibitors. In light of these advancements, patients can now receive treatment customized to their specific clinical characteristics, focusing on enhancing the depth and durability of their response while limiting the adverse effects. Despite the rapidly developing therapeutic armament against WM, a lack of high-quality evidence from extensive phase 3 trials remains a significant challenge in the research. We believe clinical outcomes will keep improving when new medicines are introduced while preserving efficacy and minimizing toxicity., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The B cell receptor (BCR) signaling pathway plays a crucial role in B cell development and contributes to the pathogenesis of B cell neoplasms. In B cell malignancies, the BCR is constitutively active through both ligand-dependent and ligand-independent mechanisms, resulting in continuous Bruton tyrosine kinase (BTK) signaling activation, which provides a survival and proliferation advantage to the neoplastic clone. Among B cell malignancies, those in which the most significant results were obtained by treatment with BTK inhibitors (BTKi) include chronic lymphocytic leukemia, mantle cell lymphoma, lymphoplasmacytic lymphoma, and diffuse large B cell lymphoma. Covalent BTKi (namely ibrutinib, acalabrutinib, and zanubrutinib) functions by irreversibly blocking BTK through covalent binding to the cysteine residue 481 (Cys-481) in the ATP-binding domain. Despite the high efficacy and safety of BTKi treatment, a significant fraction of patients affected by B cell malignancies who are treated with these drugs experience disease relapse. Several mechanisms of resistance to covalent BTKi, including Cys-481 mutations of BTK, have been investigated in B cell malignancies. Non-covalent BTKi, such as pirtobrutinib, have been developed and proven effective in patients carrying both Cys-481-mutated and unmutated BTK. Moreover, targeting BTK with proteolysis-targeting chimeras (PROTACs) represents a promising strategy to overcome resistance to BTKi in B cell neoplasms.

We performed a molecular analysis of formalin-fixed paraffin embedded and decalcified bone marrow trephine biopsies of 41 patients with a B-cell disorder with lymphoplasmacytic differentiation to enable a more precise diagnosis and to describe potentially prognostic and therapeutic relevant mutations. Analysis was performed with a commercially available next-generation sequencing (NGS) lymphoma panel (Lymphoma Solution, SophiaGenetics). Results were correlated with clinical and pathological parameters. Our group covered a spectrum of B-cell disorders with plasmacytic differentiation ranging from Waldenstroem's macroglobulinemia (WM), to small-B-cell lymphomas with plasmacytic differentiation (SBCL-PC) to IgM myeloma (MM). The most helpful diagnostic criteria included morphology and immuno-phenotype as a prerequisite for the interpretation of molecular analysis. MYD88 mutation was present in nearly all WM, but also in 50% of SBCL-PCs, while MM were consistently negative. Driver mutations, such as TP53, were already detectable early in the course of the respective diseases indicating a higher risk of progression, transformation, and reduced progression-free survival. In addition, we report on a novel BIRC3 frameshift mutation in one case of a progressive WM. Our data indicate that patients with LPL/WM might benefit from thorough pathological work-up and detailed molecular analysis in terms of precise diagnosis and targeted treatment allocation., (© 2023. The Author(s).)

Lymphoplasmacytic lymphoma often needs to be differentiated from other B-cell lymphomas with plasmacytic differentiation, especially marginal zone cell lymphoma. Molecular detection of MYD88 p.L265P hotspot mutation supports the diagnosis of lymphoplasmacytic lymphoma since it is seen in about 90% of such lymphoma, which is much higher than other B-cell lymphomas. MYD88 p.L265P is a gain-of-function mutation that enhances the activity of the NF-κB signaling pathway and therefore drives lymphomagenesis. Other mutations in MYD88 are rarely reported. This study aims to report an unusual MYD88 in-frame deletion in an aggressive lymphoplasmacytic neoplasm. This is an IgM-positive, CD5- and CD10-negative mature B-cell lymphoma with prominent plasmacytic differentiation and aggressive features. The clinical and pathologic findings were most consistent with lymphoplasmacytic lymphoma. Next-generation sequencing identified an unusual MYD88 in-frame deletion in the absence of the hotpot p.L265P mutation. Other concurrent pathogenic mutations also include truncating mutations of TRAF3 , which is a negative regulator of the NF-κB signaling pathway, and a missense mutation of TP53 . Karyotype analysis showed complex karyotypes, including chromosome 6q deletion. By searching literature and online cancer databases, we identified only 8 other mature B-cell lymphomas with MYD88 in-frame deletions, but none of them was diagnosed with lymphoplasmacytic lymphoma. Recognizing such in-frame deletions is necessary to help understand the mutational spectrum of MYD88 in B-cell lymphomas. It remains to be further investigated whether such MYD88 in-frame deletions are also overrepresented in lymphoplasmacytic lymphoma among other B-cell lymphomas., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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.)

Waldenström macroglobulinemia (WM) is a rare, indolent, and currently incurable B-cell neoplasm characterized by monoclonal immunoglobulin M gammopathy, frequent nodal involvement, and lymphoplasmacytic infiltration of the bone marrow. The clinical pattern at diagnosis is similar to that reported in developed countries but, unfortunately, the tools for a complete diagnosis and access to novel therapies are suboptimal. Older drugs such as bendamustine, cyclophosphamide, and chlorambucil may still play a role in treating WM. Prospective studies in resource-limited regions are required to further evaluate these essential aspects of the disease. In this document, we issue recommendations based on our local reality., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Lymphoplasmacytic lymphoma (LPL) is a neoplasm of small B lymphocytes, plasmacytoid lymphocytes and plasma cells usually involving the bone marrow (BM). A subset of LPL which is associated with IgM monoclonal gammopathy is called Waldenstrom's macroglobulinaemia (WM), and usually requires therapeutic intervention when a patient becomes symptomatic (Bone Marrow failure characterised by cytopenia or hyperviscosity syndrome). Here, we report the case of an 80-year-old female with clinically unsuspected WM who initially presented to the Emergency Department (ED) with nausea and vomiting. The patients' gastrointestinal symptoms subsequently settled and was awaiting discharge. Non-specific, borderline size significant lymph nodes on CT chest was the only substantial past medical history. The diagnosis of WM was made after the Biochemistry Biomedical Scientist (BMS) detected the presence of a Type I monoclonal cryoglobulin. A potential cryoprecipitate was suspected when repeated 'clotting' error flags occurred during routine laboratory analyses; the sample aspiration difficulties being attributed to the viscous nature of the sample. The investigation of inaccessible low volume lymphadenopathy in the elderly should include serum protein electrophoresis and immunoglobulins as this may have established an earlier diagnosis in this case. The application of good scientific principles informed the laboratory investigation and resulted in the identification of a large IgM monoclonal cryoglobulin that prompted further appropriate investigations resulting in the diagnosis of WM. This case also highlights the importance of good communication between the laboratory and clinical staff.

The 5th edition of the WHO classification (WHO-HAEM5) and the International Consensus Classification (ICC) have considerable overlap but also some distinct differences in categorizing indolent B‑cell lymphomas. Most differences with the expected impact on the daily diagnostic routine relate to follicular lymphoma (FL). Grading of FL remains mandatory only in the ICC; a diffuse growth pattern in an FL with > 15 blasts per high-power field (FL grade 3A) is not automatically classified as DLBCL according to WHO-HAEM5, and an FL subtype with unusual morphology (blastoid or large centrocyte) and biology is recognized as an entity only in the WHO-HAEM5. With the exception of B‑prolymphocytic leukemia, which is no longer acknowledged in WHO-HAEM5, there are only minor differences between both classifications and include updated names of entities, improved diagnostic criteria, and upgrades from provisional to definite entities., (© 2023. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Objectives: To summarize the conclusions of the 2021 Society for Hematopathology/European Association for Haematopathology workshop regarding transformations of marginal zone lymphoma (MZL) and lymphoplasmacytic lymphoma (LPL)., Methods: Nineteen cases were submitted to this portion of the workshop. Additional studies were performed in cases with sufficient material., Results: Cases included splenic MZL (n = 4), splenic diffuse red pulp small B-cell lymphoma (n = 2), nodal MZL (n = 4), extranodal MZL (n = 1), and LPL (n = 8). The most common transformation was to diffuse large B-cell lymphoma (DLBCL), but others included classic Hodgkin lymphoma, high-grade B-cell lymphomas with MYC and BCL6 rearrangements, plasmablastic lymphoma, and plasma cell leukemia. Two splenic MZLs with transformation to DLBCL contained t(14;19)(q32;q13.3) IGH::BCL3 rearrangements in both samples. Paired sequencing studies in 5 MZLs with transformation to clonally related DLBCL identified a variety of mutations and gene fusions at the time of transformation, including CARD11, IGH::MYC, NOTCH2, P2RY8, TBLX1X1, and IGH::CD274., Conclusions: Marginal zone lymphoma and LPL may undergo a variety of transformation events, most commonly to DLBCL, which is usually, although not always, directly clonally related to the underlying low-grade lymphoma. Multiparameter analysis including broad-based sequencing studies can assist in the diagnosis and classification of these uncommon cases., (© The Author(s) 2023. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Waldenström macroglobulinemia is a rare hematological malignancy and is the most common diagnosis in patients with hyperviscosity syndrome. Bilateral central retinal vein occlusion as an initial presentation of hyperviscosity syndrome in Waldenström macroglobulinemia is rare., Case Presentation: A 42-year-old Nepalese male presented with sudden-onset bilateral painless blurring of vision. Fundus examination revealed bilateral, diffusely dilated, tortuous retinal veins and intraretinal deep blot hemorrhages in all four quadrants of the retina in both eyes; features of bilateral central retinal vein occlusion. Serum electrophoresis showed hypoalbuminemia with an immunoglobulin M kappa monoclonal spike. Bone marrow picture and immunohistochemistry analysis were suggestive of lymphoplasmacytic lymphoma. The patient received systemic therapy for Waldenström macroglobulinemia, along with intravitreal bevacizumab., Conclusion: Adequate hydration, plasmapheresis, and a combination of bortezomib, dexamethasone, and rituximab regimen as a systemic therapy may represent an ideal choice for patients with hyperviscosity in Waldenström macroglobulinemia., (© 2023. The Author(s).)

A 61-year-old female was referred to our hospital because of pancytopenia and febrile neutropenia. On admission, computed tomography showed mild hepatosplenomegaly and intra-abdominal abscess formation in the right pelvic region; however, no lymphadenopathy was found. Bone marrow (BM) examination showed severe fibrosis by silver staining. Several small- to medium-sized lymphocytes with a constriction in the nuclei were observed, exhibiting CD3 (-), CD10 (-), CD20 (+), BCL-2 (+-), and CD138 (+-). Genetic testing revealed that BM cells were positive for MYD88 mutation and positive for IgH rearrangement, whereas neither JAK2 nor CALR mutation was positive. A diagnosis of BM infiltration of lymphoplasmacytic lymphoma (LPL) was made. Rituximab monotherapy was administered once a week for four times. BM examination 4 weeks after the end of treatment showed that lymphoma cells had disappeared and that myelofibrosis had been almost gone. The MYD88 mutation of BM turned out to be negative at that moment.

Plasma cell neoplasms including multiple myeloma (MM) and related terminally differentiated B-cell neoplasms are characterized by secretion of monoclonal immunoglobulin and stepwise development from a preneoplastic clonal B and/or plasma cell proliferation called monoclonal gammopathy of undetermined significance (MGUS). Diagnosis of these disorders requires integration of clinical, laboratory, and morphological features. While their classification mostly remains unchanged compared to the revised 2016 WHO classification and the 2014 International Myeloma Working Group consensus, some changes in criteria and terminology were proposed in the 2022 International Consensus Classification (ICC) of mature lymphoid neoplasms. MGUS of IgM type is now divided into IgM MGUS of plasma cell type, precursor to the rare IgM MM and characterized by MM-type cytogenetics, lack of clonal B-cells and absence of MYD88 mutation, and IgM MGUS, NOS including the remaining cases. Primary cold agglutinin disease is recognized as a new entity. MM is now formally subdivided into cytogenetic groups, recognizing the importance of genetics for clinical features and prognosis. MM with recurrent genetic abnormalities includes MM with CCND family translocations, MM with MAF family translocations, MM with NSD2 translocation, and MM with hyperdiploidy, with the remaining cases classified as MM, NOS. For diagnosis of localized plasma cell tumors, solitary plasmacytoma of bone, and primary extraosseous plasmacytoma, the importance of excluding minimal bone marrow infiltration by flow cytometry is emphasized. Primary systemic amyloidosis is renamed immunoglobulin light chain amyloidosis (AL), and a localized AL amyloidosis is recognized as a distinct entity. This review summarizes the updates on plasma cell neoplasms and related entities proposed in the 2022 ICC. KEY POINTS: • Lymphoplasmacytic lymphoma can be diagnosed with lymphoplasmacytic aggregates in trephine biopsies < 10% of cellularity and evidence of clonal B-cells and plasma cells. • IgM MGUS is subdivided into a plasma cell type and a not otherwise specified (NOS) type. • Primary cold agglutinin disease is recognized as a new entity. • The term "multiple myeloma" replaces the term "plasma cell myeloma" used in the 2016 WHO classification. • Multiple myeloma is subdivided into 4 mutually exclusive cytogenetic groups and MM NOS. • Minimal bone marrow infiltration detected by flow cytometry is of major prognostic importance for solitary plasmacytoma of bone and to a lesser extent for primary extraosseous plasmacytoma. • Localized IG light chain amyloidosis is recognized as a separate entity, distinct from systemic immunoglobulin light chain (AL) amyloidosis., (© 2022. The Author(s).)

A 93-year-old woman was diagnosed with lymphoplasmacytic lymphoma (LPL) with circulating tumor cells in her peripheral blood after presenting with anemia. LPL progressed eight months later, with anemia worsening and tumor cells increasing to 66% of leukocytes. She began tirabrutinib at a low dose (80 mg daily: 17% of the standard dose) because she preferred to maintain her quality of life (QOL). Within three weeks, she was free of transfusion dependency and had a partial response with the disappearance of peripheral tumor cells. The dosage of tirabrutinib was increased to 240 mg daily because it was well tolerated. She has been on the treatment for 13 months with no adverse effects. Tirabrutinib, a highly selective Bruton's tyrosine kinase inhibitor, has been reported to have promising efficacy for LPL, but it also has a high incidence of dermatological toxicity, which may impair QOL. Low-dose tirabrutinib initiation may be effective and assist elderly patients with LPL in maintaining their QOL.

Introduction: Waldenström macroglobulinemia (WM) represents a subset of lymphoplasmacytic lymphoma (LPL) with the immunoglobulin (Ig)M paraprotein. MYD88 L265P and CXCR4 mutations are common mutations in WM patients, and mutations in ARID1A and KMT2D (MLL2) have also been reported. However, little information has been accumulated on genetic changes in LPL with other paraproteins like IgG., Methods: We therefore aimed to evaluate genetic differences between WM and LPL with non-IgM paraprotein (non-IgM-type LPL) using targeted next-generation sequencing (NGS) in 20 Japanese patients (10 with WM, 10 with non-IgM-type LPL)., Results: Mutations were detected in ARID1A (10%), CXCR4 (20%), MYD88 (90%), and KMT2D (0%) for WM patients and in ARID1A (10%), CXCR4 (20%), MYD88 (70%), and KMT2D (10%) for non-IgM-type LPL patients. No significant differences were identified. No mutations were detected in NOTCH2, PRDM1, CD274 (PD-L1), PDCD1LG2 (PD-L2), RAG2, MYBBP1A, TP53, or CD79B., Discussion: Mutant allele frequency in MYD88 L265P did not differ significantly between WM and non-IgM-type LPL. Most mutations detected by NGS were subclonal following MYD88 L265P, although one non-IgM-type LPL patient harbored only CXCR4 S338X mutation. Our NGS analyses reveal genetic characteristics in LPL patients and suggest genetic similarities between these two subsets of LPL, WM and non-IgM-type., (© 2023 S. Karger AG, Basel.)

Lymphoplasmacytic lymphoma (LPL) with IgG or IgA paraprotein is rare and a subset of cases can mimic a plasma cell neoplasm (PCN). We studied 29 such cases to explore their clinicopathological features and the best diagnostic approaches with a focus on bone marrow findings. The cohort included 18 men and 11 women with a median age of 68 years. The median M protein was 3.1 g/dL, IgG in 19 patients (66%), IgA in 9 (31%), and dual IgG/IgA in 1 (3%). All patients had bone marrow involvement with CD138+ plasma cells (PCs) ranging from 1 to 35% (median, 10%). Two patients also had amyloidosis. Immunoglobulin light chain concordant monotypic PCs and monotypic B cells were identified in 96% of cases assessed by flow cytometry. Notably, the neoplastic PCs were consistently positive for CD45 (dim, 100%), CD19 (96%), CD81 (89%), CD27 (83%), rarely and only weakly or partially express CD56 (16%), whereas CD117 was consistently negative. Eleven cases analyzed by fluorescence in situ hybridization were negative for CCND1::IGH and myeloma-related aberrations. MYD88 mutation was detected in 17 of 24 cases (71%), and CXCR4 mutation was identified in 6 of 19 cases (32%), of which 4 had concurrent MYD88 mutation. In conclusion, the results highlight a potential diagnostic pitfall of LPL associated with marked plasmacytic differentiation and an IgG or IgA paraprotein that can resemble a PCN. Useful features in favor of LPL against PCN include the characteristic immunophenotypic profile of the PCs in LPL, absence of CCND1::IGH, and the presence of MYD88 and/or CXCR4 mutations., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Considerable healthcare resource utilization and financial burden have been associated with the treatment of WM; however, the impact of health insurance status on outcomes has not been previously reported. We conducted a National Cancer Database analysis of newly diagnosed cases of active WM between 2004 and 2017 to evaluate the impact of insurance status on outcomes. For patients <65 years old ( n  = 1249, male sex: 62.4%, median age: 58 years), significant insurance-based survival differences were observed on multivariable analysis; patients who were uninsured [ n  = 63; HR 3.11 (95%CI, 1.77-5.45), p  < 0.001], on Medicaid [ n  = 87; HR 1.88 (95% CI, 1.01-3.48), p  = 0.045], or on Medicare [ n  = 122; HR 2.78 (95%CI, 1.76-4.38), p  < 0.001], had inferior survival compared to patients with private insurance ( n  = 977; reference). In patients ≥65 years, no insurance-based survival differences were found ( p  = 0.10). Overall, significant insurance-based outcome disparities exist in WM. Further work is desperately needed to systematically uncover and address these disparities.

Bing-Neel syndrome (BNS) is a rare central nervous system manifestation of lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM). We herein report a 62-year-old man with LPL/WM after multiple chemotherapies. He had weakness of lower extremities and elevated serum IgM levels. A bone marrow examination showed lymphoplasmacytic cells infiltration. Contrast-enhanced magnetic resonance imaging suggested enhancing lesions in the cauda equina roots. He was diagnosed with BNS and started on treatment with tirabrutinib 480 mg daily. Within three months, he showed clinical and radiologic improvement. Tirabrutinib may have utility as an effective treatment for BNS.

Waldenström macroglobulinemia (WM) is a rare, incurable low grade lymphoma following a relapsing trajectory. Management strategies have evolved with the introduction of targeted therapy including new classes of Bruton tyrosine kinase inhibitor (BTKi). Treatment may however be limited particularly at relapse by a lack of drug availability and tolerability. We assessed the real-world efficacy and tolerability of bortezomib-containing regimens in patients with WM at frontline and relapse including those with prior BTKi resistance. Forty-one patients were identified with 44 bortezomib-containing regimens administered ( n = 12 frontline, n = 32 relapse). Of patients treated at relapse, the median prior lines of therapy was 3 (range 1-7). 24% (10/41) of the cohort were refractory or intolerant to BTKi prior to bortezomib delivery. The median follow-up after bortezomib administration was 34 months (range 0-131). Overall response rate was 88%; 2-year overall survival and progression-free survival were 90% (95% confidence interval [CI] 73-96) and 76% (95% CI 55-87), respectively. Median time-to-next-treatment was 66 months. Neuropathy (grade 1-2) occurred in 24% (8/34) and did not result in treatment cessation in any case. Gastrointestinal disturbance occurred in 7% (3/41). Treatment discontinuations were rare (1/44; 2%), suggesting a manageable safety profile. Major response rate was comparable in those with prior BTKi compared with those without (75% [6/8] vs 84% [27/32], p = 0.61). Bortezomib should be considered as a treatment modality particularly in those who are refractory to BTKi., Competing Interests: SDS reports speaker fees and research funding from Janssen, BeiGene and Sanofi. JK, EU, RB, KT, AR, RG, IP and CK have no conflict of interest to declare., (© 2022 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Lymphoplasmacytic lymphoma (LPL) and marginal zone lymphoma (MZL) frequently infiltrate the bone marrow with similar histologic and immunohistochemical characteristics posing diagnostic problems. Bone marrow biopsy specimens from 25 LPL and 16 MZL have been studied, correlating with clinical, laboratory parameters and the MYD88&#95;p.L265P mutation. Paratrabecular and interstitial infiltration pattern, serum IgM paraprotein levels, and MYD88&#95;p.L265P mutation were significantly more frequent in LPL. Nodular or intrasinusoidal pattern with lymphocytosis and splenomegaly were associated with MZL diagnosis. Different clinical and histological parameters should be collected when LPL or MZL is suspected in bone marrow biopsy specimens., Competing Interests: There is no conflict of interest of any of the authors with the results of this study., (© 2022 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Competing Interests: The authors declare they have no conflicts of interest.

Waldenström's Macroglobulinemia (WM) is a clonal B-lymphocyte neoplasm characterized by the presence of IgM monoclonal protein and ≥10% bone marrow involvement with lymphoplasmacytic cells. Several mature B-cell and plasma cell disorders can potentially produce monoclonal IgM immunoglobulin and hence, careful consideration of the differential diagnosis is vital. Clinico-pathological features, immunophenotype, and MYD88 mutation status help distinguish WM from other plasma cell and lymphoproliferative disorders. Treatment is only indicated in patients symptomatic from adenopathy or organomegaly, neuropathy, hyper viscosity, cryoglobulinemia, cold agglutinin disease, cytopenia's or amyloidosis. Alkylators (cyclophosphamide, bendamustine) in combination with anti-CD20 antibodies and novel targeted agents including Bruton tyrosine kinase (BTK) inhibitors like ibrutinib are the mainstay of frontline treatment in symptomatic WM., Competing Interests: Dr Surbhi Sidana reports personal fees from Magenta Therapeutics, BMS, Janssen, Sanofi, Oncopeptides, other from Magenta Therapeutics, BMS, Allogene, Janssen, outside the submitted work. The authors report no other conflicts of interest in this work., (© 2022 Cingam and Sidana.)

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.)

Bing-Neel syndrome (BNS) is a rare presentation of Waldenström macroglobulinemia (WM). BNS is a consequence of the central nervous system (CNS) involvement by lymphoplasmacytic lymphoma (LPL) and, rarely, the peripheral nervous system. The data on BNS are extremely scarce. Therefore, we performed a multicenter retrospective analysis of BNS patients diagnosed and treated in centers aligned with the Polish Lymphoma Research Group. The analysis covers the years 2014-2021. Eleven patients were included, 55% females and the median age at BNS diagnosis was 61 years. The median time from WM to BNS was 3.5 years; 27% of patients did have a diagnosis of WM and BNS made simultaneously or within 30 days from each other. Isolated parenchymal involvement was the least frequent (20%). Patients were treated with different regimens, mostly able to cross the blood-brain barrier, including 18% treated with ibrutinib first line. The cumulative objective response to treatment was 73%. With the median follow-up of 20 months (95% CI, 2-32), the 36-month estimates were: overall survival (OS) 47%, progression-free survival (PFS) 33%, and cumulative incidence of BNS-associated death 41%. The performance status according to ECOG was significant for PFS (HR = 7.79) and the hemoglobin concentration below 11 g/dL was correlated with PFS. To conclude, BNS is a very rare manifestation of WM. It is associated with a poor outcome with most patients succumbing to BNS.

Objective: The study aims to explore the clinical and biological characteristics of patients with non-IgM lymphoplasmacytic lymphoma (LPL) . Methods: The clinical data of 340 patients with LPL admitted to the Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College were collected retrospectively, including 23 cases of the non-IgM LPL and 317 cases of the Waldenström's macroglobulinemia (WM) , from July 1993 to August 2020. The clinical and biological characteristics of the two groups were compared. Results: Among 23 patients with the non-IgM type LPL, two patients secreted monoclonal IgA, 14 patients secreted monoclonal IgG, and seven patients did not secrete monoclonal immunoglobulin. The median age of the non-IgM LPL and WM were both 62 (35-81) years old. Compared with the WM group, the proportion of women (56.5% vs 27.3%, P =0.007) , the proportion of splenomegaly (60.1% vs 43.8%, P =0.100) , and the proportion of extranodal invasion (21.7% vs 12.3%, P =0.672) in non-IgM LPL group were higher. Eighteen patients were tested for MYD88 gene mutation, and the overall mutation rate of MYD88 was 55.6%. In the non-IgM LPL group, a total of 17 patients received treatment, which had a comparable proportion (94.4% vs 92.7%, P =0.488) to the WM group. Sixteen patients were evaluated for efficacy, and the overall remission rate of the first-line treatment was 87.5%. The median follow-up time was 33.9 (3.5-125.1) months, and the median PFS and OS were both not reached. The 3-year PFS and OS rates were 71.4% and 68.9%, respectively. In the WM group, the median PFS was 66.2 months and the median OS was 78.1 months. Compared with the WM group, in the non-IgM group no significant differences in PFS ( P =0.340) and OS ( P =0.544) were seen. Conclusion: The clinical and biological characteristics of the non-IgM LPL and WM patients were similar. However, the proportion of women and extranodal involvement were higher in the non-IgM LPL group. The survival and prognosis of the non-IgM LPL patients were similar to those of the WM patients.

The differential diagnosis between lymphoplasmacytic lymphoma (LPL) and marginal zone B-cell lymphoma, particularly splenic type (SMZL), can be challenging on onset of bone marrow biopsy (BMB) since morphology and phenotype are not specific and clinical features can overlap or be mildly developed at diagnosis. The LPL-specific L265P mutation in the MYD88 gene is not available in all laboratories, and genetic aberrancies identified in SMZL (del7q, mutations of NOTCH2 and KLF2) are seldom searched in routine practice. The study aim is to investigate the potential role of myeloid nuclear differentiation antigen (MNDA) expression in this specific differential diagnosis. We report MNDA reactivity in 559 patients with small B-cell lymphoma including bone marrow biopsies from 90 LPL and 91 SMZL cases. MYD88 p.Leu265Pro mutation status was assessed and confirmed as positive in 24 of 90 LPL cases, which served as the test set. MNDA staining was negative in 23 of 24 LPL cases in the test set (96%). In the 157 remaining cases (66 LPL, 91 SMZL), which served as the validation set, the MYD88 p.Leu265Pro mutation was unavailable and MNDA was more frequently expressed in SMZL (p < 0.00001). In addition, immunohistochemical features more consistent with SMZL (i.e., presence of CD23+ follicular dendritic cell meshworks, polytypic plasma cells, DBA44 reactivity) were more often present in MNDA-positive cases (statistically significant for 2 such parameters). On the widest case series so far published focusing on LPL and SMZL immunohistochemical diagnosis at onset of BMB, we demonstrated that MNDA expression significantly support the diagnosis of SMZL. This observation may be of particular help in cases where the MYD88 p.Leu265Pro mutational status and/or SMZL-related genetic aberrations are unavailable., (Copyright © 2022 Elsevier Inc. All rights reserved.)