Waldenström macroglobulinemia: a challenging case treated with anti-CD19 CAR-T cell therapy. / 华氏巨球蛋白血症：抗CD19嵌合抗原受体Tç»†èƒžç–—æ³•æ²»ç–—çš„æŒ‘æˆ˜æ€§ç— ä¾‹.

Waldenström macroglobulinemia (WM) is characterized by lymphoplasmacytic lymphoma associated with large amounts of monoclonal immunoglobulin M (IgM) protein (Owen et al., 2003). Common signs and symptoms include fatigue due to anemia, lymph node enlargement, hepatosplenomegaly, thrombocytopenia, symptoms related to high viscosity, and peripheral neuropathy, among others. Despite significant advances in WM treatment, this type of indolent lymphoma remains incurable, with a wide array of patient outcomes (Ruan et al., 2020). In recent years, chimeric antigen receptor T (CAR-T) cell therapy targeting cluster of differentiation 19 (CD19) has shown unprecedented response rates and durability in the treatment of B-cell malignancies. In this report, we describe a challenging case of WM that involved multiple extramedullary sites, relapsed, and was refractory to chemotherapy, immunotherapy, and targeted therapy. After anti-CD19 CAR-T cell therapy, the tumor burden significantly decreased and the patient's condition remained stable at the writing of this report.

Personalized neoantigen vaccines as early intervention in untreated patients with lymphoplasmacytic lymphoma: a non-randomized phase 1 trial.

Lymphoplasmacytic lymphoma (LPL) is an incurable low-grade lymphoma with no standard therapy. Nine asymptomatic patients treated with a first-in-human, neoantigen DNA vaccine experienced no dose limiting toxicities (primary endpoint, NCT01209871). All patients achieve stable disease or better, with one minor response, and median time to progression of 72+ months. Post-vaccine single-cell transcriptomics reveal dichotomous antitumor responses, with reduced tumor B-cells (tracked by unique B cell receptor) and their survival pathways, but no change in clonal plasma cells. Downregulation of human leukocyte antigen (HLA) class II molecules and paradoxical upregulation of insulin-like growth factor (IGF) by the latter suggest resistance mechanisms. Vaccine therapy activates and expands bone marrow T-cell clonotypes, and functional neoantigen-specific responses (secondary endpoint), but not co-inhibitory pathways or Treg, and reduces protumoral signaling by myeloid cells, suggesting favorable perturbation of the tumor immune microenvironment. Future strategies may require combinations of vaccines with agents targeting plasma cell subpopulations, or blockade of IGF-1 signaling or myeloid cell checkpoints.

Novel Approaches to Managing Patients with Relapsed and Refractory Waldenström Macroglobulinemia.

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.

High efficacy of CD19 CAR T cells in patients with transformed Waldenström macroglobulinemia.

ABSTRACT: Histologic transformation of Waldenström macroglobulinemia (HT-WM) carries a poor prognosis with standard treatments. Here, we report the first series of HT-WM treated with chimeric antigen receptor T cells showing a high efficacy and no unexpected toxicity.

[Diagnosis and treatment understanding of Waldenström macroglobulinemia in China: a cross-sectional study].

Objective: To conduct a nationwide physician survey to better understand clinicians' disease awareness, treatment patterns, and experience of Waldenström macroglobulinemia (WM) in China. Methods: This cross-sectional study was conducted from February 2022 to July 2022 by recruiting clinicians with WM treatment experience from hematology, hematology-oncology, and oncology departments throughout China. Quantitative surveys were designed based on the qualitative interviews. Results: The study included 415 clinicians from 219 hospitals spread across thirty-three cities and twenty-two provinces. As for diagnosis, the laboratory tests prescribed by physicians for suspected WM patients were relatively consistent (92% -99% recommendation for laboratory, 79% -95% recommendation for pathology, 96% recommendation for gene testing, and 63% -83% recommendation for imaging examination). However, from a physician's perspective, there was 22% misdiagnosis occurred in clinical practice. The rate of misdiagnosis was higher in lower-level hospitals than in tertiary grade A hospitals (29% vs 21%, P<0.001). The main reasons for misdiagnosis were that WM was easily confused with other diseases, and physicians lacked the necessary knowledge to make an accurate diagnosis. In terms of gene testing in clinical practice, 96% of participating physicians believed that WM patients would require gene testing for MYD88 and CXCR4 mutations because the results of gene testing would aid in confirming diagnosis and treatment options. In terms of treatment, 55% of physicians thought that the most important goal was to achieve remission, while 54% and 51% of physicians wanted to improve laboratory and/or examination results and extend overall survival time, respectively. Among patients with treatment indications, physicians estimated that approximately 21% of them refused to receive treatment, mainly owing to a lack of affordable care and disease awareness. When selecting the most appropriate treatment regimens, physicians would consider patient affordability (63% ), comorbidity (61% ), and risk level (54% ). Regimens containing Bruton tyrosine kinase inhibitor (BTKi) were most widely recommended for both treatment-naïve and relapsed/refractory patients (94% for all patients, 95% for treatment-naïve patients, and 75% for relapsed/refractory patients), and most physicians recommended Ibrutinib (84% ). For those patients who received treatment, physicians reported that approximately 23% of patients did not comply with the treatment regimen due to a lack of affordability and disease awareness. Furthermore, 66% of physicians believe that in the future, increasing disease awareness and improving diagnosis rates is critical. Conclusions: This study is the first national physician survey of WM conducted in China. It systematically describes the issues that exist in WM diagnosis and treatment in China, such as a high rate of misdiagnosis, limited access to gene testing and new drugs, and poor patient adherence to treatment. Chinese doctors believe that improving doctors' and patients' understanding of WM is one of the most urgent issues that must be addressed right now.

Lymphoplasmacytic lymphoma and multiple myeloma coexisting in the same patient: a case series and literature review.

The simultaneous occurrence of Waldenström macroglobulinemia and multiple myeloma in the same patient has been published as case reports. Patients with Waldenström macroglobulinemia often have a small clone of plasma cells. However, the concurrent occurrence of symptomatic myeloma with lytic bone lesions is rare. The diagnosis of this 'hybrid' entity is challenging, and there are no standard therapies. We present six patients from five centers (three in Israel and two in the United States). We describe these patients' unique clinical course and treatment approaches.

Waldenström Macroglobulinemia/Lymphoplasmacytic Lymphoma, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology.

The treatment of Waldenström macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) has evolved to include several new options. The NCCN Guidelines for WM/LPL provide a framework on which to base decisions regarding diagnosis, treatment, assessment of response to treatment, and follow-up of both newly diagnosed and previously treated WM/LPL.

A Rare Case of Subcutaneous Amyloidoma Associated with Localized Lymphoplasmacytic Lymphoma: Diagnostic Challenges and Treatment Considerations.

BACKGROUND AL amyloidomas are solitary, localized, tumor-like deposits of immunoglobulin light-chain-derived amyloid fibrils in the absence of systemic amyloidosis. A rare entity, they have been described in various anatomical sites, typically in spatial association with a sparse lymphoplasmacytic infiltrate, ultimately corresponding to a clonal, malignant, lymphomatous disorder accounting for the amyloidogenic activity. Most frequently, the amyloidoma-associated hematological disorder corresponds to either a solitary plasmacytoma or an extranodal marginal zone lymphoma of MALT. Much rarer is the association with lymphoplasmacytic lymphoma, which by itself is usually a bone marrow-bound disorder with systemic burden. The almost anecdotic combination of an amyloidoma and a localized lymphoplasmacytic lymphoma deserves attention, as it entails a thorough diagnostic workup to exclude systemic involvement and a proportionate therapeutic approach to avoid overtreatment. A review of the literature provides an insight on pathogenesis and prognosis, and can assist both pathologists and clinicians in establishing optimal patient management strategies. CASE REPORT We herein report the incidental finding of a subcutaneous amyloidoma caused by a spatially related, similarly localized lymphoplasmacytic lymphoma diagnosed in a 54-year-old female patient with no other disease localizations and a complete remission following 2 subsequent surgical excisions. CONCLUSIONS Whatever the specific combination of an amyloidoma and the related hematological neoplasm, a multidisciplinary collaboration and a comprehensive clinical-pathological staging are warranted to exclude systemic involvement and identify patients with localized diseases who would benefit from local active treatment and close follow-up.

Experience with pre-diluted plasma exchange therapy for hyperviscosity syndrome.

INTRODUCTION: Plasma exchange therapy (PE) is useful for patients with primary macroglobulinemia and multiple myeloma who present with hyperviscosity syndrome. However, hyperviscous blood may coagulate in the circuit during treatment, and in that case necessitate discontinuation of the treatment. This time, we report that we were able to prevent coagulation in the circuit by adding some ideas during the membrane separation method. METHODS: Physiological saline is injected in front of the plasma separation membrane to pre-dilute the blood, followed by filtration through the plasma separation membrane. RESULTS: As a result of pre-diluting with physiological saline to reduce the viscosity entering the separation membrane, it was possible to process the planned target amount. CONCLUSION: In patients with hyperviscosity syndrome who showed intracircuit coagulation during plasma exchange therapy, devising a predilution method should be considered as one of the ways to continue treatment.

Clinical Implications of Genomic Profile in Waldenström Macroglobulinemia.

With the increasing availability of sequencing techniques and new polymerase chain reaction-based methods, data regarding the genomic profile of Waldenström macroglobulinemia (WM) are being continuously analyzed and reproduced. MYD88 and CXCR4 mutations are highly prevalent in all the stages of WM, including the early IgM monoclonal gammopathy of undetermined significance or a more advanced stage, such as smoldering WM. Thus, there is a need to define genotypes before starting either standard treatment regimens or clinical trials. Here, we review the genomic profile of WM and its clinical implications while focusing on recent advances.

Evaluation and Management of Bing-Neel Syndrome.

Bing-Neel syndrome is a rare manifestation of Waldenström macroglobulinemia (WM), which is caused by infiltration of the malignant lymphoplasmacytic cells in the central nervous system. Patients can present with a diverse range of neurologic symptoms, and differentiation with other comorbidities seen in WM, such as immunoglobulin M-related polyneuropathy, can be challenging. Both the rarity of this disorder and the heterogeneity of the clinical presentation often cause a significant diagnostic delay with the risk of permanent neurologic damage. This review summarizes current knowledge regarding diagnosis, treatment and prognosis of Bing-Neel syndrome.

Report of Consensus Panel 3 from the 11th International workshop on Waldenström's Macroglobulinemia: Recommendations for molecular diagnosis in Waldenström's Macroglobulinemia.

Apart from the MYD88L265P mutation, extensive information exists on the molecular mechanisms in Waldenström's Macroglobulinemia and its potential utility in the diagnosis and treatment tailoring. However, no consensus recommendations are yet available. Consensus Panel 3 (CP3) of the 11th International Workshop on Waldenström's Macroglobulinemia (IWWM-11) was tasked with reviewing the current molecular necessities and best way to access the minimum data required for a correct diagnosis and monitoring. Key recommendations from IWWM-11 CP3 included: (1) molecular studies are warranted for patients in whom therapy is going to be started; such studies should also be done in those whose bone marrow (BM) material is sampled based on clinical issues; (2) molecular studies considered essential for these situations are those that clarify the status of 6q and 17p chromosomes, and MYD88, CXCR4, and TP53 genes. These tests in other situations, and/or other tests, are considered optional; (3) independently of the use of more sensitive and/or specific techniques, the minimum requirements are allele specific polymerase chain reaction for MYD88L265P and CXCR4S338X using whole BM, and fluorescence in situ hybridization for 6q and 17p and sequencing for CXCR4 and TP53 using CD19+ enriched BM; (4) these requirements refer to all patients; therefore, sample should be sent to specialized centers.

Report of Consensus Panel 6 from the 11 th International Workshop on Waldenström's Macroglobulinemia on Management of Waldenström's Macroglobulinemia Related Amyloidosis.

Consensus Panel 6 (CP6) of the 11th International Workshop on Waldenström's Macroglobulinemia (IWWM-11) was tasked with reviewing the state of the art for diagnosis, prognosis, and therapy of AL amyloidosis associated with Waldenström macroglobulinemia (WM). Since significant advances have been made in the management of AL amyloidosis an update for this rare disease associated with WM was necessary. The key recommendations from IWWM-11 CP6 included: (1) The need to improve the diagnostic process by recognizing red flags and using biomarkers and imaging; (2) The essential tests for appropriate workup; (3) The diagnostic flowchart, including mandatory amyloid typing, that improves the differential diagnosis with transthyretin amyloidosis; (4) Criteria for therapy response assessment; (5) State of the art of the treatment including therapy of wild type transthyretin amyloidosis associated with WM.

The Rory Morrison WMUK Registry for Waldenström macroglobulinaemia: The growth of a national registry for a rare disorder.

National registries are used globally to characterise patient demographics, treatment choices and mortality to inform and improve clinical management. Waldenström macroglobulinaemia (WM) is a rare, treatment-responsive B-cell lymphoproliferative disorder with diverse clinical features and variable outcomes. To prospectively chart changes in the management of WM in the UK, the Rory Morrison Registry (RMR) was developed to systematically collect real-world data. Here we describe the development of the RMR, demonstrate its feasibility and describe preliminary observations. The RMR was devised as a collaborative project between patients and clinicians, under the auspices of the UK Charity for WM in 2016. Patients may be registered after the point of diagnosis and those with historic diagnosis were also eligible. Data collection fields were compiled by focus groups of clinicians, patients, industry and commissioning partners. The RMR launched in November 2017 and as of March 2022, there were 22 participating centres and 1305 patients registered. Median follow-up was 6.4 years, five-year overall survival 90.7% (95% confidence interval [CI] 88.4%-92.5%) and 10-year overall survival 79.3% (95% CI 75.7%-82.4%). There has been a clear evolution in treatments including a rapid growth in the use of Bruton's tyrosine kinase inhibitors in relapsed disease since their availability in the UK.

[Waldenström disease: News and perspectives in 2022]. / Maladie de Waldenström : actualités et perspectives en 2022.

Waldenström's disease is a B-cell neoplasm characterized by the accumulation of lymphoplasmacytic cells (LPCs) in the bone marrow, and more rarely in the lymph nodes and the spleen, which produce a monoclonal immunoglobulin M (IgM) protein. The diagnosis requires the identification of LPCs in the bone marrow, using specific markers in flow cytometry. The MYD88L265P mutation is found in 95% of cases and the CXCR4 mutation in 30-40% of cases. These markers must be sought because they have a diagnostic and prognostic role, and they might become predictive in the future. The clinical presentation is very variable, and includes anomalies related to the bone marrow infiltration of the LPCs (such as anemia), but also anomalies of the physico-chemical and/or immunological activity of the overproduced IgM (hyperviscosity, AL amyloidosis, cryoglobulinemia, anti-MAG neuropathies, etc.). Prognostic scores (IPSSWM) now make it possible to understand the prognosis of symptomatic WM requiring appropriate treatment. The therapeutic management depends on many parameters, such as the specific clinical presentation, the speed of evolution and of course the age and comorbidities. Immuno-chemotherapy is often the 1st line treatment (rituximab-cyclophosphamide-dexamethasone (RCD) or bendamustine-rituximab (BR)) but the role of targeted therapies is becoming preponderant. Bruton tyrosine kinase inhibitors (BTKi) are used today in first relapse. Other therapeutic perspectives will certainly allow us tomorrow to better understand this incurable chronic disease, such as new generations of BTKi, BCL2 inhibitors, anti-CXCR4, bi-specific antibodies, and CAR-T cells.

Patient preferences regarding treatment options for Waldenström's macroglobulinemia: A discrete choice experiment.

INTRODUCTION: Treatment options for Waldenström's Macroglobulinemia (WM) have expanded rapidly in the last decades. However, there is no consensus on a preferred treatment. Therefore, patient preferences become increasingly important in making individualized treatment plans. Still, WM patients' priorities and perspectives regarding their treatment options are unknown. We evaluated treatment preferences of WM patients using a discrete choice experiment (DCE). METHODS: A mixed-method approach was utilized for identification and selection of attributes/levels. The DCE questionnaire included five attributes: type of agent (targeted versus chemotherapy); frequency and route of administration; 5-year progression-free survival (PFS); adverse events; and risk of secondary malignancies. An orthogonal design and a mixed logit panel data model were used to construct choice tasks and assess patient preferences, respectively. RESULTS: Three hundred thirty WM patients participated in the project. In total, 214 (65%) complete questionnaires were included for data analysis. The 5-year PFS, followed by risk of secondary malignancies were the most important attributes for making treatment choices. Regarding side effects, patients chose to avoid neuropathy the most compared to nausea/vomiting and extreme fatigue. Patients preferred a fixed-duration treatment with IV/SC administration at the hospital over a continuous daily oral regimen at home. CONCLUSION: These are the first systematic data obtained on WM patient preferences for treatment. The results may help discussions with individual patients about their treatment choices. Also, these data can help design clinical trials in WM and inform health-care decision-making regarding outcomes that are most relevant to patients.

Monoclonal Gammopathy of Undetermined Significance.

Monoclonal gammopathy of undetermined significance (MGUS) is of considerable clinical importance to primary care physicians given its high prevalence in the general population. MGUS has a variable but lifelong risk for progression to hematologic cancer, such as multiple myeloma, Waldenström macroglobulinemia, or light-chain amyloidosis. In addition, MGUS has been associated with several nonmalignant yet symptomatic disorders that require therapy directed toward eliminating the monoclonal gammopathy. Thus, it is important not only to understand the essentials of diagnosing and monitoring patients with MGUS but also to recognize when to refer patients with MGUS to a specialist.

Clinicopathological features and individualized treatment of kidney involvement in B-cell lymphoproliferative disorder.

Background: Due to the various clinical and pathological manifestations of kidney involvement in lymphoproliferative disorder (LPD), the whole spectrum of kidney disease in LPD is still unclear, and data on kidney prognosis is scarce. Methods: We retrospectively reviewed the renal pathology profiles from January 2010 to December 2021, and 28 patients with B-cell LPD combined with intact renal biopsy data were included. Results: There were 20 men and eight women aging 41 to 79 years at the time of renal biopsy (median age 62 years). According to hematological diagnosis, patients were classified into four groups: chronic lymphocytic leukemia (CLL) (group1, n=7), Waldenström macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) (group 2, n=8; WM, n=6; LPL, n=2), Other non-Hodgkin's lymphomas (NHL) (group3, n=7; diffuse large B-cell lymphoma (DLBCL), n=2; mucosa-associated lymphoid tissue (MALT) lymphoma, n=4; Low grade B-cell lymphoma, n=1), and monoclonal gammopathy of undetermined significance/monoclonal gammopathy of renal significance (MGUS/MGRS) (group 4, n=6). Median serum creatinine (Scr) level was 129 (range,59-956) umol/L. Eight patients (29%) were presented with acute kidney injury (AKI), and five patients (18%) required hemodialysis upon admission. Twenty-three patients (82%) presented with proteinuria (median protein excretion, 2.14 g/d), 11(39%) of whom had the nephrotic syndrome. Interstitial malignant infiltration was the most frequent renal lesion (n=6). Eight patients underwent immunohistochemistry of renal tissues, of which three patients (CLL, n=1; LPL, n=1; WM, n=1) had confirmed lymphoma infiltrates, and the infiltrating cells in the remaining five patients (CLL, n=1; MALT lymphoma, n=2; MGUS, n=2) were considered unrelated to lymphoma. The most common glomerular diseases were renal amyloidosis (n=4) and membranous nephropathy (n=4). Only 20 patients were treated, 13 of whom were treated with rituximab separately or in combination. The median follow-up time was 11 months. Of these, six had achieved hematological response, complete response in five cases. Eight had achieved renal response. At the end-of-study visit, four patients died and two progressed to end stage kidney disease (ESKD). Conclusion: In conclusion, the clinicopathological spectrum of renal involvement in BLPD is diverse. Renal biopsy and immunohistochemistry are required for early diagnosis and prognostic assessment.