[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.

When Waldenström macroglobulinemia hits the kidney: Description of a case series and management of a "rare in rare" scenario.

BACKGROUND: Renal injury related to Waldenström macroglobulinemia (WM) occurs in approximately 3% of patients. Kidney biopsy is crucial to discriminate between distinct histopathological entities such as glomerular (amyloidotic and non-amyloidotic), tubulo-interstitial and non-paraprotein mediated renal damage. In this context, disease characterization, management, relationship between renal, and hematological response have been poorly explored. We collected clinical, genetic and laboratory data of seven cases of biopsy-proven renal involvement by WM managed at our academic center and focused on three cases we judged paradigmatic discussing their histopathological patterns, clinical features, and therapeutic options. CASE: In this illustrative case series, we confirm that serum creatinine levels and 24 h proteinuria are parameters that when altered should prompt the clinical suspicion of WM-related renal involvement, even if at present there are not precise cut-off levels recommending the execution of a renal biopsy. In our series AL Amyloidosis (n = 3/7) and tubulo-interstitial infiltration by lymphoma cells (n = 3/7) were the two more represented entities. BTKi did not seem to improve renal function (Case 1), while bortezomib-based regimens demonstrated a beneficial activity on the hematological and organ response, even when used as second-line therapy after chemoimmunotherapy (Case 3) and also with coexistence of anti-MAG neuropathy (Case 2). In case of poor response to bortezomib, standard chemoimmunotherapy (CIT), such as rituximab-bendamustine, represents an effective option (Case 1, 6, and 7). In our series, CIT generates durable responses more frequently in cases with amyloidogenic renal damage (Case 1, 5, and 7). CONCLUSION: In this illustrative case series, we confirm that serum creatinine levels and 24 h proteinuria are parameters that when altered should prompt the clinical suspicion of WM-related renal involvement, even if at present there are not precise cut-off levels recommending the execution of a renal biopsy. Studies with higher numerosity are needed to better clarify the pathological and clinical features of renal involvement during WM and to determine the potential benefit of different therapeutic regimens according to the histopathological subtypes.

How to manage waldenström's macroglobulinemia in 2024.

Clinical management of Waldenström's Macroglobulinemia has seen major progress in the recent years, triggered by our improved understanding of the biology of the disease and the development of new therapies. Based on this there are multiple treatment options available for patients with WM ranging from classical immunochemotherapy to targeted approaches blocking key enzymes involved in lymphoma growth. This review summarizes our current knowledge about diagnostics and treatment of this rare but recurrent lymphoma subtype, which often presents a major clinical challenge in daily clinical life.

A Rare Case of Non-IgM Lymphoplasmacytic Lymphoma with Unusual Lack of Immunoglobulin Light Chain Production.

BACKGROUND Non-IgM lymphoplasmacytic lymphoma (LPL) is a rare subtype of LPL, constituting less than 5% of the cases, and is often associated with IgG, IgA, or light chain paraproteins and is rarely a non-secretor. Non-IgM LPL remains poorly studied, and the differential diagnosis from other small B-cell lymphomas with plasmacytic differentiation and plasma cell neoplasm is challenging. CASE REPORT A 67-year-old woman presented with weight loss, persistent anemia, and borderline leukopenia. Serum protein electrophoresis and immunofixation demonstrated a faint IgG and kappa band against a dense polyclonal background. Bone marrow biopsy revealed hypercellular marrow with involvement by abnormal B cells with undetectable surface and cytoplasmic immunoglobulin light chains. Interestingly, these B cells showed no expression of light chains or production of IgG and IgM; however, they showed production of intracytoplasmic IgA. The concomitant neoplastic plasma cells also displayed no definitive light chain expression. Both IgH and IgK gene rearrangements were positive for clonal process. Molecular studies showed positive MYD88 L265P mutation and CXCR4 mutation (c.1013C>G). The overall findings confirmed marrow involvement by non-IgM LPL. The patient received 6 cycles of rituximab and bendamustine treatment, and no residual marrow involvement was found on the follow-up bone marrow biopsy. CONCLUSIONS We report a non-IgM LPL case featuring no light chain production and no heavy chain secretion, which we believe is the first reported case of this kind in the literature.

A 74-Year-Old Man With Waldenström Macroglobulinemia and Progressive Dyspnea.

CASE PRESENTATION: A 74-year-old man presented to our department with progressive dyspnea on exertion over the last year. The patient did not report any other symptoms. He had previously smoked with a 60 pack-year history. He worked in an office and did not report any environmental, occupational, or domestic exposures. His history included asymptomatic Waldenström's macroglobulinemia that was diagnosed 18 months before respiratory symptoms. He was not receiving any treatment and was monitored regularly by the hematology department.

Biomarker analysis of the ASPEN study comparing zanubrutinib with ibrutinib for patients with Waldenström macroglobulinemia.

ABSTRACT: The phase 3 ASPEN trial (NCT03053440) compared Bruton tyrosine kinase inhibitors (BTKis), zanubrutinib and ibrutinib, in patients with Waldenström macroglobulinemia (WM). Post-hoc biomarker analysis was performed using next-generation sequencing on pretreatment bone marrow samples from 98 patients treated with zanubrutinib and 92 patients treated with ibrutinib with mutated (MUT) MYD88 and 20 patients with wild-type (WT) MYD88 treated with zanubrutinib. Of 329 mutations in 52 genes, mutations in CXCR4 (25.7%), TP53 (24.8%), ARID1A (15.7%), and TERT (9.0%) were most common. TP53MUT, ARID1AMUT, and TERTMUT were associated with higher rates of CXCR4MUT (P < .05). Patients with CXCR4MUT (frameshift or nonsense [NS] mutations) had lower very good partial response (VGPR) and complete response rates (CR; 17.0% vs 37.2%, P = .020) and longer time to response (11.1 vs 8.4 months) than patients with CXCR4WT treated with BTKis. CXCR4NS was associated with inferior progression-free survival (PFS; hazard ratio [HR], 3.39; P = .017) in patients treated with ibrutinib but not in those treated with zanubrutinib (HR, 0.67; P = .598), but VGPR + CR rates were similar between treatment groups (14.3% vs 15.4%). Compared with ibrutinib, patients with CXCR4NS treated with zanubrutinib had a favorable major response rate (MRR; 85.7% vs 53.8%; P = .09) and PFS (HR, 0.30; P = .093). In patients with TP53MUT, significantly lower MRRs were observed for patients treated with ibrutinib (63.6% vs 85.7%; P = .04) but not for those treated with zanubrutinib (80.8% vs 81.9%; P = .978). In TP53MUT, compared with ibrutinib, patients treated with zanubrutinib had higher VGPR and CR (34.6% vs 13.6%; P < .05), numerically improved MRR (80.8% vs 63.6%; P = .11), and longer PFS (not reached vs 44.2 months; HR, 0.66; P = .37). Collectively, patients with WM with CXCR4MUT or TP53MUT had worse prognosis compared with patients with WT alleles, and zanubrutinib led to better clinical outcomes.

Long-term outcomes by bone marrow B-cell depletion from the R2W trial of bortezomib with cyclophosphamide and rituximab in Waldenstrom macroglobulinaemia.

There remains a lack of consensus as to the most appropriate primary therapy in Waldenstrom macroglobulinemia (WM). We evaluated a novel bortezomib-based combination and developed a sensitive WM-specific flow cytometry assay (limit of detection 0.004% of leucocytes) to assess bone marrow (BM) response. Sixty treatment-naïve WM patients were enroled into this phase II trial and randomised (2:1) to receive cyclophosphamide and rituximab with either bortezomib (BRC) or fludarabine (FCR). The primary objective was to assess the overall response rate (ORR) in eligible patients receiving BRC (N = 41). An ORR of 97.6% (95%CI:87.1-99.9) was observed; 27 (65.9%) patients remain alive without progression after 62.6 months median follow-up, with 2-, 3- and 5-year progression-free survival (PFS) rates of 92.7% (95%CI:79.0-97.6), 80.5% (95%CI:64.8-89.7) and 65.5% (95%CI:48.8-77.9). Persistent WM B-cells were demonstrable in 19/38 patients at the end of treatment (median 0.24%, range 0.02-11.2%). PFS was markedly longer in patients with BM B-cell depletion (<0.004%) compared to those who had persistent BM B-cells detectable at end of treatment (HR = 0.06, 95%CI:0.01-0.47, p < 0.001), and remained independently associated after adjusting for baseline risk stratification or investigator-assessed response. BRC is a tolerable, highly efficacious regimen for treatment-naïve WM patients. BM B-cell depletion is independently associated with patient outcomes.

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.

How I use genomics and BTK inhibitors in the treatment of Waldenström macroglobulinemia.

ABSTRACT: Mutations in MYD88 (95%-97%) and CXCR4 (30%-40%) are common in Waldenström macroglobulinemia (WM). TP53 is altered in 20% to 30% of patients with WM, particularly those previously treated. Mutated MYD88 activates hematopoietic cell kinase that drives Bruton tyrosine kinase (BTK) prosurvival signaling. Both nonsense and frameshift CXCR4 mutations occur in WM. Nonsense variants show greater resistance to BTK inhibitors. Covalent BTK inhibitors (cBTKi) produce major responses in 70% to 80% of patients with WM. MYD88 and CXCR4 mutation status can affect time to major response, depth of response, and/or progression-free survival (PFS) in patients with WM treated with cBTKi. The cBTKi zanubrutinib shows greater response activity and/or improved PFS in patients with WM with wild-type MYD88, mutated CXCR4, or altered TP53. Risks for adverse events, including atrial fibrillation, bleeding diathesis, and neutropenia can differ based on which BTKi is used in WM. Intolerance is also common with cBTKi, and dose reduction or switchover to another cBTKi can be considered. For patients with acquired resistance to cBTKis, newer options include pirtobrutinib or venetoclax. Combinations of BTKis with chemoimmunotherapy, CXCR4, and BCL2 antagonists are discussed. Algorithms for positioning BTKis in treatment naïve or previously treated patients with WM, based on genomics, disease characteristics, and comorbidities, are presented.

Waldenström Disease in a Renal Transplant: a Case Report and Review of the Literature.

BACKGROUND: We report through this case, the exceptional occurrence of Waldenström's macroglobulinemia in a renal transplant. METHODS: A 65-year-old diabetic man, who had a kidney transplant in 2008, presented to the hospital in 2020 for ketoacid decompensation. The blood ionogram showed hyperproteinemia at 102 g/L. Electrophoresis and immunofixation of serum proteins revealed a monoclonal immunoglobulin of IgM Kappa isotype numbered at 46 g/L. Confirmation of Waldenström's disease was made by myelogram and immunophenotyping of tumor cells. RESULTS: The diagnosis adopted for our case is Waldenström's disease which occurred 12 years after the kidney transplantation. CONCLUSIONS: Post-transplant lymphoproliferative syndromes are secondary to immunosuppressive therapy, the main concern in this case is the involvement of the graft with the risk of losing its function, hence the interest of monitoring and identifying any hyperproteinemia.

Diagnosis of Waldenstrom Macroglobulinemia Using Postoperative Histopathology During Routine Total Knee Arthroplasty: A Case Report.

CASE: We present a 63-year-old patient diagnosed with Waldenstrom macroglobulinemia (WM) through histopathology of bone tissue after total knee arthroplasty for routine osteoarthritis. The patient, surgical team, and the pathologist were unaware of this diagnosis before the surgery. CONCLUSION: The cost-effectiveness of routine histopathologic examination of bone cuts and synovial samples after total joint arthroplasty continues to be a source of debate. Our case highlights an example of the utility of histopathology because it led to the early detection of WM, resulting in prompt treatment to improve quality of life.

Challenging diagnosis of IgM multiple myeloma.

IgM monoclonal gammopathies such as IgM myeloma and Waldenström macroglobulinaemia are distinct haematological conditions; however, differentiating between these entities can often present as a challenge.In this review, we explore the challenging diagnosis and treatment of IgM myeloma in a patient presenting with unexplained macrocytic anaemia, elevated serum protein and IgM levels in the absence of t(11;14) and lytic bone lesions that are classically associated with the diagnosis of IgM myeloma. The diagnosis was established based on 40% monoclonal plasma cell population on a bone marrow biopsy, gain of 1q21 on fluorescence in situ hybridisation, cyclin D1 positivity and absence of MYD88 mutation.

Bing-Neel syndrome: a rare neurological complication of Waldenström macroglobulinaemia.

Bing-Neel syndrome (BNS) is a very rare manifestation of Waldenström macroglobulinaemia (WM), in which lymphoplasmacytic cells invade the central nervous system. The clinical presentation includes symptoms of headaches, visual floaters, neuropathy, seizures and gait abnormalities. Here, we describe an elderly woman, who presented with complaints of visual floaters, progressive neuropathy and cognitive changes. Workup including a bone marrow biopsy confirmed the diagnosis of WM. Shortly afterwards, the patient experienced a seizure leading to hospitalisation, which revealed a right frontal lobe lesion on brain MRI. A biopsy of the lesion showed a small B cell lymphoma positive for an MYD88 mutation, confirming BNS. The patient was initially treated with ibrutinib, before transitioning to zanubrutinib. However, she developed disease progression necessitating radiotherapy with lenalidomide and rituximab maintenance therapy, which achieved remission. This case sheds light on the diagnosis and management of a very rare complication of a rare disease.

Aggressive Lymphoplasmacytic Neoplasm With an Unusual In-frame Deletion of MYD88 Associated With TRAF3 and TP53 Mutations and Complex Karyotype.

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.

Waldenström Macroglobulinemia: Targeted Agents Taking Center Stage.

With the worldwide approval of the oral covalent Bruton tyrosine kinase (BTK) inhibitors ibrutinib and zanubrutinib for treating patients with Waldenström macroglobulinemia (WM), targeted agents have certainly taken center stage in the therapeutic landscape of WM. This review discusses the biological and clinical data supporting current and up-and-coming targeted agents in WM. Bruton tyrosine kinase inhibitors induce fast, deep, and durable responses in patients with WM, comparable to chemoimmunotherapy; however, there is a glaring absence of comparative studies between these regimens. The high response and progression-free survival rate and the ease of administration of BTK inhibitors must be balanced against their specific adverse-event profile with unique toxicity (e.g., bleeding and cardiac arrhythmia) and the indefinite duration of the therapy. Novel targeted agents of interest include BCL2 antagonists (e.g., venetoclax and sonrotoclax) and non-covalent BTK inhibitors (e.g., pirtobrutinib and nemtabrutinib), among others. The therapeutic landscape of patients with WM will benefit from the robust participation of patients in clinical trials.