Optimizing BTK Inhibition in Waldenström Macroglobulinemia.

Bruton tyrosine kinase (BTK) inhibitors have become a standard of care in the treatment of patients with Waldenström macroglobulinemia (WM) and are the only medications approved by the FDA to treat these patients. As more patients with WM are treated with BTK inhibitors in the United States and worldwide, it is essential to optimize this therapy by selecting the patients who are more likely to benefit from it, and by managing the unique adverse effects associated with these agents. Herein, we propose a genomic-driven approach to selecting patients with WM who are more likely to experience fast, deep, and durable responses to BTK inhibitors, and provide practical strategies for managing adverse effects, including BTK inhibitor dose reductions, switching to other BTK inhibitors, and abandoning BTK inhibitor therapy. Ongoing clinical trials are evaluating covalent and noncovalent BTK inhibitors alone and in combination, as well as BTK degraders, with exciting results, making the horizon for BTK-targeting therapies in WM bright and hopeful.

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.

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.

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.

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.

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.

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.

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.

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.

In-depth molecular analysis of lymphomas with lymphoplasmacytic differentiation may provide more precise diagnosis and rational treatment allocation.

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.

A rare case of secondary cutaneous lymphoplasmacytic lymphoma clinically presenting as acquired cutis laxa.

Lymphoplasmacytic lymphoma (LPL) is a rare variant of non-Hodgkin lymphoma, accounting for <1% of cases. Skin involvement in LPL is quite rare-accounting for approximately 5% of extramedullary disease-and includes a variety of clinical morphologies, such as erythematous-to-violaceous plaques, violaceous nodules or tumors, and ulceration at various anatomical sites. Herein, we report the case of a 45-year-old Korean woman who presented with generalized erythematous indurated plaques and pendulous skin growths, which were asymptomatic, with marked diffuse infiltration of lymphocytes and plasma cells in the dermis. Immunohistochemical studies revealed that the lymphoid cells expressed CD3, CD79a, and cytoplasmic IgG, but lacked CD10 and IgM. Moreover, kappa light chain restriction and monoclonal immunoglobulin heavy chain gene rearrangement were observed. Upon further workup, lymphoma involvement was reported in multiple lymph nodes, including those in the cervical and axillary regions. This case shows a unique form of cutaneous LPL clinically presenting as acquired cutis laxa, emphasizing the dermatologists' need to be vigilant for variant forms of this disease.

Frontline therapy with bendamustine rituximab (BR) and rituximab cyclophosphamide vincristine prednisone (RCVP) confers similar long-term outcomes in patients with treatment naïve Waldenström macroglobulinemia in a real-world setting: a population-based analysis.

We report on outcomes of 111 patients with treatment naïve Waldenström macroglobulinemia (TN WM) treated with frontline bendamustine-rituximab (BR) (n = 57) or rituximab-cyclophosphamide-vincristine-prednisone (RCVP) (n = 54). Median follow-up was 60.7 months (range 1.9-231.6). Median progression-free survival (PFS) was 60.5 months (95% CI 47.6-73.4) for BR and 79.0 months (95% CI 31.3-126.8) for RCVP (p = .96). Median overall survival (OS) was not reached for BR and 153.4 months (95% CI 114.5-192.4) for RCVP (p = .37). While overall and major response rates did not differ between treatment groups, BR had numerically higher rate of very good partial response or better response (51% vs. 37%, p = .30) and complete response (26% vs. 13%, p = .13). RCVP confers comparable outcomes to BR in a real-world population of TN WM patients and remains an effective regimen, particularly when tolerance or frailty is an issue, or in resource-limited settings.

Waldenström's Macroglobulinemia and Cryoglobulinemic Glomerulonephritis: An Unusual Case of Monoclonal Gammopathy of Renal Significance.

Cryoglobulins are immunoglobulins that precipitate at temperatures below 37 °C and dissolve upon reheating. They can induce small-vessel vasculitis with renal involvement. Cryoglobulinemic glomerulonephritis is a rare manifestation that occurs in patients with monoclonal gammopathy, specifically Waldenström's macroglobulinemia. We present the case of a 52-year-old patient with a history of cutaneous vasculitis and hypothyroidism, who presented with generalized edema, moderate anemia, hypercholesterolemia, nephrotic range proteinuria of 12.69 g/day, microhematuria, arterial hypertension, and hypocomplementemia via the classical pathway, without acute kidney injury and with negative serological studies and positive cryoglobulins in the second determination. Serum and urine protein electrophoresis and immunofixation studies showed a monoclonal band of IgM and kappa light chain. Renal biopsy was consistent with cryoglobulinemic glomerulonephritis. In the context of dysproteinemia and cryoglobulinemic glomerulonephritis, bone-marrow aspiration and biopsy were performed, leading to the diagnosis of Waldenström's macroglobulinemia. Monoclonal gammopathies have been described in association with type I cryoglobulinemias. This described association is uncommon, which is why we present this case, along with a review of the literature.

Clonally related transformation from Waldenström macroglobulinemia to diffuse large B-cell lymphoma with central nervous system involvement at diagnosis: a case report and literature review.

Histological transformation to diffuse large B-cell lymphoma (DLBCL) rarely occurs in patients with Waldenström macroglobulinemia (WM). The median time from WM diagnosis to DLBCL is 4-5 years. Extranodal involvement is common in transformed WM. However, central nervous system (CNS) involvement is relatively uncommon. Here, we report a case of a simultaneous diagnosis of WM and clonally related DLBCL, with the involvement of CNS demonstrated by dual enhancement in MRI. Nevertheless, it is unclear if CNS infiltration is caused by DLBCL or WM for the inaccessibility of brain biopsy. Intensified chemotherapy and Bruton tyrosine kinase inhibitor were administrated, and a good response was achieved.Please check the edit made in the article title.we have checked it.

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.