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.

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.

Clinical and clonal characteristics of monoclonal immunoglobulin M-associated type I cryoglobulinaemia.

Monoclonal immunoglobulin M-associated type I cryoglobulinaemia is poorly characterised. We screened 534 patients with monoclonal IgM disorders over a 9-year period and identified 134 patients with IgM type I cryoglobulins. Of these, 76% had Waldenström macroglobulinaemia (WM), 5% had other non-Hodgkin lymphoma (NHL) and 19% had IgM monoclonal gammopathy of undetermined significance (MGUS). Clinically relevant IgM-associated disorders (including cold agglutinin disease [CAD], anti-MAG antibodies, amyloidosis and Schnitzler syndrome) coexisted in 31%, more frequently in MGUS versus WM/NHL (72% vs. 22%/29%, p < 0.001). The majority of those with cryoglobulins and coexistent CAD/syndrome had the molecular characteristics of a CAD clone (wild-type MYD88 in 80%). A half of all patients had active manifestations at cryoglobulin detection: vasomotor (22%), cutaneous (16%), peripheral neuropathy (22%) and hyperviscosity (9%). 16/134 required treatment for cryoglobulin-related symptoms alone at a median of 38 days (range: 6-239) from cryoglobulin detection. At a median follow-up of 3 years (range: 0-10), 3-year cryoglobulinaemia-treatment-free survival was 77% (95% CI: 68%-84%). Age was the only predictor of overall survival. Predictors of cryoglobulinaemia-related treatment/death were hyperviscosity (HR: 73.01; 95% CI: 15.62-341.36, p < 0.0001) and cutaneous involvement (HR: 2.95; 95% CI: 1.13-7.71, p = 0.028). Type I IgM cryoglobulinaemia is more prevalent than previously described in IgM gammopathy and should be actively sought.

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.

Advances in Treatment of Waldenström Macroglobulinemia.

PURPOSE OF REVIEW: The discovery of recurring somatic mutations, in particular MYD88 and CXCR4 mutations, in Waldenström macroglobulinemia (WM), a rare B-cell lymphoproliferative disorder, led in the last decade to the development of several therapeutic agents with high efficacy. This review aims to provide an overview of available treatments in WM and novel agents, focusing on studies published over recent years. RECENT FINDINGS: There is no international consensus on the best first-line option in treatment-naïve patients. Randomized clinical trials are rare in WM and there has been no prospective comparison of chemoimmunotherapy and BTK inhibitors in the frontline setting. Chemoimmunotherapy and BTK inhibitors, the two feasible and most widely used treatments in first-line treatment, represent very different options in terms of duration of therapy, route of administration, cost, and adverse effect. In addition to tumor genotype and patient comorbidities, choice of therapy in WM should take into account these parameters. Results of ongoing and future clinical trials evaluating fixed-duration combinations with BTK inhibitors and novel agents are awaited.

18 F-FDG PET/CT Findings in Waldenström Macroglobulinemia With Mesentery Involvement.

ABSTRACT: A 74-year-old man presented to the hospital complaining of weight loss, increasing fatigue, and blurred vision. The abdominal ultrasonography initially revealed a massive lesion in the mesentery, which was later confirmed by a contrast-enhanced CT scan. The 18 F-FDG PET/CT scan showed a single, solitary hypermetabolic mass. The patient was finally diagnosed with Waldenström macroglobulinemia with mesentery involvement by the histopathological examination.

A Case of Bing-Neel Syndrome Presenting Like Giant Cell Arteritis.

ABSTRACT: A 55-year-old woman presented with new-onset headache, scalp tenderness, shoulder arthralgias, night sweats, and loss of appetite. She was diagnosed with giant cell arteritis by her primary care physician and commenced on oral corticosteroids. However, her headache, scalp tenderness, and night sweats persisted. She then developed right Horner syndrome and trigeminal hypoesthesia. Extensive blood work-up revealed mildly elevated inflammatory markers and a paraproteinemia. Subsequent bone marrow biopsy showed lymphoplasmacytic lymphoma, with 10% of hemopoiesis, and staging led to the diagnosis of Waldenstrom macroglobulinemia without nodal or central nervous system (CNS) lesions. Immunohistochemical staining of a temporal artery biopsy showed perivascular lymphoplasmacytic cells and paraprotein deposits. She was diagnosed with CNS involvement of her macroglobulinemia-Bing-Neel syndrome (BNS). Identification of rare CNS involvement of lymphoma is challenging when a patient is already on steroid immunosuppression. In the absence of clear diagnostic criteria, the rare and heterogenous BNS remains a clinical diagnosis.

Frontline Management of Waldenström Macroglobulinemia with Chemoimmunotherapy.

Despite the introduction of effective novel agents, chemoimmunotherapy (CIT), with its widespread use, retains relevance and is one of the 2 vastly disparate strategies to treat Waldenström macroglobulinemia (WM), the alternative being the Bruton tyrosine kinase inhibitor (BTKi)-based approach. Considerable evidence over the past decades supports the integration of the monoclonal anti-CD20 antibody, rituximab, to the CIT backbone in WM, a CD20+ malignancy. Besides substantial efficacy, the finite duration of the treatment, coupled with lower rates of cumulative and long-term, clinically significant adverse effects and greater affordability, make CIT appealing, notwithstanding the lack of quality-of-life data with such an approach in WM. A phase 3 randomized controlled trial reported substantially higher efficacy and a more favorable safety profile of the bendamustine-rituximab (BR) doublet compared with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) among patients with WM. Subsequent studies reaffirmed its high efficacy and tolerability, making BR the mainstay of managing treatment-naïve patients with WM. High-quality evidence supporting the use of BR over Dexamethasone, Rituximab, and Cyclophosphamide (DRC), another commonly used regimen, is lacking, as is its comparison with the continuous BTKi-based approach. However, DRC appeared less potent than BR in cross-trial comparisons and retrospective series involving treatment-naïve patients with WM. Additionally, a recent retrospective, international study demonstrated comparable outcomes with fixed-duration BR and continuous ibrutinib monotherapy among previously untreated, age-matched patients exhibiting MYD88L265P mutation. However, unlike ibrutinib, BR appears effective irrespective of the MYD88 mutation status. CIT, preferably BR, is well suited to serve as the control arm (comparator) regimen against which novel targeted agents may be evaluated as frontline therapies for WM in high-quality trials. Purine analog-based CIT has been extensively evaluated in WM, although its use has waned, even in the multiply relapsed patient population, as effective and safer alternatives emerge.

Evaluation and Management of Disease Transformation in Waldenström Macroglobulinemia.

Histologic transformation (HT) to diffuse large B-cell lymphoma occurs rarely in Waldenström macroglobulinemia, with higher incidence in MYD88 wild-type patients. HT is suspected clinically when rapidly enlarging lymph nodes, elevated lactate dehydrogenase levels, or extranodal disease occur. Histologic assessment is required for diagnosis. HT carries a worse prognosis compared with nontransformed Waldenström macroglobulinemia. A validated prognostic score based on three adverse risk factors stratifies three risk groups. The most common frontline treatment is chemoimmunotherapy, such as R-CHOP. Central nervous system prophylaxis should be considered if feasible and consolidation with autologous transplant should be discussed in fit patients responding to chemoimmunotherapy.

The epidemiology of Waldenström macroglobulinemia.

Waldenström macroglobulinemia (WM) is a rare subtype of non-Hodgkin lymphoma characterized by the presence of lymphoplasmacytic lymphoma (LPL) in the bone marrow accompanied by a monoclonal immunoglobulin type M (IgM) in the serum. WM was first described only 80 years ago and became reportable in the US as a malignancy in 1988. Very little systematic research was conducted prior to 2000 to characterize incidence, clinical characteristics, risk factors or diagnostic and prognostic criteria, and there were essentially no WM-specific clinical interventional trials. Since the inaugural meeting of the International Workshop in Waldenström's Macroglobulinemia (IWWM) in 2000, WM has become the focus of a steadily increasing and productive body of research, engaging a growing number of investigators throughout the world. This introductory overview provides summary of the current understanding of the epidemiology of WM/LPL as a backdrop for a series of consensus panel recommendations arising from research presented at the 11th IWWM.

Bing Neel Syndrome: A Rare Contributing Factor of Psychosis and Suicidality.

ABSTRACT: Suicide rapidly increased in the United States by 30% from 2000 to 2020, accounting for more than 800,000 deaths ( Neurosci Res Program Bull . 1972; 10: 384-8). Studies have shown that there are a multitude of underlying issues, including mental illness, that elevate an individual's risk of dying by suicide ( CDC WONDER: Underlying cause of death, 1999-2019 . Atlanta, GA: US Department of Health and Human Services, CDC; 2020). Presented here is a case of Bing Neel syndrome (BNS) found in a 69-year-old man who died by suicide by jumping off a 135' bridge. His medical history was significant for traumatic brain injury, Waldenstrom macroglobulinemia (WM), major depressive disorder, suicidal ideation, and anxiety. Bing Neel syndrome is a rare central nervous system complication of WM. His wife reported an abrupt mental deterioration starting 5 years before his death, characterized by paranoia, depression, and insomnia. He had been a high-functioning university professor. His decline culminated with the loss of independence in his activities of daily living. At autopsy, it was found that he experienced blunt force injuries related to the fall, causing his death. A neuropathologic examination revealed a brisk and fulminant clonal CD20 + /immunoglobulin M+ lymphocytic infiltrate, involving all sampled regions of his brain, consistent with WM. This workup was critical to obtaining an accurate pathologic diagnosis of BNS and understanding his full clinical status before death. Although BNS was not the proximate cause of death, this diagnosis aided the death investigation as a causal factor in his suicidality and was vital to providing his family closure.

Waldenström Macroglobulinemia and Non-IgM-Type Lymphoplasmacytic Lymphoma Are Genetically Similar.

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.

Cutaneous Paraneoplastic Syndrome Affecting the Hand in a Case of Underlying Waldenström Macroglobulinemia.

Paraneoplastic syndromes represent the body's immune response to an underlying malignancy. The autoimmune response to cancer can manifest itself in multiple ways, including swelling, thickening, and changes in the hand. We report the case of a 65-year-old man who presented with hand swelling that was initially attributed to a work-related finger laceration. The patient developed edema and stiffness in the hand, which was subsequently diagnosed as Waldenström macroglobulinemia. Hand surgeons should be aware that atypical hand and wrist symptoms should raise the suspicion for the potential of a paraneoplastic syndrome and an underlying malignancy.

Targeting the immune microenvironment in Waldenström macroglobulinemia via halting the CD40/CD40-ligand axis.

Recent investigations have improved our understanding of the molecular aberrations supporting Waldenström macroglobulinemia (WM) biology; however, whether the immune microenvironment contributes to WM pathogenesis remains unanswered. First, we showed how a transgenic murine model of human-like lymphoplasmacytic lymphoma/WM exhibits an increased number of regulatory T cells (Tregs) relative to control mice. These findings were translated into the WM clinical setting, in which the transcriptomic profiling of Tregs derived from patients with WM unveiled a peculiar WM-devoted messenger RNA signature, with significant enrichment for genes related to nuclear factor κB-mediated tumor necrosis factor α signaling, MAPK, and PI3K/AKT, which was paralleled by a different Treg functional phenotype. We demonstrated significantly higher Treg induction, expansion, and proliferation triggered by WM cells, compared with their normal cellular counterpart; with a more profound effect within the context of CXCR4C1013G-mutated WM cells. By investigating the B-cell-to-T-cell cross talk at single-cell level, we identified the CD40/CD40-ligand as a potentially relevant axis that supports WM cell-Tregs interaction. Our findings demonstrate the existence of a Treg-mediated immunosuppressive phenotype in WM, which can be therapeutically reversed by blocking the CD40L/CD40 axis to inhibit WM cell growth.

Pharmacokinetics-Pharmacodynamics Modeling and Evaluation of Tumor Response to Bortezomib Proteasome Inhibitor in Waldenstrom Macroglobulinemia.

BACKGROUND: Waldenstrom's macroglobulinemia (WM), also known as lymphoplasmacytic lymphoma, is a type of non-Hodgkin's lymphoma in which the malignant cells produce many macroglobulin proteins. It originates from B cells and develops in the bone marrow, where Wm cells combine to produce distinct types of blood cells, resulting in reduced volumes of red blood cells, white blood cells, and platelets, making it harder for the body to fight diseases. Chemoimmunotherapy is being used for the clinical management of WM, but new targeted agents, the BTK inhibitor ibrutinib and the proteasome inhibitor bortezomib, have shown significant improvements in patients with relapsed/refractory WM. However, given its effectiveness, drug resistance and relapse are normal, and there is little research on the pathways responsible for drug effects on the tumor. METHODS: In this study, Pharmacokinetics-pharmacodynamic simulations were done to assess the effect of the proteasome inhibitor bortezomib on the tumor. For this purpose, the Pharmacokinetics-pharmacodynamic model was developed. The model parameters were determined and calculated using the Ordinary Differential Equation solver toolbox and the least-squares function. Pharmacokinetic profiles and pharmacodynamic analysis were performed to determine the change in tumor weight associated with the use of proteasome inhibitors. RESULTS: Bortezomib and ixazomib have been found to reduce tumor weight briefly, but once the dose is reduced, the tumor begins to grow again. Carfilzomib and oprozomib had better results, and rituximab reduced tumor weight more effectively. CONCLUSION: Once validated, it is proposed that a combination of selected drugs can be evaluated in the laboratory to treat WM.