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Summary: Bing–Neel syndrome (BNS) is an uncommon presentation of Waldenström macroglobulinaemia (WM), seen during the course of the disease in about 1% of patients. BNS occurs when WM cells gain access to the central nervous system (CNS) causing neurological deficits. The diagnosis of BNS is suggested by the presence of radiological abnormalities, such as leptomeningeal enhancement on magnetic resonance imaging and confirmed by the presence of clonal lymphoplasmacytic cells and MYD88 L265P in the cerebrospinal fluid. The treatment of BNS requires agents with good penetration into the CNS, such as fludarabine, methotrexate and cytarabine. The novel Bruton Tyrosine Kinase inhibitor ibrutinib has shown CNS‐penetrating properties, and recent data suggest a therapeutic role in BNS. In this review, we will discuss the clinical and pathological features, diagnostic criteria, treatment options and outcomes of patients with BNS. [ABSTRACT FROM AUTHOR]

Summary: MYD88 mutations are present in 95% of Waldenstrom Macroglobulinaemia (WM) patients, and support diagnostic discrimination from other IgM‐secreting B‐cell malignancies. Diagnostic discrimination can be difficult among suspected wild‐type MYD88 (MYD88WT) WM cases. We systematically reviewed the clinical, pathological and laboratory studies for 64 suspected MYD88WT WM patients. World Health Organization and WM consensus guidelines were used to establish clinicopathological diagnosis. Up to 30% of suspected MYD88WT WM cases had an alternative clinicopathological diagnosis, including IgM multiple myeloma. The estimated 10‐year survival was 73% (95% confidence interval [CI] 52–86%) for MYD88WTversus 90% (95% CI 82–95%) for mutated (MYD88MUT) WM patients (Log‐rank P < 0·001). Multivariate analysis only showed MYD88 mutation status (P < 0·001) as a significant determinant for overall survival. Diffuse large B‐cell lymphoma (DLBCL) was diagnosed in 7 (15·2%) and 2 (0·76%) of MYD88WT and MYD88MUT patients, respectively (Odds ratio 23·3; 95% CI 4·2–233·8; P < 0·001). Overall survival was shorter among MYD88WT patients with an associated DLBCL event (Log‐rank P = 0·08). The findings show that among suspected MYD88WT WM cases, an alternative clinicopathological diagnosis is common and can impact clinical care. WM patients with MYD88WT disease have a high incidence of associated DLBCL events and significantly shorter survival versus those with MYD88MUT disease. [ABSTRACT FROM AUTHOR]

Summary [ABSTRACT FROM AUTHOR]

Summary: Waldenström macroglobulinaemia (WM) is characterized by the presence of a MYD88L265P mutation. This mutation promotes growth and survival of malignant cells through Bruton tyrosine kinase (BTK) activation. Ibrutinib was the first BTK inhibitor approved for WM. Intolerance to ibrutinib frequently leads to dose reductions, though the impact of reducing ibrutinib dosing has not been systematically studied. We performed a retrospective study to determine the frequency and impact of reducing ibrutinib dosing in WM patients. With a median treatment time of 64 months, 96 (27%) of 353 WM patients required a dose reduction due to adverse events such as musculoskeletal symptoms, cardiac events, dermatologic symptoms, cytopenias, and gastrointestinal symptoms. The median time to initial dose reduction was 9.3 months (range, 0.5–74). Dose reductions were more common in those 65 years of age or older versus under 65 [hazard ratio (HR) 2.46, 95% confidence interval (CI) 1.55–3.90; p < 0.001], and in females versus males (HR 2.20, 95% CI 1.41–3.28, p < 0.001). Most patients (65%) had improvement or resolution of adverse effects after initial dose reduction. With a median follow‐up of three years from dose reduction, hematologic response sustained or deepened in 79% of patients. These data suggest that dose reduction of ibrutinib is a reasonable treatment approach for patients with intolerable side effects. [ABSTRACT FROM AUTHOR]

Summary: Ibrutinib is associated with response rate of 90% and median progression‐free survival (PFS) in excess of 5 years in Waldenström macroglobulinaemia (WM) patients. CXCR4 mutations are detected in 30–40% of patients with WM and associate with lower rates of response and shorter PFS to ibrutinib therapy. Both frameshift (CXCR4FS) and nonsense (CXCR4NS) CXCR4 mutations have been described. The impact of these mutations on outcomes to ibrutinib have not been evaluated in WM patients. We studied consecutive patients with a diagnosis of WM, on ibrutinib therapy, for the presence of CXCR4FS and CXCR4NS mutations and evaluated the differences in response and PFS between groups. Of 180 patients, 68 patients (38%) had CXCR4 mutations; 49 (27%) had CXCR4NS and 19 (11%) had CXCR4FS mutations. In multivariate models, patients with CXCR4NS had lower odds of major response (Odds ratio 0·25, 95% confidence interval [CI] 0·12–0·53; P < 0·001) and worse PFS (Hazard ratio 4·02, 95% CI 1·95–8·26; P < 0·001) than patients without CXCR4 mutations. CXCR4FS was not associated with worse major response or PFS rates than patients without CXCR4 mutations. Our results suggest different response and PFS rates to ibrutinib for WM patients with CXCR4NS and CXCR4FS, and advocate in favour of CXCR4 mutational testing as well as CXCR4‐directed therapy. [ABSTRACT FROM AUTHOR]

The article present a retrospective study on consecutive patients diagnosed with Waldenstrom Macroglobulinaemia (WM) at the age 45 years or younger. It mentions diagnosis and treatment indications were based on the 2nd International Workshop for WM (IWWM) criteria; and also mentions 43 patients needed therapy at the time of diagnosis, and for the remaining 62 patients, the median time to treatment initiation was 2-5 years.

The article discusses a study of diagnosed Waldenström macrogloblinaemia (WM) patients who were tested for von Willebrand factor antigen (VWF:Ag), VWF Ristocetin cofactor (VWF: RCo) and factor VIII (FVIII) levels. Topics include percentage of WM patients tested who had low VW markers, association between low VW markers and higher serum Immunoglobulin M (IgM) levels, and recommended screening for VW markers in WM patients with complaints of easy bruising or mucocutaneous bleeding.

Summary: Little is known about TP53 mutations in Waldenström Macroglobulinaemia (WM). We evaluated 265 WM patients for TP53 mutations by next‐generation sequencing, and validated the findings by Sanger sequencing. TP53 mutations were identified and validated in 6 (2·6%) patients that impacted the DNA‐binding domain. All six were MYD88‐ and CXCR4‐mutated. Ibrutinib showed activity in patients carrying all three mutations. With a median follow‐up of 18 months, 2 (33%) with biallelic TP53 inactivation died of progressive disease. TP53 mutations are rare in WM, and associate with MYD88 and CXCR4 mutations. WM patients with TP53 mutations show response to ibrutinib. [ABSTRACT FROM AUTHOR]

Summary: Waldenström macroglobulinaemia (WM) is a rare and incurable lymphoma. Comparative studies evaluating the efficacy of primary therapy in symptomatic WM patients have not been performed. In this study, we compared response and survival outcomes in WM patients who received primary therapy with cyclophosphamide‐dexamethasone‐rituximab (CDR), bortezomib‐dexamethasone‐rituximab (BDR) and bendamustine‐rituximab (Benda‐R), as well as maintenance rituximab following primary therapy. Analyses were adjusted for relevant clinical factors associated with response and survival. Maintenance rituximab was analysed as a time‐varying covariate. Our study included 182 patients, of which 57 (31%) received Benda‐R, 87 (48%) BDR and 38 (21%) CDR; 116 (64%) received maintenance rituximab. The median time to best response was shorter for Benda‐R and BDR than CDR (18, 20 and 30 months, respectively). Benda‐R and BDR were associated with better median progression‐free survival (PFS) than CDR (5·5, 5·8 and 4·8 years, respectively), and better 10‐year overall survival rates (OS; 95%, 96% and 81%, respectively). Maintenance rituximab was associated with higher rates of major response (97% vs. 68%), and better median PFS (6·8 years vs. 2·8 years) and 10‐year OS rate (84% vs. 66%) when compared to not receiving maintenance. Benda‐R, BDR and maintenance rituximab associate with higher response rates and longer survival in WM patients than CDR and no maintenance, respectively. [ABSTRACT FROM AUTHOR]

The article discusses research which showed that malignant pleural effusions in Waldenström macroglobulinaemia (WM) can be identified with the use of MYD88 mutations. Topics discussed include the characteristics of WM, a B-cell malignancy by bone marrow (BM) infiltration, clinical presentation and diagnostic work-up for the pleural effusions, differential diagnosis with lymphocyte-rich effusions and factors that can hinder the identification of a clonal population.

Comparative data on immunochemotherapy regimens for Waldenström macroglobulinaemia/lymphoplasmacytic lymphoma ( WM/ LPL) are lacking. We analysed overall survival ( OS), risk of hospitalizations, transfusions and plasmapheresis in a population-based cohort of patients ≥65 years old initiating WM/ LPL therapy in 1999-2013. To minimize bias, we applied a propensity score-based causal inference method. We conducted three analyses of: patients treated with or without rituximab, patients treated with rituximab monotherapy or with combination immunochemotherapy, and regimens based on classic purine analogues or alkylators. Among 1310 patients, 78·5% received rituximab. Patients who received rituximab had significantly better OS [hazard ratio ( HR) 0·62, 95% confidence interval ( CI) 0·55-0·71] and lower risk of transfusions (risk difference −3·3%, 95% CI −6·3 to −0·3) than those who did not, without a significant difference in hospitalizations or plasmapheresis. We observed no significant difference in OS ( HR 0·91, 95% CI 0·79-1·04) between rituximab monotherapy and combination immunochemotherapy, but toxicity outcomes were lower with rituximab alone. Neither survival ( HR 1·10, 95% CI 0·92-1·32) nor toxicity outcomes differed significantly between regimens based on purine analogues or alkylators. The survival advantage strongly supports rituximab as part of upfront therapy for WM/ LPL, whereas regimens with either purine analogues or alkylating agents result in similar outcomes. [ABSTRACT FROM AUTHOR]

The article discusses the myddosome assembly in the disease called Waldenstrom macroglobulinaemia (WM). Also cited are the MYD88 mutations as expressed in WM, immune-privileged lymphomas, activated B-cell (ABC) subtype of diffuse large B-cell lymphoma (DLBCL), marginal zone lymphoma, and chronic lymphocytic leukaemia (CLL), the composition of MYD88 protein, and MYD88 dimerization.

Symptomatic hyperviscosity is a common clinical manifestation in patients with Waldenström macroglobulinaemia ( WM) and high serum IgM levels. Prompt intervention is required to prevent catastrophic events, such as retinal or central nervous system bleeding. Identifying patients at high risk of symptomatic hyperviscosity might support the decision to treat asymptomatic patients before irreversible damage occurs. We carried out a large retrospective study in 825 newly diagnosed WM patients, of who 113 (14%) developed symptomatic hyperviscosity. The median serum IgM level at the time of symptomatic hyperviscosity was 61·8 g/l (range 31-124 g/l). Forty-four patients (36%) had symptomatic hyperviscosity at the time of WM diagnosis. A serum IgM level >60 g/l at diagnosis was associated with a median time to symptomatic hyperviscosity of 3 months, whereas the median time for patients with serum IgM level of 50·01-60 g/l was approximately 3 years. Adjusting for other clinical factors, the odds of developing symptomatic hyperviscosity were 370-fold higher with serum IgM levels >60 g/l, and showed an association with CXCR4 mutational status. Symptomatic hyperviscosity did not impact overall survival ( P = 0·12). The findings support the use of serum IgM level >60 g/l as a criterion for initiation of therapy in an otherwise asymptomatic WM patient. [ABSTRACT FROM AUTHOR]

Paraproteinaemic neuropathies are a heterogeneous group of disorders most frequently associated with IgM monoclonal gammopathies including Waldenström macroglobulinaemia ( WM). Their consequences are significant for affected patients, and their management challenging for their physicians. The variability in clinical presentation and time course hamper classification and management. The indications for invasive investigations such as cerebrospinal fluid analysis, nerve conduction tests and sensory nerve biopsies are unclear, and the optimum way to measure clinical response to treatment unknown. When to intervene and and how to treat, also present challenges to physicians. As part of its latest deliberations at the International Workshops on WM ( IWWM) in London, UK (August 2014), the IWWM8 panel have proposed a consensus approach to the diagnosis and management of peripheral neuropathies associated with IgM monoclonal gammopathies, including WM. Importantly, a consensus regarding the use of clinical outcome measures and recommended models of care for this group of patients is discussed, as well as appropriate treatment interventions. [ABSTRACT FROM AUTHOR]

The incidence and prognostic impact of nephropathy related to Waldenström macroglobulinaemia ( WM) is currently unknown. We performed a retrospective study to assess biopsy-confirmed WM-related nephropathy in a cohort of 1391 WM patients seen at a single academic institution. A total of 44 cases were identified, the estimated cumulative incidence was 5·1% at 15 years. There was a wide variation in kidney pathology, some directly related to the WM: amyloidosis ( n = 11, 25%), monoclonal-IgM deposition disease/cryoglobulinaemia ( n = 10, 23%), lymphoplasmacytic lymphoma infiltration ( n = 8, 18%), light-chain deposition disease ( n = 4, 9%) and light-chain cast nephropathy ( n = 4, 9%), and some probably related to the WM: thrombotic microangiopathy ( TMA) ( n = 3, 7%), minimal change disease ( n = 2, 5%), membranous nephropathy ( n = 1, 2%) and crystal-storing tubulopathy ( n = 1, 2%). The median overall survival in patients with biopsy-confirmed WM-related nephropathy was 11·5 years, shorter than for the rest of the cohort (16 years, P = 0·03). Survival was better in patients with stable or improved renal function after treatment ( P = 0·05). Based on these findings, monitoring for renal disease in WM patients should be considered and a kidney biopsy pursued in those presenting with otherwise unexplained renal failure and/or nephrotic syndrome. [ABSTRACT FROM AUTHOR]

The diagnosis of Waldenström macroglobulinaemia ( WM) can be challenging given the variety of signs and symptoms patients can present. Furthermore, once the diagnosis of WM is established, the initial evaluation should be thorough as well as appropriately directed. During the 8th International Workshop for WM in London, United Kingdom, a multi-institutional task force was formed to develop consensus recommendations for the diagnosis and initial evaluation of patients with WM. In this document, we present the results of the deliberations that took place to address these issues. We provide recommendations for history-taking and physical examination, laboratory studies, bone marrow aspiration and biopsy analysis and imaging studies. We also provide guidance on the initial evaluation of special situations, such as anaemia, hyperviscosity, neuropathy, Bing-Neel syndrome and amyloidosis. We hope these recommendations serve as a practical guidance to clinicians taking care of patients with a suspected or an established diagnosis of WM. [ABSTRACT FROM AUTHOR]

Bing-Neel syndrome ( BNS) is a rare complication seen in patients with Waldenström macroglobulinaemia ( WM), in which lymphoplasmacytic lymphoma cells colonize the central nervous system. In this retrospective multi-centre study, we present the clinicopathological features, imaging findings, therapy, response and outcomes of 34 patients with BNS. The median time from WM diagnosis to BNS diagnosis was 3 years, 15% of patients were diagnosed with BNS at the time of WM diagnosis, and 22% of patients developed BNS when responding to active treatment for WM. Patients with BNS presented with variable clinical features including limb motor deficits, change in mental status and cranial nerve palsies. The diagnosis was made using a combination of cerebrospinal fluid cytology, flow cytometry and detection of the MYD88 L265 mutation, and magnetic resonance imaging. The estimated 3-year overall survival rate was 59%. Of the survivors, 40% have evidence of pathological and/or radiological persistence of disease. Age older than 65 years, platelet count lower than 100 × 109/l, and treatment for WM prior to BNS diagnosis were associated with worse outcome. Exposure to rituximab for treatment of BNS was associated with a better outcome. Multi-institutional collaboration is warranted to improve treatment and outcomes in patients with BNS. [ABSTRACT FROM AUTHOR]

Waldenström macroglobulinaemia ( WM) is a rare and incurable lymphoma. Given that the survival of WM patients can be prolonged, our objective was to describe trends in overall survival ( OS) and analyse competing risks of death in patients with WM. The analysis included 5784 patients diagnosed with WM between 1991 and 2010 from the Surveillance, Epidemiology and End Results ( SEER) database. Multivariate hazard models for OS and cumulative incidence of death were fitted according to epoch of diagnosis (1991-2000 vs. 2001-10) while adjusting for age, sex, race, histology, site of involvement and registry. Median OS for the 1991-2000 and the 2001-10 cohorts was 6 and 8 years, respectively ( P < 0·001). In the multivariate analysis, better OS [hazard ratio ( HR) 0·73, 95% confidence interval ( CI) 0·67-0·79; P < 0·001] was seen in the 2001-10 cohort. Survival benefits were identified, for the 2001-10 cohort, in almost every stratum analysed, with the exception of patients aged <50 years and blacks. In the multivariate competing-risk analysis, the 2001-10 cohort experienced lower rates of WM-related ( HR 0·57, 95% CI 0·49-0·66; P < 0·001) and non- WM-related deaths ( HR 0·72, 95% CI 0·66-0·79; P < 0·001). In conclusion, there have been significant improvements in OS, WM-related and non- WM-related mortality in patients with WM diagnosed in the last decade. [ABSTRACT FROM AUTHOR]

CXCR4 WHIM frameshift and nonsense mutations follow MYD88L265P as the most common somatic variants in Waldenström Macroglobulinaemia ( WM), and impact clinical presentation and ibrutinib response. While the nonsense ( CXCR4S338X) mutation has been investigated, little is known about CXCR4 frameshift ( CXCR4FS) mutations. We engineered WM cells to express CXCR4FS mutations present in patients, and compared their CXCL12 ( SDF-1a) induced signalling and ibrutinib sensitivity to CXCR4wild-type (WT) and CXCR4S338X cells. Following CXCL12 stimulation, CXCR4FS and CXCR4S338X WM cells showed impaired CXCR4 receptor internalization, and enhanced AKT1 (also termed AKT) and MAPK1 (also termed ERK) activation versus CXCRWT cells ( P < 0·05), though MAPK1 activation was more prolonged in CXCR4S338X cells ( P < 0·05). CXCR4FS and CXCR4S338X cells, but not CXCR4WT cells, were rescued from ibrutinib-triggered apoptosis by CXCL12 that was reversed by AKT1, MAPK1 or CXCR4 antagonists. Treatment with an inhibitor that blocks MYD88L265P signalling triggered similar levels of apoptosis that was not abrogated by CXCL12 treatment in CXCR4WT and CXCR4WHIM cells. These studies show a functional role for CXCR4FS mutations in WM, and provide a framework for the investigation of CXCR4 antagonists with ibrutinib in CXCR4WHIM-mutated WM patients. Direct inhibition of MYD88L265P signalling overcomes CXCL12 triggered survival effects in CXCR4WHIM-mutated cells supporting a primary role for this survival pathway in WM. [ABSTRACT FROM AUTHOR]

In Waldenström macroglobulinaemia ( WM), the mechanism(s) responsible for repression of B-cell differentiation remains unknown. We found that expression of SPIB and ID 2 were significantly increased and decreased, respectively, in WM lymphoplasmacytic cells ( LPC). Ectopic expression of SPIB in healthy donor CD19+ cells inhibited plasmacytic differentiation in conjunction with decreased transcription of IRF 4 and XBP 1 spliced form. In primary WM LPC, knock-down of SPIB induced plasmacytic differentiation in conjunction with increased transcription of PRDM 1, XBP 1 spliced form, IRF 4 and ID 2. Knock-down of SPIB also led to decreased BCL 2 expression. Given that SPIB is a direct target of POU 2 AF 1 ( OBF 1) in complex with POU 2 F 2 or POU 2 F 1, we next examined their expression in WM LPC. POU 2 F 2 transcription, as well as POU2F2 and POU2 AF1 protein expression was higher in WM LPC. Ectopic expression of POU 2 F 2 in healthy donor CD19+ cells induced transcription of SPIB and suppressed transcription of PRDM 1 and IRF 4. Chromatin immunoprecipitation analysis in BCWM.1 WM cells confirmed binding of POU2F2 and POU2 AF1 in SPIB and ID 2 promoters. These findings establish a molecular hierarchy among POU 2 F 2, SPIB and ID 2 during B-cell differentiation, and suggest that aberrant expression of these transcription factors plays an important role in arresting plasmacytic differentiation in WM. [ABSTRACT FROM AUTHOR]

The article focuses on a study regarding the role of B-cell selection in determination of the MYD88 mutation status in waldenstrom macroglobulinemia (WM). It mentions that WM is characterized by bone marrow (BM) with lymphoplasmacytic lymphoma and helps in the production of a monoclonal immunoglobulin (Ig) M protein. It also mentions the importance of MYD88 mutational status in diagnostic, prognostic and treatment of WM patients.

The article presents a study which examined the therapeutic use of rituximab in patients with Waldenström macroglobulinemia (WM). The variables considered include the median age and sex distribution of patients at rituximab intolerance, common symptoms leading toward rituximab discontinuation and median immunoglobulins M (IgM). The result of a review of trials using rituximab in WM patients are mentioned.