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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]

Waldenström macroglobulinemia (WM) is a B-cell neoplasm manifested by the accumulation of clonal immunoglobulin (Ig)M-secreting lymphoplasmacytic cells. MYD88 and CXCR4 warts, hypogammaglobulinemia, infections, myelokathexis syndrome-like somatic mutations are present in >90% and 30% to 35% of WM patients, respectively, and impact disease presentation, treatment outcome, and overall survival. Familial predisposition is common in WM. Asymptomatic patients should be observed. Patients with disease-related hemoglobin <10 g/L, platelets <100 × 109/L, bulky adenopathy and/or organomegaly, symptomatic hyperviscosity, peripheral neuropathy, amyloidosis, cryoglobulinemia, cold-agglutinin disease, or transformed disease should be considered for therapy. Plasmapheresis should be used for patients with symptomatic hyperviscosity and before rituximab for those with high serum IgM levels to preempt a symptomatic IgM flare. Treatment choice should take into account specific goals of therapy, necessity for rapid disease control, risk of treatment-related neuropathy, immunosuppression and secondary malignancies, and planning for future autologous stem cell transplantation. Frontline treatments include rituximab alone or rituximab combined with alkylators (bendamustine and cyclophosphamide), proteasome inhibitors (bortezomib and carfilzomib), nucleoside analogs (fludarabine and cladribine), and ibrutinib. In the salvage setting, an alternative frontline regimen, ibrutinib, everolimus, or stem cell transplantation can be considered. Investigational therapies under development for WM include agents that target MYD88, CXCR4, BCL2, and CD27/CD70 signaling, novel proteasome inhibitors, and chimeric antigen receptor-modified T-cell therapy. [ABSTRACT FROM AUTHOR]

The article discusses a study on the drug ibrutinib in previously treated patients with Waldenström's macroglobulinemia at various medical centers in the U.S., and examines the effect of MYD88 and CXCR4 mutations on outcomes. Topics mentioned include the effect of ibrutinib on peripheral lymphocytosis, adverse events linked to ibrutinib therapy, such as neutropenia, thrombocytopenia, and atrial fibrillation, and the effect of ibrutinib therapy on extramedullary disease.

Whole genome sequencing has revealed activating somatic mutations in MYD88 (L265P) and CXCR4 in Waldenstrom macroglobulinemia (WM). CXCR4 somatic mutations in WM are the first ever reported in human cancer and are similar to nonsense (NS) and frameshift (FS) germline mutations found in warts, hypogammaglobulinemia, infections and myelokathexis (WHIM) syndrome. We genotyped lymphoplasmacytic cells from 175 WM patients and observed significantly higher bone marrow (BM) disease involvement, serum immunoglobulin-M levels, and symptomatic disease requiring therapy, including hyperviscosity syndrome in those patients with MYD88L265PCXCR4V mutations (P< .03). Patients with MYD88L265PCXCR4WHIM/FS or MYD88L265PCXCR4WILDTYPE had intermediate BM and serum immunoglobulin-M levels, those with MYD88WTCXCR4WT showed lowest BM disease burden. Fewer patients with MYD88L265P and CXCR4WHIM/FS or NS vs MYD88L265PCXCR4WT presented with adenopathy (P < .01), further delineating differences in disease tropism based on CXCR4 status. Neither MYD88 nor CXCR4 mutations correlated with SDF-1a (RS1801157) polymorphisms in 54 patients who were genotyped for these variants. Unexpectedly, risk of death was not impacted by CXCR4 mutation status, but by MYD88WT status (hazard ratio 10.54, 95% confidence interval 2.4-46.2, P = .0018). Somatic mutations in MYD88 and CXCR4 are important determinants of clinical presentation and impact overall survival in WM. Targeted therapies directed against MYD88 and/or CXCR4 signaling may provide a personalized treatment approach to WM. [ABSTRACT FROM AUTHOR]

Background: Waldenström's macroglobulinemia is an incurable, IgM-secreting lymphoplasmacytic lymphoma (LPL). The underlying mutation in this disorder has not been delineated. Methods: We performed whole-genome sequencing of bone marrow LPL cells in 30 patients with Waldenström's macroglobulinemia, with paired normal-tissue and tumor-tissue sequencing in 10 patients. Sanger sequencing was used to validate the findings in samples from an expanded cohort of patients with LPL, those with other B-cell disorders that have some of the same features as LPL, and healthy donors. Results: Among the patients with Waldenström's macroglobulinemia, a somatic variant (T→C) in LPL cells was identified at position 38182641 at 3p22.2 in the samples from all 10 patients with paired tissue samples and in 17 of 20 samples from patients with unpaired samples. This variant predicted an amino acid change (L265P) in MYD88, a mutation that triggers IRAK-mediated NF-κB signaling. Sanger sequencing identified MYD88 L265P in tumor samples from 49 of 54 patients with Waldenström's macroglobulinemia and in 3 of 3 patients with non–IgM-secreting LPL (91% of all patients with LPL). MYD88 L265P was absent in paired normal tissue samples from patients with Waldenström's macroglobulinemia or non-IgM LPL and in B cells from healthy donors and was absent or rarely expressed in samples from patients with multiple myeloma, marginal-zone lymphoma, or IgM monoclonal gammopathy of unknown significance. Inhibition of MYD88 signaling reduced IκBα and NF-κB p65 phosphorylation, as well as NF-κB nuclear staining, in Waldenström's macroglobulinemia cells expressing MYD88 L265P. Somatic variants in ARID1A in 5 of 30 patients (17%), leading to a premature stop or frameshift, were also identified and were associated with an increased disease burden. In addition, 2 of 3 patients with Waldenström's macroglobulinemia who had wild-type MYD88 had somatic variants in MLL2. Conclusions: MYD88 L265P is a commonly recurring mutation in patients with Waldenström's macroglobulinemia that can be useful in differentiating Waldenström's macroglobulinemia and non-IgM LPL from B-cell disorders that have some of the same features. (Funded by the Peter and Helen Bing Foundation and others.) [ABSTRACT FROM PUBLISHER]

Waldenström macroglobulinemia (WM) is a rare lymphoplasmacytic disorder characterized by an IgM paraprotein. The clinical presentation of WM varies and can include common manifestations such as anemia and hyperviscosity, in addition to less common features such as cryoglobulinemia, IgM-related neuropathy, and immunoglobulin light chain (AL) amyloidosis. Amyloidosis is a protein-folding disorder in which vital organ damage occurs due to the accumulation of misfolded protein aggregates. The most common type of amyloidosis in patients with an IgM paraprotein is AL amyloidosis, although other types of amyloidosis may occur. IgM-related amyloidosis has distinct clinical features when compared with other subtypes of AL amyloidosis. This review highlights the diagnostic criteria of IgM-related AL amyloidosis, as well as the clinical characteristics and treatment options for this disorder. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "MYD88 L265P Somatic Mutation in Waldenstrom's Macroglobulinemia" by S. P. Treon, L. Xu, G. Yang, et al.

The authors discuss the study conducted by S. Poulain and colleagues on the presence of MYD88 L265P somatic mutation in patients with Waldenstrom's macroglogulinemia (WM). The authors cite the discovery of Poulain and colleagues on the high prevalence and potential of the mutation in WM patients as an oncogenic event. Moreover, they mention the role of mutation in the survival and growth of WM cells.

The article offers information on the clinical trial conducted by the European Myeloma Network (EMN) depicting the activity of bortezomib, dexamethasone, and rituximab (BDR) in patients Waldenström macroglobulinemia (WM). It mentions that Carfilzomib, proteasome inhibitor is related to lower incidence of peripheral neuropathy (PN).

The article presents a case study of a patient with MYD88-mutated IgG -lambda lymphoplasmacytic lymphoma (LPL) who underwent salvage therapy with ibrutinib drug . Topics include the patient diagnosed with IgG LPL in August 2000, when experiencing fatigue and night sweats, and the patient stated to have been presented with worsening right-sided preauricular lymphadenopathy.

Keywords: Waldenstrom-s macroglobulinaemia; plasmablastic lymphoma; ibrutinib EN Waldenstrom-s macroglobulinaemia plasmablastic lymphoma ibrutinib 466 468 3 11/01/21 20211101 NES 211101 A 67-year-old female was diagnosed with Waldenström macroglobulinemia (WM) in October 2004. Plasmablastic lymphoma transformation in a patient with Waldenström macroglobulinemia treated with ibrutinib A CT-guided retroperitoneal lymph node biopsy showed lymphoid tissue diffusely effaced by sheets of large cells with ovoid to irregular nuclei, vesicular chromatin, prominent nucleoli and abundant eosinophilic cytoplasm. Abdominal computed tomography (CT) revealed bulky lymphadenopathy encasing the inferior vena cava. [Extracted from the article]

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]

Waldenström Macroglobulinemia (WM) is a low-grade B-cell lymphoma characterized by disease progression from IgM MGUS to asymptomatic and then symptomatic disease states. We profiled exosomes from the peripheral blood of patients with WM at different stages (30 smoldering/asymptomatic WM, 44 symptomatic WM samples and 10 healthy controls) to define their role as potential biomarkers of disease progression. In this study, we showed that circulating exosomes and their miRNA content represent unique markers of the tumor and its microenvironment. We observed similar levels of miRNAs in exosomes from patients with asymptomatic (smoldering) and symptomatic WM, suggesting that environmental and clonal changes occur in patients at early stages of disease progression before symptoms occur. Moreover, we identified a small group of miRNAs whose expression correlated directly or inversely with the disease status of patients, notably the known tumor suppressor miRNAs let-7d and the oncogene miR-21 as well as miR-192 and miR-320b. The study of these miRNAs’ specific effect in WM cells could help us gain further insights on the mechanisms underlying WM pathogenesis and reveal their potential as novel therapeutic targets for this disease. [ABSTRACT FROM AUTHOR]

Acquired ibrutinib resistance due to BTKCys481 mutations occurs in B-cell malignancies, including those with MYD88 mutations. BTKCys481 mutations are usually subclonal, and their relevance to clinical progression remains unclear. Moreover, the signaling pathways that promote ibrutinib resistance remain to be clarified. We therefore engineered BTKCys481Ser and BTKWT expressing MYD88-mutated Waldenström macroglobulinemia (WM) and activated B-cell (ABC) diffuse large B-cell lymphoma (DLBCL) cells and observed reactivation of BTK-PLCγ2-ERK1/2 signaling in the presence of ibrutinib in only the former. Use of ERK1/2 inhibitors triggered apoptosis in BTKCys481Ser-expressing cells and showed synergistic cytotoxicity with ibrutinib. ERK1/2 reactivation in ibrutinib-treated BTKCys481Ser cells was accompanied by release of many prosurvival and inflammatory cytokines, including interleukin-6 (IL-6) and IL-10 that were also blocked by ERK1/2 inhibition. To clarify if cytokine release by ibrutinib-treated BTKCys481Ser cells could protect BTKWT MYD88-mutated malignant cells, we used a Transwell coculture system and showed that nontransduced BTKWT MYD88-mutated WM or ABC DLBCL cells were rescued from ibrutinib-induced killing when cocultured with BTKCys481Ser but not their BTKWT-expressing counterparts. Use of IL-6 and/or IL-10 blocking antibodies abolished the protective effect conferred on nontransduced BTKWT by coculture with BTKCys481Ser expressing WM or ABC DLBCL cell counterparts. Rebound of IL-6 and IL-10 serum levels also accompanied disease progression in WM patients with acquired BTKCys481 mutations. Our findings show that the BTKCys481Ser mutation drives ibrutinib resistance in MYD88-mutated WM and ABC DLBCL cells through reactivation of ERK1/2 and can confer a protective effect on BTKWT cells through a paracrine mechanism. [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]

Waldenström macroglobulinemia (WM) is a distinct B-cell lymphoproliferative disorder for which clearly defined criteria for the diagnosis, initiation of therapy, and treatment strategy have been proposed as part of the consensus panels of the International Workshop on Waldenström's Macroglobulinemia (IWWM). At IWWM-8, a task force for treatment recommendations was impanelled to review recently published and ongoing clinical trial data as well as the impact of new mutations (MYD88 and CXCR4) on treatment decisions, indications for B-cell receptor and proteasome inhibitors, and future clinical trial initiatives for WM patients. The panel concluded that therapeutic strategies in WM should be based on individual patient and disease characteristics. Chemoimmunotherapy combinations with rituximab and cyclophosphamide-dexamethasone, bendamustine, or bortezomib-dexamethasone provide durable responses and are still indicated in most patients. Approval of the BTK inhibitor ibrutinib in the United States and Europe represents a novel and effective treatment option for both treatment-naive and relapsing patients. Other B-cell receptor inhibitors, second-generation proteasome inhibitors (eg, carfilzomib), and mammalian target of rapamycin inhibitors are promising and may increase future treatment options. Active enrollment in clinical trials whenever possible was endorsed by the panel for most patients with WM. [ABSTRACT FROM AUTHOR]

Whole-genome sequencing has identified highly prevalent somatic mutations including MYD88,CXCR4, and ARID1A in Waldenström macroglobulinemia (WM). The impact of these and other somatic mutations on transcriptional regulation in WM remains to be clarified. We performed next-generation transcriptional profiling in 57 WM patients and compared findings to healthy donor B cells. Compared with healthy donors, WM patient samples showed greatly enhanced expression of the VDJ recombination genes DNTT, RAG1, and RAG2, but not AICDA. Genes related to CXCR4 signaling were also upregulated and included CXCR4, CXCL12, and VCAM1 regardless of CXCR4 mutation status, indicating a potential role for CXCR4 signaling in all WM patients. The WM transcriptional profile was equally dissimilar to healthy memory B cells and circulating B cells likely due increased differentiation rather than cellular origin. The profile for CXCR4 mutations corresponded to diminished B-cell differentiation and suppression of tumor suppressors upregulated by MYD88 mutations in a manner associated with the suppression of TLR4 signaling relative to those mutated for MYD88 alone. Promoter methylation studies of top findings failed to explain this suppressive effect but identified aberrant methylation patterns in MYD88 wild-type patients. CXCR4 and MYD88 transcription were negatively correlated, demonstrated allele-specific transcription bias, and, along with CXCL13, were associated with bone marrow disease involvement. Distinct gene expression profiles for patients with wild-type MYD88, mutated ARID1A, familial predisposition to WM, chr6q deletions, chr3q amplifications, and trisomy 4 are also described. The findings provide novel insights into the molecular pathogenesis and opportunities for targeted therapeutic strategies for WM. [ABSTRACT FROM AUTHOR]

Activating mutations in MYD88 are present in ∼95% of patients with Waldenström macroglobulinemia (WM), as well as other B-cell malignancies including activated B-cell (ABC) diffuse large B-cell lymphoma (DLBCL). In WM, mutated MYD88 triggers activation of Bruton tyrosine kinase (BTK). Ibrutinib, a pleiotropic kinase inhibitor that targets BTK, is highly active in patients with mutated MYD88. We observed that mutated MYD88 WM and ABC DLBCL cell lines, as well as primary WM cells show enhanced hematopoietic cell kinase (HCK) transcription and activation, and that HCK is activated by interleukin 6 (IL-6). Over-expression of mutated MYD88 triggers HCK and IL-6 transcription, whereas knockdown of HCK reduced survival and attenuated BTK, phosphoinositide 3-kinase/AKT, and mitogen-activated protein kinase/extracellular signal-regulated kinase signaling in mutated MYD88 WM and/or ABC DLBCL cells. Ibrutinib and the more potent HCK inhibitor A419259, blocked HCK activation and induced apoptosis in mutated MYD88 WM and ABC DLBCL cells. Docking and pull-down studies confirmed that HCK was a target of ibrutinib. Ibrutinib and A419259 also blocked adenosine triphosphate binding to HCK, whereas transduction of mutated MYD88 expressing WM cells with a mutated HCK gatekeeper greatly increased the half maximal effective concentration for ibrutinib and A419259. The findings support that HCK expression and activation is triggered by mutated MYD88, supports the growth and survival of mutated MYD88 WM and ABC DLBCL cells, and is a direct target of ibrutinib. HCK represents a novel target for therapeutic development in MYD88-mutated WM and ABC DLBCL, and possibly other diseases driven by mutated MYD88. [ABSTRACT FROM AUTHOR]

Familial aggregation of Waldenström macroglobulinemia (WM) cases, and the clustering of B-cell lymphoproliferative disorders among first-degree relatives of WM patients, has been reported. Nevertheless, the possible contribution of inherited susceptibility to familial WM remains unrevealed. We performed whole exome sequencing on germ line DNA obtained from 4 family members in which coinheritance for WM was documented in 3 of them, and screened additional independent 246 cases by using gene-specific mutation sequencing. Among the shared germline variants, LAPTM5c403t and HCLS1g496a were the most recurrent, being present in 3/3 affected members of the index family, detected in 8% of the unrelated familial cases, and present in 0.5%of the nonfamilial cases and in <0.05 of a control population. LAPTM5 and HCLS1 appeared as relevant WM candidate genes that characterized familial WM individuals and were also functionally relevant to the tumor clone. These findings highlight potentially novel contributors for the genetic predisposition to familial WM and indicate that LAPTM5c403t and HCLS1g496a may represent predisposition alleles in patients with familial 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]

The article reports on the response to ibrutinib therapy of a 59-year-old male patient of Waldenström macroglobulinemia (WM) with Bing Neel syndrome (BNS) whose central nervous system (CNS) disease progressed despite multiple regimens. Topics covered include patient history, information on ibrutinib as a Bruton Tyrosine Kinase (BTK) inhibitor and CNS penetration of ibrutinib.

The article discusses a study to investigate whether B-cell lymphoma 2 (BCL2), an anti-apoptotic protein, protects against ibrutinib- and idelalisib-related apoptosis in CXCR4WT and CXCR4WHIM mutated Waldenstrom's Macroglobulinemia (WM) cells. It states that the mutation supports the survival of WM cells through the pathways like Bruton Tyrosine Kinase (BTK) and mentions that BCL2 is active in B-cell malignancies.

Background: Waldenström macroglobulinemia (WM) is an indolent malignancy that predominantly affects older individuals who are at risk for secondary malignancies (SMs). The objective of this study was to characterize the incidence of SMs after a diagnosis of WM with the Surveillance, Epidemiology, and End Results (SEER) database.Methods: With SEER-13 data (1992-2011), standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) were calculated for the rates of solid and hematologic SMs in WM patients versus the general population. The analysis was stratified by age, sex, race, year of diagnosis, and latency from the WM diagnosis.Results: Among 4676 patients with WM, 681 SMs were recorded. The overall SIR was 1.49 (95% CI, 1.38-1.61), and the median time to an SM was 3.7 years. The cumulative incidence of SMs was 10% at 5 years and 16% at 10 years. The risk was significantly increased for cancers of the lungs, urinary tract, and thyroid; melanoma; aggressive lymphoma; and acute leukemia. The SIR for SMs in patients with WM was increased, regardless of age, sex, race, or year of diagnosis.Conclusions: Patients with WM had a 49% higher risk of SMs than the general population. The selectively increased risk for hematologic SMs and certain solid SMs may be associated with transformation, therapy, and immune dysregulation. [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 presents research on the use of hematologic drug Idelalisib in treating patients with Waldenström macroglobulinemia (WM). Topics discussed include an overview of Waldenström macroglobulinemia, the activation of phosphatidylinositol-3-kinase (PI3K) pathway, and the benefit of idelalisib to patients..

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.

Sp1 transcription factor controls a pleiotropic group of genes and its aberrant activation has been reported in a number of malignancies, including multiple myeloma. In this study, we investigate and report its aberrant activation in Waldenström macroglobulinemia (WM). Both loss of and gain of Sp1 function studies have highlighted a potential oncogenic role of Sp1 in WM. We have further investigated the effect of a small molecule inhibitor, terameprocol (TMP), targeting Sp1 activity in WM. Treatment with TMP inhibited the growth and survival and impaired nuclear factor-κB and signal transducer and activator of transcription activity in WM cells. We next investigated and observed that TMP treatment induced further inhibition of WM cells in MYD88 knockdown WM cells. Moreover, we observed that Bruton's tyrosine kinase, a downstream target of MYD88 signaling pathway, is transcriptionally regulated by Sp1 in WM cells. The combined use of TMP with Bruton's tyrosine kinase or interleukin-1 receptor-associated kinase 1 and 4 inhibitors resulted in a significant and synergistic dose-dependent antiproliferative effect in MYD88-L265P--expressing WM cells. In summary, these results demonstrate Sp1 as an important transcription factor that regulates proliferation and survival of WM cells independent of MYD88 pathway activation, and provide preclinical rationale for clinical development of TMP in WM alone or in combination with inhibitors of MYD88 pathway. [ABSTRACT FROM AUTHOR]

The genetic basis for Waldenström macroglobulinemia (WM) remains to be clarified. Although 6q losses are commonly present, recurring gene losses in this region remain to be defined. We therefore performed whole genome sequencing (WGS) in 30 WM patients, which included germline/tumor sequencing for 10 patients. Validated somatic mutations occurring in >10% of patients included MYD88, CXCR4, and ARID1A that were present in 90%, 27%, and 17% of patients, respectively, and included the activating mutation L265P in MYD88 and warts, hypogammaglobulinemia, infection, and myelokathexis-syndrome-like mutations in CXCR4 that previously have only been described in the germline. WGS also delineated copy number alterations (CNAs) and structural variants in the 10 paired patients. The CXCR4 and CNA findings were validated in independent expansion cohorts of 147 and 30 WM patients, respectively. Validated gene losses due to CNAs involved PRDM2 (93%), BTG1 (87%), HIVEP2 (77%), MKLN1 (77%), PLEKHG1 (70%), LYN(60%), ARID1B(50%), and FOXP1 (37%). Losses in PLEKHG1, HIVEP2, ARID1B, and BCLAF1 constituted the most common deletions within chromosome 6. Although no recurrent translocations were observed, in 2 patients deletions in 6q corresponded with translocation events. These studies evidence highly recurring somatic events, and provide a genomic basis for understanding the pathogenesis of WM. [ABSTRACT FROM AUTHOR]

Myeloid differentiation factor 88 (MYD88) L265P somatic mutation is highly prevalent in Waldenström macroglobulinemia (WM) and supports malignant growth through nuclear factor κB (NF-κB). The signaling cascade(s) by which MYD88 L265P promotes NF-κB activation in WM remain unclear. By lentiviral knockdown or use of a MYD88 inhibitor, decreased phosphorylation of the NF-κB gatekeeper IκBα and survival occurred in MYD88 L265P-expressing WM cells. Conversely, WM cells engineered to overexpress MYD88 L265P showed enhanced survival. Coimmunoprecipitation studies identified Bruton tyrosine kinase (BTK) complexed to MYD88 in L265P-expressing WM cells, with preferential binding of MYD88 to phosphorylated BTK (pBTK). Increased pBTK was also observed in WM cells transduced to overexpress L265P vs wild-type MYD88. Importantly, MYD88 binding to BTK was abrogated following treatment of MYD88 L265P-expressing cells with a BTK kinase inhibitor. Inhibition of BTK or interleukin-1 receptor-associated kinase 1 and 4 (IRAK-1 and -4) kinase activity induced apoptosis of WM cells, and their combination resulted in more robust inhibition of NF-κB signaling and synergistic WM cell killing. The results establish BTK as a downstream target of MYD88 L265P signaling, and provide a framework for the study of BTK inhibitors alone, and in combination with IRAK inhibitors for the treatment of WM. [ABSTRACT FROM AUTHOR]

Abstract: Background: Little is known about the epidemiology and etiology of Waldenstrom macroglobulinemia (WM). Despite several studies of the relation between family history and B-cell disorders and WM, family history of non-hematologic cancers has not been systematically investigated. We thus examined associations of family history of breast, colorectal, lung, ovarian, and prostate cancers with WM. Methods: All probands aged 20–79 years with bone marrow biopsy-confirmed diagnosis of WM between May 1, 1999 and January 1, 2010 at the Bing Center for Waldenstrom Macroglobulinemia were eligible for inclusion in our analysis. We reviewed medical records for eligible probands to determine family history of cancer (defined as a cancer diagnosis for ≥1 first-degree relative(s) of the proband). Using expected values constructed from the United States National Health Interview Survey, we estimated age- and race-standardized rate ratios (RRs) for family history of breast, colorectal, lung, ovarian, and prostate cancers by WM subtype. Results: Family history of prostate cancer had the largest overall rate ratio (RR=1.4, 95% confidence limits [CL]: 1.1, 1.7), and among sporadic cases, family history of prostate and breast cancer had the largest rate ratios (prostate: RR=1.3, 95% CL: 1.1, 1.7; breast: RR=1.3, 95% CL: 1.2, 1.6). Conclusion: Our study suggests that it may be worthwhile to pursue these associations in a case–control study with uniform selection and data collection for cases and controls, and at least some record-based information on family history. [Copyright &y& Elsevier]