Genomic landscape of Waldenstrom's macroglobulinemia.
Ontology highlight
ABSTRACT:
SUBMITTER: Treon SP
PROVIDER: S-EPMC8925683 | biostudies-literature | 2019 Jun
REPOSITORIES: biostudies-literature
Publications
Genomic landscape of Waldenström's macroglobulinemia.
Treon Steven P SP Hunter Zachary R ZR Branagan Andrew R AR Castillo Jorge J JJ
HemaSphere 20190630 Suppl
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Project description:The diagnosis of Waldenström's macroglobulinemia (WM), an IgM-associated lymphoplasmacytic lymphoma, can be challenging due to the different forms of disease presentation. Furthermore, in recent years, WM has witnessed remarkable progress on the diagnostic front, as well as a deeper understanding of the disease biology, which has affected clinical practice. This, together with the increasing variety of tools and techniques available, makes it necessary to have a practical guidance for clinicians to perform the initial evaluation of patients with WM. In this paper, we present the consensus recommendations and laboratory requirements for the diagnosis of WM developed by the European Consortium of Waldenström's Macroglobulinemia (ECWM), for both clinical practice as well as the research/academical setting. We provide the procedures for multiparametric flow cytometry, fluorescence in situ hybridization and molecular tests, and with this offer guidance for a standardized diagnostic work-up and methodological workflow of patients with IgM monoclonal gammopathy of uncertain significance, asymptomatic and symptomatic WM.
| S-EPMC9898035 | biostudies-literature
Project description: Not available
| S-EPMC8925655 | biostudies-literature
Project description:Bruton's tyrosine kinase (BTK) inhibition is one of the treatment standards for patients with relapsed/refractory Waldenström's macroglobulinemia (WM) and for patients with WM who are unsuitable for immunochemotherapy (ICT). It offers deep and durable responses with a manageable safety profile that is generally favorable compared with ICT regimens. However, the limitations of the first approved BTK inhibitor (BTKi), ibrutinib, include reduced efficacy in patients lacking the characteristic WM mutation (MYD88L265P) and toxicities related to off-target activity. The risk of atrial fibrillation (AF) and other cardiovascular side effects are a notable feature of ibrutinib therapy. Several next-generation covalent BTKis with greater selectivity for BTK are at various stages of development. In November 2021, zanubrutinib became the first of these agents to be approved by the European Medicines Agency for the treatment of WM. Head-to-head trial data indicate that it has comparable efficacy to ibrutinib for patients with WM overall, although it may be more effective in patients with CXCR4 mutations or wild-type MYD88. In the clinical trial setting, its greater selectivity translates into a reduced risk of cardiovascular side effects, including AF. Acalabrutinib, which is pre-approval in WM, appears to offer similar advantages over ibrutinib in terms of its safety profile. Beyond the next-generation covalent BTKis, non-covalent BTKis are an emerging class with the potential to provide a therapeutic option for patients who relapse on covalent BTKis. In the future, BTKis may be increasingly utilized within combination regimens. Several ongoing trials in WM are investigating the potential for BTKi use in combination with established and novel targeted agents.
| S-EPMC9883164 | biostudies-literature
Project description:Waldenstrom's macroglobulinemia (WM) is very distinct from other indolent lymphoma subtypes: by definition it is accompanied by a monoclonal IgM gammopathy; it presents always with bone marrow infiltration and often with clinical symptoms such as neuropathy or hyperviscosity. These disease characteristics and the frequently advanced age of the WM patient pose a major challenge to the treating clinician even today. Recently, there has been not only substantial progress in our understanding of the biology of WM, but we have also significantly improved our tools to prognostify and to treat patients with this disease. This review summarizes our current knowledge about WM and aims at offering a guideline for the clinical management of patients with this lymphoma subtype, covering questions on how to manage diagnosis, prognostification and treatment based on the most recent data.
| S-EPMC3626020 | biostudies-other
Project description:Monoclonal antibodies have established an important role in the treatment armamentarium of hematological malignancies, including Waldenström's macroglobulinemia. Rituximab, an anti-CD20 monoclonal antibody, is established as standard therapy for this unique low grade lymphoma, due to its effectiveness and safety as monotherapy, in combination with chemotherapy or other targeted therapies in WM. Newer monoclonal antibodies, targeting CD20 or other surface antigens, have shown to be effective in patients with WM. In the current review we attempt to provide an overview of the mechanisms of action of monoclonal antibodies and discuss clinical evidence that support their use in WM and their therapeutic potential.
| S-EPMC9098391 | biostudies-literature
Project description:Waldenström’s macroglobulinemia (WM) is a distinct clinicobiological entity defined as a B-cell neoplasm characterized by a lymphoplasmacytic infiltrate in the bone marrow and immunoglobulin M paraprotein production. Cytogenetic analysis is limited by the difficulty in obtaining tumor metaphases and the genetic basis of the disease remains poorly defined. We performed a comprehensive analysis in 42 WM patients by using high-resolution array-based comparative genomic hybridization with the Human Genome 244A microarray. Overall, 83% of samples have chromosomal abnormalities, with a median of three abnormalities per patient (range 0 to 27). The most common abnormality was 6q deletion (40%) and four non-overlapped minimal deleted regions (MDR) were identified. Gain of 6p was the second most common abnormality (17%) and its presence was always concomitant with 6q loss. An interstitial MDR was delineated at 13q14 including MIRN15A and MIRN16-1 in 10% of patients. Other recurrent deletions were 7q22, 8p, 11q22-q23, 11q23-q24 and 17p11-p13 (7% each). Copy gains were identified in chromosomes 18 (17%), 4 (12%), 3 (10%), 8q (10%) and Xq27.1-q28 (10%). To note, we reported biallelic deletions and/or inactivating mutations with uniparental disomy in TRAF3 and TNFAIP3, two negative regulators of the NF-kB signaling pathway. Furthermore, we confirmed the association between TRAF3 inactivation and increased transcriptional activity of NF-kB target genes. Mutational activation of the NF-kB pathway, which is normally activated by ligand-receptor interactions within the bone marrow microenvironment, highlight its biologic importance, and suggest a therapeutic role for inhibitors of NF-KB pathway activation in the treatment of Waldenström’s macroglobulinemia. Keywords: gene expression profiling; array comparative genomic hybridization
2009-08-24 | GSE12668 | GEO
Project description:The current therapeutic approach in Waldenström's macroglobulinemia (WM) is being driven by insights in disease biology and genomic landscape. Bruton's tyrosine kinase (BTK) plays a key role in signaling pathways for the survival of WM clone. BTK inhibition has changed the treatment landscape of the disease. Ibrutinib has resulted in deep and durable responses both as an upfront and salvage treatment with a manageable toxicity profile. However, the need for fewer off-target effects and deeper responses has resulted in the clinical development of second-generation BTK inhibitors. Zanubrutinib has resulted in clinically meaningful antitumor activity, including deep and durable responses, with a low discontinuation rate due to treatment-related toxicities. Cardiovascular adverse events seem to be milder compared with ibrutinib. Interestingly, the efficacy of zanubrutinib in WM is significant both for MYD88L265P and MYD88WT patients. Although the randomized, phase III ASPEN clinical trial did not meet its primary endpoint in terms of showing a superiority of zanubrutinib in deep responses compared with ibrutinib, secondary efficacy and safety endpoints underscore the potential clinical role of zanubrutinib in the treatment algorithm of WM independent of the MYD88 mutational status. Combination regimens and non-covalent BTK inhibitors are emerging as promising treatment strategies. Long-term data will determine whether next-generation BTK inhibitors are more potent and safer compared with ibrutinib, and whether they are able to overcome resistance to ibrutinib, either alone or in combination with inhibitors of other interrelated molecular pathways.
| S-EPMC7874350 | biostudies-literature
Project description:The phase II study of tirabrutinib monotherapy at a daily dose of 480 mg under fasting conditions for treatment-naïve and relapsed/refractory Waldenström's macroglobulinemia (ONO-4059-05 study) demonstrated a promising efficacy and tolerable safety profile. We conducted an unplanned analysis with a median follow-up of 24.8 months to update the efficacy and safety results and to report patient-reported quality of life. Of 27 enrolled patients, 22 patients continued receiving the study drug. The major response assessed by an independent review committee was observed in 25 patients (93%), including one and five patients who newly achieved complete response and very good partial response, respectively, after the primary analysis. The progression-free and overall survival rates at 24 months were 92.6% and 100%, respectively. Serum IgM levels in all patients except one declined and were maintained at low levels, although transient increases occurred after temporal interruption of the study drug. The disease-related symptoms including recurrent fever and hyperviscosity mostly disappeared. Health-related quality of life, assessed by cancer-specific questionnaires, was mostly maintained. Grade 3-4 neutropenia, lymphopenia, and leukopenia were newly recognized in three, two, and one patient, respectively. Grade 3 treatment-related hypertriglyceridemia was also recognized. Nine patients experienced grade 1-2 bleeding events (33%), one patient experienced grade 2 treatment-related atrial fibrillation, and one patient experienced grade 1 treatment-related hypertension. Treatment-related skin adverse events were observed in 14 patients (52%). Taken together, tirabrutinib has durable efficacy with an acceptable safety profile for treatment-naïve and refractory/relapsed Waldenström's macroglobulinemia.
| S-EPMC9207369 | biostudies-literature
Project description:Waldenstrom's macroglobulinemia (WM) is a rare lymphoplasmacytic lymphoma with indolent course and prolonged disease course. The first-in-class Bruton's tyrosine kinase inhibitor, ibrutinib, has shown significant activity and a distinct adverse event profile among both newly diagnosed and relapsed/refractory WM patients. Interestingly, clinical responses to ibrutinib have been shown to be dependent on patients' MYD88 and CXCR4 mutational status. The recent outcomes of the Phase III iNNOVATE trial showed that the combination of ibrutinib with rituximab resulted in a significantly prolonged progression-free survival compared with rituximab monotherapy, which provides a novel therapeutic option in the clinical practice especially for the rituximab-refractory WM patients. However, the need for continuous drug administration along with the unique toxicity manifestations may render the patient management challenging. Furthermore, our understanding of the underlying resistant mechanisms to ibrutinib is currently being evolved.
| S-EPMC6717707 | biostudies-literature
Project description:The use of Bruton Tyrosine Kinase (BTK) inhibitors in Waldenström's Macroglobulinemia (WM) is evolving. Ibrutinib, a first-generation BTK inhibitor, is currently approved for use in frontline and relapsed/refractory disease. Second-generation BTK inhibitors are being used and studied to improve clinical outcomes and/or safety profile. Zanubrutinib, one such second-generation inhibitor, was recently approved in treatment-naive and refractory/relapsed patients. Here, we review the use of BTK inhibitors in WM in front-line and refractory or relapsed settings. We also highlight common adverse events, the emergence of BTK inhibitors resistance, and future directions of their use.
| S-EPMC9358782 | biostudies-literature