Diagnostic Next-generation Sequencing Frequently Fails to Detect MYD88L265P in Waldenström Macroglobulinemia

Kofides, Amanda; Hunter, Zachary; Liu, Xu; Tsakmaklis, Nicholas; Demos, Maria; Munshi, Manit; Liu, Xia; Guerrera, Maria Luisa; Leventoff, Carly; White, Timothy P.; Flynn, Catherine; Meid, Kirsten; Patterson, Christopher J.; Yang, Guang; Branagan, Andrew R.; Sarosiek, Shayna; Castillo, Jorge J.; Treon, Steven P.; Gustine, Joshua

doi:10.1097/hs9.0000000000000624

Cited by 17 publications

(12 citation statements)

References 25 publications

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“…A recent study demonstrated that in unselected BM samples, AS-qPCR was superior in detecting CXCR4 S338X compared to amplicon massively parallel sequencing (MPS) (63% vs. 16%) [92]. Additionally, sensitivity of both methods was higher for MYD88 L265P detection (98% and 69% respectively), confirming the subclonal nature of CXCR4 S338X but also indicating a direct dependence of MPS performance on the level of BM involvement [58,67,92].…”

Section: Referencementioning

confidence: 93%

Nucleic Acid Biomarkers in Waldenström Macroglobulinemia and IgM-MGUS: Current Insights and Clinical Relevance

et al. 2022

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Waldenström Macroglobulinemia (WM) is an indolent lymphoplasmacytic lymphoma, characterized by the production of excess immunoglobulin M monoclonal protein. WM belongs to the spectrum of IgM gammopathies, ranging from asymptomatic IgM monoclonal gammopathy of undetermined significance (IgM-MGUS), through IgM-related disorders and asymptomatic WM to symptomatic WM. In recent years, its complex genomic and transcriptomic landscape has been extensively explored, hereby elucidating the biological mechanisms underlying disease onset, progression and therapy response. An increasing number of mutations, cytogenetic abnormalities, and molecular signatures have been described that have diagnostic, phenotype defining or prognostic implications. Moreover, cell-free nucleic acid biomarkers are increasingly being investigated, benefiting the patient in a minimally invasive way. This review aims to provide an extensive overview of molecular biomarkers in WM and IgM-MGUS, considering current shortcomings, as well as potential future applications in a precision medicine approach.

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Section: Referencementioning

confidence: 93%

Nucleic Acid Biomarkers in Waldenström Macroglobulinemia and IgM-MGUS: Current Insights and Clinical Relevance

et al. 2022

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“…It is important to note, however, that there are substantial differences between the techniques used in prospective clinical trials for MYD88 and CXCR4 mutational testing, which can substantially impact the detection rate of these mutations, making the interpretation of the results across studies challenging. 33,34 Ibrutinib (with and without rituximab) and zanubrutinib are safe, effective, and reasonable treatment options for patients with WM. The longer experience and ease of administration with ibrutinib would need to be counterbalanced against the favorable side effect profile of zanubrutinib.…”

Section: How Do We Choose Between Ibrutinib and Zanubrutinib In Wm?mentioning

confidence: 99%

“…There was a low rate of AF in single‐arm studies with tirabrutinib and orelabrutinib 39,42 . A preclinical study in mice showed that exposure to ibrutinib, but not acalabrutinib, induced AF, left atrial enlargement, myocardial fibrosis, and inflammation 33,43 . C‐terminal Src kinase (Csk) was the strongest candidate for ibrutinib‐induced AF, and cardiac‐specific Csk knockouts induced a similar phenotype to ibrutinib exposure.…”

Section: Selected Management Issuesmentioning

confidence: 99%

Bruton tyrosine kinase inhibitors in the management of Waldenström macroglobulinemia

et al. 2023

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Bruton tyrosine kinase (BTK) inhibitors have taken a central role in the management of patients with Waldenström macroglobulinemia and are the only agents approved by the Food and Drug Administration (FDA) to treat these patients. Although associated with high rates of durable responses, unmet needs with BTK inhibitor therapy include indefinite duration therapy, high cost, scarcity of complete responses, and lower rates and shorter duration of response in patients with CXCR4 mutations.Herein, we review the data supporting the use of covalent BTK inhibitors, selected management issues, clinical trials with covalent BTK inhibitor combination regimens, and up-and-coming non-covalent BTK inhibitors. | INTRODUCTIONWaldenström macroglobulinemia (WM) is an indolent lymphoma characterized by the accumulation of malignant IgM-producing lymphoplasmacytic cells in the bone marrow (BM), lymph nodes, and other organs. MYD88 and CXCR4 somatic mutations (MYD88 MUT and CXCR4 MUT , respectively) are present in 95%-97%, and 30%-40% of patients with WM, respectively, and impact the clinical presentation and outcomes of therapy with Bruton tyrosine kinase (BTK) inhibitors. [1][2][3][4][5][6][7][8] Many WM patients are asymptomatic at the time of the diagnosis, and treatment should be deferred in these patients, as 20% of these patients might not need therapy for over a decade, and the life expectancy of asymptomatic patients is comparable to age and sex-matched individuals without WM. 9,10 However, most WM patients will eventually need therapy.Multiple treatment options are available for patients with WM and have classically included combinations of alkylating agents, nucleoside analogues, proteasome inhibitors, and anti-CD20 monoclonal antibodies, which have been shown to be safe and highly effective in prospective clinical trials. 11-13 BTK inhibitors have been added to the armamentarium against WM and are arguably the most active monotherapy agents in these patients. The United States Food and Drug Administration (FDA) granted the first approval of any drug specific for WM to ibrutinib in 2015. Other FDA approvals include ibrutinib plus rituximab in 2018 and, more recently, zanubrutinib in 2021.In the present document, we provide a review of the emerging data on the safety and efficacy of BTK inhibitors in the treatment of patients with WM. | THE BTK PATHWAY IN WMMYD88 is a member of the Toll-like receptor (TLR) pathway that functions as an adapter protein that triggers downstream signaling in response to pathogenic activation of TLRs. In WM, mutations in MYD88 result from missense mutations in the key signaling Toll/

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“…There is no definitive evidence from prospective clinical trials that the MYD88 or CXCR4 status is predictive of response to chemoimmunotherapy regimens, although this is complicated by the small numbers of patients in subgroups and also the different methods of assessment which can lead to different sensitivities of detection. 109,110 Prospective data from the US have demonstrated that in patients treated with ibrutinib for relapsed and refractory WM, those with MYD88 L265P CXCR4 WT had more responses than those with MYD88 L265P CXCR4 warts, hypogammaglobu linaemia, imm uno defici ency, myelokathexis (WHIM) (97% vs. 68%, p < 0.0001) with no major responses seen in the four patients who were wild-type for both genes. 28 Furthermore, there was a suggestion that in the patients with a CXCR4 mutation, nonsense mutations were associated with a poorer outcome.…”

Section: Considerations For Choice Of Therapymentioning

confidence: 99%

Diagnosis and management of Waldenström macroglobulinaemia—A British Society for Haematology guideline

et al. 2022

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Scope The objective of this guideline is to provide healthcare professionals with clear guidance on the management of patients with Waldenström macroglobulinaemia. In individual patients, circumstances may dictate an alternative approach. Methodology This guideline was compiled according to the British Society for Haematology (BSH) process at http://www.b-s-h.org.uk/guidelines/proposing-and-writing-a-new-bsh-guideline/. Recommendations are based on a review of the literature using Medline, Pubmed, Embase, Central, Web of Science searches from beginning of 2013 (since the publication of the previous guidelines) up to November 2021. The following search terms were used: Waldenström(’s) macroglobulin(a)emia OR lymphoplasmacytic lymphoma, IgM(‐related) neuropathy OR cold h(a)emagglutinin disease OR cold agglutinin disease OR cryoglobulin(a)emia AND (for group a only) cytogenetic OR molecular OR mutation OR MYD88 OR CXCR4, management OR treatment OR transfusion OR supportive care OR plasma exchange OR plasmapheresis OR chemotherapy OR bendamustine OR bortezomib OR ibrutinib OR fludarabine OR dexamethasone OR cyclophosphamide OR rituximab OR everolimus, bone marrow transplantation OR stem cell transplantation. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) nomenclature was used to evaluate levels of evidence and to assess the strength of recommendations. The GRADE criteria can be found at http://www.gradeworkinggroup.org. Review of the manuscript was performed by the British Society for Haematology (BSH) Guidelines Committee Haemato‐Oncology Task Force, the BSH Guidelines Committee and the Haemato‐Oncology sounding board of BSH. It was also on the members section of the BSH website for comment. It has also been reviewed by UK Charity WMUK; these organisations do not necessarily approve or endorse the contents.

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Diagnostic Next-generation Sequencing Frequently Fails to Detect MYD88L265P in Waldenström Macroglobulinemia

Cited by 17 publications

References 25 publications

Nucleic Acid Biomarkers in Waldenström Macroglobulinemia and IgM-MGUS: Current Insights and Clinical Relevance

Nucleic Acid Biomarkers in Waldenström Macroglobulinemia and IgM-MGUS: Current Insights and Clinical Relevance

Bruton tyrosine kinase inhibitors in the management of Waldenström macroglobulinemia

Diagnosis and management of Waldenström macroglobulinaemia—A British Society for Haematology guideline

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