Cell‐free <scp>DNA</scp> analysis for the detection of <scp>MYD88</scp> and <scp>CXCR4</scp> mutations in <scp>IgM</scp> monoclonal gammopathies; an update with clinicopathological correlations

Ntanasis‐Stathopoulos, Ioannis; Bagratuni, Tina; Gavriatopoulou, Maria; Patseas, Dimitrios; Liacos, Christine‐Ivy; Kanellias, Nikolaos; Fotiou, Despina; Tsiligkeridou, Eleni; Andreatou, Amalia; Mavrianou-Koutsoukou, Nefeli; Migkou, Magdalini; Eleutherakis‐Papaiakovou, Evangelos; Ρούσσου, Μαρία; Terpos, Evangelos; Kastritis, Efstathios

doi:10.1002/ajh.25802

Cited by 13 publications

(11 citation statements)

References 6 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A prior study of cfDNA in WM patients did not identify an impact of BM involvement on test performance; however, 12 patients with a low BM involvement were excluded in that study due to insufficient DNA, which may have confounded the findings. 10,11 Age, serum albumin, serum IgM and IgG levels, and prior treatment status did not impact the concordance for MYD88 L265P detection with cfDNA (p > .05 for all comparisons). Discordant patients by BMMC, PB19+, and PBMC tissue fractions similarly had a significantly lower BM involvement (data not shown), akin to previous studies.…”

mentioning

confidence: 88%

“…7,9 Recent studies have demonstrated the feasibility of identifying MYD88 and CXCR4 mutations by using cell-free DNA (cfDNA) from WM patients. [10][11][12] These findings prompted us to perform a comprehensive analysis comparing the use of cfDNA to matched BM and PB, with or without B-cell selection, for detection of the most common MYD88 (L265P) and CXCR4 (S338X) mutations in WM patients.…”

Section: Mutations In Waldenström Macroglobulinemiamentioning

confidence: 99%

“…The rates of concordance between the different tissue fractions and BM19+ were consistent with previous studies. 7,[9][10][11][12] We then compared the clinicopathological characteristics between patients with concordant and discordant results for MYD88 L266P by cfDNA. Discordant patients had a lower median BM involvement (9% vs. 45%; p = .04) and serum IgM level (985 vs. 1597 mg/dL; p = .02), as well as a higher hemoglobin level (12.3 vs. 10.7 g/dL; p = .03) versus concordant patients.…”

Section: Mutations In Waldenström Macroglobulinemiamentioning

confidence: 99%

See 2 more Smart Citations

Cell‐free DNA analysis for detection of MYD88^L265P and CXCR4^S338X mutations in Waldenström macroglobulinemia

et al. 2021

View full text Add to dashboard Cite

mentioning

confidence: 88%

Section: Mutations In Waldenström Macroglobulinemiamentioning

confidence: 99%

Section: Mutations In Waldenström Macroglobulinemiamentioning

confidence: 99%

See 1 more Smart Citation

Cell‐free DNA analysis for detection of MYD88^L265P and CXCR4^S338X mutations in Waldenström macroglobulinemia

et al. 2021

View full text Add to dashboard Cite

“…In WM, there is constitutive activation of BTK secondary to multiple mutations, detected by multiple methods in whole bone marrow, CD19+ selected cells, peripheral blood and cell-free deoxyribonucleic acid (DNA). 35–39 The first mutation described using whole-genome sequencing of CD19+ bone marrow cells, which is found in up to 90% of WM patients, is the somatic activating mutation of myeloid differentiation factor, MYD88 L265P Leu265Pro. 40–42 MYD88-activating mutations promote Myddosome self-assembly and trigger TLR activation via BTK interaction and signaling of interleukin 1 (IL-1), IRAK4/IRAK1 and NF-κB.…”

Section: Btk Inhibition In Wmmentioning

confidence: 99%

Current and novel BTK inhibitors in Waldenström’s macroglobulinemia

Ntanasis‐Stathopoulos

Gavriatopoulou

Fotiou

et al. 2021

Therapeutic Advances in Hematology

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…We have recently evaluated the role of peripheral blood (PB) cellfree DNA (cfDNA) in characterizing the mutational status of MYD88 and CXCR4 as a tool for a non-invasive screening of patients with IgM monoclonal gammopathies 13,14 . In continuation to this, we now describe a newly developed, highly-sensitive, costeffective competitive allele-specific quantitative real time PCR assay (Cast-PCR) for the identification of MYD88 L265P mutation in BM and PB samples from patients with IgM monoclonal gammopathies which can be easily applied in a typical real time PCR protocol as part of routine clinical.…”

Section: Introductionmentioning

confidence: 99%

Determination of MYD88L265P mutation fraction in IgM monoclonal gammopathies

et al. 2022

Self Cite

View full text Add to dashboard Cite

We here describe a novel method for the detection of MYD88L265P mutation using a competitive allele specific PCR (Cast-PCR) assay. This assay has a sensitivity of 1x10-3, is applicable in reactions containing very low amounts of DNA (as low as 20 pg) and allowed the detection of MYD88L265P somatic mutation in both tumor derived DNA (tDNA) and cell free DNA (cfDNA). In addition, using Cast-PCR assay we were able to determine the mutation allele fraction (MAF) in each tested sample. We then analyzed baseline tDNA and cfDNA samples from 163 patients (53 with IgM-MGUS and 110 with WM, of which 54 were asymptomatic and 56 symptomatic) and also in sequential samples of 37 patients. MAF in both cfDNA and tDNA was higher among patients with symptomatic compared to asymptomatic WM and in those with asymptomatic WM compared to IgM-MGUS patients. In addition, the evaluation of sequential samples showed that MAF decreased after treatment while increased in patients who relapsed or progressed to symptomatic WM. Thus, Cast-PCR is a highly-sensitive, cost-effective diagnostic tool for MYD88L265P detection, applicable in both tumor and cell free DNA samples which also provides a quantitative evaluation of the tumor load in patients with IgM monoclonal gammopathies.

show abstract

Cell‐free DNA analysis for the detection of MYD88 and CXCR4 mutations in IgM monoclonal gammopathies; an update with clinicopathological correlations

Cited by 13 publications

References 6 publications

Cell‐free DNA analysis for detection of MYD88^L265P and CXCR4^S338X mutations in Waldenström macroglobulinemia

Cell‐free DNA analysis for detection of MYD88^L265P and CXCR4^S338X mutations in Waldenström macroglobulinemia

Current and novel BTK inhibitors in Waldenström’s macroglobulinemia

Determination of MYD88L265P mutation fraction in IgM monoclonal gammopathies

Contact Info

Product

Resources

About

Cell‐free DNA analysis for the detection of MYD88 and CXCR4 mutations in IgM monoclonal gammopathies; an update with clinicopathological correlations

Cited by 13 publications

References 6 publications

Cell‐free DNA analysis for detection of MYD88L265P and CXCR4S338X mutations in Waldenström macroglobulinemia

Cell‐free DNA analysis for detection of MYD88L265P and CXCR4S338X mutations in Waldenström macroglobulinemia

Current and novel BTK inhibitors in Waldenström’s macroglobulinemia

Determination of MYD88L265P mutation fraction in IgM monoclonal gammopathies

Contact Info

Product

Resources

About

Cell‐free DNA analysis for detection of MYD88^L265P and CXCR4^S338X mutations in Waldenström macroglobulinemia

Cell‐free DNA analysis for detection of MYD88^L265P and CXCR4^S338X mutations in Waldenström macroglobulinemia