Diagnostic and prognostic contribution of targeted NGS in patients with triple‐negative myeloproliferative neoplasms

Acha, Pamela; Xandri, Marisol; Fuster‐Tormo, Francisco; Palomo, Laura; Xicoy, Blanca; Cabezón, Marta; Marcé, Sílvia; Granada, Isabel; D, Vela; Sagüés, Miguel; Boqué, Concepción; Plensa, Esther; Pineda, Alberto; Feliú, Evarist; Solé, Françesc; Zamora, Lurdes

doi:10.1002/ajh.25580

Cited by 18 publications

(14 citation statements)

References 5 publications

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“…Indeed, NGS revealed that 53% of 183 Mayo Clinic ET patients harbored one or more sequence variants/mutations other than JAK2/CALR/MPL, being TET2 and ASXL1 the most frequent ones. Interestingly, some of these variants are reported at high VAF in the literature, in a non-negligible fraction of cases within large cohort studies focusing on the topic of triple-negative MPNs (44) and clonal hematopoiesis of indeterminate potential (CHIP) (45,46). In accordance with these data, in our cohort we also found a high VAF, with a mean value of 43%.…”

Section: Discussionsupporting

confidence: 90%

Triple-Negative Essential Thrombocythemia: Clinical-Pathological and Molecular Features. A Single-Center Cohort Study

et al. 2021

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Lack of demonstrable mutations affecting JAK2, CALR, or MPL driver genes within the spectrum of BCR-ABL1-negative myeloproliferative neoplasms (MPNs) is currently referred to as a triple-negative genotype, which is found in about 10% of patients with essential thrombocythemia (ET) and 5–10% of those with primary myelofibrosis (PMF). Very few papers are presently available on triple-negative ET, which is basically described as an indolent disease, differently from triple-negative PMF, which is an aggressive myeloid neoplasm, with a significantly higher risk of leukemic evolution. The aim of the present study was to evaluate the bone marrow morphology and the clinical-laboratory parameters of triple-negative ET patients, as well as to determine their molecular profile using next-generation sequencing (NGS) to identify any potential clonal biomarkers. We evaluated a single-center series of 40 triple-negative ET patients, diagnosed according to the 2017 WHO classification criteria and regularly followed up at the Hematology Unit of our Institution, between January 1983 and January 2019. In all patients, NGS was performed using the Illumina Ampliseq Myeloid Panel; morphological and immunohistochemical features of the bone marrow trephine biopsies were also thoroughly reviewed. Nucleotide variants were detected in 35 out of 40 patients. In detail, 29 subjects harbored one or two variants and six cases showed three or more concomitant nucleotide changes. The most frequent sequence variants involved the TET2 gene (55.0%), followed by KIT (27.5%). Histologically, most of the cases displayed a classical ET morphology. Interestingly, prevalent megakaryocytes morphology was more frequently polymorphic with a mixture of giant megakaryocytes with hyperlobulated nuclei, normal and small sized maturing elements, and naked nuclei. Finally, in five cases a mild degree of reticulin fibrosis (MF-1) was evident together with an increase in the micro-vessel density. By means of NGS we were able to identify nucleotide variants in most cases, thus we suggest that a sizeable proportion of triple-negative ET patients do have a clonal disease. In analogy with driver genes-mutated MPNs, these observations may prevent issues arising concerning triple-negative ET treatment, especially when a cytoreductive therapy may be warranted.

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Section: Discussionsupporting

confidence: 90%

Triple-Negative Essential Thrombocythemia: Clinical-Pathological and Molecular Features. A Single-Center Cohort Study

et al. 2021

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“…9 The use of NGS is further supported by the observation that atypical JAK2 and MPL mutations have been identified in series of TN-MPN. [10][11][12] Our series prompted the histological review in cases with available material. Of 13 cases where no identifiable clonal marker was identified 4 patients showed morphological features of ET ( figure 1, table 4).…”

Section: Discussionmentioning

confidence: 99%

Mutational profiling in suspected triple-negative essential thrombocythaemia using targeted next-generation sequencing in a real-world cohort

et al. 2020

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Essential thrombocythaemia (ET) is driven by somatic mutations involving the JAK2, CALR and MPL genes. Approximately 10% of patients lack driver mutations and are referred as ‘triple-negative’ ET (TN-ET). The diagnosis of TN-ET, however, relies on bone marrow examination that is not always performed in routine practice, and thus in the real-world setting, there are a group of cases with suspected TN-myeloproliferativeneoplasm.In this real-world cohort, patients with suspected TN-ET were initially rescreened for JAK2, CALR and MPL and then targeted next-generation sequencing (NGS) was applied.The 35 patients with suspected TN-ET had a median age at diagnosis of 43 years (range 16–79) and a follow-up of 10 years (range 2–28). The median platelet count was 758×109/L (range 479–2903). Thrombosis prior to and following diagnosis was noted in 20% and 17% of patients. Six patients were JAK2V617F and two patients were CALR positive on repeat screening. NGS results showed that 24 of 27 patients harboured no mutations. Four mutations were noted in three patients.There was no evidence of clonality for the majority of patients with suspected TN-ET with targeted NGS analysis. Detection of driver mutations in those who were previously screened suggests that regular rescreening is required. This study also questions the diagnosis of TN-ET without the existence of a clonal marker.

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“…The identification of myeloid neoplasm-related gene derangements constitutes a major diagnostic criterion (i) to prove the clonal nature of the disease (particularly in TN cases); and/or (ii) to support/exclude specific disease subtypes [55]. With its increasing availability in the clinical setting, targeted NGS also allows the detection of atypical mutations in driver genes and of genetic derangements impacting on disease progression [56][57][58]. The quantitative assessment of VAF can also provide clinically relevant information on the disease burden and on the risk of adverse events.…”

Section: Mpn With Unconventional Molecular Featuresmentioning

confidence: 99%

“…It should also be noted that large cohort studies on TN MPNs [56] and CHIP [75,76] report high allele burdens for the above-mentioned variants in a substantial fraction of patients, implying a relevant role for such (even "high risk") imbalances in sustaining clonal hematopoiesis.…”

Section: Mpn With Chip-like Molecular Featuresmentioning

confidence: 99%

The Classification of Myeloproliferative Neoplasms: Rationale, Historical Background and Future Perspectives with Focus on Unclassifiable Cases

Pizzi

Croci

Ruggeri

et al. 2021

Cancers

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Myeloproliferative neoplasms (MPNs) are a heterogeneous group of clonal hematopoietic stem cell disorders, characterized by increased proliferation of one or more myeloid lineages in the bone marrow. The classification and diagnostic criteria of MPNs have undergone relevant changes over the years, reflecting the increased awareness on these conditions and a better understanding of their biological and clinical-pathological features. The current World Health Organization (WHO) Classification acknowledges four main sub-groups of MPNs: (i) Chronic Myeloid Leukemia; (ii) classical Philadelphia-negative MPNs (Polycythemia Vera; Essential Thrombocythemia; Primary Myelofibrosis); (iii) non-classical Philadelphia-negative MPNs (Chronic Neutrophilic Leukemia; Chronic Eosinophilic Leukemia); and (iv) MPNs, unclassifiable (MPN-U). The latter are currently defined as MPNs with clinical-pathological findings not fulfilling the diagnostic criteria for any other entity. The MPN-U spectrum traditionally encompasses early phase MPNs, terminal (i.e., advanced fibrotic) MPNs, and cases associated with inflammatory or neoplastic disorders that obscure the clinical-histological picture. Several lines of evidence and clinical practice suggest the existence of additional myeloid neoplasms that may expand the spectrum of MPN-U. To gain insight into such disorders, this review addresses the history of MPN classification, the evolution of their diagnostic criteria and the complex clinical-pathological and biological features of MPN-U.

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Diagnostic and prognostic contribution of targeted NGS in patients with triple‐negative myeloproliferative neoplasms

Cited by 18 publications

References 5 publications

Triple-Negative Essential Thrombocythemia: Clinical-Pathological and Molecular Features. A Single-Center Cohort Study

Triple-Negative Essential Thrombocythemia: Clinical-Pathological and Molecular Features. A Single-Center Cohort Study

Mutational profiling in suspected triple-negative essential thrombocythaemia using targeted next-generation sequencing in a real-world cohort

The Classification of Myeloproliferative Neoplasms: Rationale, Historical Background and Future Perspectives with Focus on Unclassifiable Cases

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