Clinical and Molecular Characterization of Triple-Negative Essential Thrombocythemia: Data from the Prospective Spanish Registry of Essential Thrombocythemia

Media type: E-Article

Title: Clinical and Molecular Characterization of Triple-Negative Essential Thrombocythemia: Data from the Prospective Spanish Registry of Essential Thrombocythemia

Contributor: Gil-Manso, Rodrigo; Carreño, Gonzalo; Hernandez Boluda, Juan Carlos; Perez Lopez, Raul; Gómez-Casares, Maria Teresa; Ferrer Marin, Francisca; Arellano-Rodrigo, Eduardo; Angona, Anna; García Gutiérrez, Valentín; Noya, Maria Soledad; Senin, María Alicia; Magro, Elena; Pastor, Irene; Mata, María Isabel; Cuevas, Beatriz; Mora, Elvira; Martinez, Cristina; Alonso-Dominguez, Juan M.; Pérez-Encinas, Manuel; Caballero Navarro, Gonzalo; Cortes Vázquez, Miguel A.; del Río, Carmen; Martinez Lopez, Joaquin; Ayala, Rosa;

Published: American Society of Hematology, 2023

Language: English

DOI: 10.1182/blood-2023-188875

ISSN: 1528-0020; 0006-4971

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Description: Introduction Triple-negative Essential Thrombocythemia (TN-ET) accounts for up to 10-20% of patients with a histological diagnosis of ET. Despite being considered an indolent disease, it remains a diagnostic and therapeutic challenge as it can be confused with non-clonal thrombocytosis and its prognostic factors and management are not standardized. Objectives The aim of this study was to evaluate the utility of a Next Generation Sequencing (NGS) panel targeting recurrently mutated genes in myeloid pathology for detecting genetic variants in patients diagnosed with TN-ET and to assess the significance of these variants in the risk of thrombosis and hemorrhage, progression to Acute Leukemia (AL) or Myelofibrosis (MF), and overall survival. Materials and Methods Data from 151 TN-ET patients with confirmed biopsy and NGS sequencing from the Spanish Registry of Essential Thrombocythemia of the Spanish Group of Philadelphia-Negative Myeloproliferative Neoplasms was obtained. This registry includes information on diagnosis, molecular biology, clinical characteristics, and molecular biology. In addition, 39 patients whose molecular diagnosis was performed at the Molecular Biology Laboratory of the Hematology Department at Hospital Universitario 12 de Octubre, Madrid, Spain were included. This last panel included the genes: ANKRD26, ASXL1, ATG2B, BCOR, BCORL1, CALR, CBL, CEBPA, CSF3R, CUX1, DDX41, DNMT3A, EGLN1, EPAS1, EPOR, ETNK1, ETV6, EZH2, FLT3, GATA2, GNAS, GNB1, GSKIP, IDH1, IDH2, JAK2, KDM6A, KIT, KMT2A, KRAS, MBD4, MPL, NF1, NFE2, NPM1, NRAS, PHF6, PPM1D, PRPF8, PTPN11, RAD21, RIT1, RRAS, RUNX1, SAMD9, SAMD9L, SETBP1, SF3A1, SF3B1, SH2B3, SMC1A, SMC3, SRSF2, STAG2, TERC, TERT, TET2, THPO, TP53, U2AF1, VHL, WT1, ZRSR2. Statistical analyses were performed using SPSS v.29.0. Results A canonical mutation was detected in 20 out of the 190 studied patients, ( JAK2 V617F n=13, CALR n=3 and MPL n=4) being discarded from subsequent studies. Among the other 170 samples, 206 genetic variants were detected in a total of 86 patients (median 2, range 1-9). A total of 39 pathogenic (P) or probably pathogenic (PP) variants were found in 28 patients, whereas 59 uncertain significance (US) and 108 benign (B) variants were found in 44 and 54 patients, respectively. The distribution of genes in which P/PP/US variants were detected is shown in Figure 1. Patients with P /PP mutations had a statistically higher age compared to the remaining (50 vs. 64.8 years; p&lt;0.001). The prevalence of males was higher in the group where P/PP mutations were detected (57.14% vs. 28.87%; p=0.004). No differences were found regarding cardiovascular comorbidity or symptomatology at diagnosis, but the P/PP group presented a higher frequency of thrombosis prior to diagnosis (28.57% vs. 5.64%; p=0.001). There were no differences in hemoglobin, leukocyte, or platelet counts at diagnosis according to the presence of P/PP variants. The presence of P/PP mutations was associated with a higher risk of progression to AL and a lower overall survival. A higher risk of thrombosis or progression to MF was not found (Figure 2). No differences were found in the risk of thrombosis, transformation, or overall survival between patients with or without the presence of US, PB or B variants. Conclusions The use of NGS technology is useful for the diagnosis and prognostication of TN-ET. The detection of P/PP mutations in patients diagnosed with TN-ET is associated with a higher risk of transformation to AL and lower overall survival, but not with higher risk of thrombosis or progression to MF. It is necessary to evaluate the individual risk of each of these mutations and the potential prognostic role of variants of US.

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