Genomic profiling for decision-making in post-polycythemia vera and post-essential thrombocythemia myelofibrosis

Secondary myelofibrosis (SMF) represents a late stage of polycythemia vera and essential thrombocythemia, with overall survival (OS) currently defined by the MYelofibrosis SECondary to PV and ET (MYSEC) Prognostic Model (MYSEC-PM). To identify additional myeloid neoplasm-associated cancer gene variants (CGVs) associated with SMF outcome, we evaluated next-generation sequencing panel testing in 644 patients within the MYSEC cohort. Overall, 429 (66.6%) subjects reported at least one CGV, with ASXL1, TET2 and DNMT3A being the most frequently involved. Specific molecular profiles affected OS (p < .001): U2AF1, TP53 or SRSF2 variants (UTS, 9.3% of cases, median OS 4.1 years) and ASXL1 without UTS (25.3%, median OS 8.4 years). By integrating these genetic signatures within the MYSEC-PM through penalized Cox regressions, we identified the following independent predictors (p from < .0001 to .02) and weighted: hemoglobin <11 g/dl (1 point), circulating blasts ⩾3% (2), platelets <150 × 109/l (2), age (0.21 points/year), ASXL1 without UTS mutations (1) and any UTS mutations (3). Finally, we developed the MYSEC-molecular prognostic model (MYSEC-mPM) allocating 582 SMF patients into four categories with different OS (p < .001): low (median OS 18.0 years, 95%CI: 14.2-not reached; score <14), intermediate-1 (8.8. years, 95%CI: 7.7-9.7; score 14-16), intermediate-2 (4.6 years, 95%CI: 3.1-7.2; score 17-18), and high risk (1.9 years, 95%CI: 1.2-2.5; score ⩾19). Additionally, in 381 SMF with available cytogenetics, the MYSEC-mPM was implemented with complex/monosomal karyotype, generating the karyotype-enhanced MYSEC-kmPM. Our study shows that genomic and cytogenetic profiling improve survival prediction in SMF, outperforming the MYSEC-PM.

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Journal
Blood
Published
2026-03-05
DOI
https://doi.org/10.1182/blood.2025031366
Primary Topic
Myeloproliferative Neoplasms: Diagnosis and Treatment
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article
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article

Genomic profiling for decision-making in post-polycythemia vera and post-essential thrombocythemia myelofibrosis

Marta Bortolotti, Bárbara Mora, F. Orsini, M. Franchi et al.
Blood
Myeloproliferative Neoplasms: Diagnosis and Treatment
article

Genomic profiling for decision-making in post-polycythemia vera and post-essential thrombocythemia myelofibrosis

Marta Bortolotti, Bárbara Mora, F. Orsini, M. Franchi, Giorgia Micucci, Andrew Tucker Kuykendall, Francisco Cervantes, Ilaria Colugnat, Margherita Maffioli, Timothy Devos, Filippo Branzanti, Silvia Salmoiraghi, Chiara Pessina, Ludovica Margotto, Jean-Jacques Kiladjian, J Gotlib, Valerio De Stefano, Marianna Caramella, Daniele Cattaneo, Giada Rotunno, Tiziano Barbui, Alessandra Iurlo, Marco Ruggeri, Giulia Benevolo, Matteo G. Della Porta, Giuseppe Alberto Palumbo, Francesco Albano, Elisa Rumi, Alessandro M. Vannucchi, Paola Guglielmelli, Francesca Palandri, Daniela Cilloni, Patrizia Chiusolo, Federico Itri, Francesco Passamonti, Rami S. Komrokji, Massimo Breccia, David M. Ross
article en

Abstract

Secondary myelofibrosis (SMF) represents a late stage of polycythemia vera and essential thrombocythemia, with overall survival (OS) currently defined by the MYelofibrosis SECondary to PV and ET (MYSEC) Prognostic Model (MYSEC-PM). To identify additional myeloid neoplasm-associated cancer gene variants (CGVs) associated with SMF outcome, we evaluated next-generation sequencing panel testing in 644 patients within the MYSEC cohort. Overall, 429 (66.6%) subjects reported at least one CGV, with ASXL1, TET2 and DNMT3A being the most frequently involved. Specific molecular profiles affected OS (p < .001): U2AF1, TP53 or SRSF2 variants (UTS, 9.3% of cases, median OS 4.1 years) and ASXL1 without UTS (25.3%, median OS 8.4 years). By integrating these genetic signatures within the MYSEC-PM through penalized Cox regressions, we identified the following independent predictors (p from < .0001 to .02) and weighted: hemoglobin <11 g/dl (1 point), circulating blasts ⩾3% (2), platelets <150 × 109/l (2), age (0.21 points/year), ASXL1 without UTS mutations (1) and any UTS mutations (3). Finally, we developed the MYSEC-molecular prognostic model (MYSEC-mPM) allocating 582 SMF patients into four categories with different OS (p < .001): low (median OS 18.0 years, 95%CI: 14.2-not reached; score <14), intermediate-1 (8.8. years, 95%CI: 7.7-9.7; score 14-16), intermediate-2 (4.6 years, 95%CI: 3.1-7.2; score 17-18), and high risk (1.9 years, 95%CI: 1.2-2.5; score ⩾19). Additionally, in 381 SMF with available cytogenetics, the MYSEC-mPM was implemented with complex/monosomal karyotype, generating the karyotype-enhanced MYSEC-kmPM. Our study shows that genomic and cytogenetic profiling improve survival prediction in SMF, outperforming the MYSEC-PM.

Blood
Royal Adelaide Hospital (AU), Cancer Prevention Institute of California (US), Humanitas University (IT), University of Milan (IT), Université Paris Cité (FR), Ospedale di Circolo e Fondazione Macchi (IT), Agostino Gemelli University Polyclinic (IT), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT), Moffitt Cancer Center (US), University of Catania (IT), Azienda Ospedaliera Citta' della Salute e della Scienza di Torino (IT), Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda (IT), Assistance Publique – Hôpitaux de Paris (FR), Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IT), Ospedale Papa Giovanni XXIII (IT), Hospital Clínic de Barcelona (ES), Azienda Ospedaliero-Universitaria Careggi (IT), Azienda USL di Bologna (IT), Istituto Nazionale di Documentazione Innovazione e Ricerca Educativa (IT), Ospedale di Circolo di Busto Arsizio (IT), Hôpital Saint-Louis (FR), Policlinico San Matteo Fondazione (IT), Ospedale San Bortolo (IT), Istituti di Ricovero e Cura a Carattere Scientifico (IT), Ospedale San Luigi Gonzaga (IT), Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES), Stanford Cancer Institute, University of Florence (IT), University of Turin (IT), University of Bari Aldo Moro (IT), University of Milano-Bicocca (IT), Sapienza University of Rome (IT), University of Bologna (IT)
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Myeloproliferative Neoplasms: Diagnosis and Treatment
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