Bárbara Mora, Francesca Palandri, Paola Guglielmelli, Andrew Kuykendall, Margherita Maffioli, Alessandra Iurlo, Valerio De Stefano, Silvia Salmoiraghi, Timothy Devos, Federico Itri, Francisco Cervantes, Jean‐Jacques Kiladjian, Matteo G. Della Porta, Francesco Albano, J Gotlib, Giulia Benevolo, Marianna Caramella, Marco Ruggeri, Elisa Rumi, David M. Ross, Chiara Pessina, Ilaria Colugnat, F. Orsini, Giorgia Micucci, Giada Rotunno, Rami S. Komrokji, Daniele Cattaneo, Patrizia Chiusolo, Marta Bortolotti, Tiziano Barbui, Daniela Cilloni, Massimo Breccia, Giuseppe Alberto Palumbo, Filippo Branzanti, Ludovica Margotto, M. Franchi, Alessandro M. Vannucchi, Francesco Passamonti
ABSTRACT: Secondary myelofibrosis (SMF) represents a late stage of polycythemia vera (PV) and essential thrombocythemia (ET), with overall survival (OS) currently defined by the myelofibrosis secondary to PV and ET 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%) patients reported at least 1 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%; 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< .0001 to .02): hemoglobin level <11 g/dL (1 point), circulating blasts ≥3% (2 points), platelet count <150 × 109/L (2 points), age (0.21 points/y), ASXL1 without UTS mutations (1 point), and any UTS mutations (3 points). Finally, we developed the MYSEC-molecular prognostic model (MYSEC-mPM) allocating 582 patients with SMF into 4 categories with different OS (P < .001): low (median OS, 18.0 years; score <14), intermediate-1 (8.8. years; score, 14-16), intermediate-2 (4.6 years; score, 17-18), and high risk (1.9 years; score ≥19). Additionally, in 381 patients with SMF and 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 improves survival prediction in SMF, outperforming the MYSEC-PM.