Genomic analysis of primary and secondary myelofibrosis redefines the prognostic impact of <i>ASXL1</i> mutations: a FIM study
Damien Luque Paz, Jérémie Riou, Emmanuelle Verger, Bruno Cassinat, Aurélie Chauveau, Jean‐Christophe Ianotto, Brigitte Dupriez, Françoise Boyer, Maxime Renard, Olivier Mansier, Anne Murati, Jérôme Rey, Gabriel Étienne, Véronique Mansat‐De Mas, Suzanne Tavitian, Olivier Nibourel, Stéphane Girault, Yannick Le Bris, François Girodon, Dana Ranta, Jean‐Claude Chomel, Pascale Cony‐Makhoul, Pierre Sujobert, Margot Robles, Raouf Ben Abdelali, Olivier Kosmider, Laurane Cottin, Lydia Roy, Ivan Sloma, Fabienne Vacheret, Mathieu Wémeau, Pascal Mossuz, Borhane Slama, Vincent Cussac, Guillaume Denis, Anouk Walter‐Petrich, Barbara Burroni, Nathalie Jézéquel, Stéphane Giraudier, Éric Lippert, Gérard Socié, Jean‐Jacques Kiladjian, Valérie Ugo
Abstract
We aimed to study the prognostic impact of the mutational landscape in primary and secondary myelofibrosis. The study included 479 patients with myelofibrosis recruited from 24 French Intergroup of Myeloproliferative Neoplasms (FIM) centers. The molecular landscape was studied by high-throughput sequencing of 77 genes. A Bayesian network allowed the identification of genomic groups whose prognostic impact was studied in a multistate model considering transitions from the 3 conditions: myelofibrosis, acute leukemia, and death. Results were validated using an independent, previously published cohort (n = 276). Four genomic groups were identified: patients with TP53 mutation; patients with ≥1 mutation in EZH2, CBL, U2AF1, SRSF2, IDH1, IDH2, NRAS, or KRAS (high-risk group); patients with ASXL1-only mutation (ie, no associated mutation in TP53 or high-risk genes); and other patients. A multistate model found that both TP53 and high-risk groups were associated with leukemic transformation (hazard ratios [HRs] [95% confidence interval], 8.68 [3.32-22.73] and 3.24 [1.58-6.64], respectively) and death from myelofibrosis (HRs, 3.03 [1.66-5.56] and 1.77 [1.18-2.67], respectively). ASXL1-only mutations had no prognostic value that was confirmed in the validation cohort. However, ASXL1 mutations conferred a worse prognosis when associated with a mutation in TP53 or high-risk genes. This study provides a new definition of adverse mutations in myelofibrosis with the addition of TP53, CBL, NRAS, KRAS, and U2AF1 to previously described genes. Furthermore, our results argue that ASXL1 mutations alone cannot be considered detrimental.