Genomic profiling for decision-making in post–polycythemia vera and post–essential thrombocythemia myelofibrosis
Abstract
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.
Article Details
Authors (38)
Barbara Mora
1Hematology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
Francesca Palandri
2Seragnoli Hematology Institute, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
Paola Guglielmelli
3Center for Research and Innovation of Myeloproliferative Neoplasms, AOU Careggi, University of Florence, Florence, Italy
Andrew T. Kuykendall
4Malignant Hematology Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
Margherita Maffioli
5Hematology, ASST Sette Laghi, Ospedale di Circolo, Varese, Italy
Alessandra Iurlo
1Hematology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
Valerio De Stefano
6Section of Hematology, Department of Radiological and Hematological Sciences, Catholic University, Fondazione Policlinico Gemelli IRCCS, Rome, Italy
Silvia Salmoiraghi
7FROM Research Foundation, ASST Papa Giovanni XXIII, Bergamo, Italy
Timothy Devos
8Department of Hematology, University Hospitals Leuven and Department of Microbiology and Immunology, Laboratory of Molecular Immunology (Rega Institute), KU Leuven, Leuven, Belgium
Federico Itri
9SCDU Internal Medicine with Haematological Focus, Onco-Haematological DH, AOU San Luigi Gonzaga, Orbassano, Italy
Francisco Cervantes
10Hematology Department, Hospital Clinic, IDIBAPS, University of Barcelona, Barcelona, Spain
Jean-Jacques Kiladjian
Matteo G. Della Porta
Francesco Albano
14Hematology and Stem Cell Transplantation Unit, Department of Precision and Regenerative Medicine and Ionian Area, Aldo Moro University of Bari, Bari, Italy
Jason Gotlib
15Division of Hematology, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA
Giulia Benevolo
16Hematology Unit, Città della Salute e della Scienza of di Torino, Turin, Italy
Marianna Caramella
17Hematology, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy
Marco Ruggeri
Elisa Rumi
19Department of Molecular Medicine, University of Pavia, Pavia, Italy
David M. Ross
21Haematology Directorate, SA Pathology, Royal Adelaide Hospital and Flinders Medical Centre, Adelaide, Australia
Chiara Pessina
22SSD Specialized Laboratory of Medical Genetics, Cytogenetics and Medical Genetics, ASST Sette Laghi, Ospedale di Circolo, Varese, Italy
Ilaria Colugnat
22SSD Specialized Laboratory of Medical Genetics, Cytogenetics and Medical Genetics, ASST Sette Laghi, Ospedale di Circolo, Varese, Italy
Francesco Orsini
22SSD Specialized Laboratory of Medical Genetics, Cytogenetics and Medical Genetics, ASST Sette Laghi, Ospedale di Circolo, Varese, Italy
Giorgia Micucci
23Hematology Unit, Istituto Romagnolo per lo Studio dei Tumori “Dino Amadori” IRCCS, Meldola, Italy
Giada Rotunno
3Center for Research and Innovation of Myeloproliferative Neoplasms, AOU Careggi, University of Florence, Florence, Italy
Rami S. Komrokji
H. Lee Moffitt Cancer Center, Tampa, Florida, United States
Daniele Cattaneo
1Hematology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
Patrizia Chiusolo
6Section of Hematology, Department of Radiological and Hematological Sciences, Catholic University, Fondazione Policlinico Gemelli IRCCS, Rome, Italy
Marta Bortolotti
1Hematology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
Tiziano Barbui
7FROM Research Foundation, ASST Papa Giovanni XXIII, Bergamo, Italy
Daniela Cilloni
24Hematology Division, Mauriziano Hospital, Department of Clinical and Biological Sciences, University of Turin, Turin, Italy
Massimo Breccia
25Hematology, Department of Translational and Precision Medicine, Azienda Policlinico Umberto I, Sapienza University, Rome, Italy
Giuseppe A. Palumbo
26Dipartimento di Scienze Mediche, Chirurgiche e Tecnologie Avanzate “G.F. Ingrassia,” University of Catania, Catania, Italy
Filippo Branzanti
27Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
Ludovica Margotto
28Laboratory of Healthcare Research & Pharmacoepidemiology, Department of Statistics and Quantitative Methods, University of Milan-Bicocca, Milan, Italy
Matteo Franchi
28Laboratory of Healthcare Research & Pharmacoepidemiology, Department of Statistics and Quantitative Methods, University of Milan-Bicocca, Milan, Italy
Alessandro M. Vannucchi
3Center for Research and Innovation of Myeloproliferative Neoplasms, AOU Careggi, University of Florence, Florence, Italy
Francesco Passamonti
University of Milan, Milan