A Novel Prognostic Model Including Cytogenetic and Molecular Data in Patients with Primary and Post-Essential Thrombocythemia (ET)/Polycythemia Vera (PV) Myelofibrosis (MF)

Abstract Introduction: MF is a Philadelphia-negative myeloproliferative neoplasm (Ph-negative MPN) with an heterogeneous outcome. In 2009, Cervantes et al. published the International Prognostic Score System (IPSS) to better determine outcomes in this disease. In the last decade, several recurrently mutated genes have been described in MF, some of them associated with prognostic impact in survival. We propose a novel prognostic score that incorporates molecular and cytogenetic data in patients with MF. Methods: We analyzed clinical, cytogenetic and molecular data from 623 patients with a diagnosis of primary MF (N=445), post-PV MF (N=109) and post-ET MF (N=69). Data was extracted from medical records at time of sample collection for analysis. Mutation data was obtained by next-generation sequencing analysis, performed with either paired tumor-normal whole exome sequencing (N=46) or selected gene panel for genes associated with myeloid malignancies (N=577). The following 16 genes were analyzed in all 623 patients and were considered as the common denominator for analysis: ASXL1, CALR, DNMT3A, EZH2, FLT3, IDH1, IDH2, JAK2, KIT, KRAS, MPL, NRAS, RUNX1, TET2, TP53, WT1. RAS mutations were considered as oncogenic mutations in NRAS and/or KRAS. Molecular high risk (MHR) mutations were considered as mutations in any one of the 4 genes: ASXL1, EZH2, IDH1, IDH2 (SRSF2 mutations were not included since they were not evaluated in all cases). Cytogenetic data was stratified into 4 risk categories (based on Tam et al, Blood 2009): (1) Diploid; (2) Del(13q)/Del(20q)/Trisomy 9; (3) Abnormalities of chromosomes 5, 7, 17 and complex karyotype; (4) Other abnormalities. To develop the model, the data was split into a training dataset (N=434) and a test dataset (N=189). Variables initially included in the initial training model were those with a p-value Results: In the training cohort, after a median follow-up of 30.8 months, there were 176 deaths (40.5%). The initial variables included in the multivariate Cox model were: age (>65 years), hemoglobin ( 25x109/L), peripheral blood blasts (>1%), presence of constitutional symptoms, sex (male vs female), platelet count ( Conclusion: Incorporating molecular data, including MHR mutations, karyotype and RAS mutations leads to the development of an improved prognostic model. Further validation of this model in other cohorts is necessary. The impact of novel therapies should be evaluated among the different risk categories. Download : Download high-res image (469KB) Download : Download full-size image Disclosures Rampal: Stemline: Research Funding; Celgene: Honoraria; Constellation: Research Funding; Incyte: Honoraria, Research Funding; Jazz: Consultancy, Honoraria. Verstovsek: Celgene: Membership on an entity's Board of Directors or advisory committees; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Consultancy.