JAK2 617V>F mutation occurs in a homozygous state in 25% to 30% of patients with polycythemia vera (PV) and 2% to 4% with essential thrombocythemia (ET IntroductionPatients with Philadelphia-negative chronic myeloproliferative disorders (CMPDs) 1 harbor a recurrent mutation in the Janus tyrosine kinase 2 (JAK2) gene, consisting of a valine-tophenylalanine change at position 617 (JAK2 617VϾF) in the JH2 pseudo-kinase domain. [2][3][4][5] The JAK2 617VϾF mutation is present in the vast majority of patients with polycythemia vera (PV) 2-5 and in 40% to 60% of those with essential thrombocythemia (ET) 6-8 or myelofibrosis with myeloid metaplasia (MMM). 9,10 JAK2 617VϾF can also occasionally be detected in "atypical" MPD, myelodysplastic syndromes, chronic myelomonocytic leukemia, systemic mastocytosis, chronic neutrophilic leukemia, and eosinophilic disorders. 11-13 Mutant JAK2 is a constitutively active tyrosine kinase that confers growth factor independence in transfected hematopoietic cell lines [2][3][4][5] and is at the basis of the phenomenon of erythropoietin-independent erythroid colony (EEC) growth that is a hallmark of most PV patients and is also less frequently reported in patients with ET. 14 A key role for the "gain-of-function" 15 of mutated JAK2 in the pathogenesis of CMPD is supported by in vitro studies, which showed enhanced JAK-STAT signaling in cells bearing the mutant allele, and by in vivo animal models in which erythrocytosis 3,16 and eventually myelofibrosis 16,17 developed following transplantation of hematopoietic cells transfected with mutant JAK2 into mice.About 25% to 30% of PV and MMM patients, and 2% to 4% of ET patients, harbor the mutation in the homozygous state, a condition where at least 51% of JAK2 alleles in granulocytes are mutated as the result of a mitotic recombination process. 2-5 While a consistent number of reports have investigated the impact of the presence of 617VϾF mutation per se on the clinical and hematologic profile of CMPD patients, a few studies have specifically addressed the consequences of JAK2 617VϾF mutation when harbored in the homozygous state. 18 The complete loss of normal JAK2 allele is expected to have profound effects on cell phenotype. As a matter of fact, in cotransfection experiments, the wild-type

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Ruxolitinib (RUX) is extensively used in myelofibrosis (MF). Despite its early efficacy, most patients lose response over time and, after discontinuation, have a worse overall survival (OS). Currently, response criteria able to predict OS in RUX-treated patients are lacking, leading to uncertainty regarding the switch to second-line treatments. In this study, we investigated predictors of survival collected after six months of RUX in 209 MF patients participating in the real-world ambispective observational RUXOREL-MF study (NCT03959371). Multivariable analysis identified the following risk factors: (i) RUX dose <20 mg twice daily at baseline, month 3, and 6 (hazard ratio, HR, 1.79, 95% confidence interval, CI, 1.07-3.00, p=0.03), (ii) palpable spleen length reduction from baseline ≤30% at month 3 and 6 (HR 2.26, 95% CI 1.40-3.65, p=0.0009), (iii) red blood cell (RBC) transfusion need at month 3 and/or 6 (HR 1.66, 95% CI 0.95-2.88, p=0.07), and (iv) RBC transfusion need at all time points, i.e. baseline and months 3 and 6 (HR 2.32, 95% CI 1.19-4.54, p=0.02). Hence, we developed a prognostic model, named Response to Ruxolitinib after 6 months (RR6), dissecting three risk categories: low (median OS not reached), intermediate (median OS 61 months, 95% CI 43-80), and high (median OS 33 months, 95% CI 21-50). The RR6 model was validated and confirmed in an external cohort comprised of 40 MF patients. In conclusion, the RR6 prognostic model allows for the early identification of RUX-treated MF patients with impaired survival who might benefit from a prompt treatment shift.