br Treatment decisions are generally based on MPN

Treatment decisions are generally based on MPN subtype, risk category, age, and disease manifestations. For PV and ET, thrombosis risk category often guides the decision to use cytoreductive and anti-platelet therapies (and phlebotomy for PV). Historically, treatment of MF has been guided by the patient\'s symptom profile and burden of disease, and has involved managing cytopenias (androgens, erythropoiesis stimulating agents, immunomodulatory agents) and splenomegaly (HU, busulfan, cladribine, splenectomy, splenic radiation, and immunomodulatory agents) and providing measures to prevent infections, control symptoms, and improve QOL (e.g., corticosteroids and stimulants) (Gowin et al., 2013; Tefferi et al., 2009b). Treatment has also been based in part on the risk category (as an aid for selecting transplant candidates), assessed by the International Prognostic Scoring System (IPSS) or Dynamic IPSS/plus. Allogeneic hematopoietic stem cell transplant, typically reserved for fit patients with intermediate-2 or high-risk disease, is the only curative treatment option and may resolve bone marrow fibrosis, lead to molecular remission, restore normal hematopoiesis, and lead to cure in 40–70% of patients (Kröger et al., 2009; Ballen et al., 2010). However, its association with significant morbidity and mortality limits its utility. The oral selective JAK1/2 inhibitor ruxolitinib was assessed in a phase 1/2 study of 153 MF patients requiring therapy, identifying 25mg orally twice daily or 100mg once daily as the maximum tolerated doses, along with evidence of dose-dependent suppression of phosphorylated STAT3 (Verstovsek et al., 2010). In the phase 2 portion, based on responses (at least 50% ARCA of splenomegaly), toxicity, and need for dose reductions, 15mg twice-daily was established as the optimal starting dose, and most patients experienced rapid improvement in debilitating MF-related symptoms. Ruxolitinib was FDA- and EMA-approved for the treatment of MF in 2011 and 2012, respectively, based on the results of two phase 3 studies in which ruxolitinib was compared to either placebo (COMFORT-1) or to best available therapy (COMFORT-2) (Verstovsek et al., 2012; Harrison et al., 2012). Among the ruxolitinib-treated patients, a 35% or higher reduction in spleen size was achieved and maintained in 41.9% (versus 0.7% of placebo-treated patients) at week 24 in COMFORT-1 and in 32% and 28% (versus 0% of patients who received best available therapy) at weeks 24 and 48, respectively, in COMFORT-2. Moreover, in COMFORT-1, 45.9% of ruxolitinib-treated patients (versus 5.3%) achieved an improvement of at least 50% in the total symptom score (Verstovsek et al., 2012). In COMFORT-2, pre-specified exploratory analyses showed that ruxolitinib-treated patients experienced improvements in quality of life, role functioning, and physical condition and reductions in MF-associated symptoms as compared to the patients who received best available therapy (Harrison et al., 2012). The efficacy of ruxolitinib appeared to be dose-dependent and was not influenced by the presence or absence of the JAK2 V617F mutation, as patients with mutant and wild-type JAK2 responded similarly. Extended follow-up of these two studies demonstrated a survival advantage with the use of ruxolitinib among intermediate- and high-risk MF patients, while reduction in spleen size seemed to correlate with longer survival (Cervantes et al., 2013; Vannucchi et al., 2015a). In the UK open-label, phase 2 ROBUST trial, involving 48 MF patients, 50% of all patients and 57% of intermediate-1 risk patients achieved the primary composite endpoint of treatment success, which was defined as ≥50% reduction in palpable spleen length and/or a ≥50% decrease in the Myelofibrosis Symptom Assessment Form Total Symptom Score at 48weeks (Mead et al., 2015). An exploratory analysis of COMFORT-1 showed a reduction in MF-related hepatomegaly among the ruxolitinib-treated patients, providing rationale for using ruxolitinib in MF patients who undergo splenectomy (Verstovsek et al., 2015). There are also reports of resolution of marrow fibrosis, reduction in JAK2 mutant allele burden, and even achievement of complete molecular remission with its long-term use (Wilkins et al., 2013; Deininger et al., 2015).