Ruxolitinib s FDA and EMA approvals were expanded

Ruxolitinib\'s FDA and EMA approvals were expanded in 2014 and 2015, respectively, to the treatment of PV patients who are intolerant of or resistant to HU, based on results from the RESPONSE trial, a phase 3 trial in which ruxolitinib was shown to be superior in regard to hematocrit control and spleen volume neurokinin receptor as well as in suppressing disease-related symptoms (Vannucchi et al., 2015b). The most common adverse events, albeit usually low-grade, associated with ruxolitinib are anemia and thrombocytopenia, and other reported adverse events include headache, fatigue, diarrhea, nausea, and infections (Verstovsek et al., 2012; Harrison et al., 2012; Vannucchi et al., 2015b). Progressive multifocal leukoencephalopathy has been reported to occur in an elderly patient receiving the drug (Wathes et al., 2013). The infectious complications of ruxolitinib may be at least partially explained by its impairment of dendritic cell development and function, including impairment of the dendritic cell\'s activation, migration, and ability to induce T-cell responses (Heine et al., 2013b). These observations have prompted some investigators to recommend an infectious risk assessment and prophylaxis strategy (Heine et al., 2013a). Three-year follow-up of the COMFORT studies showed that the rates of many of the adverse events generally decreased with longer exposure to ruxolitinib treatment, with the highest rates occurring within the first 6months (Cervantes et al., 2013). It is also important to keep in mind that sudden withdrawal of ruxolitinib has been associated with a shock-like syndrome from the reemergence of suppressed inflammatory cytokines (Tefferi and Pardanani, 2011). However, such a severe withdrawal syndrome was not reported in the COMFORT and RESPONSE studies, but return of baseline MF-related symptoms typically occurs within approximately a week upon discontinuation of ruxolitinib (Verstovsek et al., 2012; Harrison et al., 2012; Vannucchi et al., 2015b). In assessing ruxolitinib\'s position in the grand scheme of MPN treatment, two critical appraisals of the data from both the COMFORT trials suggested that the evidence to support ruxolitinib for the treatment of MF was limited, for various reasons, including trial design bias, limited sample size, comparator choice, and outcome indirectness (Barosi et al., 2015; Marti-Carvajal et al., 2015). Alternatively, an argument could be made that the data to support ruxolitinib\'s role in the treatment of MPNs are derived from randomized controlled trials with a relatively large sample size for an orphan disease, particularly one in which there is a paucity of other effective therapies. To further define ruxolitinib\'s role, cost effectiveness studies have been conducted. The National Institute for Health and Care Excellence (NICE) obtained clinical and cost-effectiveness data from the drug manufacturer (derived from COMFORT-1 and COMFORT-2), and with this data, an independent study group concluded that there was significant uncertainty of the manufacturer\'s cost-effectiveness model due to its limitations. Despite conceding that ruxolitinib was clinically effective, NICE decided that ruxolitinib was not a cost effective use of National Health Service resources for treatment MF-related splenomegaly or disease symptoms in adults (Wade et al., 2013). A Finnish study assessed the cost effectiveness of ruxolitinib for the treatment of MF by creating a survival-based decision model based on data from COMFORT-2 and found that ruxolitinib produced 2.43 incremental quality-adjusted life years when compared to best available therapy, concluding that these gains came at reasonable costs, given the improvements in overall survival (Hahl et al., 2015).
Other JAK Inhibitors Beyond ruxolitinib, there are other JAK inhibitors under clinical investigation. The most advanced in development include momelotinib and pacritinib. As with ruxolitinib, momelotinib is a dual JAK1/2 inhibitor that has been shown to decrease splenomegaly and MPN-related symptoms in patients with intermediate or high-risk MF (Pardanani et al., 2013). Based on the International Working Group (IWG) criteria, 59% of evaluable patients in that phase I–II study experienced a response to anemia, and 70% of patients who had received red cell transfusions in the month prior to study entry achieved a minimum 12-week period of transfusion-independence. Grade 3/4 adverse reactions included thrombocytopenia in nearly third of the patients, while treatment-related grade 1 sensory peripheral neuropathy was seen in about a fifth of the patients. Currently ongoing are randomized studies of ruxolitinib versus momelotinib in MF patients (NCT01969838) and momelotinib versus best available therapy among MF patients who have already been treated with ruxolitinib (NCT02101268).