BACKGROUND Ruxolitinib, a selective JAK1 and JAK2 inhibitor, has clinically significant activity in myelofibrosis. METHODS In a double-blind trial, patients with intermediate-2 or high-risk myelofibrosis were randomized to twice-daily oral ruxolitinib (n=155) or placebo (n=154). The primary endpoint was the proportion of patients with ≥35% spleen volume reduction at 24 weeks assessed by magnetic resonance imaging. Secondary endpoints included durability of response, changes in symptom burden (assessed by Total Symptom Score [TSS]), and overall survival. RESULTS In the ruxolitinib group, 41.9% achieved the primary endpoint versus 0.7% in the placebo group (P<0.001). Spleen response was maintained while taking ruxolitinib: 67% of responding patients maintained response for ≥48 weeks. A ≥50% improvement in TSS at 24 weeks was achieved by 45.9% of ruxolitinib-treated versus 5.3% of placebo-treated patients (P<0.001). Thirteen deaths occurred in the ruxolitinib and 24 in the placebo group (hazard ratio, 0.50; 95% CI, 0.25–0.98; P=0.04). Discontinuations for adverse events were similar between groups (11% each). Among ruxolitinib-treated patients, anemia and thrombocytopenia were the most common adverse events, but rarely led to discontinuation (1 patient for each event). Two patients underwent transformation to acute myeloid leukemia (AML), both in the ruxolitinib group. CONCLUSIONS Ruxolitinib provided significant clinical benefits in patients with myelofibrosis by reducing spleen size, improving debilitating myelofibrosis-related symptoms, and improving overall survival. Improvement came at a cost of more frequent anemia and thrombocytopenia in the early part of the treatment period. The imbalance in AML transformation requires attention in further studies. (Funded by Incyte Corporation; ClinicalTrials.gov, NCT00952289)

Background Myelofibrosis is a Philadelphia chromosome–negative myeloproliferative neoplasm associated with cytopenias, splenomegaly, poor quality of life, and shortened survival. About half of patients with myelofibrosis carry a gain-of-function mutation in the Janus kinase 2 gene (JAK2 V617F) that contributes to the pathophysiology of the disease. INCB018424 is a potent and selective Janus kinase 1 (JAK1) and JAK2 inhibitor. Methods We conducted a phase 1–2 trial of INCB018424 in patients with JAK2 V617F–positive or JAK2 V617F–negative primary myelofibrosis, post–essential thrombocythemia myelofibrosis, or post–polycythemia vera myelofibrosis. Results A total of 153 patients received INCB018424 for a median duration of more than 14.7 months. The initial dose-escalation phase established 25 mg twice daily or 100 mg once daily as maximum tolerated doses, on the basis of reversible thrombocytopenia. A dose-dependent suppression of phosphorylated signal transducer and activator of transcription 3 (STAT3), a marker of JAK signaling, was demonstrated in patients with wild-type JAK2 and in patients with the JAK2 V617F mutation. We studied additional doses and established that a 15-mg twice-daily starting dose, followed by individualized dose titration, was the most effective and safest dosing regimen. At this dose, 17 of 33 patients (52%) had a rapid objective response (≥50% reduction of splenomegaly) lasting for 12 months or more, and this therapy was associated with grade 3 or grade 4 adverse events (mainly myelosuppression) in less than 10% of patients. Patients with debilitating symptoms, including weight loss, fatigue, night sweats, and pruritus, had rapid improvement. Clinical benefits were associated with a marked diminution of levels of circulating inflammatory cytokines that are commonly elevated in myelofibrosis. Conclusions INCB018424 was associated with marked and durable clinical benefits in patients with myelofibrosis for whom no approved therapies existed.

Mechanistic information and structure-based design methods have been used to design a series of nonpeptide cyclic ureas that are potent inhibitors of human immunodeficiency virus (HIV) protease and HIV replication. A fundamental feature of these inhibitors is the cyclic urea carbonyl oxygen that mimics the hydrogen-bonding features of a key structural water molecule. The success of the design in both displacing and mimicking the structural water molecule was confirmed by x-ray crystallographic studies. Highly selective, preorganized inhibitors with relatively low molecular weight and high oral bioavailability were synthesized.

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