BACKGROUND: MF is a progressive illness associated with cachexia and weight loss (
METHODS: Symptomatic patients with MF enrolled in a phase I/II trial (www.ClinicalTrials.gov, NCT00509899) with INCB018424, were analyzed for the impact of therapy on nutritional status and cachexia. Specifically, in addition to traditional endpoints of IWG-MRT response (reported elsewhere) patients were assessed for changes in body mass index (BMI), serum cholesterol values, spleen size, and patient reports of early satiety and anorexia. Additionally, leptin, an adipose-derived protein hormone that plays a key role in regulating energy balance and circulates at levels proportional to body fat in health and disease (
RESULTS:Patients: Thirty four MF patients, treated for at least 2 months with 25 mg twice daily of INCB018424, were included in this analysis. Among this group 85% demonstrated splenomegaly (median 20 cm below left costal margin, range 4 cm to 32 cm; 2 patients had prior splenectomy) and had a median BMI of 24.8 (range 17.9 to 49.7). Although the median BMI at baseline would be considered in the “normal range” (18.5–24.9), loss of lean body mass at enrollment would be underestimated by the contribution of splenomegaly or edema. Appetite: At enrollment, a clearly positive correlation between the presence of anorexia and early satiety (by patient’s report) and significant splenomegaly was observed. Treatment with INCB018424 led to resolution of the symptoms of poor appetite and early satiety, along with the reduction in splenomegaly. Weight: MF patients on therapy initially lost weight, which reflects resolution of excess extravascular water (based on investigators reported decreases in peripheral edema, ascites, or splenomegaly). As the trial progressed MF patients on INCB018424 treatment progressively gained weight (mean increase of 0.40 kg @ 1 month, 2.93 kg @ 2 mo, 3.70 @ 3 mo), and exhibited improved appetite. Importantly, weight gain was more consistent, of greater magnitude and more durable in patients who entered the study in the lowest quartile for BMI. Cholesterol: We previously reported that hypocholesterolemia (total cholesterol <150 or 100 mg/dL; HDL < 60mg/dL) is associated with decreased survival in MF patients (
CONCLUSIONS: Therapy with INCB018424 improves the nutritional status of MF patients, including improving pathologic weight loss, hypercatabolism associated hypocholesterolemia, and pathologically decreased serum leptin. The improved nutritional status of MF patients treated with INCB018424 may reflect the ability of JAK inhibition to target the underlying pathophysiology of MF cachexia by reducing the organomegaly, levels of pro-inflammatory cytokines, and pro-inflammatory cytokine signaling.
Disclosures: Mesa:Incyte Co.: Research Funding. Verstovsek:Incyte Co.: Research Funding. Kantarjian:Incyte: Research Funding. Pardanani:Incyte: Research Funding. Friedman:Incyte: Employment. Newton:Incyte: Employment. Erickson-Viitanen:Incyte Co: Employment. Hunter:Deborah Hunter: Employment. Redman:John Redman: Employment. Yeleswaram:Incyte: Employment. Bradley:Incyte: Employment. Tefferi:Incyte Co.: Research Funding.