Ruxolitinib Can Lead to Weight Gain in Patients with Myeloproliferative Neoplasms By Uncoupling Feeding from Central Leptin Signaling Via JAK2/STAT3

▪ Ruxolitinib (rux) was originally approved for treatment of symptomatic patients with advanced myelofibrosis due to its significant activity shrinking spleen size and reducing cytokine-driven symptom burden (1). Rux has since received approval as second line therapy for polycythemia vera (2, 3) and is in clinical trials for essential thrombocythemia (4). Accordingly, rux use among patients with Philadelphia-chromosome negative (Ph-) myeloproliferative neoplasms (MPNs) is increasingly common. Weight gain among cachectic patients is thought to be a beneficial effect of rux therapy in this patient population (1, 5), but its underlying mechanism on body weight has not been studied. Rux is a JAK1/2 tyrosine kinase inhibitor that blocks both normal and pathogenic JAK/STAT signaling via receptors that utilize these adapter proteins. Leptin (LEP) signaling is part of a complex homeostatic mechanism regulating appetite, metabolism and body weight. In animal models, disruption of LEPR-mediated JAK2 activation in the ventral-medial hypothalamus (VMH) phenocopies LEPR disruption (6) thereby implicating JAK2 inhibition in body weight homeostasis. Our study aimed to investigate the role of rux on JAK/Stat signaling in mouse brain. We identified 79 patients with Ph-MPNs treated with rux at Weill Cornell Medicine by Silver MPN Center physicians. We identified baseline demographics including age, gender, diagnosis, date of diagnosis, transformation, height, weight, body mass index (BMI), systolic and diastolic blood pressure, Lipid profile, HGBA1C, glucose, and diabetic and hypertensive medications at the start and during ruxolitinib therapy. Body weight, BMI and effects on glucose, lipids and blood pressure were assessed during rux therapy. To assess the effect of rux on VMH LEPR signaling, 8-week old male C57BL6/J mice were divided into 3 groups: Fasted (overnight), Fed, and Fed treated with rux. Rux (60mg/kg) or vehicle control was administered by gavage the day prior to perfusion. Mice were perfused with PFA 4% and brains were cryopreserved. Stat3 phosphorylation was used to report VMH Lepr activation. MPN patients received rux for a median of 80 weeks (range: 3.2-243) during which 64 (81.0%) patients gained weight and 29 (36.7%) gained more than 10% of their pre-treatment weight (Figure 1A). On average, patients gained 8% of their starting weight while on rux. Weight gain among those gaining weight ranged between 3% and 38% of their starting weight and the median wei