Hunter, Deborah

Abstract BACKGROUND: MF is a progressive illness associated with cachexia and weight loss (Mesa et al, Cancer2007;109: 68). These clinical signs, resulting from both hypercatabolism (secondary to increased pro-inflammatory cytokines) and MF associated splenomegaly, are associated with decreased survival (Dupriez et al., Blood1996;88:1013). Currently, there is no therapy that decreases the progressive cachexia of MF. INCB018424 is a selective JAK1/2 inhibitor which has the potential to improve both the aberrant myeloproliferation in MF through decreasing constitutively active JAK-STAT signaling, and nutritional status by decreasing both splenomegaly and the pathologically increased cytokines. 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 (Mantovani et al, J Mol Med2001; 79:406), was assessed serially. 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 (Mesa et al, Blood2007; 2007;110:a2548), potentially from hypercatabolism and splenic consumption of lipids. At enrollment, median total cholesterol was 95 mg/dl (range), with 94% and 55% below 150 mg/dl and 100 mg/dl, respectively. Following treatment with INCB018424, median total cholesterol increased to 145 mg/dl (range 72–289 mg/dL) with 73% increasing to an improved range above their baseline (either to the >100mg/dl or >150 mg/dl range). Leptin: At enrollment, MF patients had very low leptin levels (mean = 2.55 ng/mL with 50% below 1 ng/mL vs. a range of 6–12 ng/mL for normal volunteers). Low plasma levels are associated with shortened survival in cancer patients. The plasma leptin levels increased 176% on average after one month of treatment with INCB018424, and continued to increase to levels matching healthy volunteers with time on study (mean = 7.04 ng/mL (range 0.25 – 35 ng/mL) after 2 months on INCB018424) and correlated to weight increases. 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.

Abstract Background: Polycythemia vera (PV) is characterized by erythrocytosis, thrombocytosis, and/or leukocytosis and a broad range of disease-related symptoms. In high-risk patients, the most common first-line treatment is hydroxyurea (HU). The open-label RESPONSE trial demonstrated that ruxolitinib (RUX), a JAK1/JAK2 inhibitor, provided superior efficacy compared with best available therapy in patients with PV who were resistant to or intolerant of HU according to modified European LeukemiaNet (ELN) criteria. This study (RELIEF) was conducted in patients receiving a stable dose of HU and who were generally well controlled but reporting disease-associated symptoms, comparing the change in PV-related symptom burden in patients continuing their HU therapy with those switching to RUX treatment. Methods: RELIEF was a randomized, multicenter, double-blind, double-dummy, phase 3b study of patients with PV aged ≥18 years on a stable dose of HU monotherapy and reporting PV-related symptoms. Patients were required to be receiving HU for ≥12 weeks prior to enrollment and on the same dose level for the last 4 weeks, and have a score ≥8 on the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) cytokine total symptom score (TSS-C). The TSS-C comprised symptoms of itching, tiredness, muscle ache, night sweats, and sweats while awake; each symptom was rated on a scale of 0=absent to 10=worst imaginable, with a maximum TSS-C score of 50. Patients also had to meet one of the following: ≤1 phlebotomy in the previous 6 months or no palpable splenomegaly. Those eligible were randomized 1:1 to receive RUX 10 mg BID and HU-placebo, or HU at the same dose/schedule and RUX-placebo. Dose adjustments were permitted for safety and efficacy. After Week 16, patients could receive open-label RUX until Week 48. The primary endpoint was the proportion of patients with a ≥50% reduction in TSS-C at Week 16; secondary endpoints included proportion of patients with a ≥50% reduction in individual TSS-C symptoms and safety. Results: Overall, 54 and 56 patients were randomized to RUX and HU, respectively; 87.0% and 89.3% remained on treatment through Week 16. At baseline, the median age (range) was 64 (36-87) in the RUX group and 66 (19-85) in the HU group; 44% and 61% were men. The majority of patients in the RUX and HU groups did not have baseline platelet counts or WBC above ELN thresholds: platelets >400 and ≤600 x 109/L (RUX 31.5%, HU 28.6%), >600 x 109/L (3.7%, 8.9%); WBC >10 and ≤15 x 109/L (16.7%, 16.1%), >15 x 109/L (11.1%, 14.3%). In the RUX and HU groups, the mean TSS-C at screening (22.4, 23.1) was higher than that at baseline (16.7, 18.0); the ratio of screening to baseline TSS-C was 1.7 and 1.6. The proportion of patients achieving a ≥50% reduction from baseline in TSS-C at Week 16 (primary endpoint) was 43.4% in the RUX group and 29.6% in the HU group (P=0.139; OR, 1.82; 95% CI, 0.82-4.04). The proportions of patients in the RUX vs HU groups achieving a ≥50% reduction in scores for itching and tiredness at Week 16 were 40.0% vs 26.4% and 54.2% vs 32.0%, respectively. Median percentage changes in individual TSS-C symptoms are shown in Table 1. Additional analyses found no correlation between individual changes in HU dose from baseline to Weeks 13-16 and percentage change in TSS-C in the HU arm (r2=0.030). Even patients maintaining the same HU dose from prior to study entry through Week 16 reported symptom improvement: 12/35 (34.3%) with no dose change, 4/12 (33.3%) with a dose increase, and 0/9 (0%) with a dose decrease had a ≥50% reduction in TSS-C. The most common nonhematologic adverse events in the RUX arm on randomized treatment were fatigue (20.4% RUX vs 10.7% HU), headache (16.7% vs 5.4%), and dizziness (13.0% vs 8.9%). The most common adverse events on HU were diarrhea (9.3% RUX vs 19.6% HU) and constipation (7.4% vs 12.5%); most events were grade 1 or 2. Grade 3 or 4 anemia or thrombocytopenia (lab values) were not reported in the RUX group; two patients in the RUX group had grade 3 or 4 neutropenia. Conclusion: In generally well controlled PV patients receiving a stable dose of HU, there was a positive trend in symptom improvement for patients switched to RUX therapy versus those continuing on HU therapy, although this was not statistically significant. The 34% response rate among patients who continued to receive a stable HU dose suggests a placebo effect that led to an underpowered study. Further analyses are required to better interpret these findings. Disclosures Off Label Use: Ruxolitinib is a JAK1/JAK2 inhibitor approved for the treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis. Vannucchi:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Yacoub:Alexion Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Sanofi Aventis: Membership on an entity's Board of Directors or advisory committees. Koschmieder:Novartis Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Byrne:Novartis Pharmaceuticals: Honoraria. Verstovsek:Incyte Corporation: Research Funding. Hunter:Incyte Corporation: Employment, Equity Ownership. Jones:Incyte Corporation: Employment, Equity Ownership. He:Incyte Corporation: Employment, Equity Ownership. Morozov:Novartis Pharmaceuticals: Employment, Equity Ownership.

SummaryThe randomized, double‐blind, double‐dummy, phase 3b RELIEF trial evaluated polycythaemia vera (PV)‐related symptoms in patients who were well controlled with a stable dose of hydroxycarbamide (also termed hydroxyurea) but reported PV‐related symptoms. Patients were randomized 1:1 to ruxolitinib 10 mg BID (n = 54) or hydroxycarbamide (prerandomization dose/schedule; n = 56); crossover to ruxolitinib was permitted after Week 16. The primary endpoint, ≥50% improvement from baseline in myeloproliferative neoplasm ‐symptom assessment form total symptom score cytokine symptom cluster (TSS‐C; sum of tiredness, itching, muscle aches, night sweats, and sweats while awake) at Week 16, was achieved by 43·4% vs. 29·6% of ruxolitinib‐ and hydroxycarbamide‐treated patients, respectively (odds ratio, 1·82; 95% confidence interval, 0·82–4·04; P = 0·139). The primary endpoint was achieved by 34% of a subgroup who maintained their hydroxycarbamide dose from baseline to Weeks 13–16. In a post hoc analysis, the primary endpoint was achieved by more patients with stable screening‐to‐baseline TSS‐C scores (ratio ≤ 2) receiving ruxolitinib than hydroxycarbamide (47·4% vs. 25·0%; P = 0·0346). Ruxolitinib treatment after unblinding was associated with continued symptom score improvements. Adverse events were primarily grades 1/2 with no unexpected safety signals. Ruxolitinib was associated with a nonsignificant trend towards improved PV‐related symptoms versus hydroxycarbamide, although an unexpectedly large proportion of patients who maintained their hydroxycarbamide dose reported symptom improvement.

SummaryPatients with myelofibrosis (MF) have significant debilitating symptoms, physical disabilities, and poor health‐related quality of life (HRQoL). Here, we report post‐hoc analyses of the impact of ruxolitinib, a potent and selective JAK1 and JAK2 inhibitor, on disease‐related symptoms and HRQoL in MF patients from the large phase 3 COMFORT‐II study (N = 219). During the follow‐up period of 48 weeks, HRQoL and MF‐associated symptoms improved from baseline for ruxolitinib‐treated patients but remained the same or worsened for best available therapy (BAT)‐treated patients. Based on the European Organization for Research and Treatment of Cancer QoL Questionnaire core 30 items (EORTC QLQ‐C30), treatment‐induced differences in physical and role functioning, fatigue, and appetite loss significantly favoured ruxolitinib versus BAT from week 8 (P < 0·05) up to week 48 (P < 0·05). Ruxolitinib resulted in significantly higher response rates in global health status/QoL and Functional Assessment of Cancer Therapy‐Lymphoma (FACT‐Lym) summary scores versus BAT at most time points (P < 0·05). Significant improvements in the Lymphoma subscale (including symptoms of pain, fever, itching, fatigue, weight loss, loss of appetite, and other patient concerns), FACT‐General, FACT‐Lym trial outcome index, and FACT‐Lym total were also observed with ruxolitinib versus BAT starting at week 8 and continuing thereafter. Overall, these data demonstrated that ruxolitinib improved HRQoL in MF patients and further support the use of ruxolitinib for the treatment of symptomatic MF.