Peng, Wei Jun

Abstract Background In the primary analysis of the phase III COMFORT-I study, the JAK1/JAK2 inhibitor ruxolitinib (RUX) significantly improved splenomegaly, myelofibrosis (MF)-related symptoms, and quality of life (QoL) measures in patients (pts) with MF versus placebo (PBO). An additional analysis (median follow-up 51 weeks [wks)]) showed RUX was associated with a survival advantage versus PBO (Verstovsek et al. N Engl J Med2012). Longer term follow-up (median 102 wks) showed durable SV reductions and QoL improvements. At this time point, RUX continued to be associated with a survival advantage, despite all pts originally randomized to PBO having discontinued or crossed over to ruxolitinib shortly after the primary analysis (Verstovsek et al. ASH 2012. abstract 800). We report additional longer-term follow-up of pts from COMFORT-I. Methods In COMFORT-I, 309 pts were randomized (1:1) to RUX or PBO. RUX starting dose depended on baseline platelet count (100–200´109/L: 15 mg BID; >200´109/L: 20 mg BID). Doses could be titrated for lack of efficacy or excess toxicity as specified in the protocol. Pts receiving PBO could crossover to RUX after the primary analysis (ie, when all pts completed 24 wks and half the pts completed 36 wks of therapy) or at any time if they met protocol-specified criteria for worsening splenomegaly. The primary endpoint was the proportion of pts who achieved a ≥35% reduction in spleen volume (SV) at wk 24. Symptoms were assessed up to wk 24 using the modified MF Symptom Assessment Form v2.0. QoL continued to be evaluated beyond wk 24 using the EORTC QoL Questionnaire-Core 30 (QLQ-C30). Survival was estimated by Kaplan-Meier analysis according to original randomized treatment. To better understand the effect of crossover on the PBO arm, statistical modeling of survival was conducted using a generalized Gamma distribution. Results Median follow-up was 149 wks at the time of this updated analysis. Of 155 pts originally randomized to RUX, 77 remain on therapy. Of 154 pts originally randomized to PBO, 111 crossed over to RUX; the median time to crossover was 41.1 wks (range, 5.1–65.4). At wk 24, pts originally randomized to RUX had a mean SV reduction of −31.6%; this was durable for pts who continued on RUX, where the mean SV reduction at wk 144 was −34.1%. Fifty-nine percent (91/155) of pts originally randomized to RUX achieved a ≥35% SV reduction at any time during study; for these pts, the probability of maintaining this response for >132 weeks from the time of their initial response was 0.53. Pts originally randomized to RUX who continued on therapy experienced durable improvements in the Global Health Status/QoL and functional domains of the EORTC QLQ-C30. Overall survival favored RUX (HR=0.69; 95% CI: 0.46, 1.03; P= 0.067; Fig 1), with 42 and 54 deaths among pts originally randomized to RUX and PBO, respectively. Modeling of the hazard function of death over time to explore the effect of crossover to RUX in pts originally randomized to PBO showed a decrease in hazard for these pts, which corresponded to an increased proportion of pts crossing over to RUX. In pts originally randomized to RUX who continued on therapy, there was no substantial change in the rate, distribution, or severity of nonhematologic adverse events (AEs) with longer-term therapy; most nonhematologic AEs were grade 1 or 2. Mean and median hemoglobin and platelet count remained stable with longer-term therapy. Consistent with this, the incidence of new onset grade 3 or 4 anemia and thrombocytopenia observed after the first 6 months of RUX therapy decreased relative to that seen in the first 6 months of therapy (Fig 2). With approximately 1 year of additional follow up, 4 new cases of acute myeloid leukemia were reported: 2 pts originally randomized to PBO (376 and 666 days after crossover to RUX) and 2 pts originally randomized to RUX (848 and 1143 days after starting RUX). Conclusions After a median follow-up of 149 wks, the hazard ratio for overall survival favored pts originally randomized to RUX over those originally randomized to PBO, the majority of whom crossed over to RUX. The hazard of death for pts originally randomized to PBO decreased as pts crossed over to RUX. SV reductions and QoL improvements were sustained with longer-term therapy. The incidence of new onset grade 3 or 4 anemia and thrombocytopenia decreased with longer-term therapy. Collectively, these data reinforce the durable efficacy and longer-term safety of RUX in pts with MF. Disclosures: Verstovsek: Incyte Corporation: Research Funding. Mesa:Genentech: Research Funding; NS Pharma: Research Funding; Gilead: Research Funding; Incyte Corporation: Research Funding; Lilly: Research Funding. Gotlib:Incyte Corporation: Travel support, Travel support Other; Incyte Corporation: Membership on an entity’s Board of Directors or advisory committees; Incyte Corporation: Research Funding. Levy:Incyte Corporation: Equity Ownership; Incyte Corporation: Employment. Gupta:Incyte Corporation: Consultancy; Novartis: Consultancy; Inctye Corporation: Research Funding; Novartis: Research Funding; Novartis: Speakers Bureau. Deininger:BMS, ARIAD, NOVARTIS: Consultancy; BMS, NOVARTIS, CELGENE, GILEAD: Research Funding; ARIAD, NOVARTIS: Advisory Boards, Advisory Boards Other. Miller:Novartis: Consultancy; Incyte Corporation: Consultancy; Novartis: Research Funding; Incyte Corporation: Research Funding; Novartis: Honoraria; Incyte Corporation: Honoraria. Talpaz:Ariad: Consultancy; Novartis: Consultancy; BMS: Consultancy; Pfizer: Consultancy; Ariad: Membership on an entity’s Board of Directors or advisory committees; Novartis: Membership on an entity’s Board of Directors or advisory committees; BMS: Membership on an entity’s Board of Directors or advisory committees; Pfizer: Membership on an entity’s Board of Directors or advisory committees. Winton:Incyte Corporation: Research Funding; Incyte Corporation: Membership on an entity’s Board of Directors or advisory committees. Arcasoy:Incyte Corporation: Research Funding. Lyons:Lilly: Research Funding; Amgen: Research Funding; Celgene: Research Funding; Incyte Corporation: Research Funding; Gilead: Consultancy; Seattle Genetics: Research Funding; Gilead: Research Funding; Ariad: Research Funding; GlaxoSmithKline: Research Funding; Novartis: Research Funding. Paquette:Incyte Corporation: Consultancy. Raza:Novartis: Speakers Bureau; Onconova Inc: Research Funding. Vaddi:Incyte Corporation: Employment; Incyte Corporation: Equity Ownership. Sun:Incyte: Employment; Incyte: Equity Ownership. Peng:Incyte Corporation: Employment; Incyte Corporation: Equity Ownership. Sandor:Incyte: Employment; Incyte: Equity Ownership. Kantarjian:Ariad: Research Funding; Novartis: Research Funding; BMS: Research Funding; Pfizer: Research Funding.

Abstract Background: Patients with polycythemia vera (PV) can have a pronounced symptom burden that negatively impacts their quality of life (QoL). Traditional treatment options such as phlebotomy, hydroxyurea, and interferon provide clinical benefit but frequently do not alleviate symptoms. The ongoing REVEAL study is being conducted to describe contemporary demographics, burden of disease, clinical management, patient-reported outcomes, and healthcare resource utilization among patients with PV in the US. This preliminary analysis describes the burden of PV based on patient-reported outcomes (PROs), including health-related QoL and work productivity. Methods: REVEAL is a multicenter, noninterventional, nonrandomized, prospective, observational study. Eligible patients are ≥18 years of age with a PV diagnosis and currently under active management by a physician in the US. PROs are being collected at study enrollment and every 3 months thereafter. Each of the 10 items on the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) are graded from 0 (absent) to 10 (worst imaginable), with individual symptom scores ≥7 considered severe; total symptom score (TSS) ranges from 0-100. Raw scores for items on the 30-item European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire-Core 30 (EORTC QLQ-C30) are standardized by linear transformation to 0-100. Higher scores on the EORTC QLQ-C30 indicate better functioning for global health status/QoL and functional subscales and worse severity for symptom subscales. Outcomes with the 6-item Work Productivity and Activity Impairment Specific Health Problem questionnaire (WPAI-SHP) are presented as a proportion from 0% (minimal/no impairment) to 100% (maximal impairment/productivity loss). Analyses of these preliminary data were descriptive. Results: At the time of data cutoff (June 9, 2015), REVEAL had enrolled 865 patients (total planned enrollment, n=2000), the majority were male (55.5%) and white (89.5%), with a median age of 67 (range, 22-95) years. 782 patients had completed the PRO questionnaires at the enrollment visit. A majority of patients reported ≥1 PV-related symptom. Mean (SD) MPN-SAF symptom scores were highest for fatigue (3.5 [2.7]), early satiety (2.7 [2.8]), inactivity (2.7 [2.9]), itching (2.6 [3.1]), and concentration problems (2.1 [2.6]). The mean (SD) MPN-SAF TSS (sum of 10 symptom scores) was 19.6 (16.1). The most frequently reported severe symptoms were fatigue, itching, inactivity, early satiety, night sweats, concentration problems, and bone pain (Table 1). Mean (SD) global health status/QoL reported on the EORTC QLQ-C30 was 72.8 (23.4); functional subscales were as follows: cognitive functioning, 80.3 (24.5); emotional functioning, 80.7 (24.0); physical functioning, 83.1 (20.6); role functioning, 84.3 (26.1); and social functioning, 85.0 (25.0). The most severe mean (SD) symptom subscale scores were fatigue (30.7 [28.5]), insomnia (29.5 [34.5]), pain (20.9 [29.3]), and dyspnea (17.3 [28.6]). Among patients who were employed at baseline (n=273), mean (SD) PV-related WPAI-SHP scores were as follows: absenteeism (ie, work time missed), 2.9% (10.6%); presenteeism (ie, impairment at work/reduced on-the-job effectiveness), 10.7% (20.4%); work productivity loss (ie, absenteeism plus presenteeism), 12.0% (22.2%); and activity impairment, 21.0% (28.0%). Conclusion: Preliminary descriptive data from patients currently enrolled in REVEAL suggest that patients with PV have notable impairment in QoL because of their disease; patient-reported scores on the MPN-SAF and EORTC QLQ-C30 were similar to those reported previously for patient populations with MPNs. Similarly, PV is associated with marked work productivity loss among patients who are currently employed. Subsequent analyses from REVEAL will evaluate changes over time in PROs and investigate correlations with disease progression and treatment. REVEAL can provide novel insights into questions related to the contemporary real-world QoL burden and its impact on PV-related symptoms and work productivity. Disclosures Mesa: Pfizer: Research Funding; NS Pharma: Research Funding; Gilead: Research Funding; Genentech: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; Incyte Corporation: Research Funding; CTI Biopharma: Research Funding; Promedior: Research Funding. Boccia:Incyte Corporation: Honoraria. Moliterno:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees. Naim:Incyte Corporation: Employment, Equity Ownership. Cordaro:Incyte Corporation: Employment, Equity Ownership. Peng:Incyte Corporation: Employment, Equity Ownership. Sun:Incyte Corporation: Employment, Equity Ownership. Parasuraman:Incyte Corporation: Employment, Equity Ownership. Stein:Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Abstract Background: Patients with polycythemia vera (PV) have an increased symptom burden (eg, fatigue, pruritus, and splenomegaly-related symptoms) and an increased risk of mortality compared with the general population, often resulting from thrombotic events, disease transformation to myelofibrosis, or secondary malignancies. There are limited data regarding PV burden and treatment patterns in a contemporary, real-world US setting. REVEAL is an ongoing observational study being conducted to describe contemporary demographics, burden of disease, clinical management, patient-reported outcomes, and healthcare resource utilization among patients with PV in the US. The objective of this assessment is to describe the clinical characteristics at enrollment among patients currently enrolled in REVEAL (enrollment from July 22, 2014 to June 9, 2015). Methods: REVEAL is a multicenter, noninterventional, nonrandomized, prospective, observational study. Eligible patients are ≥18 years of age with a PV diagnosis and currently under active management by a physician in the US. Data regarding disease and clinical characteristics, patient-reported outcomes, and health resource utilization are being collected at usual-care visits over a planned 36-month observation period. Analyses of these preliminary data were descriptive. Results: At data cutoff, 865 patients were enrolled (total planned enrollment, n=2000) from 174 sites (academic, n=27; community, n=147). Median (range) age at enrollment was 67 (22-95) years, 55.5% were male, 89.5% were white, and 45.4% had a history of smoking. Most patients (99.4%) had health insurance, including Medicare (56.0%), PPO (24.3%), or HMO (11.6%). Fifty-two percent were retired, 29.6% were employed, and 4.5% were unable to work or disabled. A total of 40.2% of patients completed a college/graduate degree, 19.9% had some college, and 32.5% completed high school or the equivalent. Documented major World Health Organization diagnostic criteria included JAK2V617F mutation in 50.9% of patients, elevated hemoglobin in 52.3%, and red cell mass in 5.5%. A bone marrow biopsy was conducted in 24.0% of patients, approximately half of whom (52.4% of the 24.0%) had trilineage myeloproliferation. Erythropoietin levels were abnormal in 19.7% of patients. Approximately half (46.6%) of patients had physician-reported PV-related symptoms at diagnosis, most frequently fatigue (25.2%) and pruritus (14.0%). At enrollment, median disease duration was 52.6 months; 42.3% of patients were diagnosed ≥5 years before enrollment. The most common comorbidities were hypertension (51.3%), obesity (14.2%), dyspnea (13.4%), myalgia (11.2%), and diabetes mellitus (11.1%). Mean hematocrit was 44.9%, hemoglobin was 14.5 g/dL, white blood cell count was 11.4×109/L, platelet count was 363.7×109/L, and absolute neutrophil count was 363.7×109/L. Twenty-one percent of patients had a history of thrombotic events, with 13.1% and 8.6% of patients experiencing ≥1 venous or arterial thromboembolic event, respectively. Of the 261 reported thrombotic events, 43.7% occurred after diagnosis of PV. The most common PV symptoms recorded at enrollment (using the Myeloproliferative Neoplasm Symptom Assessment Form) were fatigue (37.1%), pruritus (24.0%), headache (18.6%), insomnia (17.0%), dizziness (13.2%), bone pain (10.5%), and blurred vision (7.9%); 19.7% of 518 evaluable patients had palpable splenomegaly. Fewer than half of patients were receiving aspirin at enrollment (47.7%). The most common PV treatments ± aspirin were phlebotomy (PBT; 63.5%), hydroxyurea (HU; 42.2%), watchful waiting (5.3%), and ruxolitinib (3.1%); 23.0% of patients received PBT + HU. Conclusion: The REVEAL study is unique in that it captures data from both academic and community centers, and therefore includes a broader segment of the PV population typically not described in the literature. REVEAL can provide novel insights into questions related to the contemporary demographics of PV, practice patterns regarding diagnosis and therapy, and the real-world burden of PV and its impact on patients' quality of life and work productivity. Preliminary descriptive data from this early subset of patients suggest that a high proportion of patients report having PV-related symptoms at diagnosis, fewer patients are treated with aspirin than expected, and that thromboembolic event rates remain high after diagnosis. Disclosures Stein: Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees. Moliterno:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees. Boccia:Incyte Corporation: Honoraria. Naim:Incyte Corporation: Employment, Equity Ownership. Cordaro:Incyte Corporation: Employment, Equity Ownership. Peng:Incyte Corporation: Employment, Equity Ownership. Sun:Incyte Corporation: Employment, Equity Ownership. Parasuraman:Incyte Corporation: Employment, Equity Ownership. Mesa:Promedior: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; NS Pharma: Research Funding; CTI Biopharma: Research Funding; Gilead: Research Funding; Pfizer: Research Funding; Incyte Corporation: Research Funding; Genentech: Research Funding.

Abstract Abstract 2847 Background and Purpose: Myelofibrosis (MF) is a progressive Philadelphia-negative myeloproliferative neoplasm characterized by debilitating symptoms, massive splenomegaly, and anemia, which severely impairs quality of life. When medical therapy is not effective or tolerated, splenectomy may be required to ease symptoms in patients with symptomatic portal hypertension, massive splenomegaly, and/or frequent red blood cell transfusions (Barbui et al. J Clin Oncol. 2011;29:761–770). In a recent study (Tefferi et al. Mayo Clin Proc. 2012;87:25–33) up to 27% of patients diagnosed with MF eventually underwent splenectomy. However, splenectomy is associated with limited duration of symptom response, high rates of perioperative morbidity and mortality, and acceleration of hepatomegaly. Clinical studies in patients with MF have demonstrated that ruxolitinib, an oral JAK1/JAK2 inhibitor, provides significant and durable reductions in splenomegaly, the burden of MF-associated symptoms, and also improved quality of life. In this post hoc analysis of pooled data from these studies, we determined the incidence of splenectomy in patients treated with ruxolitinib and those who received placebo or best available therapy (BAT) to evaluate whether ruxolitinib therapy may affect the need for splenectomy. Methods: This analysis included patients who participated in the ruxolitinib phase I/II trial (N=153; Verstovsek et al. N Engl J Med. 2010;363:1117–1127); COMFORT-I, a phase III, 24-month placebo-controlled trial of ruxolitinib (N=309; Verstovsek et al. N Engl J Med. 2012;366:799–807); and COMFORT-II, a phase III, 48-month randomized trial comparing the effects of ruxolitinib and BAT (N=219; Harrison et al. N Engl J Med. 2012;366:787–798). Incidence of splenectomy while on treatment or during the protocol-specified follow-up period, adjusted for differences in the duration of follow up, was calculated for patients on ruxolitinib, placebo, or BAT. Results: As a result of the crossover rules and a higher discontinuation rate on the comparator arms in the phase III studies, mean follow-up duration for placebo (0.67 years) or BAT (0.95 years) overall was substantially shorter than mean follow-up duration for ruxolitinib (1.78 years). Baseline characteristics of the 14 patients who underwent splenectomy were as follows: median age=63 years; median time since initial diagnosis=7.8 years; median spleen length (n=13): 17.0 cm (range: 0–28.0 cm); median spleen volume (in those with measurement, n=11)=2924 cm3 (range: 1203–6807 cm3); IPSS high risk=50%, intermediate-2 risk=43%, intermediate-1=7%. Among patients originally randomized and treated with ruxolitinib, the incidence of splenectomy was 1.1 events per 100 patient years (Table). For patients treated with placebo or BAT in the phase III studies, the incidence of splenectomy was approximately three times higher at 2.9 events per 100 patient years, despite the fact that patients on placebo or BAT were allowed to crossover to ruxolitinib if they had worsening symptomatic splenomegaly. Conclusions: Although limited by small numbers, results of this analysis suggest that ruxolitinib reduces the need for splenectomy in patients with MF. Because of crossover to ruxolitinib and higher discontinuation rates in placebo and BAT, follow-up duration was shorter in these treatment arms compared with ruxolitinib. Further, ruxolitinib treatment in crossover patients may have prevented progression of symptomatic splenomegaly in some patients who may have otherwise become candidates for splenectomy. Our analysis may underestimate the true incidence of splenectomy among patients not receiving ruxolitinib therapy and therefore, the relative reduction in splenectomy rate in patients receiving this therapy. Longer-term follow up will better define the splenectomy rate in ruxolitinib-treated patients. Disclosures: Verstovsek: Incyte Corporation: Research Funding. Kiladjian:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Shire: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding. Mesa:Incyte: Research Funding; Lilly: Research Funding; Sanofi: Research Funding; NS Pharma: Research Funding; YM Bioscience: Research Funding. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees. Gotlib:Incyte Corporation: Consultancy, Honoraria, Support for travel to meeting for the study or other purposes from Incyte Other. Kantarjian:Incyte: grant support Other. Sirulnik:Novartis: Employment, Equity Ownership. Peng:Incyte Corporation: Employment, Equity Ownership. Sandor:Incyte Corporation: An employee of Incyte and receiving stock options as part of his compensation Other, Employment. Harrison:Novartis: Honoraria, Research Funding, Speakers Bureau; YM Bioscience: Consultancy, Honoraria; Sanofi Aventis: Honoraria; Shire: Honoraria, Research Funding.