Miller, Carole B.

Abstract PAC203 is a randomized dose-finding study of pacritinib, an oral JAK2/IRAK1 inhibitor, in patients with advanced myelofibrosis who are intolerant of or resistant to ruxolitinib. Patients were randomized 1:1:1 to pacritinib 100 mg once per day, 100 mg twice per day, or 200 mg twice per day. Enhanced eligibility criteria, monitoring, and dose modifications were implemented to mitigate risk of cardiac and hemorrhagic events. Efficacy was based on ≥35% spleen volume response (SVR) and ≥50% reduction in the 7-component total symptom score (TSS) through week 24. Of 161 patients, 73% were intolerant of and 76% had become resistant to ruxolitinib; 50% met criteria for both. Severe thrombocytopenia (platelet count <50 × 103/μL) was present in 44%. SVR rates were highest with 200 mg twice per day (100 mg once per day, 0%; 100 mg twice per day, 1.8%; 200 mg twice per day, 9.3%), particularly among patients with baseline platelet counts <50 × 103/μL (17%; 4 of 24). Although TSS response rate was similar across doses (100 mg once per day, 7.7%; 100 mg twice per day, 7.3%; 200 mg twice per day, 7.4%), median percent reduction in TSS suggested a dose-response relationship (–3%, −16%, and −27%, respectively). Pharmacokinetic and pharmacodynamic modeling based on all available data showed greatest SVR and TSS reduction at 200 mg twice per day compared with lower doses. Common adverse events were gastrointestinal events, thrombocytopenia, and anemia. There was no excess of grade ≥3 hemorrhagic or cardiac events at 200 mg twice per day. Pacritinib 200 mg twice per day demonstrated clinical activity and an acceptable safety profile and was selected as the recommended dose for a pivotal phase 3 study in patients with myelofibrosis and severe thrombocytopenia. This trial was registered at www.clinicaltrials.gov as #NCT03165734.

Abstract Momelotinib (MMB) is a JAK1/2 and ACVR1 inhibitor with demonstrated clinical activity in all 3 hallmarks of myelofibrosis (MF): anemia, constitutional symptoms, and splenomegaly. In this phase 2 open-label translational biology study (NCT02515630) of 41 transfusion-dependent patients with MF, we explored mechanisms underlying the favorable activity of MMB on MF-associated iron-restricted anemia, including its impact on serum hepcidin levels, and markers of iron storage and availability, erythropoiesis, and inflammation. A transfusion-independent response (TI-R), defined as red blood cell transfusion independence (TI) ≥12 weeks at any time on study, occurred in 17 patients (41%; 95% confidence interval [CI], 26%-58%), including 14 patients (34%; 95% CI, 20%-51%) who achieved TI-R by week 24. In addition, 78% of TI nonresponse (TI-NR) patients achieved a ≥50% decrease in transfusion requirement for ≥8 weeks. Adverse events (AEs) were consistent with previous studies of MMB in MF, with cough, diarrhea, and nausea as the most common. Twenty-one patients experienced grade ≥3 AEs, most commonly anemia and neutropenia. Consistent with preclinical data, daily MMB treatment led to an acute and persistent decrease in blood hepcidin associated with increased iron availability and markers of erythropoiesis. Baseline characteristics associated with TI-R were lower inflammation and hepcidin as well as increased markers of erythropoiesis and bone marrow function. Overall, the study demonstrates that MMB treatment decreases hepcidin in conjunction with improving iron metabolism and erythropoiesis, suggesting a mechanistic explanation for the reduced transfusion dependency observed in transfusion-dependent MF patients treated with MMB, thereby addressing the key unmet medical need in the MF population.

6624 Background: RUX is a JAK1/JAK2 inhibitor that demonstrated significant clinical benefit in patients (pts) with MF in COMFORT-I (NCT00952289), a phase 3, randomized (1:1), double-blind, placebo (PBO)-controlled study (N=309). Methods: Pts assessed MF-related symptoms daily using the modified Myelofibrosis Symptom Assessment Form v2.0; Total Symptom Score (TSS) was calculated from individual scores for abdominal discomfort, pain under left ribs, early satiety, night sweats, itching, and bone/muscle pain. Therapy was interrupted if platelet or absolute neutrophil count fell below 50,000/µL or 500/µL, respectively. AEs were evaluated during treatment interruption or discontinuation. The protocol suggested an optional tapering strategy and possible addition of steroids if RUX therapy was discontinued for reasons other than thrombocytopenia. Results: In RUX-treated patients with treatment interruption, TSS gradually returned to baseline levels over approximately 1 week. The most common AE leading to treatment interruption or discontinuation in each group was thrombocytopenia (n=11, RUX) and abdominal pain (n=4, PBO). Of these, only 1 RUX pt discontinued for thrombocytopenia. A summary of new onset/worsening AE data after treatment interruption or discontinuation is presented (Table). Of 58 pts who discontinued study treatment, 23 (n=10, RUX; n=13, PBO) experienced a total of 43 SAEs (19, RUX; 24, PBO) that showed no specific pattern or difference between treatment groups. Four of 21 RUX-treated pts had dose tapering following study drug discontinuation. Conclusions: Apart from the expected return of MF-related symptoms, there was no pattern of AEs to suggest that RUX interruption or discontinuation is associated with a specific withdrawal syndrome. [Table: see text]

Abstract Background: In 2 phase III studies comparing the Janus kinase (JAK) 1 and JAK2 inhibitor ruxolitinib with placebo (Controlled Myelofibrosis Study with Oral JAK Inhibitor Treatment I [COMFORT-I]) or best available therapy (COMFORT-II), ruxolitinib treatment was associated with rapid and durable reductions in spleen volume, improved myelofibrosis (MF)-related symptoms and quality of life measures, and prolonged survival. However, the key measures of efficacy used in the COMFORT studies—magnetic resonance imaging/computed tomography (MRI/CT) to measure change in spleen volume and the modified Myelofibrosis Symptom Assessment Form v2.0 to assess change in MF-related symptoms—are not commonly used in clinical practice. Therefore, we analyzed the efficacy of ruxolitinib in COMFORT-I using practical, community-based measures of clinical benefit (spleen palpation and the Patient Global Impression of Change [PGIC] questionnaire). Methods: In COMFORT-I, patients (N = 309) with primary MF, post–polycythemia vera MF or post–essential thrombocythemia MF were randomized to receive ruxolitinib (n = 155) or placebo (n = 154). For this analysis, patients were divided into groups by degree of palpable spleen reduction and symptom improvement at week 12 as follows: patients with clinically relevant reductions in palpable spleen as defined by the International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European LeukemiaNet (ELN) consensus criteria (SPL), patients with “much improved” or “very much improved” symptoms as measured by the PGIC (PGIC), or patients who did not achieve SPL or PGIC (Neither). The Neither group encompassed patients with “minimally improved” symptoms with no worsening in palpable spleen or patients who achieved 10% reduction in palpable spleen with no worsening in symptoms (Minor), and patients who did not achieve any palpable spleen reduction or PGIC-assessed symptom improvement (None). Nonevaluable patients (4/155 for ruxolitinib and 13/154 for placebo) were not included in the analysis. Additional measures of clinical benefit assessed at week 12 included changes in spleen volume and changes in white blood cell (WBC) count. Durability of all measures of clinical benefit with longer-term ruxolitinib therapy was also evaluated. Results: At week 12, the majority (91.4%) of patients randomized to ruxolitinib achieved some clinical benefit as measured by palpable spleen reduction and/or PGIC-assessed symptom improvement, vs 31.9% of those assigned to placebo (Figure 1). Benefits in palpable spleen length reduction and PGIC-assessed symptom improvement achieved at week 12 with ruxolitinib were sustained at week 24. Benefits in palpable spleen length reduction were sustained with longer-term ruxolitinib therapy (median follow-up: 149 weeks). At week 12, ruxolitinib treatment was associated with meaningful reductions in spleen volume by MRI or CT and WBC count in patients who achieved SPL and PGIC criteria, while worsening spleen volume and WBC count was observed with placebo (Figure 2); these effects were durable with longer-term therapy. Patients who achieved neither SPL nor PGIC criteria by week 12 (n = 47; 31.1%) achieved a clinically meaningful reduction in spleen volume by MRI or CT (mean change, −25.6%) and decreased WBC counts (mean change, −7.4%) at week 12 (Figure 2). Patients who did not achieve any palpable spleen reduction or PGIC-assessed symptom improvement (n = 13; 8.6%) were generally older, more likely to have high-risk MF as assessed by the International Prognostic Scoring System, and had higher WBC counts, lower platelet counts, and worse fibrosis grade at baseline compared with those achieving defined palpable spleen length reduction and/or PGIC-assessed symptom improvement with ruxolitinib. Conclusions: Nearly all patients treated with ruxolitinib achieved some clinical benefit as assessed by practical measures of assessing efficacy (ie, palpable spleen reduction or PGIC-assessed symptom improvement) within 12 weeks of treatment initiation. Meaningful reductions in spleen volume and WBC count were observed in patients receiving ruxolitinib whether or not they achieved palpable spleen reduction by IWG-MRT/ELN consensus criteria or PGIC symptom improvement (“much improved” or “very much improved”) at week 12; these reductions were durable with long-term ruxolitinib therapy. Disclosures Miller: Incyte Corporation: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Komrokji:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Mesa:CTI: Research Funding; NS Pharma: Research Funding; Gilead: Research Funding; Incyte Corporation: Research Funding; Celgene: Research Funding. Sun:Incyte Corporation: Employment. Montgomery:Incyte Corporation: Employment. Verstovsek:Incyte Corporation: Research Funding.

Abstract Background: Phlebotomy is a common and established treatment in patients diagnosed with polycythemia vera (PV) to reduce the risk of thromboembolic events, in both acute and chronic settings. However, phlebotomy may not alleviate all PV-related symptoms and its frequent application can cause moderate to profound iron deficiency, which may worsen PV-related symptoms. This analysis of MPN Landmark survey data examined patient-reported quality of life (QoL) and productivity outcomes in patients with PV based on phlebotomy treatment history. Methods: Patients who were diagnosed with a myeloproliferative neoplasm (MPN) were recruited to participate in the MPN Landmark survey in the US (fielded May - July 2014). This analysis describes responses from patients with PV on questions regarding PV-related symptom burden, QoL, and productivity. Patient responses were analyzed based on phlebotomy treatment history and included patients who were actively receiving phlebotomy within the last 3 months (≥1 per month, every other month, and every 3 months or longer), had discontinued phlebotomy, or were phlebotomy-naive. Descriptive statistical analyses were used to evaluate these outcomes based on phlebotomy frequency, as appropriate. Results: Overall, 813 patients completed the Landmark survey, and 274 out of the 380 patients with PV who completed the survey were evaluable for this analysis. Mean age ranged from 61.6-65.4 years among phlebotomy subgroups (Table 1). The average duration of PV was longest among patients with PV who had discontinued phlebotomy (12.0 years) compared with phlebotomy-naive patients (6.3 years) and patients actively treated with phlebotomy (5.9-8.9 years). The percentage of patients diagnosed within 1 year of the survey ranged from 4.1% to 11.5% among the patients who had been treated with phlebotomy and was 15.4% in the phlebotomy-naive subgroup. Most patients reported PV-related symptoms; symptom burden was similar in all phlebotomy subgroups. Fatigue was the most common symptom reported in all subgroups (range, 71.4%-80.8%). QoL measures were generally worse with higher phlebotomy frequency (Table 1). Similarly, more frequent phlebotomy procedures was found to be associated with reduced productivity: patients who received ≥1 phlebotomy per month had the highest mean number (in the preceding 30 days) of sick days (among patients employed), days spent in bed, and days with plans canceled. Of note, approximately one third of patients receiving more frequent phlebotomy procedures were also receiving concomitant hydroxyurea to manage their PV (≥1 per month, 38.5%; every other month, 36.4%). Conclusion: Patients with PV may experience disease-related symptoms and reductions in QoL and work productivity. Frequent phlebotomy procedures were associated with increasingly worsened QoL and decreased work productivity. Further research is needed to better understand the impact of phlebotomy on patient-reported outcomes in patients with PV. Disclosures Fazal: Bristol Myers Squibb: Consultancy, Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Ariad: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Miller:Incyte Corporation: Honoraria, Research Funding. Mascarenhas:Promedior: Research Funding; Roche: Research Funding; CTI Biopharma: Research Funding; Kalobios: Research Funding; Novartis Pharmaceuticals Corporation: Research Funding; Incyte Corporation: Research Funding. Thyne:Incyte Corporation: Speakers Bureau. Paranagama:Incyte Corporation: Employment, Equity Ownership. Parasuraman:Incyte Corporation: Employment, Equity Ownership. Naim:Incyte Corporation: Employment, Equity Ownership. Mangan:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees. Mesa:Promedior: Research Funding; Genentech: Research Funding; Gilead: Research Funding; NS Pharma: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; CTI Biopharma: Research Funding; Pfizer: Research Funding; Incyte Corporation: Research Funding.

Abstract Introduction: Patients develop anemia as a result of myelofibrosis (MF) or its treatment, including Janus kinase (JAK) inhibitors. However, momelotinib (MMB), a JAK1/2 and Activin A receptor type I (ACVR1) inhibitor with demonstrated clinical activity in MF, improved anemia in prior clinical trials. JAK1/2 and ACVR1 respond to inflammation and iron stores to control iron availability through hepcidin, the key regulator of the entry of iron into circulation. Like other inflammatory diseases, MF is characterized by high hepcidin. MMB inhibited ACVR1 to modulate hepcidin and ameliorate anemia in a rodent model (Asshoff, Blood 2017). The impact of MMB was investigated on blood hepcidin, along with markers of iron storage and availability, erythropoiesis, and inflammation to explore mechanisms of the favorable effects of MMB on MF-associated anemia. Methods: In a phase 2 open-label study, MMB 200 mg once daily was given for 24 weeks to transfusion-dependent (TD; ≥4 units red blood cells [RBC] transfusion in the 8 weeks prior to first dose of MMB) patients with primary or post-ET/PV MF (age ≥18 yrs, required MF therapy, CrCl ≥ 60 mL/min, platelets ≥50 K, and absence of Gr ≥2 peripheral neuropathy, baseline palpable spleen was not required, patients with prior splenectomy were excluded). Patients were evaluated for MMB efficacy and safety. Total symptom score (TSS) was based on a modified Myeloproliferative Neoplasm Symptom Assessment Form. Transfusion-independent response/non-response (TI-R/NR) was defined as RBC transfusion-independence ≥12 weeks at any time on study. Serial blood samples were analyzed for a panel of biomarkers and liver iron content (LIC) was measured by MRI. Blood hepcidin was evaluated at every study visit in the morning (8-10am) pre-dose and 6 hours post-dose using a mass spectrometry assay and, prior to first dose, the normal daily increase of blood hepcidin was observed in half the population. Results: 41 patients (mean age 70, 63% male, 88% white) received MMB. By week 24, 14 (34.1%, 90% CI: 22.0-48.1%) patients had a TI-R and 39.0% had no RBC transfusion for ≥8 weeks at any time (90% CI: 26.2-53.1%). Six patients (15.8%, 90% CI: 7.1-28.8%) had a ≥50% reduction from baseline to week 24 in TSS and 5 patients (12.2%, 90% CI: 4.9-23.9%) had a ≥35% reduction in spleen volume; in those patients with week 24 data, the TSS and splenic response rates were 28.6% and 19.2% respectively. TSS and spleen volume assessments were not available for 17 (44.5%) and 15 (36.6%) patients, respectively, and these patients were considered non-responders. Adverse events were consistent with previous studies of MMB in MF, with cough, diarrhea, nausea, and fatigue as the most common. AEs ≥Gr 3 were experienced by 21 patients, most commonly anemia and neutropenia. At every study visit, median blood hepcidin decreased 6 hours after dosing with MMB (Fig. 1). Daily inhibition of hepcidin did not lead to an increase in serum iron for the entire population. However, serum iron, transferrin, hemoglobin, reticulocytes, and hematocrit increased at week 2 in patients with TI-R. Following this peak, serum iron decreased while hemoglobin, hematocrit and platelet count increased through week 24. At baseline, TI-R was associated with lower hepcidin, LIC, serum iron, reduced inflammation (C-reactive protein and ferritin), and higher hematocrit, erythrocytes, reticulocytes, platelets, and hemoglobin than TI-NR (Fig. 2). In multivariable analysis, TI-R was strongly associated with baseline hemoglobin ≥8g/dL (p=0.036) and lower morning hepcidin (p=0.013), weakly associated with younger age (p=0.070) and lower DIPSS score (p=0.075), but not with gender, type of MF (primary vs post-ET/PV), spleen volume, TSS, or JAK2V617F mutation. Conclusion: Safety findings and rate of TI-R were similar to TD MF patients in other MMB trials. Consistent with preclinical data, daily MMB treatment led to a transient decrease in blood hepcidin. In patients with TI-R, hepcidin suppression was associated with increased iron availability and markers of erythropoiesis. At baseline, TI-R associated with reduced inflammation, lower hepcidin, and increased markers of erythropoiesis and bone marrow function. Overall, the study suggests that transient modulation of hepcidin by MMB is sufficient to boost erythropoiesis in those transfusion-independent MF patients with lower baseline inflammation and greater erythropoietic potential. Disclosures Oh: Takeda: Research Funding; Janssen: Research Funding; CTI Biopharma: Research Funding; Gilead: Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Gerds:Celgene: Consultancy; Apexx Oncology: Consultancy; CTI Biopharma: Consultancy; Incyte: Consultancy. Gupta:Novartis: Consultancy, Honoraria, Research Funding; Incyte: Research Funding. Verstovsek:Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees. Mesa:Novartis: Consultancy; Celgene: Research Funding; NS Pharma: Research Funding; Genentech: Research Funding; Incyte Corporation: Research Funding; Promedior: Research Funding; Pfizer: Research Funding; CTI Biopharma: Research Funding; Gilead: Research Funding; UT Health San Antonio - Mays Cancer Center: Employment. Miller:Gilead Sciences, Inc.: Consultancy, Research Funding; Incyte: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau. Heaney:Decipheral: Research Funding; Novartis: Research Funding; Blueprint: Research Funding; Incyte: Research Funding; Roche: Consultancy, Research Funding. O'Connell:Incyte: Research Funding. Arcasoy:Gilead Sciences, Inc.: Research Funding; Incyte: Research Funding; CTI BioPharma: Research Funding; Samus Therapeutics: Research Funding. Zhang:Gilead Sciences, Inc.: Employment. Kawashima:Gilead Sciences, Inc.: Employment, Equity Ownership. Ganz:Intrinsic LifeScience: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Silarus Pharma: Consultancy, Equity Ownership; Keryx Pharma: Consultancy, Research Funding; Akebia: Consultancy, Research Funding; Vifor: Consultancy; Gilead: Consultancy; Ablynx: Consultancy; La Jolla Pharma: Consultancy, Patents & Royalties: Patent licensed to La Jolla Pharma by UCLA. Baker Brachmann:Gilead Sciences, Inc.: Employment, Equity Ownership.

Abstract Abstract 278 Background: Overactive JAK-STAT signaling as a result of gain-of-function mutations (eg, JAK2V617F) and/or high circulating levels of inflammatory cytokines is considered to play a key role in the pathogenesis of myeloproliferative neoplasms. Ruxolitinib, a selective oral inhibitor of JAK1 and JAK2, demonstrated a significant reduction in spleen volume (SV) and improvements in myelofibrosis (MF)-related symptoms in a double-blind placebo-controlled trial (COMFORT-I). The objective of this analysis was to evaluate the efficacy of ruxolitinib across patient (pt) subgroups in COMFORT-I. Methods: Pts with MF were randomized to start placebo or ruxolitinib at a dose of 15 mg or 20 mg PO BID depending on baseline platelet count (100–200 ×109/L or >200 ×109/L, respectively). The dose was optimized for efficacy and safety during treatment. SV change was measured by MRI; MF symptoms were assessed using a daily diary (modified Myelofibrosis Symptom Assessment Form [MFSAF] v2.0) over 1 wk prior to dosing and throughout the 24 wks of dosing. The percent changes from baseline to wk 24 in SV and MFSAF Total Symptom Score (TSS, a measure of combined scores for abdominal discomfort, pain under ribs on left side, early satiety, itching, night sweats, and bone/muscle pain) were compared for ruxolitinib and placebo pts across the following subgroups: MF disease subtype, age, International Prognosis Scoring System (IPSS) risk group, presence/absence of JAK2V617F mutation, baseline hemoglobin, baseline spleen size (palpable spleen length), and baseline TSS. Survival was estimated by Kaplan-Meier method. Changes in SV and TSS Across Subgroups: 309 pts were randomized: 155 to ruxolitinib and 154 to placebo. Ruxolitinib demonstrated consistent benefit compared with placebo in both SV and TSS across all subgroups evaluated (Table). The impact of symptom severity on response was evaluated by baseline TSS quartiles (maximum score for TSS = 60). Ruxolitinib pts with baseline TSS of <8.5, 8.5-<16.5, 16.5-<25.5 and ≥25.5 had mean percent changes in SV of −28.0, −31.4, −31.7 and −34.8, respectively, vs +8.1 for all placebo pts combined. The mean percent change in TSS for these same subgroups was −40.5, −47.2, −48.1 and −48.2 vs +41.8 for all placebo pts combined. These data indicate that pts with modest to marked symptoms all benefit from ruxolitinib therapy in terms of both SV and TSS. Survival Analysis: 13 ruxolitinib and 24 placebo pts died during the study or during extended follow-up (median follow-up of 52 and 51 wks, respectively), representing a hazard ratio (95% CI) of 0.499 (0.254, 0.98) (p=0.0395). For ruxolitinib- and placebo-treated pts, respectively, the probability of survival (95% CI) >48 wks was 0.98 (0.92, 0.99) and 0.90 (0.81, 0.95) for pts with baseline hemoglobin values ≥10 g/dL and 0.84 (0.72, 0.91) and 0.77 (0.63, 0.86) for pts with baseline hemoglobin <10 g/dL. Conclusions: Pts receiving ruxolitinib had higher response rates than placebo based on reductions in SV and improvements in TSS at wk 24 regardless of baseline subgroup: MF disease subtype, age (≤65 or >65 y), IPSS risk group (intermediate-2 or high-risk), presence or absence of JAK2V617F mutation, hemoglobin level (≥10 g/dL or <10 g/dL), palpable spleen length (≤10 cm or >10 cm), and symptom severity (TSS quartile). In addition, the overall survival analysis suggested a benefit with ruxolitinib therapy over placebo. Disclosures: Verstovsek: Incyte: Research Funding. Mesa:Incyte: Research Funding; Lilly: Research Funding; SBio: Research Funding; Astra Zeneca: Research Funding; NS Pharma: Research Funding; Celgene: Research Funding. Gotlib:Incyte: Consultancy, Research Funding. Levy:Incyte: Employment, Equity Ownership. Gupta:Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Catalano:Incyte: Honoraria; Novartis: Honoraria. Deininger:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Genzyme: Research Funding. Miller:Incyte: Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau. Winton:Incyte: Consultancy. Arcasoy:Incyte: Research Funding. Lyons:Alexion: Consultancy, Honoraria; Telik: Research Funding; Incyte: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Novartis: Research Funding. Vaddi:Incyte: Employment. Erickson-Viitanen:Incyte: Employment. Sun:Incyte: Employment. Sandor:Incyte: Employment. Kantarjian:Incyte: Research Funding; Novartis: Consultancy, Research Funding.

Abstract Abstract 5146 Background: Myelofibrosis (MF) is characterized by splenomegaly, debilitating symptoms, hematologic abnormalities, and shortened survival. COMFORT-I is a Phase III randomized, double-blind, placebo-controlled study of the JAK1 and JAK2 inhibitor ruxolitinib in patients (pts) with MF. The placebo arm of this ongoing study provides a unique population in which to assess the clinical burden of MF in a controlled setting. Methods: 151 pts with intermediate-2 or high-risk primary-MF (PMF), post-polycythemia vera-MF (PPV-MF), or post-essential thombocythemia-MF (PET-MF) who were not candidates for other therapies were randomized to receive placebo in COMFORT-I after a 28-day washout of previous MF therapies. Assessments included MF symptoms measured daily using an electronic diary (modified Myelofibrosis Symptom Assessment Form [MFSAF] v2.0), spleen volume measured every 12 wks by blinded abdominal MRI or CT scans, and laboratory measures at least monthly through wk 24. The Patient-Reported Outcomes Measurement System (PROMISE) Fatigue and Patient Global Impression of Change (PGIC) questionnaires were administered at each visit. Pts with missing data (baseline or post-baseline assessment measured), or pts who withdrew or crossed over to active treatment before a study visit were not included in analyses. Results: 151 pts received 1 or more doses of placebo (median exposure 204 days). The study included 65% high-risk and 35% intermediate-2 risk pts, with a median of 2.5 years since diagnosis. 55% had PMF, 31% PPV-MF, and 14% PET-MF. Regardless of prior MF therapy (57% were on hydroxyurea), there was continual worsening of symptoms over time as assessed by the MFSAF Total Symptom Score (TSS, comprised of scores for night sweats, itching, abdominal pain and discomfort, early satiety and bone/muscle pain) (see Figure). At wk 24, mean/median spleen volume increased by +8.1%/+8.5%, and both intermediate-2 and high-risk pts demonstrated progressive disease over the course of the study. Mean/median PROMIS Fatigue score worsened by 9.1%/6.5%. Mean/median score for the PGIC (a 7-point scale ranging from 1 = very much improved to 7 = very much worse, with 4 = no change) was 4.2/4.0 at wk 24; 19.6% of pts reported feeling much worse or very much worse. Mean/median total body weight changed from 72.0 kg/72.2 kg to 70.1 kg/69.7 kg at wk 24. Hematology assessments (median, baseline vs wk 24) were as follows: hemoglobin, 105 vs 106 g/L; platelets, 233 vs 219 x109/L; neutrophils, 14.8 vs 16.0 x109/L; white blood cell count, 18.4 vs 20.1 x109/L. Two of 151 pts had new-onset (new or worsening) grade 3 or grade 4 thrombocytopenia, and 23/151 pts had new-onset grade 3 or grade 4 anemia. 16 pts met protocol-specified criteria for unblinding and crossover to active treatment before wk 24, which was a 25% increase in MRI-based spleen volume either with or without increased pain or weight loss; thus, mean and median values reported at wk 24 may represent an underestimate of the degree of worsening in disease parameters. Conclusion: The signs and symptoms of MF continued to worsen over a 6-month time frame in this placebo population. The data illustrate the progressive nature of MF and support the need for effective therapeutic interventions. Moreover, treatment benefit must be benchmarked against continual evolution of the disease in the absence of treatment. Early recognition of the debilitating symptoms of MF and intervention with effective therapy to prevent continual worsening of the disease should be strongly considered. Disclosures: Verstovsek: Incyte: Research Funding. Mesa:Incyte: Research Funding; Lilly: Research Funding; SBio: Research Funding; Astra Zeneca: Research Funding; NS Pharma: Research Funding; Celgene: Research Funding. Gotlib:Incyte: Consultancy, Research Funding. Levy:Incyte: Employment, Equity Ownership. Gupta:Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Catalano:Incyte: Honoraria; Novartis: Honoraria. Deininger:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Genzyme: Research Funding. Miller:Incyte: Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau. Winton:Incyte: Consultancy. Arcasoy:Incyte: Research Funding. Lyons:Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Telik: Research Funding; Alexion: Consultancy, Honoraria; Novartis: Research Funding. Vaddi:Incyte: Employment. Erickson-Viitanen:Incyte: Employment. Sun:Incyte: Employment. Sandor:Incyte: Employment. Kantarjian:Incyte: Research Funding; Novartis: Consultancy, Research Funding.

Abstract Abstract 3842 Background: Dysregulated JAK-STAT signaling is a key feature in MF, which is characterized by splenomegaly, debilitating symptoms, poor quality of life (QoL), cytopenias, and shortened survival. Ruxolitinib is a selective JAK1 and JAK2 inhibitor with clinical activity in MF. COMFORT-I is a Phase III, double-blinded, placebo-controlled study of ruxolitinib in patients with MF. At wk 24, 41.9% of patients receiving ruxolitinib reached the protocol-defined threshold of a ≥35% reduction in spleen volume (SV) compared to 0.7% in the placebo group (p<0.0001). The objective of this analysis was to evaluate the relationship between SV reduction achieved with ruxolitinib treatment and changes in symptoms and QoL. Methods: 309 patients were randomized to receive ruxolitinib (n=155) or placebo (n=154). Initial dosing was based on baseline platelet counts: 15 mg BID for counts of 100–200 x109/L and 20 mg BID for >200 x109/L. SV was measured by blinded imaging (MRI or CT scan) every 12 wks. Via electronic diary, patients reported MF symptoms daily using the modified Myelofibrosis Symptom Assessment Form (MFSAF) v2.0. The Total Symptom Score (TSS) from the MFSAF represents a combined score for the individual symptoms of abdominal discomfort, pain under ribs on left side, early satiety, itching, night sweats, and bone/muscle pain. The European Organization for Research and Treatment of Cancer Quality-of-Life 30 (EORTC QLQ-C30) and Patient-Reported Outcomes Measurement System (PROMISE) Fatigue questionnaires were administered at each visit; Patient Global Impression of Change (PGIC) was administered at every visit beginning at wk 4. The PGIC rates a patient's overall sense of whether a treatment has been beneficial or not on a 7-point scale, ranging from 1 = very much improved to 7 = very much worse, with 4 = no change. Results: Baseline QoL scores reflected debilitating disease, and were similar to scores for similar-aged patients with other cancers (Scott NW, Fayers PM, Aaronson NK, et al. EORTC QLQ-C30 Reference Values Manual, July 2008). The impact on patients was particularly evident on the PROMIS Fatigue scale and QLC-C30 Global Health, Physical Functioning, Role Functioning, and Social Functioning subscales. Baseline Symptom and QoL Measures* Associations between changes in symptoms and QoL with the objectively measured changes in SV were evaluated. Patients receiving ruxolitinib were grouped according to SV reduction at 24 wks of treatment: ≥35% reduction in SV (n=65), 10-<35% (n=51), and <10% (n=23). Symptom and QoL responses were evaluated among the various subgroups (of the SV reduction percentage strata) and comparisons were made across these and the total placebo group (n=106). Shown in the Figure are mean changes at wk 24 relative to baseline for TSS, QoL indicators, and PGIC scores. Conclusions: Changes in SV as low as 10% in ruxolitinib-treated patients were associated with improvements on EORTC QLQ-C30 Global Health subscale, PROMISE Fatigue scale, and the MFSAF v2.0 diary TSS. Moreover, commensurate improvements in these outcomes were observed as the SV reduction increased. Importantly, the simple PGIC questionnaire allowed patients to characterize a meaningful change in their condition that was consistent with more comprehensive measures of MF symptoms and quality of life, reflecting a doctor-patient assessment easily applied to clinical practice. Disclosures: Mesa: Incyte: Research Funding; Lilly: Research Funding; SBio: Research Funding; Astra Zeneca: Research Funding; NS Pharma: Research Funding; Celgene: Research Funding. Gotlib:Incyte: Consultancy, Research Funding. Gupta:Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Catalano:Incyte: Honoraria; Novartis: Honoraria. Deininger:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Genzyme: Research Funding. Shields:Incyte: Consultancy. Miller:Incyte: Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau. Winton:Incyte: Consultancy. Hare:Incyte: Employment. Erickson-Viitanen:Incyte: Employment. Sun:Incyte: Employment. Sandor:Incyte: Employment. Levy:Incyte: Employment, Equity Ownership. Kantarjian:Incyte: Research Funding; Novartis: Consultancy, Research Funding. Verstovsek:Incyte: Research Funding.

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.