Gotlib, Jason

Abstract Abstract 1733 Background: Patients with myelofibrosis (MF) suffer from cytopenias, debilitating symptoms, and splenomegaly, all of which may contribute to shortened life expectancy. Cachexia is a common manifestation of MF. Its causes are multifactorial and include elevated inflammatory cytokines and mechanical effects of splenomegaly. It is a predictor of poor survival in patients with MF. Cachexia manifests as weight loss with low body-mass index (BMI; <20–21 kg/m2) (Strasser F. Sixth Research Congress of the European Association of Palliative Care; Wagner PD. Eur Respir J. 2008;31:492–501) and with metabolic indicators of poor nutritional status including hypocholesterolemia (total cholesterol <150 mg/dL or <3.89 mmol/L), which has been linked to poor prognosis in MF (Mesa et al. Blood 2007;110:abstract 2548). In the phase III, placebo-controlled, COMFORT-I study, ruxolitinib treatment significantly reduced spleen volume, improved MF-related symptoms, and exhibited a survival advantage compared with placebo in patients with MF. In this post hoc analysis, we investigated the effects of ruxolitinib treatment on weight and total cholesterol and the association of these changes with survival in COMFORT-I. Methods: Eligible patients in COMFORT-I were randomized to receive placebo (n=154) or ruxolitinib (n=155) at starting doses of 15 and 20 mg PO BID depending on baseline platelet count. Body weight was measured at baseline, and weeks 4, 8, 12, 16, and 24 and then every 12 weeks thereafter. Total serum cholesterol was measured at baseline and weeks 4, 12, 24, and then every 24 weeks thereafter. All patients receiving PBO completed crossover or discontinued within 3 months of the primary data analysis (when all patients completed 24 weeks and when half the patients remaining on study completed 36 weeks of treatment); thus, data for these patients were available for up to week 36 for weight and week 24 for total cholesterol. Kaplan-Meier analyses of overall survival were conducted in patients randomized to ruxolitinib stratified into 2 groups based on the median values separately for maximum weight gain and for maximum increase in total cholesterol during randomized treatment. Results: At baseline, mean body weight was similar between the treatment groups (72 kg, both) and mean total cholesterol was low (<150 mg/dL) in both treatment groups (ruxolitinib: 118 mg/dL; placebo: 115 mg/dL). The proportion of patients with BMI <22 were similar between the treatment groups (ruxolitinib: 23%; placebo: 28%) as was the proportion with total cholesterol <150 mg/dL (82%, both). Patients randomized to ruxolitinib experienced a gradual increase in body weight that stabilized by week 36 of treatment whereas patients receiving placebo experienced decreases in body weight over time (Figure 1). Similarly, total cholesterol increased in patients randomized to ruxolitinib and decreased in patients receiving placebo (Figure 2). Although total cholesterol increased over time in ruxolitinib-treated patients, increases did not exceed the upper limit of normal (199 mg/dL or 5.15 mmol/L). Nearly all patients randomized to ruxolitinib experienced weight gain (96% of patients) or an increase in total cholesterol (97% of patients). In patients randomized to ruxolitinib, weight gain above the median was associated with prolonged survival relative to lesser degrees of weight gain (HR=0.40; 95% CI: 0.18, 0.90; P=0.022; Figure 3). Similarly, increase in total cholesterol above the median was also associated with prolonged survival relative to a lesser degree of total cholesterol increase (HR=0.46; 95% CI: 0.21, 1.01; P=0.048; Figure 4). Meaningful comparisons with the placebo group based on the same stratification criteria could not be conducted as the majority of such patients experienced weight loss and decreases in total cholesterol while on the study; however, overall survival favored both ruxolitinib groups relative to all patients randomized to placebo even for ruxolitinib-treated patients with lower than median levels of weight gain or increase in total cholesterol. Conclusions: Ruxolitinib therapy promotes weight gain and improves total cholesterol in MF patients. These results suggest that the survival advantage exhibited by ruxolitinib over placebo in MF patients may be partly explained by reversal of the catabolic state and cachexia. Disclosures: Mesa: Incyte: Research Funding; Lilly: Research Funding; Sanofi: Research Funding; NS Pharma: Research Funding; YM Bioscience: Research Funding. Verstovsek:Incyte Corporation: Research Funding. Gupta:Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; YM Biosciences: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi#x2610;#x0025; Aventis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Mascarenhas:Incyte Corporation: Consultancy; Novartis: Clinical Trial Support, Clinical Trial Support Other. Atallah:Incyte: Consultancy, Research Funding. Sun:Incyte Corporation: Employment, Equity Ownership. Sandor:Incyte Corporation: Employment, Equity Ownership. Gotlib:Incyte Corporation: Consultancy, Honoraria, Support for travel to meeting for the study or other purposes from Incyte Other.

Abstract Abstract 1732 Background: In addition to chronic myelogenous leukemia (CML), the classic myeloproliferative neoplasms (MPNs) include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). The JAK2 V617F mutation (V617F) can be detected through genomic analysis of peripheral blood in 95% of PV and 50–60% of ET and MF patients (pts). These MPNs are often associated with debilitating symptoms and decreased quality of life (QOL). Systemic mastocytosis (SM) is an uncommon MPN in which proliferation of mast cells can result in mediator symptoms, as well as organ damage in advanced disease. We sought to compare the symptom burden of individuals with CML and SM to pts with classic MPNs in a more quantitative manner using a web-based recruitment design. Methods: Individuals with MPN were recruited through a web-based outreach effort. Participants gave IRB-approved consent, and completed on-line surveys of demographic information and questions based on the validated MPN-symptom assessment form (MPN-SAF). In addition, pts submitted saliva samples which were genotyped with SNP arrays based on the Illumina OmniExpress BeadChip, including probes for V617F. Regression analysis was used to evaluate the correlation between symptom responses and genotype data for 495 pts (118 PV, 121 ET, 97 MF, 85 SM, and 74 CML). For each MPN diagnosis, mean scores were calculated based on six fatigue-focused questions (Fatigue-6) and for six other symptoms (Symptom-6): early satiety, abdominal pain/discomfort, inactivity, night sweats, pruritis, and bone pain (ranked from 0–10; 10 = worst). ET pts' scores were used as the reference in the regression analysis based on prior data showing that ET pts have the lowest symptom burden among the classic MPNs. Individual symptoms, Fatigue-6, Symptom-6, and QOL (ranked 0–10; 10=worst) were analyzed using regression analysis against age, gender, diagnosis and V617F status. Results: Median age was 56 years (7–87), with 70% women. V617F was detected in 63% of classic MPN pts (87% PV, 46% ET, 56% MF). Analysis of Fatigue-6 scores revealed that age in years was negatively correlated with reported fatigue (β=-0.007 per year, P=0.032), while female gender and SM diagnosis were positively correlated with fatigue (female: β=0.33, P=2.4×10−4; SM: β=0.46, P=7.6×10−4). This trend was also seen for the Symptom-6: age (β=-0.025, P=5.8×10−4), female gender (β=0.73, P=1.4×10−4), and SM (β=1.8, P=5.0×10−10). Both Fatigue-6 and Symptom-6 were positively correlated with QOL, but Fatigue-6 had a much stronger association with QOL than did Symptom-6 (β=1.3, P=1.5×10−28 vs. β=0.36, P=1.2×10−11). When analyzed individually, abdominal pain/discomfort, pruritis, and bone pain were significantly correlated with V617F (β=0.676, P=0.0371; β=0.768, P=0.0241; β=0.791, P=0.0341, respectively), though these associations were not significant when all six symptoms were evaluated together (Symptom-6: β=0.315, P=0.171). There was no statistically significant correlation between V617F and Symptom-6. In addition, there was no correlation between any symptom and a germline variant in telomerase reverse transcriptase (TERT) rs2853677, identified as a novel predisposition allele for MPNs using a genome-wide association study of this cohort. Conclusion: Using a novel, web-based recruitment design combining MPN symptom assessment and genotyping of saliva samples, we identified significant correlations between 3 specific symptoms (pruritis, abdominal pain/discomfort, and bone pain) with V617F. Fatigue was also more strongly associated than other symptoms with QOL. There was no association between symptoms and TERT. This design is a powerful tool for future studies seeking to correlate symptoms with genotyping analysis. Disclosures: Hinds: 23andMe: Employment, Equity Ownership, Patents & Royalties. Barnholt:23andMe, Inc.: Employment. Kiefer:23andMe, Inc.: Employment. Do:23andMe, Inc.: Employment, Equity Ownership, Patents & Royalties. Eriksson:23andMe, Inc.: Employment, Equity Ownership, Patents & Royalties. Mountain:23andMe, Inc.: Consultancy, Employment, Honoraria, Patents & Royalties, Research Funding. Francke:23andMe, Inc.: Employment, Honoraria, Research Funding; Locus Development: Consultancy, Membership on an entity's Board of Directors or advisory committees. Tung:23andMe, Inc.: Employment. Zehnder:23andMe, Inc.: Unpaid advisor and collaborator Other. Gotlib:23andMe, Inc.: Unpaid advisor and collaborator Other. Mesa:23andMe, Inc: Unpaid advisor and collaborator Other.

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.

Abstract Abstract 1727 Background: Myelofibrosis (MF) is characterized by cytopenias, splenomegaly, and burdensome symptoms that may worsen over time. Ruxolitinib (RUX) has been shown to reduce splenomegaly and improve MF-associated symptoms in 2 phase III studies, including COMFORT-I, a randomized, double-blind, placebo (PBO)-controlled trial, which also showed prolonged survival in favor of RUX. Purpose: In this post hoc analysis of COMFORT-I, the efficacy of RUX in patients with varying degrees of splenomegaly and symptom severity at baseline was evaluated to assess the potential effects of earlier versus later intervention in this progressive disease. Methods: COMFORT-I participants randomized to RUX (n=155) or PBO (n=154) had MF with an International Prognostic Scoring System (IPSS) score ≥2 and a platelet count of ≥100 × 109/L. Patients with protocol-defined worsening splenomegaly were permitted to cross over from PBO to RUX. The primary endpoint was the percentage of patients with ≥35% reduction in spleen volume (SV) at week (wk) 24. Change in Total Symptom Score (TSS) was a secondary endpoint. TSS was the sum of 6 symptom scores (night sweats, itching, abdominal discomfort, pain under ribs on left side, early satiety, muscle/bone pain) assessed with the modified MF Symptom Assessment Form (MFSAF) v2.0 on a scale of 0 (“absent”) to 10 (“worst imaginable”). Patients were stratified by palpable spleen length (SL) (≤ 10 cm, <10 to 20 cm, >20 cm) and TSS tertile (≤11.1, >11.1 to 22.0, >22.0) at baseline. SV and TSS stratified by baseline values as described were summarized over time. To account for PBO crossover, modeling was performed to predict SV after crossover using a nonlinear mixed model that best predicted individual patient data. Last observation carried forward was used to impute missing TSS data. Results: Mean absolute SV and TSS worsened over time in the PBO group regardless of baseline SL and TSS, demonstrating the progressive nature of MF. In patients treated with RUX, mean absolute SV and TSS at wk 24 were lower for patients with smaller SL and less severe TSS at baseline, respectively (Table); absolute differences with PBO were significant within each subgroup. Therefore, patients who initiated RUX therapy with more advanced MF were less likely to achieve the same clinical status experienced by patients initiating therapy with less advanced MF. Notably, even after 24 wks of RUX treatment, SV and TSS reductions in the cohorts with larger SL or greater TSS at baseline did not achieve levels equivalent to baseline of the next lesser baseline severity group (Table; Figure). Although the severity of splenomegaly and symptoms at baseline influenced the absolute SV and TSS achieved at wk 24, RUX treatment resulted in similar percent reductions in SV and improvements TSS across all subgroups, with the exception of the lower TSS tertile (where there is less room for improvement). In contrast, PBO treatment resulted in increases in SV and worsening of symptoms and patients with less severe SV and TSS at baseline experienced the greatest percent increases in SV and TSS at wk 24. Conclusions: RUX therapy was associated with SV reduction and symptom improvement regardless of spleen size or symptom severity at baseline, whereas patients on PBO experienced disease progression across all subgroups. Patients receiving RUX with less advanced disease achieved an overall better clinical status, as defined by lower absolute SV and symptom scores. This analysis suggests that initiation of RUX in patients with less severe splenomegaly and symptoms may contribute to improved patient outcomes. Disclosures: Mesa: Incyte: Research Funding; Lilly: Research Funding; Sanofi: Research Funding; NS Pharma: Research Funding; YM Bioscience: Research Funding. Gotlib:Incyte: Consultancy. Kantarjian:Incyte: grant support Other. Sun:Incyte: Employment. Verstovsek:Incyte Corporation: Research Funding.

Abstract Abstract 178 Background: CYT387 is a potent and selective small molecule inhibitor of JAK 1 and JAK 2 which is in clinical development for the treatment of myelofibrosis. Previously reported preliminary results from a phase I/II multicenter study demonstrated improvements in splenomegaly and constitutional symptoms as well as in RBC transfusion requirements. Enrollment has been completed and all subjects have now reached a minimum of 9 months on study. Updated safety and efficacy results are presented. Methods: Subjects with high or intermediate-risk primary myelofibrosis (PMF) and post-polycythemia vera (post-PV) or post-essential thrombocythemia (ET) myelofibrosis were enrolled. Following an initial dose expansion phase, subjects were treated in a 9 month core study at an initial dose of 150 mg QD, 300 mg QD or 150 mg BID. Continued treatment with CYT387 was permitted in an extension phase for subjects who maintained at least stable disease. Responses were assessed by International Working Group (IWG) criteria with transfusion independence response defined as achieving a minimum 12 week transfusion-free period. Results: Enrollment of 166 subjects was completed at 6 study sites. Initial doses included 52 subjects at 150 mg QD, 60 subjects at 300 mg QD and 42 subjects at 150 mg BID. An additional 12 subjects were enrolled in other dose groups (100 mg QD, 200 mg QD, 400 mg QD) during the initial dose escalation phase. The median duration (range) of follow-up is 16.1 months (0.7 to 31.0 months). Durable transfusion independence responses were observed in more than half of the RBC transfusion dependent subjects with a maximal transfusion-free period exceeding 2 years and ongoing. In addition, the percentage of all subjects requiring RBC transfusions substantially decreased over the treatment period. Treatment with CYT387 resulted in rapid and sustained reductions in splenomegaly with a maximal response duration approaching 2 years. The majority of subjects reporting constitutional symptoms at baseline experienced complete resolution or marked improvement by 6 months with measurable improvement within the first month of therapy. Higher transfusion independence and spleen response rates were seen in the 300 mg dose group compared to the 150 mg QD or 150 mg BID dose groups. For the first 60 consecutively enrolled subjects for whom the most mature data is available, the median follow-up period (range) is 21.5 months (2.9–31.0 months). The anemia and spleen response rates in these subjects, per IWG-MRT, were 59% and 48%, respectively; among 33 of these subjects who were RBC transfusion dependent by IWG-MRT criteria, 70% achieved a minimum 12-week period without transfusions with a maximal transfusion-free period of greater than 2 years and ongoing. While 90% of subjects reported at least one treatment-related AE, the majority were reported as Grade 1. The most common treatment-related AEs were thrombocytopenia, peripheral neuropathy, dizziness, diarrhea, nausea, and headache. Treatment-related peripheral neuropathy was sensory, with almost all events reported as Grade 1. The most common Grade 3–4 treatment-related AEs included thrombocytopenia and hyperlipasemia. Only 5% of subjects reported treatment-related AEs resulting in study drug discontinuation. There were no treatment-related deaths. Conclusions: CYT387 has proven safe and well tolerated even with prolonged administration for over 2.5 years. Treatment with CYT387 results in clinical improvement by effecting a rapid, meaningful and durable reduction of splenomegaly and the achievement of sustained RBC transfusion independence in a substantial number of subjects. CYT387 is also effective in improving constitutional symptoms. These results support the development of CYT387 at a dose of 300 mg QD for the treatment of myelofibrosis. Final analyses of safety and efficacy will be available at the time of the meeting. Disclosures: Pardanani: Bristol-Myers Squibb: Clinical trial support, Clinical trial support Other; YM BioSciences: Clinical trial support, Clinical trial support Other; Sanofi-Aventis: Clinical trial support Other. Off Label Use: Data from the ongoing Phase-1/2 study of CYT387 use in myelofibrosis treatment will be described. Gotlib:YM Biosciences: Research Funding. Gupta:Celgene: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; YM Biosciences: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi-Aventis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Roberts:YM BioSciences: clinical trial support Other. Wadleigh:Incyte: Membership on an entity's Board of Directors or advisory committees. Sirhan:Novartis: Consultancy, Honoraria. Bavisotto:YM BioSciences: Consultancy. Kawashima:YM BioSciences: Employment. Kowalski:YM BioSciences: Employment.

Abstract Abstract 1737 Background: The somatic JAK2 V617F (V617F) mutation is found in approximately 95% of polycythemia vera (PV) and 50–60% of essential thrombocythemia (ET) and primary myelofibrosis (PMF) patients. Detection of this mutation occurs primarily through genomic analysis of peripheral blood samples of myeloproliferative neoplasm (MPN) patients. This study demonstrates a novel broad screening mechanism for detection of V617F from myeloid cells in saliva samples from an online cohort of MPN patients and from a broader database of genotyped individuals. Methods: MPN patients were recruited primarily through social media and patient-mediated outreach efforts. Patients gave IRB-approved consent and completed surveys through an online 23andMe account. Participation in the MPN research initiative was free. In collaboration with an uncompensated panel of academic experts, online surveys were developed to collect patient-reported data on diagnosis and results of genetic testing for the V617F mutation. Participants were genotyped on SNP arrays based on the Illumina Omni Express, with additional custom content, including four probes for the V617F mutation. We estimated V617F mutation burden as the median across the four probes of B/(A+B) where A and B were normalized intensities for the reference and mutated alleles, respectively. We estimated sensitivity and specificity of our estimated V617F allele ratio, using the self-reported V617F-positive individuals to approximate the distribution of true positives, and 23andMe members from the broad database (outside of the MPN research cohort) and younger than 40 as likely true negatives. Results: Web-based recruitment efforts led to the accrual of over 900 MPN patients of different subtypes over 12 months. Of these participants, 745 patients have been genotyped and provided MPN-related health history and outcomes through online surveys. The cohort is disproportionately female (71%), with an average age of 53.1 ± 14.9 years. More than 57% of patients indicated a classic MPN diagnosis (PV, ET, PMF, or post PV/ET MF), 19.2% reported an atypical MPN diagnosis (systemic mastocytosis or hypereosinophilic syndrome), 14.5% indicated chronic myelogenous leukemia, and 9.3% of the cohort reported other diagnoses. From this MPN cohort, a total of 345 participants reported mutation test results. Consistent with expectations, the V617F variant was reported by patients in nearly all PV cases (105 of 110 patients with a self-reported diagnosis of PV), and at a lower rate in ET and MF cases (59 of 95 patients and 48 of 61 patients, respectively). In addition to self-reported data, we were specifically able to detect the V617F mutation using SNP array data. We determined a detection threshold for the V617F variant at which 86% of self-reported V617F carriers were scored as positive (i.e. test sensitivity), and 99.975% of young 23andMe customers were scored as negative (i.e. test specificity). Participants with a classic diagnosis in the MPN cohort who carry the V617F variant tended to be older (mean age=59.5 versus 54.6 years) and were less likely to be female (62.5% versus 72.0%) than non-carriers. At this threshold, we detected 133 individuals who likely carry the V617F mutation among a broader set of 23andMe participants (n= 99,700) who were not specifically recruited for the MPN study, corresponding to a prevalence of 0.14%. We estimated the positive predictive value of the test in this cohort, or the expected proportion of positive test results that are true, as 81%. Within the general 23andMe cohort, the frequency of the V617F variant increases with participant age, from a rate of 0.017% for age 20 to 30, to 1.1% for age 80 to 90. We also observed that patients with a high allele burden of V617F frequently had acquired uniparental disomy of chromosome 9p, as determined from calculated heterozygosity scores and no-call rates for this chromosomal arm. Conclusion: We can detect V617F with high specificity and sensitivity from myeloid cells in saliva. This non-invasive source for DNA extraction offers new possibilities for detecting genomic alterations and for finding novel genetic associations in MPN patients as well as the general population. This study demonstrates the feasibility of online technology to significantly accelerate recruitment and research progress in MPNs and other rare diseases. Disclosures: Barnholt: 23andMe, Inc.: Employment. Hinds:23andMe: Employment, Equity Ownership, Patents & Royalties. Kiefer:23andMe, Inc.: Employment. Do:23andMe, Inc.: Employment, Equity Ownership, Patents & Royalties. Eriksson:23andMe, Inc.: Employment, Equity Ownership, Patents & Royalties. Mountain:23andMe, Inc.: Consultancy, Employment, Honoraria, Patents & Royalties. Francke:23andMe, Inc.: Employment, Honoraria, Research Funding; Locus Development: Consultancy, Membership on an entity's Board of Directors or advisory committees. Tung:23andMe, Inc.: Employment. Mesa:23andMe, Inc.: Unpaid advisor and collaborator Other. Gotlib:23andMe, Inc.: Unpaid advisor and collaborator Other. Zehnder:23andMe, Inc.: Unpaid advisor and collaborator Other.

Abstract Background: PAC is an oral kinase inhibitor with specificity for JAK2, FLT3, IRAK1, and CSF1R that has demonstrated significant and sustained spleen volume reduction (SVR) and symptom control vs BAT (excluding JAK2 inhibitors) in MF pts regardless of platelet count (PERSIST-1). The PERSIST-2 study was a randomized, controlled, open-label, phase 3 trial of PAC 200 mg BID and PAC 400 mg QD vs BAT (including JAK1/JAK2 inhibitor ruxolitinib [RUX]) in pts with 10 or 20 MF whose platelet counts were ≤100,000/µL, a recognized adverse prognostic variable. Prior JAK2 inhibitor use was allowed. Methods: Pts were randomized 1:1:1 to PAC BID, PAC QD, or BAT. The co-primary efficacy endpoints were the percentages of pts achieving ≥35% SVR (MRI or CT) and ≥50% reduction in total symptom score (TSS; MPN-SAF TSS 2.0), both from baseline to Week 24. The primary objective was to compare the efficacy of pooled PAC (BID+QD) to BAT and the secondary objectives were to compare PAC BID and PAC QD individually to BAT. PK samples were collected and analyzed for PAC. Safety analyses were based on all pts exposed to study treatment of any duration (safety population); efficacy analyses were based on ITT pts with a randomization date allowing Week 24 endpoint evaluations prior to the full clinical hold* (ITT efficacy population). Results: 311 pts were randomized (107 PAC BID, 104 PAC QD, 100 BAT), 308 received study drug, and 221 were included in the ITT efficacy population (74 PAC BID, 75 PAC QD, 72 BAT). Demographics and baseline disease characteristics were generally balanced among the treatment arms (Table) and analysis populations. A total of 32 (44%) BAT pts in the ITT efficacy population received RUX as treatment at some point on study. Population PK analyses showed that the steady-state plasma levels achieved with BID were higher than with QD, however the Cmax levels were lower. A significantly higher percentage of pts in the pooled PAC arm achieved SVR ≥35% (18% [27/149]) vs the BAT arm (3% [2/72]; p=0.001; Figure 1A). 25% of PAC pts (37/149) had ≥50% reduction in TSS vs 14% of BAT pts (p=0.079; Figure 1B). In secondary analyses vs BAT, PAC BID demonstrated significant improvement over BAT for both efficacy endpoints with 22% achieving SVR ≥35% (BAT=3%; p=0.001) and 32% achieving ≥50% reduction in TSS (BAT=14%; p=0.011). The PAC QD arm had a significant SVR ≥35% (15% v 3%, respectively; p=0.017), but a similar proportion with ≥50% reduction in TSS (17% v 14%, respectively; p=0.652). More PAC pts reduced their red blood cell transfusion dependence at Week 24 (defined as a ≥50% reduction in average transfusions/month for 3 months relative to baseline) with 19% (7/37) in the PAC QD arm, 22% (8/36) in PAC BID, and 9% (3/35) in BAT. There was no significant difference observed in OS across the treatment arms (Figure 2). Hazard ratios for OS (95% confidence intervals) were 0.68 (0.30, 1.53) for PAC BID v BAT, 1.18 (0.57, 2.44) for PAC QD v BAT, and 0.61 (0.27, 1.35) for PAC BID v QD. PAC BID maintained this survival advantage vs BAT across nearly all demographic and MF-associated risk factors. During the course of the study, 10 (9%), 15 (14%), and 15 (14%) died on PAC BID, PAC QD, and BAT, respectively. The most common treatment-emergent adverse events (AEs) associated with PAC were gastrointestinal (diarrhea, nausea, vomiting) and hematologic (anemia and thrombocytopenia), and were generally less frequent for BID vs QD administration. Grade 3/4 cardiac AEs occurred in 7%, 13% and 9% of PAC BID, PAC QD, and BAT pts, respectively, and grade 3/4 bleeding AEs occurred in 14%, 7%, and 7%, respectively. Grade 3/4 bleeding AEs were associated with grade 3/4 thrombocytopenia, which was also more common in the PAC BID group. Nine pts had cardiac failure (2% PAC QD, 4% PAC BID, 3% BAT) and 1 (1%, PAC QD) had intracranial hemorrhage.* Conclusions: The PERSIST-2 study is the only randomized, controlled trial to date in pts with MF and thrombocytopenia (platelets ≤100,000/µL), allowed prior JAK2 inhibitor treatment exposure (including RUX), and allowed RUX as BAT comparator. Irrespective of prior JAK2 inhibitor treatment, both PAC arms were more effective at SVR than BAT; however, PAC BID appeared more active than QD dosing and achieved significance versus BAT for both SVR and TSS. The most frequent AEs with PAC were gastrointestinal and hematologic toxicities. *PAC on full clinical hold by the FDA on 2/8/2016 based on concerns around excess deaths and cardiac and hemorrhagic events in PERSIST-1. Disclosures Mascarenhas: Incyte: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; CTI BioPharma: Research Funding; Janssen: Research Funding; Roche: Research Funding; Promedior: Research Funding. Talpaz:CTI BioPharma: Research Funding; Pfizer: Research Funding; Incyte Corporation: Research Funding; Ariad: Other: Expense reimbursement, travel accomodation expenses, Research Funding; Gilead: Other: Travel, Accommodations, Expenses, Research Funding; BMS - Canada: Consultancy. Gerds:CTI BioPharma: Research Funding; Astra-Zeneca: Research Funding; Roche: Research Funding; Incyte: Research Funding. Stein:Incyte Corporation: Consultancy. Gupta:Incyte Corporation: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Drummond:CTI BioPharma: Honoraria; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Roche: Speakers Bureau. Granston:CTI BioPharma Corp.: Employment. Daly:CTI BioPharma Corp.: Employment. Dean:CTI BioPharma Corp.: Employment, Equity Ownership. Al-Fayoumi:CTI BioPharma Corp.: Employment, Equity Ownership. Callahan:CTI BioPharma: Employment. Singer:CTI BioPharma Corp.: Employment, Equity Ownership, Other: Leadership . Gotlib:Novartis: Other: Travel, Accommodations, Expenses; Steering Committee Chairman, Research Funding; Promedior: Research Funding; CTI BioPharma: Research Funding; Gilead: Research Funding; Incyte: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding. Jamieson:GSK: Research Funding; Johnson & Johnson: Research Funding; CTI BioPharma: Research Funding. Harrison:Novartis: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; CTI BioPharma: Consultancy, Honoraria, Speakers Bureau; Baxter: Consultancy, Honoraria; Shire: Speakers Bureau; Gilead: Speakers Bureau; Incyte: Speakers Bureau. Mesa:Novartis: Consultancy, Honoraria; Incyte: Research Funding; Gilead: Research Funding; CTI BioPharma: Research Funding; Celgene: Research Funding; Genetech: Research Funding; Promedior: Research Funding. Verstovsek:CTI BioPharma Corp: Research Funding.

Abstract Background:The Janus kinase (JAK) 1/JAK2 inhibitor ruxolitinib has been evaluated for patients with MF in the phase 3 COMFORT studies. In both trials, ruxolitinib prolonged OS, reduced splenomegaly, and improved MF-related symptoms and quality of life compared with controls. Here, we report the results of an exploratory pooled analysis of OS in the COMFORT studies at 5 years of follow-up. Methods: The double-blind COMFORT-I trial and the open-label COMFORT-II trial were randomized phase 3 studies that evaluated the safety and efficacy of ruxolitinib in patients with intermediate-2 (int-2) or high-risk primary MF (PMF), post-polycythemia vera MF (PPV-MF), or post-essential thrombocythemia MF (PET-MF). The comparator was placebo in COMFORT-I and best available therapy (BAT) in COMFORT-II. The ruxolitinib starting dose was 15 or 20 mg twice daily based on baseline platelet counts (100-200 and >200 × 109/L, respectively); dose modifications were permitted for safety and efficacy. Patients were allowed to cross over to ruxolitinib from the control arm for progressive splenomegaly, defined as a ≥25% increase in spleen volume from baseline (COMFORT-I) or study nadir (COMFORT-II), or select protocol-defined progression events; crossover was mandatory following treatment unblinding in COMFORT-I. OS was a secondary endpoint in both studies and was evaluated in an intent-to-treat (ITT) analysis using a Cox proportional hazard model that estimated the treatment effect stratified by clinical trial and International Prognostic Scoring System (IPSS) risk. The crossover-corrected treatment effect was estimated using a rank-preserving structural failure time (RPSFT) method. Results: Overall, 528 patients were randomized: 301 to ruxolitinib (COMFORT-I, n=155; COMFORT-II, n=146) and 227 to placebo (n=154) or BAT (n=73). All ongoing patients in the control arms crossed over to ruxolitinib by the 3-year follow-up. Patient populations were similar between the two trials and their details were previously published. In the combined ruxolitinib group, 162 patients (53.8%) had high-risk MF and 139 (46.2%) had int-2 risk MF based on IPSS criteria. At the 5-year ITT analysis, 128 patients (42.5%) died in the ruxolitinib group compared with 117 (51.5%) in the control group. The risk of death was reduced by 30% with ruxolitinib compared with control (median OS: ruxolitinib, 63.5 mo; control, 45.9 mo; HR, 0.70; 95% CI, 0.54-0.91; P=0.0065; Figure A). After correcting for crossover using RPSFT, OS advantage was more pronounced for patients originally randomized to ruxolitinib (median OS: ruxolitinib, 63.5 mo; control, 27 mo; HR, 0.35; 95% CI, 0.23-0.59; Figure B). An analysis of OS censoring patients at the time of crossover also demonstrated that ruxolitinib prolonged survival compared with control (median OS: ruxolitinib, 63.5 mo; control, 28.3 mo; HR, 0.53; 95% CI, 0.36−0.78; P=0.0013; Figure C). Among all patients treated with ruxolitinib, those with lower-risk disease had longer survival compared with those with high-risk disease (median OS: int-2, not reached [estimated, 102 mo]; high-risk, 50 mo; HR, 2.86; 95% CI, 1.95-4.20; P<0.0001; Figure D). In a subgroup analysis, OS favored ruxolitinib compared with placebo for patients with int-2 or high-risk MF (data not shown). At 5 years, median OS appeared to favor patients with int-2 (n=58) or high-risk (n=89) PMF who were originally randomized to ruxolitinib compared with historical (Cervantes et al; J Clin Oncol 30:2981-2987) controls (int-2 PMF, not reached [estimated, 70 mo] vs 48 mo; high-risk PMF, 34 vs 27 mo); OS was longer among patients with int-2 vs high-risk PMF (P=0.0003). Subgroup analyses showed that ruxolitinib provided an OS advantage regardless of age (>65 or ≤65 y), sex, disease type (PMF, PPV-MF, PET-MF), risk status (int-2 or high), JAK2V617F mutation status, baseline spleen volume (>10 or ≤10 cm), anemia, white blood cell count (>25 or ≤25 × 109L), or platelet count (>200 or ≤200 × 109/L). Conclusion: Long-term treatment with ruxolitinib up to 5 years prolonged survival in patients with MF compared with BAT or placebo. Corrections for patients who crossed over to ruxolitinib suggested that the separation between ruxolitinib and control OS curves was primarily caused by a delay in ruxolitinib treatment. The results suggest that earlier treatment with ruxolitinib may provide a greater survival advantage for patients with MF. Disclosures Gupta: Incyte Corporation: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Mesa:Incyte: Research Funding; Ariad: Consultancy; Novartis: Consultancy; Celgene: Research Funding; CTI: Research Funding; Promedior: Research Funding; Galena: Consultancy; Gilead: Research Funding. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Kiladjian:AOP Orphan: Research Funding; Novartis: Research Funding. Cervantes:AOP Orphan: Membership on an entity's Board of Directors or advisory committees; Baxalta: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Sun:Incyte Corporation: Employment, Equity Ownership. Gao:Incyte Corporation: Employment, Equity Ownership. Dong:Novartis Pharmaceutical Corporation: Employment, Equity Ownership. Naim:Incyte Corporation: Employment, Equity Ownership. Gopalakrishna:Novartis Pharma AG: Employment, Equity Ownership. Harrison:Incyte Corporation: Honoraria, Speakers Bureau; Baxaltra: Consultancy, Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; CTI Biopharma: Consultancy, Honoraria, Speakers Bureau; Shire: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau.

Abstract Background: JAK2 inhibitors have been shown to improve symptoms and produce durable reductions in splenomegaly in patients with myelofibrosis (MF), and ruxolitinib has been shown to improve survival in MF patients (Cervantes et al., 2013; Verstovsek et al., 2013). Current prognostic models such as DIPSS plus (Gangat et al., 2011) predict survival in MF based on clinical, laboratory, and cytogenetic information, but their value in predicting clinical response or survival during treatment with JAK2 inhibitors remains unknown. We hypothesized that clinical features such as bone marrow fibrosis and splenomegaly may have independent effects on therapy response. Therefore, we conducted a retrospective analysis to create a new model to risk stratify patients with respect to their likelihood of responding to oral JAK2-inhibitor therapy. Methods: We studied a cohort of 203 patients with bone marrow biopsy-proven MF seen at University of Michigan, Stanford University, and Mayo Clinic in Scottsdale, AZ. These patients were all treated with ruxolitinib or an experimental JAK2 inhibitor. Our primary endpoint was defined as IWG-MRT criteria for splenic response by palpation (Tefferi et al., 2013). Response in patients with spleen size of less than 5 cm was defined as complete resolution of splenomegaly. Of the 203 patients studied, splenic response was evaluated after 3 months of therapy in 167 patients and after 6 months of therapy in 138 patients; 127 patients were in both groups. A logistic regression was performed to identify factors that would predict clinical response. Results: The following characteristics were significantly associated with spleen response at 3 and 6 months: initial spleen size, European consensus criteria grading of MF on bone marrow biopsy, initial DIPSS plus score, and initial WBC count. Cellularity on marrow biopsy was not significant. We enriched a baseline logistic model of initial dose of oral JAK2 therapy and DIPSS plus score with additional prognostic factors. We found the following clinical characteristics to be jointly associated with splenic response: normalized initial dose of oral JAK2 inhibitor, initial spleen size, DIPSS plus score, degree of fibrosis by European consensus criteria. Duration of disease from time of diagnosis to time of treatment initiation was not prognostic for splenic response. We used this model to calculate the probability of splenic response based on a risk score: Risk score = –1.18(Dose) + 0.09(Initial Spleen Size in cm) + 0.20(DIPSS-plus Points) +0.92 (if fibrosis is MF-3). The probability at 6 months can then be calculated from the risk score as follows: [1/(1+e(risk score-2.6))]. The figure demonstrates the prognostic gain of our model over a model based on DIPSS plus alone. Conclusion: With this observational study, we propose a predictive model which may serve as a clinical tool to identify which patients are most likely to benefit from JAK2 inhibitor-based therapies. Further validation in independent data sets will be required before this model can be more widely applied. Disclosures Mesa: Incyte Corporation, CTI, NPS Pharma, Inc., Gilead Science Inc., Celgene: Research Funding. Gotlib:Incyte: Consultancy, Honoraria, Research Funding, Travel Reimbursement Other; Gilead: Research Funding; Sanofi: Research Funding; Novartis: Research Funding, Travel Reimbursement, Travel Reimbursement Other. Talpaz:ARIAD Pharmaceuticals, Inc., BMS, Sanofi, Incyte, Pfizer: Research Funding.

Abstract Abstract 800 Background: Ruxolitinib (RUX), an oral JAK1/JAK2 inhibitor, reduced spleen volume (SV), improved myelofibrosis (MF)-associated symptoms and quality of life (QoL), and appeared to exhibit a survival advantage over placebo (PBO) in patients (pts) with MF regardless of JAK2V617F mutation status in the phase III COMFORT-I study. We describe long-term efficacy and safety of RUX from COMFORT-I, with 1 year of additional follow up beyond previously published data. Methods: Eligible pts (N=309) were randomized (1:1) to RUX or PBO. The primary analysis occurred when all pts completed 24 weeks (wks) and when half the pts completed 36 wks of treatment. All pts receiving PBO were eligible for crossover to RUX after the primary analysis; crossover before wk 24 was permitted if pts met protocol-defined criteria for worsening splenomegaly. The proportion of pts with ≥35% SV reduction at 24 wks (primary endpoint) and durability of SV response were assessed. Although symptom burden (measured daily using the modified MF Symptom Assessment Form v2.0) was only measured up to wk 24, QoL continued to be evaluated beyond wk 24 (every 24 wks) using the EORTC QoL Questionnaire-Core 30 (QLQ-C30). Overall survival (OS) was assessed according to original randomized treatment. Results: In this updated analysis, median follow-up of pts randomized to RUX was 102 wks. All pts receiving PBO completed crossover or discontinued within 3 months of the primary analysis. Of 134 pts randomized to RUX who remained on treatment after the primary data analysis, 100 continue on study. Mean SV reduction in pts randomized to RUX was 31.6% at wk 24 and has remained stable with additional follow up through wk 96 (Table). In pts who achieved a ≥35% SV reduction, response was durable, with a median response duration of 108 wks. RUX treatment was also associated with durable improvements in the Global Health Status/QoL (Table) and the 5 functional domains of the EORTC QLQ-C30. Twenty-seven (27) pts randomized to RUX and 41 pts randomized to PBO died, representing a continued OS benefit in favor of RUX (HR=0.58; 95% CI: 0.36, 0.95; P = 0.028; Fig 1) similar in magnitude to that previously reported. OS favored RUX across subgroups including starting dose as well as baseline risk status and hemoglobin (Hgb). Of 34 pts randomized to RUX who discontinued after the primary analysis, 4 discontinued for an adverse event (AE). In pts who continued on RUX, anemia and thrombocytopenia remained the most frequently reported AEs. New onset of grade 3 or 4 anemia and thrombocytopenia was reported in only 12 and 5 pts, respectively. One pt discontinued for anemia. Overall, among all pts randomized to RUX, Grade 3 and 4 anemia regardless of baseline Hgb was reported in 37.4% and 14.8% of pts, respectively. Similarly, Grade 3 and 4 thrombocytopenia was reported in 11.0% and 5.2% of pts, respectively. These rates were similar to those reported in the primary analysis. By wk 36, the proportion of pts receiving red blood cell transfusions decreased to the level seen with PBO and remained stable thereafter (Fig 2). Rates of nonhematologic AEs adjusted for increased follow-up duration remain similar to those seen at the time of the primary data analysis. No additional cases of acute myeloid leukemia (AML) in pts randomized to RUX were reported. Two pts originally randomized to PBO developed AML, 21 and 178 days after crossover to RUX. There continued to be no reports of a withdrawal syndrome after RUX discontinuation. Conclusions: RUX provides durable reductions in SV and improvements in QoL. Although all pts randomized to PBO crossed over to RUX shortly after the primary analysis, with 1 year of additional follow up, RUX continues to be associated with a survival advantage over PBO. RUX continues to be well tolerated; the AE profile with long-term treatment is consistent with that previously reported. The proportion of pts receiving transfusions decreased over time to rates similar to PBO, and there were no reports of a specific withdrawal syndrome or cytokine rebound phenomenon after RUX discontinuation. Disclosures: Verstovsek: Incyte Corporation: Research Funding. Mesa:Incyte: Research Funding; Lilly: Research Funding; Sanofi: Research Funding; NS Pharma: Research Funding; YM Bioscience: Research Funding. Gotlib:Incyte: Consultancy, travel to congress Other. Levy:Incyte: Employment, Equity Ownership. Gupta:Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; YM Biosciences: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofiå]Aventis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Catalano:Incyte: Consultancy. Deininger:Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy; Ariad: Consultancy. Miller:Novartis: Consultancy, Research Funding, Speakers Bureau, development of educational presentations Other; Incyte: development of educational presentations, development of educational presentations Other. Talpaz:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; B.M.S.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Teva: 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: Consultancy, Honoraria. Arcasoy:Incyte: Research Funding. Lyons:Incyte: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Novartis: Research Funding; Telik: Research Funding. Paquette:Incyte: Consultancy. Vaddi:Incyte: Employment, Equity Ownership. Erickson-Viitanen:Incyte: Employment, Equity Ownership. Sun:Incyte Corporation: Employment, Equity Ownership. Sandor:Incyte Corporation: Employment, Equity Ownership. Kantarjian:Incyte: grant support Other.