Mesa, Ruben A.

Abstract Abstract 972 Background: Myelofibrosis (MF) is a Philadelphia chromosome–negative myeloproliferative neoplasm. Common disease manifestations include bone marrow failure, enlarged spleen due to extramedulary hematopoiesis (splenomegaly), debilitating symptoms including fatigue, night sweats, pruritus, early satiety, abdominal pain and discomfort, and marked decrement in patient's quality of life (QoL). Decreased survival is a hallmark of the disease as a result of infections, bleeding and leukemic transformations. There are no recent literature estimates looking at clinical and economic burden of illness of this rare disease. The objective of this study was to describe patient demographics, prevalence, comorbidities, utilization and costs for MF using real-world data. Methods: The US IMPACT® insurance claims database was used to retrospectively identify unique patients with any MF (including all primary and secondary MF cases) between 1/1/08 and 12/31/10. The IMPACT database is a fully de-identified, HIPAA compliant national database that captures the complete medical history for over 100 million managed-care individuals, including patient demographics, disease description, laboratory results, details of medical, pharmacy, outpatient, and inpatient claims. These databases can track patients longitudinally over multiple years, are linked at the patient level by a unique identifier that is consistent across services, health plans, and time and are representative of the US population. ICD-9-CM codes were used to identify MF. The Charlson Comorbidity Index (CCI) was employed to assess overall comorbid disease status. Enrollment was restricted to those with full year of medical and pharmacy benefit. Control group was age and gender matched but without any diagnosis of myelofibrosis. Medical costs include inpatient, outpatient and emergency room cost. Results: In 2010, 433 patients with MF (mean age 60, 50% female) were identified from about 12 million enrollees. This corresponds to an age-adjusted prevalence of 5.4 per 100,000 patients. Compared with age-gender matched control patients, MF patients had higher overall comorbidities (mean CCI of 2.1 vs. 0.9), were hospitalized more often (34% vs. 11%), had higher number of average hospital days (7 vs. 1 day), and had more outpatient office visits (58 vs. 22) in 2010. Accordingly, MF patients incurred much higher average annual cost ($54,168 vs $10,203) driven by both medical ($45,646 vs $7,987) and pharmacy ($8,523 vs $2,216) cost. Over a period of 3 years, annual cost of MF ranged from $54,000-$68,000. The utilization rate and total cost in each of conditions were significantly higher than those of their matched patients in each of the three years. Conclusions: Myelofibrosis is associated with a significant burden of illness. Patient with MF incurred about five times healthcare expenditure than those in the control group. Our study indicates that MF-associated medical resource utilization and the corresponding expenditures for those services are substantive. Continued efforts in the development of more efficacious treatments for myelofibrosis are needed in order to reduce the burden of illness associated with this disease. Disclosures: Wang: Sanofi: Employment, Equity Ownership. Mehta:Sanofi: Employment. Iqbal:Sanofi: Employment, Equity Ownership. Mesa:Incyte: Research Funding; Lilly: Research Funding; Sanofi: Research Funding; NS Pharma: Research Funding; YM Bioscience: Research Funding.

Abstract BackgroundPacritinib, a JAK2, JAK2 V617F and FLT3 kinase inhibitor is in Phase III development in myelofibrosis. In preclinical models and in Phase 1 studies in both non-Hodgkin lymphoma and myelofibrosis, it appeared unique among this class of agents in its lack of myelosuppression at doses that inhibited the JAK2/STAT3 pathway and resulted in significant clinical efficacy. This potentially important clinical observation was verified in two Phase II studies in myelofibrosis that had no exclusion restriction for low platelets. Pacritinib was effective at reducing spleen size and symptoms regardless of starting platelet counts and there was no apparent decline in either platelet count or hemoglobin levels, or an increase in transfusion requirements. Aims and Methods: To help elucidate the mechanisms for pacritinib’s lack of myelosuppression, a kinome screening analysis against 429 recombinant kinases at 100 nM pacritinib concentration was performed, followed by titration from 1-100nM against those that were >50% inhibited at 100nM (Anastassiadis et al.; Nature Biotechnology; 2011). In humans, pacritinib achieves steady state free drug levels of approximately 200nM at the standard 400 mg daily dose. Results:All kinases with IC50 values of <50nM are included in the table. Table Kinase IC50 (nM) JAK2; JAK2(V617F) 6.0; 9.4 FLT3; FLT3-ITD; FLT3 (D835Y) 6.4; 12.0; 8.3 TYK2 27.0 JAK3 18.3 IRAK1 (IL-1 receptor kinase) 13.6 HIPK4 (PT kinase for P53 ser-9) 14.5 FMS 39.5 c-KIT and most common mutations except (V560G), (V559D/V654A) 43.8 c-Src; (c-Src (T341M)) 47.0 (55.5) Of note, pacritinib did not affect JAK1 (82% control at 100nM). As the concentrations of pacritinib achieved clinically are likely inhibit signaling the kinases listed in the table, these data suggest that the lack of myelosuppression with pacritinib may be either due to inhibition of JAK2 without affecting JAK1 or to suppression of IRAK1, an IL-1 receptor kinase, downstream from Toll-Like Receptors, and associated with the inflammatory response and suppression of normal hematopoiesis in myelodysplasia models (Rhyasen et al.; Cancer Cell; 24:90, 2013). Conclusions: The kinase profile for pacritinib is unique among agents in development for myelofibrosis combining lack of suppression of JAK1 with suppression of inflammatory signaling through IRAK1. Moreover, the kinase inhibition profile of pacritinib suggests its potential therapeutic utility in AML, MDS, and particularly in CMML due to CMML’s upregulation of JAK2, c-FMS, and IRAK1. Disclosures Singer: CTI BioPharma, Corp: Employment, Equity Ownership. Mesa:Incyte Corporation, CTI, NS Pharma, Inc., Gilead Science Inc., Celgene: Research Funding. Verstovsek:CTI BioPharma, Corp: Research Funding.

Abstract Background: NS-018 is an oral, selective, small molecule inhibitor of Janus kinase 2 (JAK2). Pre-clinically NS-018 inhibited JAK2 kinase with an IC50 value in the subnanomolar range and demonstrated splenomegaly reduction at low doses in a JAK2V617F-bearing mouse model (Blood Cancer J 2011; 1: e29.). Methods: This multicenter, Phase 1/2, 3+3 dose-escalation study of NS-018 enrolled patients with IPSS intermediate-1, intermediate-2, or high risk PMF, postPV MF, or postET MF. Patients were ≥ 18 years, had ECOG PS ≤ 2 and required therapy but were not required to have splenomegaly in Phase 1. NS-018 was dosed orally daily (QD) or twice daily (BID) in 28-day cycles. Responses were assessed according to IWG consensus criteria, changes in spleen size by manual palpation and quality of life with the Myelofibrosis Symptom Assessment Form (MF-SAF). The Phase 1 portion of the study completed enrollment and is presented here. Results: Patients: 42 patients were enrolled across 10 cohorts. Patient characteristics: 33 PMF, 5 postPV MF, 4 postET MF; median age (range) 69 yrs (43-83); M/F:28/14; 31 JAK2V617F+, and 17 previously treated with a different JAK inhibitor. Dosing and tolerability: Dose levels included 75, 125, 200, 300 and 400 mg QD and 100, 200, 250, 300 and 400 mg BID. Systemic exposures based on Cmax were approximately dose proportional across the tested range from 75 to 400 mg. The recommended Phase 2 dose (RP2D) was 300 mg BID, based on drug-related neurological adverse events (AEs) at 400 mg BID including dizziness (Grade 2 or 3), dysphagia (Grade 2) or hypoesthesia (Grade 1) in one patient each that led to dose reduction or drug discontinuation. Study drug-related serious AEs (SAEs) included non-cardiac chest pain (Grade 2, 200 and 300 mg BID), lower GI hemorrhage (Grade 3, 300mg BID), paresthesia (Grade 3, 300mg BID), increased lipase (Grade 2, 300mg BID), and dizziness (Grade 3, 400 mg BID) in one patient each. For the 300 mg BID cohort (n=11), the most frequent drug-related AEs across all grades were nausea (Grade 1, 18%), decreased platelet count (≤ Grade 2, 18%), and dizziness (≤ Grade 2, 27%); Grade 3 related AEs included anemia, lower GI bleed, leukopenia, neutropenia or paresthesia (1 patient each, 9%); and no Grade 4 AEs. Overall, 22 patients (52%) discontinued treatment due to AEs (n=7), progressive disease (PD) (n=7), or MD/patient decision (n=8). The AEs leading to discontinuation included thrombocytopenia (Grade 4), transient ischemic attack (Grade 2), muscle contraction involuntary (Grade 2), light headedness (Grade 1), insomnia (Grade 1), hemolytic anemia (Grade 3), dizziness (Grade 2), dysphagia (Grade 2), and hypoesthesia (Grade 1). Nine patients had a hemoglobin decrease ≥ 2 g/dL and 8 patients a platelet decrease ≥ 50%. Responses: Of 33 evaluable patients with baseline splenomegaly ≥ 5 cm and treatment for ≥ 1 cycle, 16 (48%) patients showed ≥ 50% reduction in spleen size (confirmed for ≥ 8 weeks in 11 patients). In addition, 11 patients showed splenic clinical improvement (CI, for ≥ 8 weeks), 3 patients hemoglobin CI, and 2 patients platelet CI. Median (range) time to splenic response and duration of response: 1.5 cycle (1-12) and 4.5 cycles (1-29). Splenic reductions ≥50% are shown in the Table for the specified patient groups. Changes in MF-SAF and PK and PD results will be presented. Table Splenic reduction(in evaluable patients) All doses 16/33 (48%) 300mg BID 3/6 (50%) 300mg QD 4/7 (57%) Prior different JAK inhibitor treated 8/16 (50%) Conclusions: The dose of NS-018 determined to be the RP2D in Phase 1 was 300 mg BID. This dose provided a durable dosing schedule with an acceptable safety profile, and was associated with splenic size reduction and clinical improvements. The Phase 2 portion of the study is ongoing and includes only patients previously treated with a different JAK inhibitor. Disclosures Verstovsek: NS Pharma, Inc: Research Funding. Talpaz:Ariad, BMS, Sanofi, Pfizer, Incyte: Research Funding. Ritchie:Celgene, Incyte: Speakers Bureau. Odenike:Suneisis Pharmaceuticals, Incyte, Sanofi-Aventis, Algeta Pharmaceuticals, Spectrum Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Jamieson:Roche, Johnson&Johnson, CTI: Research Funding. Stein:Incyte Corporation: Honoraria, Speakers Bureau; Sanofi Oncology: Honoraria. Tomonori:NS Pharma, Inc.: Employment. Mesa:Incyte, CTI, NS Pharma, Inc., Gilead, Celgene: 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.

Abstract Abstract 2071 Background: PV and ET are clonal stem cell diseases belonging to the 3 BCR ABL negative myelopoliferative neoplasms. Patients with PV and ET suffer from splenomegaly and disease associated symptoms such as pruritus, night sweats, fatigue, and bone pain. Both diseases, if progressive despite standard therapies, are associated with an increased risk of thrombosis, bleeding, and progression to MF or even acute myeloid leukemia. Literature estimates looking at burden of illness are lacking for these disorders. Hence, real world analyses evaluating economic burden are imperative. The objective of this study was to evaluate the clinical and economic burden of these disorders by describing the patient demographics, prevalence, comorbidities, utilization and costs using large scale databases. Method: The US IMPACT® claims database was used to retrospectively identify unique patients with PV and ET between 1/1/08 and 12/31/10. This database is a fully de-identified, HIPAA compliant national database that captures the complete medical history for over 100M managed care individuals, including patient demographics, disease description, laboratory results, and details of medical, pharmacy, outpatient, and inpatient claims. ICD9 CM codes were used to identify PV and ET. Charlson Comorbidity Index (CCI) was used to assess overall comorbid disease status. Enrollment was restricted to those with a full year of medical and pharmacy benefit. Control group was age and gender matched but without any diagnosis of PV or ET. Medical costs include inpatient, outpatient and ER cost. Result: In 2010, we identified 5752 PV patients from ∼12M enrollees. This corresponds to an age adjusted prevalence of 56.5 cases/100000 patients. Compared with age gender matched control patients, PV patients had higher overall comorbidities (mean CCI 1.2 vs 0.7), were hospitalized more often (16% vs 8%), had higher average number of hospital days spent (1.7 vs 0.8), and had more outpatient visits (31 vs 18). PV patients incurred much higher average annual cost ($14,903 vs $7,913) than age gender matched controls driven by both medical ($12,006 vs $6,188) and pharmacy ($2,897 vs $1,724) cost. In 2010, we identified 5483 ET patients from ∼12M enrollees. This corresponds to an age adjusted prevalence of 56.1 cases/100000 patients. Compared with age gender matched control patients, ET patients had higher overall comorbidities (mean CCI 1.4 vs 0.7), were hospitalized more often (30% vs 9%), had higher average number of hospital days spent (5 vs 0.9 days), and had more outpatient visits (37 vs 19). ET patients incurred much higher average annual cost ($29,553 vs $8,026) than age gender matched controls driven by both medical ($26,287 vs $6,394) and pharmacy ($3,267 vs $1,631) cost. Similar trend was observed in 2008 and 2009. Over a period of 3 years, annual cost of PV ranged from $14,000-$16,000 and those of ET ranged from $29,000-$31,000. The utilization rate and total cost in each of conditions were significantly higher than those of their matched patients in each of the 3 years. Conclusion: PV and ET are associated with significant burden of illness. Healthcare expenditure was twice as higher in PV patients compared with the control group. ET patients incurred more than 3 times the healthcare expenditure than the control group. Our study indicates that PV and ET associated medical resource utilization and the corresponding expenditures for those services are substantive. In order to reduce the burden of illness associated with these diseases, continued efforts in the development of more efficacious treatments for these disorders are needed. Disclosures: Mehta: Sanofi: Employment. Wang:Sanofi: Employment, Equity Ownership. Iqbal:Sanofi: Employment, Equity Ownership. Mesa:Incyte: Research Funding; Lilly: Research Funding; Sanofi: Research Funding; NS Pharma: Research Funding; YM Bioscience: Research Funding.

Abstract Abstract 707 Background: Myeloproliferative neoplasms (MPNs) are disorders that result in unregulated overproduction of one or more myeloid blood cell types by the bone marrow. Polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) comprise the three classic MPNs. The somatic JAK2 V617F mutation is present in 95% of PV patients, and 50–60% of ET and PMF patients. Past work has identified a germline haplotype in JAK2 associated with risk of developing a V617F-positive MPN (Kilpivaara et al; Olcaydu et al; Jones et al, Nat. Genet., 2009). Methods: We recruited a web-based participatory cohort of individuals with MPNs to better understand the genetic basis of these conditions. Participation in this MPN research initiative included free genotyping, and participants provided informed consent and responses to surveys online, under a protocol approved by the external AAHRPP-accredited IRB, Ethical & Independent Review Services. We enrolled and collected saliva samples from more than 700 participants with the following self-reported diagnoses: systemic mastocytosis (n=142), ET (n=145), PV (n=137), PMF (n=50), chronic myelogenous leukemia (n=108), and 97 with overlapping diagnoses (e.g. ET or PV with PMF). Participants were genotyped using a derivative of the Illumina HumanOmniExpress BeadChip with additional custom content, including probes for the JAK2 V617F variant. We performed a genome-wide association study (GWAS) of classic MPN diagnoses (at least one of ET, PV, or MF), using 407 cases from this MPN research initiative and 94,037 controls drawn from the broader 23andMe research participant community. Association was assessed by logistic regression adjusted for age, gender, and 5 principal components to model ancestry. Results: We replicated the known association between germline variation in JAK2 and classic MPNs (rs12340895: odds ratio=2.5, P=7.4 × 10−35). We also identified a novel genome-wide-significant association in TERT, or telomerase reverse transcriptase (rs2853677: odds ratio=1.6 per G allele, P=6.3 × 10−11). The association is consistent with an additive model on the logistic scale (odds ratio=2.6 for 2 versus 0 G alleles). Another variant in TERT, rs2736100, has previously been associated with several non-hematological cancers and with red blood cell count, and our lead SNP is in linkage disequilibrium with TERT variant rs2736100 (r2=0.54). While no other loci reached the threshold of genome-wide significance (P<5.0 × 10−8), we saw a suggestive association with a germline missense variant (F858L) in ATM, or ataxia telangiectasia mutated gene (rs1800056: odds ratio=2.6 per C allele, P=1.4 × 10−5). This variant has also been reported to be associated with breast cancer and chronic lymphocytic leukemia. The rs2853677 TERT variant was associated with each of ET, PV, and PMF, with similar effect sizes. It was not associated with JAK2 V617F mutation status within the MPN cohort (odds ratio=1.0, P=1.0), while the germline JAK2 variant was preferentially associated with V617F-positive MPNs (odds ratio=2.1, P=3.0 × 10−6). The high-risk allele of rs2853677 was also predictive of V617F status among 23andMe participants who had not been recruited into the MPN community (odds ratio=1.6, P=0.0012). These results suggest that while variation in TERT facilitates either acquisition or proliferation of V617F-positive myeloid cells, it also predisposes to MPNs through a V617F-independent mechanism. Conclusion: We have identified a germline variant in TERT which is a new predisposition allele for classic MPNs. These results demonstrate the potential for web-based recruitment methods to contribute to genetic research for uncommon diseases. Disclosures: Hinds: 23andMe: Employment, Equity Ownership, Patents & Royalties. Barnholt:23andMe, Inc.: Employment. Zehnder:23andMe, Inc.: Unpaid advisor and collaborator Other. 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. Mesa:23andMe, Inc: Unpaid advisor and collaborator Other. Gotlib:23andMe, Inc.: Unpaid advisor and collaborator Other.

Abstract Background Polycythemia vera (PV) is a clonal myeloproliferative disorder characterized by erythrocytosis, splenomegaly and a frequently burdensome symptom profile. Despite current guidelines of aspirin, phlebotomy, and selective cytoreduction, many patients have inadequately controlled PV-related symptoms and/or disease features. We performed a comparison of PV symptom burden/disease feature phenotypes to understand unmet needs in current medical management. Methods Data was collected prospectively amongst an international cohort of PV patients including symptom burden, demographics, and disease features. Subgroups were identified who had previously failed hydroxyurea (PV-HU), required ongoing phlebotomy (PV-P), had palpable splenomegaly (PV-S), or had all 3 features (PV-HUPS). Control groups were derived from the remaining PV patients lacking the specified subgroup trait; patients in whom the trait status was unknown were excluded from each respective control group. All participants completed the MPN specific symptom burden questionnaire (MPN-SAF TSS (MPN-10 – Table 1)) and had no prior history of splenectomy. Surveyed symptoms on the MPN-10 included the patient's perceptions of common MPN-related symptoms and overall quality of life (QOL) on a 0 (absent) to 10 (worst imaginable) scale. PV risk scores were calculated using the 2013 criteria (Leukemia 2013). Comparison of symptoms between groups employed t-tests. Results Patient Demographics and Disease Features Between Phenotypic Groups A total of 1334 PV patients completed the MPN-10, and were assigned to categories of PV-HU (499 [37%]), PV-P (646 [48%]), PV-S (369, [28%]), and PV-HUPS (148 [12%]). The demographics between these groups were similar (comparable age (median range 60-63), PV risk scores (mean risk range: Low 16.4-23.7%; Intermediate 31.4%-36.6%; High 42.8%-47%). Mean hemoglobin was similar among PV subgroups (range 14.4-14.9); PV-HUPS had a higher mean WBC count (20.3 g/dL vs. 8.8-11.8 g/dL) and platelet count (703.5 x 10(9)/L vs. 327.5-462.8 x 10(9)/L), and disease duration (11.5 years vs. 6.4-8.8 years). Prior thrombosis was most common in PV-S patients (28.5% vs. 21.8-25.2%) and prior hemorrhage was most common in PV-HUPS patients (23.8% vs. 13.7-15.8%). Symptom Burden The MPN-10 scores of each problematic PV phenotype (HU, P, S, HUPS) were compared to the remainder of the PV cohort lacking the trait (PV-control; Table 1). Both individual symptom scores and TSS were highest for PV-HUPS patients (mean TSS 32.5 vs. 27.7-29.2). All problematic PV subgroups demonstrated significant differences for individual symptoms and TSS compared to PV-control. Comparing "problematic" subgroup responses, PV-HU patients described more inactivity whereas PV-S patients described more early satiety and pruritus. No statistical differences were noted in PV-HU, PV-P and PV-HUPS patient responses to MPN-10 items of "fever" and "weight loss". Discussion PV patients who have either failed HU, are undergoing phlebotomy and/or have splenomegaly exhibit moderate to severe symptomatology and demonstrate unmet medical need for management. As evidenced in this study, considerable overlap in symptomatology exists in PV-HU, PV-P, PV-S and PV-HUPS. Current randomized trials of JAK inhibitors have demonstrated benefits in a PV-HUPS phenotype. This data suggests that PV patients with any evidence of inadequate control (PV-HU, P, or S) have similarly unmet needs and may be candidates for clinical trials, intensification of medical therapy or perhaps JAK inhibitor therapy. Disclosures Kiladjian: Shire Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Zweegman:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees, Research Funding. Besses:Shire Pharmaceuticals: honoraria for educational lectures Other. Birgegard:Shire Pharmaceuticals: Consultancy, Honoraria, Research Funding. Etienne:Novartis, BMS, Pfizer, Ariad: Honoraria. Roy:Merck: Peg-Interferon provided for academic clinical trial in CML Other. te Boekhorst:Novartis: Consultancy. Griesshammer:Novartis: Honoraria; Shire: Honoraria; Sanofi: Honoraria; Amgen: Honoraria; Roche: Honoraria. Mesa:Incyte Corporation, CTI, NPS Pharma, Inc., Gilead Science Inc., Celgene: Research Funding.

Abstract Abstract 5061 Background: Ruxolitinib was approved for commercial use for the therapy of intermediate- and high-risk myelofibrosis (MF) in the USA in November 2011. We sought to assess the initial clinical experience on the use of ruxolitinib outside of the clinical trial setting at our high volume MPN program. Methods: Twenty-eight patients with intermediate- or high-risk myelofibrosis (including PMF, post-PV and post-ET myelofibrosis) prescribed ruxolitinib at our center within the first seven months after FDA approval were included in this analysis. Baseline disease information, treatment history, dynamics of ruxolitinib dosing, impact on cytopenias, splenic response, and symptoms were assessed. Results: A total of 28 patients with post-ET MF (n=7), post-PV MF (n=6) and primary MF (n=15) began ruxolitinib between November, 2011 and May, 2012. Twenty-seven patients had been treated with previous therapies. The JAK2V617F mutation was present in 79% of patients. The mean number of weeks from diagnosis of MF to treatment with ruxolitinib was 218 (8–929). The average spleen size at the start of therapy was 11. 5cm (0–36) below the left costal margin. DIPSS Plus scores classified patients as Intermediate-1 (53%), Intermediate-2 (29%) and High risk (18%). Symptoms at the start of therapy included fatigue (78%), early satiety (25%), night-sweats (68%), abdominal pain (61%), pruritis (32%), weight-loss (57%), bone pain (21%), and fevers (11%). The average hemoglobin concentration, WBC count and platelet counts were 10. 9 g/dL (7. 6–13. 8), 13. 5 × 10(9)/L (3. 1–53. 8) and 295 × 10(9)/L (32–844) respectively. The median duration to follow-up was 72 days (4–144 days). The majority of patients began therapy at 20 mg BID (68%). Most patients seen in follow-up experienced reduction in splenic size (64%), 36% of which had complete resolution of palpable splenomegaly within a mean follow-up of 78 days (10–142). Significant improvements were noted in symptoms including fatigue (68%), early satiety (71%), night sweats (47%), abdominal pain (71%), pruritis (55%), weight loss (69%), bone pain (33%) and fevers (33%). Dosage reductions were required for four patients with anemia (n=3) and thrombocytopenia (n=1). Two patients required the addition of anagrelide/hydroxyurea for platelet counts >1, 000 × 10(9)/L. Excluding patients with preexisting thrombocytosis >600 × 10(9)/L, the percentage reduction of platelets from baseline by weeks 4, 9 and 15 were 34%, 13%, and 12% respectively. Eight patients required red blood cell transfusions for anemia, three of which who had begun therapy with hemoglobin concentrations under 9 g/dL. Excluding the 8 transfusion-dependent patients, the percentage reduction in hemoglobin concentration from baseline by weeks 4, 9, and 15 was 7%, 6%, and 14% respectively. Non-hematological toxicities requiring dosage adjustments included hyperkalemia (n=1) and fatigue/dizziness/headaches (n=1). Five patients underwent dose increases for lack splenic (n=3) and symptomatic (n=2) response. Six patients discontinued the drug for disease progression requiring stem cell transplant (n=2), lack of constitutional symptom improvement (n=1), diarrhea (n=1), thrombocytopenia (n=1) and anemia (n=2). Five patients had platelet counts below 100 × 10(9)/L (19–94 × 10(9)/L) and began therapy at reduced starting doses. All patients seen in follow-up reported significant improvements in symptoms and splenomegly was reduced >50% in two patients seen in follow-up within 4 weeks of initiating therapy. Two patients underwent dose increases after 5 months of therapy to enhance response. No bleeding events were reported. By week 15, no decrease was noted in platelet levels from baseline in the 3 patients seen in follow-up. Two patients required danzol (n=1) or platelet transfusions (n=1) for thrombocytopenia. Conclusion: Randomized controlled trials have proven ruxolitinib's efficacy in reducing constitutional symptoms, cytopenias and splenomegaly in myelofibrosis patients. This study represents a confirmation of the efficacy this drug provides in reducing splenomegaly and symptoms observed in clinical trials when utilized in a standard practice setting. Toxicities are minimal and have been generally well controlled with dose reductions, even in patients with baseline thrombocytopenia. In conclusion, ruoxlitinib appears to be an efficacious and well-tolerated therapy with limited adverse effects. Disclosures: Mesa: Incyte: Research Funding; Lilly: Research Funding; Sanofi: Research Funding; NS Pharma: Research Funding; YM Bioscience: Research Funding.

Abstract Abstract 414 Background: SGI-110 is a dinucleotide of decitabine (DAC) and deoxyguanosine formulated as a low volume and pharmaceutically stable SQ injection allowing more extended decitabine exposure than DAC IV infusion. The anticipated differentiated PK profile offers the potential of improved biological and clinical activity and safety over currently available HMAs. Methods: A randomized Phase 1–2 FIH Pharmacokinetics/Pharmacodynamics (PK/PD)-guided, dose-escalation study has been conducted in patients with relapsed/refractory intermediate or high-risk MDS or AML. The objective of the first stage (dose escalation) is to determine safety and tolerability and to establish the Maximum Tolerated Dose (MTD) and Biologically Effective Dose (BED). Patients were randomized to one of two SQ regimens (dailyx5 or once weeklyx3, 28-day courses). PD is evaluated by LINE-1 global DNA hypomethylation. The second stage (dose expansion) is to determine the clinical activity and safety in AML and MDS using the established BED and MTD. We report here the results of the dose escalation phase which has completed enrolment. Results: 78 patients (64 AML, 14 MDS) were enrolled in the dose escalation phase: 44 patients in the dailyx5 regimen and 34 in the weeklyx3 regimen. Median age was 69 years (range 29–86), 65% were male, and 82% had ECOG PS of 0–1. Median number of prior regimens was 3 (range 1–9), 59% of patients had prior HMA treatment (50% of AML patients, and 100% of MDS patients). Six patients are still ongoing treatment. The PK profile demonstrated efficient conversion of SGI-110 to decitabine as predicted from the SGI-110 rational design, resulting in longer decitabine exposure window (beyond 8 hrs) compared to DAC IV (3–4 hrs). At SGI-110 dose range of 60–125 mg/m2, observed mean decitabine AUCs (88–231 ng*hr/mL) reach or exceed the therapeutic range seen with 20 mg/m2 DAC IV (115 ng*hr/mL) while achieving only a small fraction of the Cmax (26–64 ng/mL vs 146 ng/mL for DAC IV). The effective half-life for decitabine after SQ SGI-110 injection appeared to be prolonged (up to 4-fold or ∼2.4 hrs) compared to DAC IV (0.58 hrs). Decitabine exposures (AUC) increased in a dose-proportional manner regardless of the regimen and no accumulation was observed. Dose-related LINE-1 hypomethylation was observed in patients treated with the daily regimen between 18 and 60 mg/m2; a plateau in maximum average hypomethylation (∼25%) was evident at higher daily doses (90-125 mg/m2) and therefore the BED for the dailyx5 schedule is established at 60 mg/m2. The 25% average hypomethylation of LINE-1 compares favorably with that observed historically after DAC IV at the dose of 20 mg/m2 dailyx5. The extent of LINE-1 hypomethylation after weeklyx3 SGI-110 was inferior as the maximum average hypomethylation plateaued at ∼8% from baseline. Starting at 36 mg/m2 daily and 60 mg/m2 weekly (44 AML, and 7 MDS patients), clinical responses were observed: 2CRs, 1CRp, and 1CRi in heavily pretreated AML patients; 1 mCR and 1 HI in MDS patients previously treated with azacitidine. All responses were in patients who achieved >10% LINE-1 hypomethylation. The most common Adverse Events (AEs), regardless of relationship to SGI-110, were diarrhea (21%), febrile neutropenia (17%), fatigue/injection site pain/nausea at 15% each. The most common drug-related AEs were injection site pain (15%), fatigue (8%), nausea (6%), and thrombocytopenia (5%). MTD was not reached with the weekly regimen up to 125 mg/m2 weeklyx3. With the daily regimen, 125 mg/m2dailyx5 resulted in 2 Dose-Limiting Toxicities (DLTs) of febrile neutropenia in 3 MDS patients (1 associated with bacteremia, and the other with sepsis and thrombocytopenia Grade 4) while none of the 9 patients with AML had DLT at that dose. Conclusions: SGI-110 is well tolerated at doses higher than BED which is established at 60 mg/m2 dailyx5 where average hypomethylation of ∼25% was achieved. MTD estimated to be 90 mg/m2 dailyx5 for MDS and 125 mg/m2dailyx5 for AML patients. SQ administration of SGI-110 achieved efficient conversion to decitabine resulting in an improved PK profile over DAC IV. Clinical responses were observed in this heavily pretreated population and they seem to correlate with the extent of LINE-1 hypomethylation. Study is currently enrolling patients in the dose-expansion Phase 2 stage. Disclosures: Kantarjian: Astex Pharmaceuticals: Research Funding. Roboz:Astex Pharmaceuticals: Research Funding. Rizzieri:Astex Pharmaceuticals: Research Funding. Stock:Astex Pharmaceuticals: Research Funding. O'Connell:Astex Pharmaceuticals: Research Funding. Griffiths:Astex Pharmaceuticals: Research Funding. Yee:Astex Pharmaceuticals: Research Funding. Tibes:Astex Pharmaceuticals: Research Funding. Garcia-Manero:Astex Pharmaceuticals: Research Funding. Ravandi:Astex Pharmaceuticals: Research Funding. Walsh:Astex Pharmaceuticals: Research Funding. Feldman:Astex Pharmaceuticals: Research Funding. Ritchie:Astex Pharmaceuticals: Research Funding. Rao:Astex Pharmaceuticals: Research Funding. Decastro:Astex Pharmaceuticals: Research Funding. Schimmer:Astex Pharmaceuticals: Research Funding. Mesa:Astex Pharmaceuticals: Research Funding. Syed:Astex Pharmaceuticals: Research Funding. Choy:Astex Pharmaceuticals: Employment. Oganesian:Astex Pharmaceuticals: Employment. Taverna:Astex Pharmaceuticals: Employment. Azab:Astex Pharmaceuticals: Employment. Chung:Astex Pharmaceuticals: Research Funding. Issa:Astex Pharmaceuticals: Honoraria, Research Funding.

Abstract Abstract 756 Background: Myelofibrosis (MF) is the most serious of chronic myeloproliferative neoplasms (MPNs) for which there is no approved therapy. Exaggerated JAK2 signaling, either by gain-of-function mutations (eg, JAK2V617F) or high circulating levels of JAK1/2 activating cytokines (eg, interleukin [IL]-6), is believed to play a key role in MPN pathogenesis. INCB018424 (424), a selective oral inhibitor of JAK1/2, has demonstrated clinical benefits including reduction of splenomegaly and improvement of symptoms in a Phase I/II trial in MF patients. Thrombocytopenia was identified as the dose limiting toxicity occurring in 30% of patients at 25mg BID. Methods: Patients with primary, post-PV or post-ET MF were enrolled in the study. Following the characterization of multiple dosing regimens, an individually optimized dose regimen strategy was developed, based on available efficacy and safety data. In a subset of patients, spleen volume change was measured by MRI at 1, 3 and 6 months of treatment in order to establish an objective measure of spleen response. The impact of 424 on MF associated symptoms was assessed using a validated instrument, MFSAF (Mesa et al., Leukemia Research 2009). As a surrogate marker of functional benefit, exercise capacity was assessed with a standardized 6-minute walk test (6MWT) at baseline, 1, 3 and 6 months of therapy. Results: 155 patients were enrolled in the study, with median duration of treatment of 1+ years and the duration of drug exposure of >150 patient years (76 patients received >1 year of therapy). Clinical responses have been maintained over the entire duration of treatment and most patients remain on therapy (115 of 155 patients; 74%). Progression to AML occurred in 3 patients, which is below the expected frequency based on published data (Barosi et al., Blood 2007). SAEs related to 424 occurred in 12 patients, and are generally related to bone marrow suppression or return of or exacerbation of signs and symptoms of MF when therapy is discontinued. Further optimization of the dosing regimen utilized baseline platelet count to determine the starting dose (10 or 15mg BID) and allowed dose titration after 1 and 2 months of therapy; most patients were optimized to 15 or 20mg BID. This approach significantly reduced the incidence of thrombocytopenia (<5%, N=35), while providing equivalent efficacy to higher dose regimens. With an optimized dosing regimen, spleen volume reduction was evident as early as 1 month, and durable over 6 months, of therapy (33 % median decrease after 6 months, N=23). Eleven of 23 (48%) of patients achieved ≥ 35% reduction (equivalent to IWG clinical improvement criteria of 50% reduction by palpation) from baseline in spleen volume at month 6. MF patients have impaired exercise capacity at baseline (decreased 6MWT performance by 60-90 meters vs. age-matched controls). Treatment with 424 resulted in improved 6MWT performance, with median increase from baseline of 33, 58 and 70 meters after 1,3 or 6 months of therapy, respectively. Rapid and durable reduction of a total symptom score based on key symptoms (fatigue, abdominal discomfort/pain, bone/muscle pain, night sweats and pruritus) was noted (51 % and 58% of patients achieving 50% reduction in the total score following 1 and 6 months of treatment, respectively). Improvement in symptoms coincided with a rapid and sustained reduction in pro-inflammatory cytokines, including IL-1b, IL-1ra, IL-6 and TNFa, without tachyphylaxis to therapy. Finally, spleen response was associated with greater improvements in total symptom score, exercise capacity, and reduced fatigue (see Table). Conclusion: An optimized dosing regimen of INCB018424 resulted in sustained clinical, symptomatic and functional benefits in MF patients with an improved hematological safety profile compared to a 25 mg BID regimen. Safety and efficacy of 424 in MF patients is further supported by the follow-up data of >1 yr of 424 therapy. Disclosures: Verstovsek: Incyte: Research Funding. Bradley:Incyte Corporation: Employment, Equity Ownership. Erickson-Viitanen:Incyte Corporation: Employment, Equity Ownership. Vaddi:Incyte Corporation: Employment, Equity Ownership. Levy:Incyte Corporation: Employment, Equity Ownership.