Winton, Elliott F.

Abstract Ruxolitinib reduces spleen volume, improves symptoms, and increases survival in patients with intermediate- or high-risk myelofibrosis. However, suboptimal response may occur, potentially because of signaling via the phosphoinositide 3-kinase (PI3K)/protein kinase B pathway. This phase 2 study evaluated dosing, efficacy, and safety of add-on PI3Kδ inhibitor parsaclisib for patients with primary or secondary myelofibrosis with suboptimal response to ruxolitinib. Eligible patients remained on a stable ruxolitinib dose and received add-on parsaclisib 10 or 20 mg, once daily for 8 weeks, and once weekly thereafter (daily-to-weekly dosing; n = 32); or parsaclisib 5 or 20 mg, once daily for 8 weeks, then 5 mg once daily thereafter (all-daily dosing; n = 42). Proportion of patients achieving a ≥10% decrease in spleen volume at 12 weeks was 28% for daily-to-weekly dosing and 59.5% for all-daily dosing. Proportions of patients achieving ≥50% decrease at week 12 in Myelofibrosis Symptom Assessment Form and Myeloproliferative Neoplasms Symptom Assessment Form symptom scores were 14% and 18% for daily-to-weekly dosing, and 28% and 32% for all-daily dosing, respectively. Most common nonhematologic treatment-emergent adverse events were nausea (23%), diarrhea (22%), abdominal pain and fatigue (each 19%), and cough and dyspnea (each 18%). New-onset grade 3 and 4 thrombocytopenia were observed in 19% of patients, each dosed daily-to-weekly, and in 26% and 7% of patients dosed all-daily, respectively, managed with dose interruptions. Hemoglobin levels remained steady. The addition of parsaclisib to stable-dose ruxolitinib can reduce splenomegaly and improve symptoms, with manageable toxicity in patients with myelofibrosis with suboptimal response to ruxolitinib. This trial was registered at www.clinicaltrials.gov as #NCT02718300.

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

Background Interferons are recognized as active agents in the treatment of patients with high risk essential thrombocythemia (ET) or polycythemia vera (PV), both in the upfront setting as well as beyond. Several trials have shown high rates of hematologic and molecular responses with the use of interferons, however, data on direct comparison of interferon activity in patients with early disease in comparison to patients refractory or resistant to prior therapies, such as hydroxyurea (HU) are lacking. We conducted a controlled analysis of the activity of pegylated interferon alfa-2a (PEG) in two prospective parallel clinical trials conducted in these two unique patient populations. Methods The MPD-RC 111 (NCT01259817) was an international, multicenter, phase 2 open-label clinical trial that evaluated PEG therapy in patients with high risk PV and high-risk ET who were either refractory or intolerant (R/I) to HU by modified ELN criteria. The MPD-RC 112 trial (NCT01258856) enrolled patients with high risk ET/PV who were treatment-naïve (TN) (HU <3 months) and randomized them (1:1) to PEG or HU. All patients randomized to PEG were included in this analysis. Both protocols were conducted concurrently at the MPD-RC member institutions and utilized a similar primary endpoint of overall response rate (complete and partial response rates) by ELN Criteria at 12 months confirmed by the same blinded central review committee. Both studies utilized the same PEG starting dose of 45 mcg weekly and was titrated for response to a maximum of 180 mcg weekly. Secondary endpoints included safety information, impact on disease biomarkers, bone marrow (BM) response, and quality of life data. Results Patients ET: 39 TN and 65 R/I ET patients were available for this analysis. Median disease duration was 2.9 months in TN and 37.3 months in R/I patients. Baseline characteristics and demographics were similar in the two cohorts except lower baseline hemoglobin level in RI patients. (Table1A) PV: 43 TN and 50 R/I PV patients were included. Median disease duration was 2.5 months in TN and 54.8 months in R/I patients. Baseline characteristics only differed by lower frequency of phlebotomy rate in R/I patients. (Table1B) Baseline symptoms scores and quality of life were similar in TN and RI groups (Table 2) Response ET: CR/PR/ORR at 12 months were observed in 43.1%/26.2%/69.2% in R/I ET patients and in 43.6%/25.6%/69.2% in TN ET patients (p=0.99 for ORR). (Table 3, Figure 1) PV: CR/PR/ORR at 12 months were observed in 22%/38%/60% in R/I PV patients, and in 27.9%/58.1%/86% in TN PV patients (p=0.005 for ORR). (Table 3, Figure 1) Safety PEG was equally well tolerated throughout both treatment groups with treatment discontinuation due to adverse events occurring in 14.6% in TN patients and 13.9% in R/I patients. The mean (SD) dose of PEG was 102.7 (52.3) mcg in R/I ET patients and 128.7mcg (46.4) in R/I PV patients. For TN patients, mean dose was 85.7mcg (59.7) in ET and 93.5 mcg (44.0) in PV. Adverse events were consistent with historic reports of PEG use and the distribution of events was similar in R/I and TN patients. (Table 4) Conclusion This intention to treat response analysis included TN and R/I ET and PV patients with balanced baseline characteristics who received prospective therapy with PEG. Patients with ET had a higher overall response rate at 12 months that was equivalent in patients who were treatment-naïve and in patients who were intolerant or refractory to HU. By contrast, patients with PV who were treatment-naïve had a higher ORR than patients those intolerant or refractory to HU. We conclude that treatment with PEG is an effective therapeutic option both treatment naïve PV and ET as well as those previously treated with HU, however PEG as a second line agent is especially effective in ET patients. Disclosures Yacoub: Hylapharm: Equity Ownership; Agios: Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; Ardelyx: Equity Ownership; Cara: Equity Ownership; Dynavax: Equity Ownership. Mascarenhas:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Roche: Consultancy, Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Pharmaessentia: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; Promedior: Research Funding; Merus: Research Funding. Mesa:AbbVie: Research Funding; Samus: Research Funding; Incyte: Research Funding; Sierra Onc: Consultancy; Genotech: Research Funding; Promedior: Research Funding; Novartis: Consultancy; Celgene: Research Funding; CTI Biopharma: Research Funding; La Jolla Pharma: Consultancy. Rampal:Agios, Apexx, Blueprint Medicines, Celgene, Constellation, and Jazz: Consultancy; Constellation, Incyte, and Stemline Therapeutics: Research Funding. Silver:PharmEssentia: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. McMullin:Daiko Sanyo: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Speakers Bureau; Italopharma: Membership on an entity's Board of Directors or advisory committees. Ewing:Novartis: Honoraria, Other: Meeting attendance sponsorship ; Bristol Myers-Squibb: Other: Meeting attendance sponsorship . O'Connell:Astex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Shionogi: Membership on an entity's Board of Directors or advisory committees. Mead:Bristol Myers-Squibb: Consultancy; Novartis: Consultancy, Honoraria, Other: Travel/accommodation expenses, Research Funding, Speakers Bureau; CTI: Honoraria, Research Funding; Celgene: Consultancy, Research Funding; Pfizer: Consultancy. De Stefano:Alexion: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau. Baer:Astellas: Research Funding; Al Therapeutics: Research Funding; Abbvie: Research Funding; Incyte: Research Funding; Forma: Research Funding; Kite: Research Funding; Takeda: Research Funding. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kremyanskaya:La Jolla: Consultancy; Incyte, Celgene, Constellation, Protagonist.: Research Funding. Hexner:novartis: Research Funding. Rambaldi:Amgen: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding, Speakers Bureau; Italfarmaco: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding, Speakers Bureau; Omeros: 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, Other: travel support, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding, Speakers Bureau; Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau, travel support. Ritchie:Genentech: Other: Advisory board; Tolero: Other: Advisory board; agios: Other: Advisory board; Pfizer: Other: Advisory board, travel support; Celgene: Other: Advisory board; Jazz Pharmaceuticals: Research Funding; Celgene, Novartis: Other: travel support; AStella, Bristol-Myers Squibb, Novartis, NS Pharma, Pfizer: Research Funding; Ariad, Celgene, Incyte, Novartis: Speakers Bureau; Celgene, Incyte, Novartis, Pfizer: Consultancy. Kiladjian:Novartis: Honoraria, Research Funding; AOP Orphan: Honoraria, Research Funding; Celgene: Consultancy. Harrison:Promedior: Honoraria; Incyte: Speakers Bureau; Sierra Oncology: Honoraria; Celgene: Honoraria, Speakers Bureau; Janssen: Speakers Bureau; CTI: Speakers Bureau; AOP: Honoraria; Shire: Speakers Bureau; Roche: Honoraria; Gilead: Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau. Hoffman:Merus: Research Funding. OffLabel Disclosure: Pegylated Interferon Alfa-2a for in Patients with Polycythemia Vera or Essential Thrombocythemia

Abstract Background: Patients (pts) with polycythemia vera (PV) and essential thrombocythemia (ET) suffer from difficult MPN associated symptoms which impact quality of life (QoL). The impact of initial cytoreduction on ET/PV symptoms, resulting toxicity and QoL have not been prospectively studied. Methods: MPD-RC 112 trial (NCT01258856) randomized 168 therapy-naive (hydroxyurea [HU] <3 mo) high risk ET/PV pts (<5 years of disease) to response adjusted pegylated interferon alpha 2a (PEG) or HU. MPN symptoms, in depth toxicity assessment, and QoL were measured by two symptom instruments (MPN-SAF, EORTC QLQ-C30: baseline,3, 6, 9, and 12 mo) and toxicity questions. Blinded response review by European Leukemia Net (ELN) hematological responses (HR) was conducted at 12 months. Individual time point and longitudinal group comparisons were based on mixed models adjusting for age. Results: Patients: Of 168 randomized pts (86 HU, 82 PEG), 164 (98%) completed the survey package at baseline and 151 (HU 83%; PEG 98%) completed at least 1 survey during treatment. Median age was 61 (range 18-87) with 70 (42%) females; 81 (48%) / 87 (52%) with ET / PV; 46 (27%) had a history of a thrombosis. 119 (71%) received prior HU (up to 3 months). Baseline characteristics were balanced between arms with the exception of age (median HU 63 vs. PEG 60 yrs; p=0.02). Baseline Symptom Burden /QoL: Mean MPN-SAF Total Symptom Score (TSS), scale 0 [absent]-100 [worst imaginable] was 15.8 (SD 12.6; range 0-62.0) with means of 15.1 (SD 12.6) / 16.5 (SD 12.6) for ET / PV which were slightly lower than reported means of a previous cohort receiving any line of treatment (Scherber RM, JCO 2012). Median number of moderate (defined as score >=3) symptoms in ET patients was 3.0 and PV 4.0. Most common moderate symptoms were fatigue (65.9%), insomnia (37.2%), numbness (33.5%) , itching (29.9%), dizziness (27.4%), early satiety (26.8%) , headache (23.2%), sad mood (23.2%), inactivity (22%), concentration (20.7%). 50.6% of patients had one or more symptom with a score >=6. Mean QLQ-C30 global health status/QoL (GHS/QoL) was 70.8 (SD 21.9) - comparable to a general population (mean 71.2, SD 22.4) and better than a general cancer population (mean 61.3, SD 24.2; QLQ-C30 Reference Manual 2008). At baseline, TSS, symptoms, and QoL were similar between treatment arms. In patients with TSS >20 at baseline (highly symptomatic, n=50; ET:20, PV:30), median TSS was 28.0 (range 20.0 to 62.0); the highest scored symptom was fatigue (median=7.0), itching (median=4.5) and insomnia (median=4.0). Impact of Therapy on Symptom Burden/QoL: On HU, pts experienced worsening QoL (physical, cognitive functioning, HRQoL) and some persistent or transient worsened symptoms (inactivity, concentration (p<0.05) (Table 1)). On PEG, pts experienced worsening of fever, dyspnea, appetite loss and PEG-related symptoms including flu-like symptoms, injection site irritation, blurry vision, and visual changes (all p<0.05), but not sad mood (not corrected for antidepressants). In comparing arms, change in TSS significantly differed (p=0.01) between arms with increasing symptoms on HU vs PEG at 3 and 6 mo, but lower symptom burden at 9 and 12 mos (Figure 1). In highly symptomatic pts (with a baseline TSS > 20, n=50), improvements in weight loss, abdominal discomfort, fatigue, itching, fever, early satiety (12 m.) were observed in pts on HU. For PEG, in highly symptomatic pts, improvements were observed for overall TSS score, fatigue, inactivity, night sweats, and itching (with similar toxicities to all PEG patients). ELN Response and Symptom Burden/QoL: Among the 133 pts with 12-mo symptom data, complete hematologic response (CHR) rate was 43%. Inactivity and sad mood were worse in those patient achieving a CHR (inactivity: CHR worsening 0.68 vs PHR/NR better 0.26; p=0.03; sad mood: CHR worsening 0.67 vs PHR/NR better 0.67, p=0.002)). These latter changes were not related to higher doses utilized (in either arm), suggesting obtaining CHR may have negative effects on patient symptoms. Conclusions:In pts with a significant baseline MPN symptom burden, cytoreductive therapy has both a beneficial impact on baseline MPN symptom burden but also leads to therapy associated toxicity, although different patterns of efficacy and toxicity between HU and PEG. Achievement of a CHR in PV/ET may be associated with higher rates of drug related toxicities, and the value of achieving CHR may need further validation. Disclosures Mesa: Incyte Corporation: Research Funding; CTI Biopharma: Research Funding; Gilead: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding; Novartis: Consultancy; Celgene: Research Funding; UT Health San Antonio - Mays Cancer Center: Employment; Genentech: Research Funding; Pfizer: Research Funding. Mascarenhas:Merck: Research Funding; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding; Promedior: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Janssen: Research Funding. Rambaldi:Omeros: Consultancy; Roche: Consultancy; Celgene: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Italfarmaco: Consultancy; Amgen Inc.: Consultancy. Yacoub:Novartis: Honoraria, Speakers Bureau; Cara Therapeutics: Equity Ownership; Ardelyx, INC.: Equity Ownership; Inycte: Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau; Dynavax: Equity Ownership. Harrison:Gilead: Honoraria, Speakers Bureau; CTI BioPharma: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau. Kiladjian:AOP Orphan: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Mead:Elstar: Research Funding; Celgene: Research Funding; ARIAD: Consultancy; Cell Therapeutics: Consultancy; Evotek: Research Funding; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy. Kessler:Sangamo: Research Funding; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Honoraria, Research Funding; Dimension Advisory boards: Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; DSMB: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Biomarin: Research Funding. Kremyanskaya:Incyte: Research Funding. Rampal:Incyte: Honoraria, Research Funding; Constellation: Research Funding; Jazz: Consultancy, Honoraria; Stemline: Research Funding; Celgene: Honoraria. Hoffman:Incyte: Research Funding; Janssen: Research Funding; Merus: Research Funding; Formation Biologics: Research Funding; Summer Road: Research Funding. Dueck:Pfizer: Honoraria; Bayer: Employment; Phytogine: Employment.

Abstract Introduction HU is the treatment of choice for patients (pts) with high risk ET/PV, however, PEG has been proposed as an alternative option due to its proposed potential to modify disease course. An interim analysis of MPN-RC 112 (Blood 2016 128:479;) did not reveal a difference in PR/CR rates between HU and PEG therapy after 12 months in the first evaluable 75 pts treated. Here we present the results and long-term follow-up of all pts participating in this pivotal study [NCT01259856]. Methods MPN-RC 112 was a randomized, open label, phase 3 clinical trial comparing HU and PEG in pts with high risk ET/PV. Pts were treated for up to 12 months to achieve PR or CR (ELN/IWG-MRT response criteria). Pts who achieved a PR/CR continued therapy for up to a maximum of 6 years. Minimum follow up was 1 year from the time the last pt was randomized. The primary objective was to compare the CR rate following HU vs. PEG at 12 months with 3 month confirmation. Secondary objectives included a comparison of toxicity and tolerability; PR rates; incidence of specific pre-defined toxicities and tolerance to therapy; impact of therapy on key biomarkers; survival and incidence of myelodysplastic syndrome, myelofibrosis, or leukemic transformation; and incidence of major cardiovascular events. Bone marrow pathologic responses were evaluated by central blinded expert review at baseline, 12, 24 months and end of study. Results The study accrued 168 pts; 86 were randomized to HU and 82 to PEG. A summary of pt baseline characteristics by treatment arm is shown in Table 1 and were well balanced between the treatment arms except for median age which was higher in the HU arm (p=0.02). Median duration of follow up was 89.9 weeks (range, 0 to 292.3) and the median treatment duration was 86.0 weeks (range, 0 to 287.3). At 12 months, the overall response rate (ORR= PR+CR) was 69.8% and 78% for HU and PEG, respectively (p=0.22). Figure 1 shows the distribution of responses stratified by disease type. At 24 months, 59 pts were on treatment with an ORR of 22/25 (88%) for HU and 31/34 (91%) for PEG. When considering all 106 pts who were eligible to receive treatment for 24 months (due to study closure), the ORR was 22/54 (40.7%, PR: 11 (20.4%), CR: 11 (20.4%)) for HU and 31/52 (59.6%, (PR: 15 (28.9%), CR: 16 (30.8%)) for PEG, p=0.04. Best ORR at any time on study was seen in 70.9% and 81.7% of HU and PEG treated pts, respectively, p=0.10. The median maximum change from baseline spleen volume was -6% (-100.0 - +53.8) in 112 evaluable pts and was similar between arms, p=0.99. Bone marrow morphologic responses are shown in Table 2 and the best response (CR) seen at any time on study for ET treated with HU was 52% (12/23) vs PEG 32% (8/25) and for PV treated with HU 19% (6/31) vs PEG 6% (2/34). Cytogenetic analyses at diagnosis were available in 86% (144/168). An abnormal karyotype was seen in 15% (22/144). Five PV and one ET pt lost their chromosomal abnormalities: 3 after one year (HU=1, PEG=2) and three after two years of therapy (HU=2, PEG=1). AE information is available for 162 pts (HU: 80; PEG: 82) (Table 3). Six pts randomized to HU never received treatment due to study withdrawal prior to initiation of treatment. Sixty pts had a grade 3 or higher event [HU: 22 (27.5%) and PEG: 38 (46.3%)]. 28 PV pts had a grade 3/4 [HU: 10 (24.4%) and PEG: 18 (41.9%)]. Four pts had a grade 4/5 event [HU: 3 (7.3%) and PEG: 1 (2.3%)]. 32 ET pts had a grade 3/4 [HU:12 (30.8%) and PEG:20 (51.3%)]. Two pts had a grade 4/5 event [HU:1 (2.6%), PEG:1 (2.6%)]. Additional outcomes of interest on study include one death attributed to new diagnosis of lung cancer (HU:1), progression to myelofibrosis (HU:1), vertebral artery occlusion (HU:1), and cerebral vascular accident (PEG:1). Reasons for study discontinuation are shown in Table 4. The effect of therapy on symptom burden and quality of life will be presented in a companion abstract (Mesa et al). The impact of mutation status on therapeutic outcome as well as the molecular responses will be presented at the meeting. Conclusion The final analysis of MPN-RC 112 revealed that the CR rates in pts with high risk ET/PV treated with PEG and HU at 12 and 24 months were similar. PEG was associated with a higher rate of grade 3/4 toxicity. Each drug appeared equally capable of modifying the natural history of high risk ET/PV based upon their effects on spleen size, karyotypic abnormalities, histopathological parameters and the low incidence of thrombotic complications and disease evolution in both arms. Disclosures Mascarenhas: Novartis: Research Funding; Promedior: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Merck: Research Funding; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding. Rambaldi:Amgen Inc.: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Italfarmaco: Consultancy; Omeros: Consultancy; Roche: Consultancy; Celgene: Consultancy. Harrison:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; CTI BioPharma: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Gilead: Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau. Kiladjian:AOP Orphan: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Mead:Bristol-Myers Squibb: Consultancy; Elstar: Research Funding; Celgene: Research Funding; ARIAD: Consultancy; Evotek: Research Funding; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Cell Therapeutics: Consultancy. Kessler:Genentech: Research Funding; Sangamo: Research Funding; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Biomarin: Research Funding; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; DSMB: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Honoraria, Research Funding; Dimension Advisory boards: Membership on an entity's Board of Directors or advisory committees. Kremyanskaya:Incyte: Research Funding. Rampal:Stemline: Research Funding; Incyte: Honoraria, Research Funding; Constellation: Research Funding; Jazz: Consultancy, Honoraria; Celgene: Honoraria. Mesa:CTI Biopharma: Research Funding; Novartis: Consultancy; Genentech: Research Funding; Promedior: Research Funding; UT Health San Antonio - Mays Cancer Center: Employment; Pfizer: Research Funding; Celgene: Research Funding; Incyte Corporation: Research Funding; Gilead: Research Funding; NS Pharma: Research Funding. Dueck:Pfizer: Honoraria; Bayer: Employment; Phytogine: Employment. Hoffman:Incyte: Research Funding; Formation Biologics: Research Funding; Merus: Research Funding; Janssen: Research Funding; Summer Road: Research Funding.

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

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

Abstract Background The JAK1/JAK2 inhibitor ruxolitinib (RUX) is approved for treatment of myelofibrosis (MF). However, some patients do not respond to RUX, while others lose responsiveness or develop intolerance to RUX over time. Preclinical data also suggest that certain JAK2 mutations (eg the gatekeeper mutation M929I) may confer resistance to RUX (Leukemia 2012;26:708). Options for these RUX resistant/intolerant patients, particularly with regard to further JAK inhibitor therapy, are unclear. Fedratinib (SAR302503) is a JAK2-selective inhibitor which has demonstrated clinically meaningful reductions in splenomegaly and symptom burden in patients with MF, with an acceptable and consistent safety profile (J Clin Oncol 2011;29:789. Haematologica 2013;98:S1113). Fedratinib sensitivity in vitro is unaffected by the M929I mutation. This pre-specified interim analysis of the JAKARTA-2 study (NCT01523171) investigated the efficacy and safety of fedratinib in MF patients previously treated with RUX. Methods JAKARTA-2 is a Phase II, multicenter, open-label, single-arm study of patients who previously received RUX for MF. Patients ≥18 yrs with splenomegaly and platelet count ≥50 ×109/L received fedratinib 400 mg orally, once daily for consecutive 4-wk cycles (permitted dose adjustment to 200–600 mg daily). Eligible patients had received ≥14 d RUX treatment, and had discontinued RUX for ≥14 d prior to starting fedratinib. Although there is no consensus definition of RUX resistance/intolerance, for the purpose of this study patients were classed (investigator assessment) as resistant (lack or loss of response) or intolerant to RUX. Primary endpoint for the interim analysis: spleen response rate (RR) (≥35% reduction in spleen volume from baseline at Wk 12 [MRI/CT blinded central review]) in the per-protocol (PP) population. Secondary endpoints: symptom RR (≥50% reduction in total symptom score [TSS: modified Myelofibrosis Symptom Assessment Form] from baseline to Wk 12) and safety. Results At the cut-off date for this interim analysis, 27 patients had received fedratinib treatment (median RUX exposure 10.7 months [range 1.9–34.4]): median age 69 yrs; 56% male; 67% primary MF; 63% high-risk MF; 67% JAK2V617F positive; 41% platelet count <100 × 109/L; baseline median spleen volume 3190 mL [1072–7815]; baseline median TSS 19.6 [4.9–46.0]. Eighteen patients were considered resistant by the treating physician (8 lack of response, 3 disease progression, 7 loss of response; median RUX exposure 11.1 months [range 1.9–34.4]) and 9 intolerant (6 hematologic, 3 non-hematologic toxicity; median RUX exposure 9.2 months [2.9–33.2]) to RUX. Median fedratinib exposure to cut-off date: 4 cycles (range 1–10); 19 patients remain on treatment. Spleen RRs were 40% (8/20 PP patients) and 43% (3/7) in patients with baseline platelet count <100 ×109/L. Overall, 19% (5/26 evaluable patients) had a symptom response by Wk 12 (Table). The majority of patients had a reduction in TSS at Wk 12 (Figure). The most common non-hematologic treatment-emergent adverse events (AEs) were gastrointestinal (nausea 67%; diarrhea 56%; vomiting 48%). Grade 3/4 diarrhea occurred in 2 patients; no Grade 3/4 vomiting or nausea. Anemia was the most common hematologic AE (all grades, 93%; Grade 3, 41%; Grade 4, 0%). Thrombocytopenia (all grades) occurred in 19 (70%) patients; Grade 3 in 6 patients and Grade 4 in 2 patients. One patient had Grade 3 AST elevations and 1 patient had Grade 3 hyperbilirubinemia. Seven patients (26%) discontinued treatment due to AEs. There were 2 deaths on study, both due to disease progression. Conclusions Interim results from the JAKARTA-2 study indicate that once-daily fedratinib provides clinical benefit, through reduced splenomegaly and symptom burden, in MF patients previously treated with RUX. The safety profile was acceptable and manageable, with safety results to date consistent with those reported in previous trials of fedratinib. Sponsored by Sanofi. Disclosures: Harrison: Novartis: Research Funding; Novartis, Sanofi, YM Bioscience, Celgene, SBio, Gilead: Honoraria; Novartis, Sanofi, Shire: Speakers Bureau; Novartis, Sanofi, YM Bioscience, SBio, Gilead: Membership on an entity’s Board of Directors or advisory committees. Jourdan:Sanofi: Honoraria. Kiladjian:Novartis, Celgene, AOP Orphan: Research Funding; Novartis, Sanofi, AOP Orphan: Honoraria; Novartis, Sanofi, AOP Orphan: Membership on an entity’s Board of Directors or advisory committees. Cervantes:Novartis: Speakers Bureau; Novartis and Sanofi: Membership on an entity’s Board of Directors or advisory committees. Niederwieser:Novartis Pharma: Consultancy. Cortes:Incyte, Sanofi: Consultancy; Incyte, Sanofi: Research Funding. Passamonti:Novartis, Celgene, Incyte, Sanofi, Roche: Honoraria. Reiter:Sanofi: Honoraria. Heidel:Novartis Inc.: Honoraria; Novartis Inc.: Research Funding; Novartis Inc.: Membership on an entity’s Board of Directors or advisory committees. Silver:Sanofi: Consultancy; Sanofi: Research Funding; Sanofi: Honoraria. Winton:Sanofi: Research Funding. Gupta:Incyte, Novartis: Consultancy; Incyte, Novartis: Research Funding; Novartis: Honoraria. Gisslinger:AOP Orphan Pharmaceuticals, Novartis, Sanofi, Shire, Celgene, Janssen: Membership on an entity’s Board of Directors or advisory committees; AOP Orphan Pharmaceuticals, Novartis, Sanofi, Shire, Celgene, Janssen: Honoraria. Vannucchi:Novartis: Membership on an entity’s Board of Directors or advisory committees. Talpaz:Novartis, Bristol-Myers Squibb, Ariad, Deciphera: Research Funding; Novartis, Bristol-Myers Squibb, Ariad, Deciphera: Speakers Bureau. Zhang:Sanofi: Employment. Shi:Sanofi: Employment. Mesa:Incyte, Genentech, Lilly, MS Pharma, Gilead: Research Funding.

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

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