Arcasoy, Murat O.

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

Abstract Allogeneic hematopoietic cell transplantation (HCT) is the only curative therapy for myelofibrosis (MF). In this large multicenter retrospective study, overall survival (OS) in MF patients treated with allogeneic HCT (551 patients) and without HCT (non-HCT) (1377 patients) was analyzed with Cox proportional hazards model. Survival analysis stratified by the Dynamic International Prognostic Scoring System (DIPSS) revealed that the first year of treatment arm assignment, due to upfront risk of transplant-related mortality (TRM), HCT was associated with inferior OS compared with non-HCT (non-HCT vs HCT: DIPSS intermediate 1 [Int-1]: hazard ratio [HR] = 0.26, P < .0001; DIPSS-Int-2 and higher: HR, 0.39, P < .0001). Similarly, in the DIPSS low-risk MF group, due to upfront TRM risk, OS was superior with non-HCT therapies compared with HCT in the first-year post treatment arm assignment (HR, 0.16, P = .006). However, after 1 year, OS was not significantly different (HR, 1.38, P = .451). Beyond 1 year of treatment arm assignment, an OS advantage with HCT therapy in Int-1 and higher DIPSS score patients was observed (non-HCT vs HCT: DIPSS-Int-1: HR, 2.64, P < .0001; DIPSS-Int-2 and higher: HR, 2.55, P < .0001). In conclusion, long-term OS advantage with HCT was observed for patients with Int-1 or higher risk MF, but at the cost of early TRM. The magnitude of OS benefit with HCT increased as DIPSS risk score increased and became apparent with longer follow-up.

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 Introduction: Allogeneic hematopoietic stem cell transplantation (HCT) is the only curative therapy for myelofibrosis (MF). Consideration of HCT is recommended by international working groups and national guidelines for MF patients (pts) age <70 with intermediate-1 with adverse indicators, intermediate-2 or high-risk disease by the Dynamic International Prognostic Scoring System (DIPSS) for MF- a recommendation made in the absence of clear data indicating the optimal timing of HCT for MF. In this large multicenter retrospective study, we analyze overall survival in MF pts treated with and without HCT. Methods: Disease characteristics, treatments, and outcome data from MF pts receiving non-transplant therapy at 14 US academic medical centers between 2000-2014 were retrospectively collected. MF pts who underwent HCT were identified from the Center for International Blood and Marrow Transplant Research (CIBMTR). The Cox proportional hazards model was used. The reference time point (time zero) was time of referral for the non-transplant (non-HCT) arm and the time of transplant for the HCT arm. The main effect variable (HCT vs. non-HCT) violated the proportionality assumption where comparing to non-HCT, mortality was higher with HCT in early time period from time zero but then was lower in late time period; therefore, the comparison is presented as early time period and late time period. The Cox model identified 14 months from time zero as the ideal cut point to define early and late time periods. The proportionality assumption is satisfied within each of these two periods. Results: A total of 1377 and 551 pts were included in the non-HCT and HCT arms, respectively (Table 1). In the overall cohort, survival was higher with non-HCT vs. HCT in early time period (relative risk [RR]: 0.34, P< .0001, Figure 1D), but in late time period survival was lower with non-HCT vs. HCT (RR: 2.37, P< 0.001) (Table 2). In the DIPSS low-risk MF group, while survival was higher with non-HCT vs. HCT in the early time period (RR: 0.19, P=0.007, Figure 1A), survival was lower with non-HCT in the late time period, but the latter did not reach statistical significance (RR: 1.45, P=0.39). In the DIPSS intermediate-1 risk group, a survival advantage was present with non-HCT treatments vs. HCT in the early time period (RR: 0.27, P < .0001, Figure 1B), however survival was lower with non-HCT in the late time period (RR: 3.13, P < .0001). Similarly, in those with DIPSS intermediate-2 and high-risk MF, survival advantage was observed with non-HCT in the early time period (RR: 0.41, P< .0001, Figure IC), but survival was lower with non-HCT in the late time period (RR: 2.82, P < .0001). Conclusion: A long-term survival advantage with transplant was observed for pts with intermediate-1 or higher risk MF, but at the cost of potential early mortality. The magnitude of benefit increased as DIPSS risk score increased. Although this retrospective study has limitations, the results have an impact on clinical practice by suggesting that transplantation could be considered earlier in the disease course and supports the recommendation for consideration of HCT in the setting of intermediate-1 risk MF. Disclosures Gowin: Incyte: Consultancy, Other: Scientific Advisory Board, Speakers Bureau. Verstovsek:Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Consultancy; Italfarmaco: Membership on an entity's Board of Directors or advisory committees. Ali:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees. Gupta:Novartis: Consultancy, Honoraria, Research Funding; Incyte: Research Funding. Gerds:Celgene: Consultancy; Apexx Oncology: Consultancy; CTI Biopharma: Consultancy; Incyte: Consultancy.

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

Abstract 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.