Verstovšek, Srđan

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

Abstract Background: The myeloproliferative neoplasms (MPNs), including essential thrombocythemia (ET), polycythemia vera (PV) and myelofibrosis (MF) can be characterized by heterogeneous symptoms, disease features, and prognosis. Timely monitoring of blood counts and if needed, referral for discussion of stem cell transplant (SCT), are critical to optimizing survival and quality of life. In connection with the MPN SCT Transplantation Timing Taskforce's (MS3T's) work in developing the DIPPS-based Stem Cell Spectrum Timing Tool, the survey was deployed to explore factors contributing to delayed entry to SCT. National Comprehensive Cancer Network (NCCN) guidelines for MPNs strongly recommend referral to specialized centers with expertise in the management of MPNs (Mesa et. al. 2017). To date, efforts to assess the timing and quality of MPN patient care from the patient's perspective have been minimal. Methods: Patients were recruited from MPN-related Facebook pages, subscribers of MPNforum Magazine and E-mail support groups including the MPN-NET, MPDchat, and the MPN Research Foundation. Hematologists, MPN patients, and advocates constructed the 11-item survey questions and content. The survey was available for patient response between July 4-11th2018. Patients were queried on MPN type, time of diagnosis, and details regarding knowledge of their MPN disease features and care. Data: Demographics.Overall 2382 MPN patients responded to the online survey. Of these, 901 (38%) patients had ET, 865 (36%) had PV, 561 (24%) had MF, 41 (2%) had MPN-unclassifiable or MPN/MDS overlap and 15 (1%) did not respond. Among MF patients, 56% reported having primary MF, 42% secondary MF, 1% prefibrotic MF, and 1% reported having already undergone SCT (1% did not specify type of MF or transplant). The majority of patients were diagnosed with their MPN by a hematology/oncology (77.8%) or family practice (15 %) physician. MPN Care provider and monitoring: Out of all respondents, 35% reported being cared for by an MPN specialist, 36% were not cared for by an MPN specialist and 27% were unsure if their provider was an MPN specialist. Overall less than half (42%) of patients reported having sought a second opinion from an MPN specialist. The majority (87%) of participants knew their mutational status relating to the highly publicized and widely tested JAK2 V617F mutation (73.8%) and CALR (10.2%). However, a statistically insignificant number of patients had any idea of other driving and secondary mutations including MPL, EZH2, SRSF2, IDH1/2 or ASLX-1. Blood counts were reviewed by a hematologist for the majority of patients (93% responded "yes", 4% responded "sometimes", 3% responded "no"). SCT Referral: Among ET and PV, <1% of patients reported being referred to SCT. For MF, 34% of participants reported having been referred for SCT discussion (30% for primary MF and 28% for secondary MF). Conclusions: MPN patients often report receiving care outside of the care of an MPN specialist. Additionally, despite the poor outcomes and higher likelihood of progression to AML, less than a third of patients with secondary MF report being referred for SCT discussion. Independent validation of patient responses, particularly in regards to MPN specialized care and timing of transplant discussion should be investigated further. However, these patient responses suggest many patients may be receiving less than optimal MPN care. These results demonstrate the importance of community hematology/oncology physician and patient education regarding optimal MPN care. Disclosures Mesa: UT Health San Antonio - Mays Cancer Center: Employment; Celgene: Research Funding; Novartis: Consultancy; Incyte Corporation: Research Funding; Pfizer: Research Funding; CTI Biopharma: Research Funding; Genentech: Research Funding; Promedior: Research Funding; NS Pharma: Research Funding; Gilead: Research Funding. Palmer:Novartis: Research Funding. Harrison:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; CTI BioPharma: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Speakers Bureau. Verstovsek:Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; 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. Scherber:Gilead: Honoraria.

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 with chronic myelomonocytic leukemia (CMML) have historically had poor outcomes, with overall response rates (ORR) of ~16% for hypomethylating agents (HMA) in first-line registration studies with a median overall survival (OS) of ~4-7 months in the relapsed/refractory (R/R) setting. Allogeneic stem cell transplant is not an option for the majority, due to older age at diagnosis and comorbidities. Tagraxofusp (Elzonris™, SL-401) is a novel targeted therapy directed to the interleukin-3 receptor-α (CD123), a target expressed on a variety of malignancies. In CMML, CD123 is expressed on malignant progenitor cells as well as microenvironmental plasmacytoid dendritic cell (pDC) infiltrates, now shown to be part of the malignant clone (Solary, EHA 2018). We thus hypothesized that therapeutic targeting of CD123-expressing malignant cells and infiltrating clonal pDCs may offer a novel therapeutic approach. Tagraxofusp has already demonstrated high levels of clinical activity against blastic plasmacytoid dendritic cell neoplasm (BPDCN), a CD123+ malignancy derived from pDCs. Methods: This multicenter, two-stage Phase 1/2 trial is enrolling patients with relapsed/refractory (r/r) CMML or other myeloproliferative neoplasms (MPNs). Primary objectives include assessment of safety, determining optimal dose/regimen, and evaluating efficacy outcomes in patients with r/r CMML. In the Stage 1 dose escalation cohort (completed), tagraxofusp was administered as a daily IV infusion at 7, 9, and 12 mcg/kg/day, on days 1-3 every 21 days (cycle 1-4), every 28 days (cycles 5-7), and every 42 days (cycles 8+). In Stage 2 (ongoing), patients received the optimal dose determined in Stage 1 (12 mcg/kg; no MTD reached). Results: As of July 2018, 18 patients with CMML (CMML-1 [n=10]; CMML-2 [n=8]) received tagraxofusp. 13 patients were treated in second-line setting and 5 patients were treated in third-line and beyond, with HMAs being the most commonly administered prior therapy. Median age was 70 years (range 42-80); 78% patients were male. 53% (9/17) of patients had baseline splenomegaly (range: 2 to 22 cm palpable below left costal margin (BCM) by physical exam). Most common treatment-related adverse events (TRAEs) were hypoalbuminemia and nausea (each 38%), vomiting (31%), fatigue, edema, and thrombocytopenia (each 25%). Most common ≥grade 3 TRAEs were thrombocytopenia (13%) and nausea (6%). Capillary leak syndrome was reported in 3 patients (19%; all grade 2). 100% (8/8) of patients with baseline splenomegaly had a spleen response, including 75% (6/8) who had reduction in splenomegaly of 50% or more. 60% (3/5) of patients with baseline spleen size ≥5cm had reduction in splenomegaly of 50% or more. Two patients treated with tagraxofusp achieved bone marrow CRs. 43% (6/14) of evaluable patients had a treatment duration of 6 months or more, including one at 8+ and one at 14+ months. Conclusions: Tagraxofusp monotherapy resulted in significant reductions in spleen sizes along with bone marrow morphological responses in relapsed/refractory patients with CMML, with a manageable safety profile. Given CD123 expression on both neoplastic myeloid cells and pDCs infiltrates, tagraxofusp may offer a novel targeted approach for patients with CMML, an area of unmet medical need. Enrollment continues, and updated safety and efficacy data will be presented. A registrational trial in this patient population is planned. Clinical trial information: NCT02268253. Disclosures Ali: Incyte Corporation: Membership on an entity's Board of Directors or advisory committees. Gupta:Novartis: Consultancy, Honoraria, Research Funding; Incyte: Research Funding. Schiller:Celator/Jazz Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding. Lee:AstraZeneca: Consultancy; Clinipace: Consultancy; Karyopharm Therapeutics Inc: Consultancy; LAM Therapeutics: Research Funding; Amgen: Consultancy. Yacoub:Cara Therapeutics: Equity Ownership; Ardelyx, INC.: Equity Ownership; Dynavax: Equity Ownership; Inycte: Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Sardone:Stemline Therapeutics: Employment, Equity Ownership. Wysowskyj:Stemline Therapeutics: Employment, Equity Ownership. Shemesh:Stemline Therapeutics: Employment, Equity Ownership. Chen:Stemline Therapeutics: Employment, Equity Ownership. Olguin:Stemline Therapeutics: Employment, Equity Ownership. Brooks:Stemline Therapeutics: Employment, Equity Ownership. Dunn:Stemline Therapeutics: Employment, Equity Ownership. Verstovsek: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; Celgene: Membership on an entity's Board of Directors or advisory committees. Khoury:Stemline Therapeutics: Research Funding. Pemmaraju:celgene: Consultancy, Honoraria; novartis: Research Funding; Affymetrix: Research Funding; samus: Research Funding; cellectis: Research Funding; daiichi sankyo: Research Funding; stemline: Consultancy, Honoraria, Research Funding; plexxikon: Research Funding; abbvie: Research Funding; SagerStrong Foundation: Research Funding.

Abstract Introduction: PRM-151, a recombinant human pentraxin-2 molecule, has been shown to prevent and reverse fibrosis in animal models of myelofibrosis (MF) by postulated targeting differentiation of fibrocytes (essential cells in fibrotic process) from monocytes. In the first stage of a two-stage trial, 27 patients (pts) with primary myelofibrosis (PMF), post-essential thrombocythemia/polycythemia vera (post-ET/PV) MF, and Grade 2 or 3 bone marrow fibrosis (BMF) received PRM-151 10 mg/kg IV ± ruxolitinib (RUX) for 6 cycles (24 weeks). A reduction in BMF, decrease in symptoms (MPN-SAF Total Symptom Score [TSS]), and a reduction of palpable splenomegaly were observed, along with a favorable safety profile. Pts experiencing clinical benefit were allowed to continue beyond 24 weeks in an open label extension (OLE) study. Here, we report interim efficacy and safety data for 18 pts enrolled in the OLE, who had been treated for up to 35 cycles (140 weeks). Methods: All pts in the OLE received a monthly infusion of PRM-151 10 mg/kg IV. Pts receiving PRM-151 alone or in combination with RUX in the main study continued with their respective drugs. Safety and hematology parameters were assessed monthly, and MPN-SAF TSS Q3 months. BM biopsies were obtained at baseline, end of main study, and at physician discretion in the OLE. These were evaluated centrally by two independent, blinded hematopathologists for the degree of reticulin and collagen fibrosis. Immunostaining for fibrocytes was performed on available biopsies. The primary objective of the OLE was to assess safety and efficacy of long-term administration of PRM-151. Results: Of the 18 pts enrolled in the OLE, 9 received PRM-151 as single agent, and 9 in conjunction with RUX. Baseline characteristics included median age of 66 years (51-78); 8 pts were DIPSS Int-1, 9 Int-2, and 1 high-risk; 6 (33%) had Hgb < 100 g/L, 12 (67%) had PLT < 100 x 109/L; 7 (39%) had PLT <50 x 109/L; 8 pts had PMF, 10 had post-ET/PV MF; 13 pts (72%) had a palpable spleen, and 9 (50%) had Grade 3 BMF. Median time on study for these 18 pts was 30.9 months (15.9-47.2 months). All pts experienced at least 1 adverse event (AE), with 8 pts (44%) reporting a possible study drug-related AE. No unexpected AEs were observed, and no deaths were reported during the study period. The mean best percent change (by palpation) in spleen size from baseline was −37%, with a median percent reduction of −26.1% (Figure). The mean best percent improvement in MPN-SAF TSS was −54%, with a median percent reduction of TSS of −64%. Pts in the PRM-151 monotherapy group showed similar improvements in MPN-SAF TSS and splenomegaly as those receiving PRM-151 + RUX (Figure). Complete data on hematology parameters will be available at the time of presentation. Improvement in BM reticulin grade was observed in 5 of 7 pts (71%) with Grade 2 BMF at baseline, and in 4 of 9 pts (44%) with Grade 3 BMF at baseline. Of the pts with Grade 3 BMF at baseline, 2 of 9 pts (22%) had a 2-grade reduction (Table). In addition, 5 of 6 pts (83%) with Grade 2 collagen fibrosis at baseline had a 1-grade reduction, with 2 of 6 pts (33%) improving to Grade 0. Also, 2 of 7 pts (28%) with Grade 3 collagen fibrosis had a reduction of 1-grade with 1 of 7 (14%) improving to Grade 0 (Table). Eight of 18 pts had BM fibrocyte immunostaining done: mean fibrocyte count in the hematopoietic BM decreased from 378.0 ± 255.3 per mm2 (11.2 ± 7.7% of total cells) at study baseline to 81.3 ± 86.5 per mm2 (2.0 ± 2.1% of total cells; 7 of 8 pts evaluable) at cycle 25, with continuous reduction in fibrocyte numbers observed at interim. Over the same period, improvement in BM reticulin grade was detected in 4 of 7 pts (57%), and collagen fibrosis grade was decreased in 3 of 7 pts (43%). Conclusions: This long-term follow-up study of 18 pts with MF who received PRM-151 for a median of 31 months showed the drug to be well tolerated. An overall improvement in BM reticulin and collagen fibrosis grade, as well as reductions in MPN-SAF TSS and splenomegaly were observed. In a subset of pts for whom bone marrow fibrocyte immunostaining data were available, a mean reduction in fibrocyte counts was observed, as well as improved bone marrow reticulin and collagen fibrosis grade. These data warrant confirmation in a larger controlled study. Figure. Figure. Disclosures Verstovsek: Incyte: Consultancy; 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; Celgene: Membership on an entity's Board of Directors or advisory committees. Pozdnyakova:Promedior, Inc.: Consultancy. Mesa:Promedior: Research Funding; Incyte: Research Funding; Ariad: Consultancy; Novartis: Consultancy; Celgene: Research Funding; Galena: Consultancy; Gilead: Research Funding; CTI: Research Funding. Foltz:Incyte: Research Funding; Promedior: Research Funding; Gilead: Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Mascarenhas:Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Roche: Research Funding; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Promedior: Research Funding. Ritchie:Astellas Pharma: Research Funding; NS Pharma: Research Funding; Pfizer: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; ARIAD Pharmaceuticals: Speakers Bureau; Novartis: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Celgene: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau; Incyte: Consultancy, Speakers Bureau. Palmer:Novartis: Research Funding. Kremyanskaya:Incyte: Research Funding. van den Blink:Promedior, Inc.: Employment. Gupta:Promedior, Inc.: Employment. Gotlib:Deciphera: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Kartos: Consultancy; Promedior: Research Funding; Gilead: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Blueprint Medicines: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding.

Abstract Background: Patients with myelofibrosis (MF) that have failed or are intolerant to JAK inhibitors (JAKi) have no standard treatment options. Tagraxofusp (Elzonris™; SL-401) is a novel targeted therapy directed to the interleukin-3 receptor-α (CD123), a target expressed on a variety of malignancies, including certain myeloproliferative neoplasms (MPNs) such as MF. CD123 is also expressed on plasmacytoid dendritic cells (pDCs), which reside in the tumor microenvironment and may play a role in promoting growth of MPNs and other malignancies. Therefore, targeting of CD123-expressing malignant cells and/or neighboring pDCs may offer a novel therapeutic approach. Tagraxofusp has demonstrated high levels of clinical activity against blastic plasmacytoid dendritic cell neoplasm (BPDCN), a CD123+ malignancy derived from pDCs. Methods: This multicenter, two-stage Phase 1/2 trial is enrolling patients with MF that were relapsed, refractory, or unable to tolerate JAKi. Primary objectives include assessment of safety, determining optimal dose/regimen, and evaluating efficacy outcomes. In the Stage 1 dose escalation cohort (completed), tagraxofusp was dosed as a daily IV infusion at 7, 9, and 12 mcg/kg/day, on days 1-3 every 21 days (cycle 1-4), every 28 days (cycles 5-7), and every 42 days (cycles 8+). In Stage 2 (ongoing), patients received the optimal dose determined in Stage 1 (12 mcg/kg/day). Results: As of July 2018, 18 patients with MF received tagraxofusp. Five patients were treated in the second line setting and 12 patients were treated in third-line setting, and beyond. Median age was 69 years (range 55-81); 60% patients were female. Of the 18 patients with DIPSS Plus risk group assessment available, 3 patients (17%) were intermediate-1, 10 patients (55%) were intermediate-2, and 5 patients (28%) were high-risk. Median platelet count was 66 K/uL (range 15-579). 70% (14/20) of patients had baseline platelets <100K/uL, of which 6 patients had platelets <50K/uL at study entry. 89% (17/19) of patients had baseline splenomegaly defined as palpable spleen 5 cm or more below costal margin (BCM) by physical exam. Most common treatment-related adverse events (TRAEs) include hypoalbuminemia and thrombocytopenia (each 27%), and alanine aminotransferase increased, anemia, dizziness, fatigue, headache and nausea (each 20%). Most common ≥grade 3 TRAEs include anemia (20%) and thrombocytopenia and fatigue (each 7%). Capillary leak syndrome was reported in 1 patient (5%; grade 3). 50% (6/12) of evaluable patients, with baseline spleen size 5 cm or more BCM, had a spleen response, of which 33% (4/12) had splenomegaly reduction by 33% or more and 25% (3/12) had splenomegaly reduction by 35% or more. 50% (3/6) of patients with spleen response had treatment duration 8+ months, including 8+, 12+ and 14+ months (all 3 ongoing). Four patients with baseline thrombocytopenia had treatment durations 8+ months, 3 of which are ongoing. Conclusions: Tagraxofusp monotherapy demonstrated improvements in splenomegaly, with a manageable safety profile, in patients with relapsed/refractory MF, an area of unmet medical need. Given CD123 expression on myeloid neoplastic cells and pDCs in the tumor microenvironment, tagraxofusp may offer a novel targeted approach for MF patients. Enrollment continues, and updated safety and efficacy data will be presented. Registrational designs are being evaluated. Clinical trial information: NCT02268253. Disclosures Pemmaraju: celgene: Consultancy, Honoraria; abbvie: Research Funding; cellectis: Research Funding; stemline: Consultancy, Honoraria, Research Funding; samus: Research Funding; novartis: Research Funding; Affymetrix: Research Funding; SagerStrong Foundation: Research Funding; plexxikon: Research Funding; daiichi sankyo: Research Funding. Gupta:Incyte: Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Schiller:Pharmacyclics: Research Funding; Celator/Jazz Pharmaceuticals: Research Funding. Lee:LAM Therapeutics: Research Funding; AstraZeneca: Consultancy; Clinipace: Consultancy; Karyopharm Therapeutics Inc: Consultancy; Amgen: Consultancy. Yacoub:Ardelyx, INC.: Equity Ownership; Cara Therapeutics: Equity Ownership; Dynavax: Equity Ownership; Inycte: Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Ali:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees. Sardone:Stemline Therapeutics: Employment, Equity Ownership. Wysowskyj:Stemline Therapeutics: Employment, Equity Ownership. Shemesh:Stemline Therapeutics: Employment, Equity Ownership. Chen:Stemline Therapeutics: Employment, Equity Ownership. Olguin:Stemline Therapeutics: Employment, Equity Ownership. Brooks:Stemline Therapeutics: Employment, Equity Ownership. Dunn:Stemline Therapeutics: Employment, Equity Ownership. Verstovsek:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees. Khoury:Stemline Therapeutics: Research Funding.

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

Abstract Since the identification of the JAK family of intracellular tyrosine kinases and their downstream signaling partners, the STATs (Signal Transducers and Activators of Transcription), evidence has accumulated that activation of JAK signaling pathways can contribute to proliferation and survival of cancer cells. A direct link to oncogenesis was made when an activated form of JAK2 (JAK2 V617F) was identified in the majority of patients with myeloproliferative disorders (MPDs) including approximately half of patients with myelofibrosis (MF). Introduction of this JAK2 mutation into the bone marrow of mice induced erythrocytosis [Wernig et al. (2006) Blood107:4274] supporting JAK2 as a relevant target for treatment of myeloproliferative disorders. We have identified a novel small molecule inhibitor of JAK2, XL019, which may prove to have utility in treating MPDs. XL019 is a potent and reversible inhibitor of the JAK2 enzyme, with a Ki of 2 nM, and shows excellent selectivity (minimum of 50-fold selectivity against >120 protein kinases tested including other JAK family members). XL019 downregulates STAT signaling in cell lines expressing both wild type and activated forms of JAK2. IC50s for inhibition of STAT5 phosphorylation by XL019 ranged from 623 nM (HEL92.1.7) to 3398 nM (KG-1) in tumor cell lines. XL019 showed increased potency in primary human erythroid cells in vitro, where the IC50 for inhibition of EPO-stimulated phospho-STAT5 was 64 nM. XL019 inhibits proliferation in cell lines harboring activated or overexpressed JAK2, including certain lines derived from patients with Hodgkin’s Lymphoma (L-1236, 928 nM IC50), AML (MV4-11, 992 nM IC50), essential thrombocythemia (SET-2, 386 nM IC50), and erythroleukemia (HEL92.1.7, 6777 nM IC50). Preclinical single-dose pharmacodynamic studies demonstrate a potent effect of XL019 on JAK-STAT signaling in HEL92.1.7, CFPAC-1 and DU 145 xenograft tumors. Twice daily dosing (bid) led to substantial tumor growth inhibition in the DU145 and HEL models (maximum tumor growth inhibition of 86% and 60%, respectively), accompanied by increases in tumor cell apoptosis (4 – 4.4 fold increase) and decreases in tumor microvasculature (44% reduction in DU 145 xenograft tumors). Based on these encouraging data, XL019 is being evaluated in subjects with primary or post PV/ET MF in a Phase I dose escalation study, which has completed enrollment of the first cohort. The primary objectives of this study are to determine the safety and tolerability of XL019 when administered orally once daily for 21 days in 28 day cycles. Secondary objectives include determination of the pharmacokinetics and pharmacodynamics of XL019, and to evaluate response using the International Working Group for MF consensus response criteria. We have developed a flow-based mechanistic assay for JAK2 activity, which measures GM-CSF-stimulated phospho-STAT5 in peripheral granulocytes in whole blood samples. Additional pharmacodynamic assessments for this study include JAK2 V617F allele burden, erythropoietin-independent colony formation, cytokine levels, and changes in bone marrow histology. Our initial findings regarding the pharmacokinetics, pharmacodynamics, tolerability and efficacy of XL019 in MF patients will be presented.

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 2814 Background: The majority of primary and secondary MF, PV, and ET neoplasms are characterized by gain-of-function activation of JAK2 V617F/STAT5 signaling. Given that wild-type JAK2 plays a pivotal role in multiple stages of hematopoiesis it is desirable to treat JAK2 V617F-positive cases by selectively inhibiting JAK2 V617F while minimizing inhibition of wild-type JAK2 in order not to impede normal marrow function. In murine MPN models and in vitro cell based assays, a novel JAK2 inhibitor, LY2784544, demonstrates selective inhibition of JAK2 V617F/STAT5 signaling and mutant cell proliferation (Ma et al. Abstract 4087 ASH 2010). These results provided the basis for the LY2784544 Phase I trial in MF, PV, and ET patients (I3X-MC-JHTA, NCT01134120). Methods: The primary objectives are to determine the safety and tolerability of LY2784544 and define a recommended oral daily dose for further study in patients with JAK2 V617F-positive MF, ET, or PV. Secondary objectives include determination of pharmacokinetics and evaluation of response using the IWG-MRT response criteria, European Leukemia Net response criteria for PV and ET (EULN), and symptom burden using the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) (Scherber et. al. Blood 2011). The study has a standard 3+3 dose-escalation design to define the maximum tolerated dose (MTD). The study was recently amended to allow cohort expansions at lower than MTD doses demonstrating potential clinical merit. Results: To date, 19 patients have been treated: 1 PV, 1 post-ET MF, and 17 MF patients. Four patients discontinued therapy, 1 for each of the following: Adverse Event, progressive disease, investigator decision, and subject's decision. Reported drug-related serious adverse events were seen in 4 patients, and include: creatinine increase (n=4 grade 2), hyperuricemia (2 grade 4), and hyperkalemia (1 grade 1). All resolved within 14 days with temporary treatment interruption. Analysis of collected laboratory studies using the definitions of Cairo and Bishop (BJH 2004, 2010) demonstrated that 1 instance of laboratory tumor lysis syndrome (LTLS) and 3 instances of Grade 2 clinical tumor lysis syndrome (CTLS) occurred. Hyperuricemia and creatinine increases in cases of TLS were reported as dose-limiting toxicities at 240 and 200 mg with 1 and 3 instances at each respective dose. The most frequently reported drug-related AEs across all grades were diarrhea (3 grade 2, 5 grade 1), nausea (3 grade 2, 4 grade 1), transient increased creatinine (4 grade 2), anemia (3 grade 2, 1 grade 1), and hyperuricemia (2 grade 4). A palpable spleen length reduction of at least 35% was seen in 13 of 17 evaluable patients (76% including 16 MF and 1PV). A partial response by EULN for PV involving 100% reduction in spleen size was observed for >10 months. In MF, 7 patients had a ≥50% reduction, including 4 with sufficient stability or duration of follow-up to qualify as a clinical improvement by IWG-MRT. After 5 cycles of therapy, a reduction in bone marrow fibrosis grade was observed in 3 of the 5 MF patients for whom follow-up biopsy results are available. Using the MPN-SAF questionnaire, patients reported improvements in symptom burden within the first 2 cycles of therapy. Fifty-nine percent (59%) reported a ≥50% improvement in the Key MPN Related Symptoms, and 47% reported a ≥50% improvement in the categories of Fatigue-Enjoyment of Life, Fatigue-Walking Ability, itching, and early satiety. A similar level of improvement was reported by 65% of patients for inactivity, while 35% had improvements in bone pain and night sweats. At tested doses, a reduction in mutant allele burden has not been observed. Conclusions: An MTD for daily dosing of LY2784544 was identified as 120 mg. Based on PK analysis, exposure from doses associated with TLS appear to overlap the lower boundary of the predicted biologically efficacious dose (BED) range established in murine JAK2 V617F models. To allow testing of doses within the BED, the dosing regimen has been amended to include a lower dose lead-in period, intended to reduce tumor burden, prior to further testing of dose escalation. This trial amendment will also further evaluate the bone marrow fibrosis response. Disclosures: Verstovsek: Eli Lilly: Research Funding. Off Label Use: Study of LY2784544 - Purpose is to present results of a study. Mesa:NS Pharma: Research Funding; Astra Zeneca: Research Funding; SBio: Research Funding; Lilly: Research Funding; Incyte: Research Funding; Celgene: Research Funding. Kloeker Rhoades:Eli Lilly: Employment, Equity Ownership. Giles:Eli Lilly: Employment, Equity Ownership. Pitou:Eli Lilly: Employment, Equity Ownership. Jones:Eli Lilly: Employment, Equity Ownership. Walgren:Eli Lilly: Employment, Equity Ownership.