Gotlib, Jason

Eosinophilic disorders and related syndromes represent a heterogeneous group of neoplastic and nonneoplastic conditions, characterized by more eosinophils in the peripheral blood, and may involve eosinophil-induced organ damage. In the WHO classification of myeloid and lymphoid neoplasms, eosinophilic disorders characterized by dysregulated tyrosine kinase (TK) fusion genes are recognized as a new category termed, myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA , PDGFRB or FGFR1 or with PCM1-JAK2 . In addition to these aforementioned TK fusion genes, rearrangements involving FLT3 and ABL1 genes have also been described. These new NCCN Guidelines include recommendations for the diagnosis, staging, and treatment of any one of the myeloid/lymphoid neoplasms with eosinophilia (MLN-Eo) and a TK fusion gene included in the 2017 WHO Classification, as well as MLN-Eo and a FLT3 or ABL1 rearrangement.

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]

Introduction: Approximately two-thirds of patients with primary or post-essential thrombocythemia/polycythemia vera myelofibrosis (MF) have anemia, many of whom require red blood cell (RBC) transfusions. In this heavily transfused population there are severely limited treatment options; effective treatment for anemia in MF is a critically unmet medical need. Luspatercept is a first-in-class erythroid maturation agent which binds to select TGF-β superfamily ligands to reduce aberrant Smad2/3 signaling and enhance late-stage erythropoiesis. Here we report the interim results of the ongoing open-label, phase 2 trial evaluating luspatercept in patients with MF and anemia. Methods: Seventy-four patients with MF and anemia were enrolled, including 41 not receiving concomitant ruxolitinib at study entry who received either no RBC transfusions (n = 20; Cohort 1) or 2-4 RBC U/28 d in the 12 wks prior to treatment (n = 21; Cohort 2). Thirty-three enrolled patients were receiving a stable dose of ruxolitinib for at least 16 wks, of which 14 were not receiving RBC transfusions (Cohort 3A) and 19 were (Cohort 3B). Patients in Cohorts 3A and 3B received a median dose of ruxolitinib of 20 mg/d (range, 5-50 mg/d) for a median of 41 and 43 wks, respectively. Patients received luspatercept every 21 d at a starting dose of 1.0 mg/kg in doses escalating up to 1.75 mg/kg. The primary endpoint in patients not receiving transfusions was a hemoglobin (Hb) increase ≥ 1.5 g/L at every assessment from baseline for ≥ 12 consecutive wks, within the first 24 wks on study. In patients receiving RBC transfusions, the primary endpoint was RBC transfusion-independence (RBC-TI) for ≥ 12 consecutive wks, within the first 24 wks on study. Additional endpoints included proportion of patients achieving mean Hb increase ≥ 1.5 g/dL in Cohorts 1 and 3A, and ≥ 50% decrease in RBC transfusions (minimum 4 RBC U decrease from baseline) in Cohorts 2 and 3B, with both responses lasting ≥ 12 consecutive wks, within 24 wks of study entry. Intent-to-treat (ITT) data were analyzed as of May 10, 2019. Results: Median age was 71 y (range, 50-88 y) and 42 (57%) were male. Median interval from MF diagnosis to study entry was 3.3 y (range, 19 d-13.5 y). Seven patients were Dynamic International Prognostic Scoring System (DIPSS) intermediate-1, 58 were intermediate-2, and 8 were high risk. Median Hb concentration at study entry was 8.8 g/dL (range, 6.7-9.8 g/dL) for Cohort 1 and 8.6 g/dL (range, 6.7-9.1 g/dL) for Cohort 3A. Patients in Cohort 2 received a median of 2.7 RBC U/28 d (range, 1-5 U/28 d) and patients in Cohort 3B received a median of 2.3 RBC U/28 d (range, 2-4 U/28 d). Patients received a median of 8 cycles of luspatercept (range, 1-24 cycles). Efficacy data are displayed in the Table, per ITT data. Two of twenty (10%) and 3/14 (21%) patients in Cohorts 1 and 3A, respectively, achieved an absolute Hb increase ≥ 1.5 g/dL at every measurement from baseline over any consecutive 12 wks. Two of twenty-one (10%) and 6/19 (32%) patients in Cohorts 2 and 3B, respectively, achieved RBC-TI over any consecutive 12 wks. Median duration of Hb response was 20 wks (range, 12-27 wks) in Cohort 1 and 12 wks (range, 12-13 wks) in Cohort 3A. Median duration of RBC-TI was 23 wks (range, 16-31 wks) in Cohort 2 and 32 wks (range, 12-65 wks) in Cohort 3B. Three (15%) and 8 (57%) patients in Cohorts 1 and 3A, respectively, achieved a mean Hb increase of ≥ 1.5 g/dL. Eight (38%) and 10 (53%) patients in Cohorts 2 and 3B, respectively, achieved a ≥ 50% reduction in RBC transfusion burden from baseline. Ruxolitinib exposure remained stable throughout the 24-wk treatment period in both Cohorts 3A and 3B. There was no difference in spleen size between responders and non-responders. Four (5%) patients had grade 3-4 treatment-related adverse events (AEs). There were no treatment-related deaths. Treatment-related AEs occurring in ≥ 3% of patients were hypertension (11%), bone pain (8%), and diarrhea (4%). Seven (9%) patients had ≥ 1 AE resulting in treatment discontinuation; 23 (31%) remain on study. Conclusions: The initial results from this ongoing study suggest clinically significant activity of luspatercept in patients with MF-associated anemia, including those receiving concomitant ruxolitinib. A minority of AEs were grade 3-4 in severity, consistent with previous studies in MDS and beta-thalassemia. Disclosures Gerds: CTI Biopharma: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Pfizer: Consultancy; Imago Biosciences: Research Funding; Roche: Research Funding; Celgene Corporation: Consultancy, Research Funding; Sierra Oncology: Research Funding. Vannucchi:Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; CTI: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Passamonti:Roche: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene Corporation: Consultancy, Speakers Bureau. Kremyanskaya:La Jolla: Consultancy; Incyte, Celgene, Constellation, Protagonist.: Research Funding. Gotlib:Celgene Corporation: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Promedior: Consultancy, Research Funding; Kartos: Consultancy, Honoraria, Research Funding; CTI Biopharma: Research Funding. Ribrag:BMS: Membership on an entity's Board of Directors or advisory committees; AZ: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; argenX: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; Infinity: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Epizyme: Honoraria, Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees. Mead:Celgene: Consultancy, Research Funding; CTI: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel/accommodation expenses, Research Funding, Speakers Bureau; Bristol Myers-Squibb: Consultancy; Pfizer: Consultancy. Harrison:Sierra Oncology: Honoraria; Gilead: Speakers Bureau; CTI: Speakers Bureau; Roche: Honoraria; Promedior: Honoraria; Janssen: Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Incyte: Speakers Bureau; Celgene: Honoraria, Speakers Bureau; AOP: Honoraria; Shire: Speakers Bureau. Mesa:Shire: Honoraria; Promedior: Research Funding; Genotech: Research Funding; Novartis: Consultancy, Honoraria, Other: travel, accommodations, expenses; LaJolla: Consultancy; AbbVie: Research Funding; NS Pharma: Research Funding; CTI: Research Funding; Gilead Sciences: Research Funding; Samus: Research Funding; Baxalta: Consultancy; Galena Biopharma: Consultancy; Celgene Corporation: Research Funding; Sierra Oncology: Consultancy; PharmaEssentia: Research Funding; Genentech: Consultancy; Pfizer: Research Funding; AOP Orphan Pharmaceuticals: Honoraria, Other: travel, accommodations, expenses; Incyte: Other: travel, accommodations, expenses, Research Funding. Kiladjian:AOP Orphan: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene: Consultancy. Gale:Celgene Corporation: Employment. Laadem:Celgene Corporation: Employment, Equity Ownership. Pariseau:Celgene Corporation: Employment. Gerike:Celgene Corporation: Employment. Zhang:Celgene Corporation: Employment, Equity Ownership. Linde:Abbott Laboratories, Inc.: Equity Ownership; Acceleron Pharma: Employment, Equity Ownership; Fibrogen, Inc.: Equity Ownership. Reynolds:Acceleron Pharma: Employment, Equity Ownership. Verstovsek:Gilead: Research Funding; NS Pharma: Research Funding; Celgene: Consultancy, Research Funding; Promedior: Research Funding; CTI BioPharma Corp: Research Funding; Genetech: Research Funding; Blueprint Medicines Corp: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Research Funding; Pharma Essentia: Research Funding; Astrazeneca: Research Funding; Ital Pharma: Research Funding; Protaganist Therapeutics: Research Funding; Constellation: Consultancy; Pragmatist: Consultancy; Roche: Research Funding; Incyte: Research Funding. OffLabel Disclosure: Luspatercept is an investigational therapy that is not approved for any use in any country. Luspatercept is currently being evaluated for potential use in patients with anemia due to myelodysplastic syndromes, beta-thalassemia, or myelofibrosis.

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 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 Myeloproliferative disorders (MPDs), diagnosed in 15,000 individuals annually, are characterized by overproduction of lineage-committed blood cells, thrombotic events, occasionally marrow fibrosis or progression to acute myelogenous leukemia and frequently a point mutation (V617F) in the JAK2 kinase. Mutant JAK2 expression results in erythrocyte overproduction in almost all cases of polycythemia Vera (PV). We investigated the molecular mechanisms driving erythroid skewed differentiation and the capacity of a selective JAK2 inhibitor (TG101348) to normalize PV progenitor differentiation. Both JAK2 V617F+ transduced cord blood and PV progenitor erythroid colony formation was potently inhibited by TG101348 (300 nM). Bioluminescent immunocompromised mouse transplantation studies revealed that TG101348 (150 mg/kg) treatment significantly reduced human erythroid engraftment by both PV and JAK2 V617F+ cord blood progenitors. Moreover, the imbalance between GATA-1 and PU.1 transcripts typical of JAK2 V617F+ progenitors normalized after treatment with TG101348. In addition, TG101348 inhibited both JAK2-mediated STAT5 phosphorylation and AKT-regulated GATA-1 phosphorylation in an erythropoietin responsive cell line suggesting a dual mechanism for the erythroid inhibitory effects of TG101348. Because of selective inhibition of JAK2 V617F+ progenitors both in vitro and in vivo, TG101348 may be an effective molecularly targeted inhibitor of JAK2 V617F+ driven MPDs in clinical trials.

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

Abstract Background: The recent discovery of JAK2V617F, as an activating mutation in the majority of patients with myeloproliferative neoplasms, has spurred development of JAK2-selective small molecule inhibitors for the treatment of these diseases. TG101348 is a potent (enzyme IC50=3 nM) and selective (35- and 334-fold selectivity over JAK1 and JAK3, respectively) orally bioavailable JAK2 inhibitor that is effective in treating a murine model of Polycythemia vera (PV) (Cancer Cell. 2008 13:311). TG101348 selectively inhibits growth of hematopoietic colonies harboring V617F, MPLW515K, or JAK2 exon 12 mutations (Leukemia. 2008 Mar 20, Epub). Methods: A Phase I dose-escalation study of TG101348 is ongoing for patients with high- or intermediate-risk (with symptomatic disease) primary myelofibrosis (PMF) and post-PV or post-essential thrombocythemia (ET) myelofibrosis (Cancer.2007109:2083). TG101348 was administered orally once daily in 28-day cycles in cohorts of at least 3 patients. Additional eligibility criteria included absolute neutrophil count of ≥1 × 109/L and platelet count of ≥50 × 109/L, but a JAK2 mutation was not required. Primary objectives were determination of safety and tolerability, as well as pharmacokinetic behavior of TG101348. The secondary objectives were evaluation of treatment response (Blood.2006108:1497), pharmacodynamic activity, and drug effect on V617F allele burden and plasma cytokine levels. The spleen response was documented as change in palpable spleen tip from the costal margin. For patients achieving less than a complete remission after 3 cycles of treatment at their initial dose, step-wise escalation was permitted at each cycle if a cohort had been shown to have tolerated that dose. Results: Fifteen patients (9 males; median age=66 years; range=53 to 79 years) have been enrolled in the study to date – 10 with PMF (8 V617F+) and 5 with post-PV MF (all V617F+). The median follow-up to date is 13 weeks (range 1–28). Treatment was discontinued in 1 patient, in cohort 1, on the 2nd day of dosing after it was discovered that the patient had baseline QTcF prolongation (Grade 1). In the remaining 14 patients, no dose-limiting toxicities or other significant non-hematological adverse events have been observed to date. The pharmacokinetic parameters of TG101348 in plasma were well characterized following single daily oral doses of 30 mg, 60 mg, 120 mg or 240 mg. Dose-proportional pharmacokinetics were observed following single and multiple doses of TG101348. Treatment response data are as follows: Cohort 1 (starting dose=30 mg; 3 patients; median follow-up=26 weeks): 2 of the 3 patients had improvement in constitutional symptoms including fatigue, night sweats and pruritus. No other benefits were noted. These patients have now been dose escalated to either 120 or 240 mg/day. Cohort 2 (starting dose=60 mg; 3 patients; median follow-up=18 weeks): 1 patient had a 40% decrease in spleen size (18 to 10 cm). All 3 patients have now been dose escalated to 120 or 240 mg/day. Cohort 3 (starting dose=120 mg; 3 patients; median follow-up=13 weeks): 2 of the 3 patients reported improvement in constitutional symptoms including fatigue, night sweats, and pruritus. 1 patient had a 25% decrease in spleen size (28 to 21 cm). 2 patients have been dose escalated to 240 mg/day. Cohort 4 (starting dose=240 mg; 3 patients; median follow-up=8 weeks): 1 patient developed Grade 3 anemia (baseline Grade 1) at the end of the first cycle. 1 patient reported decreased fatigue. All 3 patients have experienced a 20 to 53% reduction in spleen size; baseline measurements were 10, 13, and 17 cm. Cohort 5 (starting dose=360 mg; 2 patients; median follow-up=1 week). Both patients had decreased splenomegaly within 1 week of therapy, including 1 with disappearance of palpable splenomegaly from a baseline of 20 cm; this patient also reported significant improvement in constitutional symptoms. Conclusions: Preliminary findings indicate that TG101348 is well tolerated in patients with myelofibrosis. Although it is too early to make valid conclusions, a decrease in spleen size has been noted at higher dose levels. Similarly, improvement in constitutional symptoms has been reported by some patients. Updated results on current and future patients, including data on pharmacokinetics, pharmacodynamics, and changes in V617F allele burden and plasma cytokine levels will be presented at the meeting.

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

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