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Abstract Introduction: The clinical phenotype of patients with myeloproliferative neoplasms (MPNs) including primary myelofibrosis (PMF), polycythemia vera (PV), and essential thrombocytosis (ET) who manifest WHO grade 1 (on a 0-3 scale) for intramedullary fibrosis is poorly defined, and may represent MPN patients in a transitional state. We have specifically observed patients with existing PV and ET who manifest clinical progression towards a post PV/ET phenotype (IWG-MRT criteria) yet fail to progress to a 2+ marrow fibrosis. In contrast, the 2008 WHO definition of PMF does not require a minimum fibrosis threshold as long as patients meet the diagnostic criteria. In this study, we retrospectively analyzed the clinical characteristics and outcomes of MPN patients with 1+ marrow fibrosis. Methods: MPN patients with WHO grade 1 (scale 0-3) fibrosis within two institutional databases were identified. The clinical characteristics, laboratory, and outcome data were collected. Data were compared between PMF and PV/ET patients. 2008 IWG-MRT criteria were applied to PV/ET patients with exclusion of fibrosis component. Results: 91 MPN patients with WHO grade 1 fibrosis were identified, PMF in 33 patients (36%), PV in 37 (41%), ET in 20 (22%), and MPN-U in 1 (1%). The population characteristics are reported in Table 1. The majority (56%) of patients exhibited one or more symptoms (weight loss, night sweats, early satiety, bone pain, fatigue). The presence of symptomatic disease was similar between groups, with 52% PMF versus 57% PV/ET exhibiting at least one symptom. Symptoms were more severe in the PMF group with DIPSS risk of intermediate 2 or higher being present in 39%(PMF) versus 29% (PV/ET). Erythrocyte transfusion dependence occurred in a small percentage of overall population (9%), and was seen primarily in the PMF group (6/8 patients). Incidence and severity of splenomegaly was higher in the PMF group, with 55% having splenomegaly versus 43% of the PV/ET group. A higher incidence of a leukoerythoblastic blood smears was seen in PMF (45%) than PV/ET (38%). Two or more prior medical therapies were utilized in 45/90 (49%) of patients, with the most common prior therapies including hydroxyurea (71%), pegylated interferon (28%), anagrelide (18%), Jak inhibitor (13%), lenalidomide (4%), and prednisone (4%). At the time of this analysis, 78/91 patients (86%) were alive. When IWG-MRT criteria were applied to the PV/ET group, 38/58 (66%) of patients fulfilled criteria for diagnosis of post-PV/ET myelofibrosis (except for the 2+fibrosis requirement). Table 1 Patient characteristics UPN Age (yrs) Sex System Risk Activity Tx BRAFV600E (%) 1 56 F Multi High Inactive Yes 0 2 38 F Single High Inactive Yes 0 3 65 F Multi High Active Yes 2.59 4 48 M Single High Inactive Yes 0 5 41 F Single High Inactive Yes 0 6 28 M Multi High Inactive Yes 0 7 29 M Multi High Active No 1.00 8 47 F Multi High Active Yes 6.16 Discussion and Conclusion: PV and ET patients with WHO grade 1 marrow fibrosis manifest a phenotype that suggests progression to post-PV/ET myelofibrosis, and clinically overlap with PMF phenotype; however, these patients currently fail to meet 2008 IWG-MRT diagnostic criteria for this diagnosis on basis of sub-threshold fibrosis. MPN progression represents a biological spectrum and definitions of progression in ET/PV may benefit from other criteria not restricted by degree of fibrosis. Disclosures Mesa: Incyte, CTI, NS pharma, Gilead, Celgene: Research Funding.

Background The presence of a durable left ventricular assist device ( LVAD ) is associated with increased risk of vasoplegia in the early postoperative period following heart transplantation ( HT ). However, preoperative predictors of vasoplegia and its impact on survival after HT are unknown. We sought to examine predictors and outcomes of patients who develop vasoplegia after HT following bridging therapy with an LVAD . Methods and Results We identified 94 patients who underwent HT after bridging with continuous‐flow LVAD from 2008 to 2018 at a single institution. Vasoplegia was defined as persistent low vascular resistance requiring ≥2 intravenous vasopressors within 48 hours after HT for >24 hours to maintain mean arterial pressure >70 mm Hg. Overall, 44 patients (46.8%) developed vasoplegia after HT . Patients with and without vasoplegia had similar preoperative LVAD , echocardiographic, and hemodynamic parameters. Patients with vasoplegia were significantly older; had longer LVAD support, higher preoperative creatinine, longer cardiopulmonary bypass time, and higher Charlson comorbidity index; and more often underwent combined organ transplantation. In a multivariate logistic regression model, older age (odds ratio: 1.08 per year; P =0.010), longer LVAD support (odds ratio: 1.06 per month; P =0.007), higher creatinine (odds ratio: 3.9 per 1 mg/dL; P =0.039), and longer cardiopulmonary bypass time (odds ratio: 1.83 per hour; P =0.044) were independent predictors of vasoplegia. After mean follow‐up of 4.0 years after HT , vasoplegia was associated with increased risk of all‐cause mortality (hazard ratio: 5.20; 95% CI, 1.71–19.28; P =0.003). Conclusions Older age, longer LVAD support, impaired renal function, and prolonged intraoperative CPB time are independent predictors of vasoplegia in patients undergoing HT after LVAD bridging. Vasoplegia is associated with worse prognosis; therefore, detailed assessment of these predictors can be clinically important.

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 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 Background SGI-110 is second generation HMA formulated as a dinucleotide of decitabine (DAC) and deoxyguanosine delivered as a small volume, pharmaceutically stable SQ injection allowing longer half-life and more extended decitabine exposure than DAC IV infusion. SGI-110 differentiated pharmacokinetic profile resulted in potent hypomethylation and clinical responses in previously treated MDS and AML patients in the phase 1 trial (Kantarjian et al. 2012). Methods In a randomized Phase 2 study, relapsed/refractory AML, or elderly treatment naïve AML patients who were not suitable for induction chemotherapy (poor major organ function; poor cytogenetics; or secondary AML) were randomized to one of two SQ doses – the biologically effective dose (BED) of 60 mg/m2 QDx5 or 90 mg/m2 QDx5. The primary endpoint of the phase 2 study is the overall remission rate (CR, CRi, and CRp) based on the International Working Group Criteria 2003. Safety findings based on adverse events (AEs) as graded by the CTCAE v4 criteria and pharmacodynamic data on Long Interspersed Nucleotide Element (LINE-1) DNA methylation (an index of global DNA methylation) activity were also assessed and reported. Results As of June 30, 2013, sixty-seven patients (50 relapsed/refractory AML, 17 treatment naïve elderly AML) were treated and had a minimum follow up of 3 months. Patients were randomized to either 60 mg/m2 dose (32 patients) or 90 mg/m2 dose (35 patients). The median age was 66 years (range, 22–84), 69% were male, and ECOG PS of 0/1/2 was reported in 11/47/9 patients respectively. Median number of prior regimens was 2 (range, 0–10). Patients’ characteristics were well balanced between the 2 dose groups. The primary endpoint of overall remissions (CR, CRp, or CRi) was observed in 17/67 patients (25% with 95% CI, 16–37%). There were 8 complete remissions (CR, CRp, or CRi) in 50 patients with relapsed/refractory AML (16% with 95% CI, 7-29%); and 9 complete remissions (CR, CRp, or CRi) in 17 treatment-naïve elderly AML patients (53% with 95% CI, 28-77%). Five patients (4 relapsed/refractory, and one treatment-naïve elderly AML) subsequently received a stem cell transplant. There was no difference in the complete remission rate between 60 and 90 mg/m2 doses (8 remissions in 32 patients at 60 mg/m2, and 9 remissions in 35 patients at 90 mg/m2). LINE-1 DNA methylation data before and after treatment was available in 50 (75%) patients enrolled. LINE-1 demethylation ≥ 10% post treatment was observed in 83% and 78% in the 60 mg/m2 and 90 mg/m2, respectively. The median maximum LINE-1 demethylation for responders is 25% as compared to 19% for non-responders. The most common adverse events (AEs) regardless of relationship to SGI-110 ≥ Grade 3 include febrile neutropenia, thrombocytopenia, anemia, leukopenia, neutropenia, and pneumonia. The 90 mg/m2 dose showed a greater frequency of Grade 3/4 related AEs ≥ 10% (anemia, febrile neutropenia, leukopenia, neutropenia, and thrombocytopenia) compared to the 60 mg/m2 dose. Conclusions SQ SGI-110 is a new HMA which is well tolerated and clinically active in the treatment of AML. Complete remissions and potent demethylation of ≥10% were equally observed at the 2 dose groups of 60 and 90 mg/m2. These data support further phase 3 investigation of this agent in the treatment of AML. Preliminary overall remission rate of 53% in treatment-naïve elderly AML seems to compare favorably with previous results reported for HMA treatment but this needs to be confirmed in a larger number of patients and randomized studies. Disclosures: Kantarjian: Astex Pharmaceuticals, Inc.: Research Funding. Jabbour:Astex Pharmaceuticals, Inc.: Research Funding. Yee:Astex Pharmaceuticals, Inc.: Research Funding. Kropf:Astex Pharmaceuticals, Inc.: Research Funding. O'Connell:Astex Pharmaceuticals, Inc.: Research Funding. Stock:Astex Pharmaceuticals, Inc.: Research Funding. Tibes:Astex Pharmaceuticals, Inc.: Research Funding. Rizzieri:Astex Pharmaceuticals, Inc.: Research Funding. Walsh:Astex Pharmaceuticals, Inc.: Research Funding. Griffiths:Astex Pharmaceuticals, Inc.: Research Funding. Roboz:Astex Pharmaceuticals, Inc.: Honoraria, Research Funding. Savona:Astex Pharmaceuticals, Inc.: Research Funding. Ervin:Astex Pharmaceuticals, Inc.: Research Funding. Podoltsev:Astex Pharmaceuticals, Inc.: Research Funding. Pemmaraju:Astex Pharmaceuticals, Inc.: Research Funding. Daver:Astex Pharmaceuticals, Inc.: Research Funding. Garcia-Manero:Astex Pharmaceuticals, Inc.: Research Funding. Borthakur:Astex Pharmaceuticals, Inc.: Research Funding. Wierda:Astex Pharmaceuticals, Inc.: Research Funding. Ravandi:Astex Pharmaceuticals, Inc.: Research Funding. Cortes:Astex Pharmaceuticals, Inc.: Research Funding. Brandwein:Astex Pharmaceuticals, Inc.: Research Funding. Odenike:Astex Pharmaceuticals, Inc.: Research Funding. Feldman:Astex Pharmaceuticals, Inc.: Research Funding. Chung:Astex Pharmaceuticals Inc.: Research Funding. Naim:Astex Pharmaceuticals, Inc.: Employment. Choy:Astex Pharmaceuticals, Inc.: Employment. Taverna:Astex Pharmaceuticals, Inc.: Employment. Hao:Astex Pharmaceuticals Inc.: Employment. Dimitrov:Astex Pharmaceuticals, Inc.: Employment. Azab:Astex Pharmaceuticals, Inc.: Employment. Issa:Astex Pharmaceuticals, Inc.: Consultancy, Research Funding.

Abstract Background: SL-401 is a novel targeted therapy directed to the interleukin-3 receptor (CD123), a target overexpressed by many hematologic malignancies. SL-401 is currently being advanced through clinical trials in patients with a variety of CD123+ malignancies including blastic plasmacytoid dendritic cell neoplasm (BPDCN), acute myeloid leukemia (AML) in remission with high relapse risk, and multiple myeloma. CD123 has been shown to be expressed on myeloproliferative neoplasm (MPN) cells as well as microenvironmental immune cells, namely plasmacytoid dendritic cells (pDCs), in the bone marrows of some patients with MPN including chronic myelomonocytic leukemia (CMML). Microenvironmental pDCs have been implicated in promoting plasma cell disorders and preliminary data suggest that pDCs could play a related role in some myeloid neoplasms. Accordingly, a therapy directed at both CD123-expressing myeloid cells and neighboring CD123-expressing pDCs could provide therapeutic benefit. SL-401 is being evaluated in patients with advanced, high-risk MPN, including systemic mastocytosis (SM), myelofibrosis (MF), primary eosinophilic disorders (PED), and CMML. Preliminary results are reported here. Methods & Results: This multicenter, single-arm Phase 2 trial of patients with advanced, high risk MPN includes a lead-in (stage 1) and expansion (stage 2). In stage 1, patients receive SL-401 as a daily IV infusion at 7, 9, 12 ug/kg/day, or higher for days 1-3 of a 21-28 day cycle in a 3x3 design. In stage 2, patients receive SL-401 at the dose determined in stage 1. Study objectives include characterization of the safety profile, including determination of the maximum tolerated or tested dose, and detection of preliminary efficacy signals including evaluation of tumor response and progression free survival by standard criteria. As of 7/20/16, 6 patients with MPN (MF, n=3; CMML-2, n=2; CMML-1, n=1) received SL-401 (7 ug/kg, n=3; 9 ug/kg, n=3). The median age was 66 years (range: 42-81 years). Patients treated at all doses received 1+ to 2+ cycles (ongoing) of SL-401. The most common treatment-related adverse events (AEs) were thrombocytopenia (2/6; 33%) and fatigue (2/6; 33%); the most common ≥ Grade 3 treatment-related AEs were thrombocytopenia (2/6; 33%) and anemia (1/6; 17%); there has been no DLT. Efficacy assessments are ongoing. Patients are currently enrolling in the 12 ug/kg/day cohort. Conclusions: Initial dosing of SL-401 appears to be well-tolerated in patients with MPN and CMML, with no unexpected AEs observed. Given CD123 expression on myeloid neoplastic cells as well as microenvironmental immune cells (namely, pDCs), SL-401 may offer a novel, targeted therapeutic approach in patients with high-risk MPN and CMML of unmet medical need. Enrollment continues in stage 1 of this ongoing Phase 2 trial and updated safety and efficacy data will be presented. Clinical trial information: NCT02268253. Disclosures Gupta: Novartis: Consultancy, Honoraria, Research Funding; Incyte Corporation: Consultancy, Research Funding. Carraway:Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Baxalta: Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees. Schiller:Incyte Corporation: Research Funding. Talpaz:Incyte Corporation: Other: Travel expense reimbursement, Research Funding; Ariad: Other: Expense reimbursement, travel accomodation expenses, Research Funding; Novartis: Research Funding; Pfizer: Consultancy, Other: travel accomodation expenses, Research Funding. McCloskey:Novartis: Speakers Bureau; Incyte: Consultancy; Ariad: Consultancy, Speakers Bureau; Amgen: Speakers Bureau. Lee:Alexion Pharmaceuticals: Consultancy; Amgen: Consultancy; Baxalta: Consultancy; Boehringer Ingelheim: Consultancy; Pfizer Inc: Consultancy. Yacoub:Alexion: Honoraria; Seattle Genetics: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau. Ali:Incyte Corporation: Research Funding. Chen:Stemline Therapeutics, Inc.: Employment, Equity Ownership. Shemesh:Stemline Therapeutics: Employment, Equity Ownership. Brooks:Stemline Therapeutics, Inc.: Employment, Equity Ownership, Patents & Royalties.

Abstract Background: The bone marrow (BM) niche protects acute myeloid leukemia (AML) cells from chemotherapy. BM homing of AML cells is dependent on CXCR4 and its ligand CXCL12; high levels of CXCR4 expression correlate with poor survival in AML. It is postulated that blocking the CXCL12/CXCR4 axis with a potent CXCR4 antagonist will disrupt the interaction of the leukemic blasts with the BM and augment the anti-leukemic effect of chemotherapy. BL-8040 (BKT140) is a short synthetic peptide which inhibits the binding of CXCR4 to CXCL12, resulting in the mobilization of leukemic blasts from the bone marrow to the peripheral blood. BL-8040 also inhibits CXCR4/CXCL12 mediated pro-survival ERK/Akt signaling and alters balance of pro/anti-apoptotic Bcl-2 proteins. BL-8040 has strong affinity for the CXCR4 receptor with long receptor occupancy, and, in contrast to other CXCR4 inhibitors, as a single agent induces apoptosis of leukemia cells ex-vivo in clinical samples. A clinical trial assessing the safety and efficacy of BL-8040 in combination with cytarabine (Ara-C) for the treatment of adult relapsed/refractory AML patients is currently ongoing (NCT01838395). Objective: To assess the safety, efficacy and pharmacodynamics/pharmacokinetic parameters of BL-8040 in combination with Ara-C in first or second relapse and refractory AML patients. Method: The study includes a dose escalation phase (3+3 design) followed by an expansion phase. Each patient receives a once daily SC dose of BL-8040 monotherapy on days 1-2 followed by the same dose of BL-8040 plus Ara-C (1.5 g/m2 for patients ≥60; 3 g/m2 for patients <60) on days 3-7. Five dose levels of BL-8040 (0.5, 0.75, 1, 1.25 and 1.5 mg/kg) have been tested. Extensive pharmacodynamic parameters such as CXCR4 expression on the leukemic cells, receptor occupancy, mobilization of leukemic cells and induction of apoptosis are being assessed after monotherapy with BL-8040 using peripheral blood sampling (PB) and BM aspirates at baseline and on day 3 prior to Ara-C administration. Clinical response to treatment is evaluated by BM biopsy on day 30 (-/+ 2). Results: Twenty two patients (median age, 61 y; range, 43-74 y) with relapsed/refractory AML were treated during the escalation phase. BL-8040 was escalated up to 1.5 mg/kg (recommended phase 2 dose) without reaching the MTD. Combination of BL-8040 with Ara-C was safe and well tolerated at all doses tested. Only one SAE (Sweet Syndrome) was reported as possibly related to study drug. The primary treatment related AEs were transient injection site and systemic reactions. The composite complete remission including complete remission (CR) and complete remission with incomplete blood count recovery (CRi) rate was 38% in subjects receiving BL-8040 doses of 1 mg/kg and higher (n=16). Two days of BL-8040 monotherapy triggered an average 40.2-fold (range 1.0-350.9) mobilization of immature AML progenitors (CD45+Low/CD34+/CD117+/HLA-DR+) from the BM to the PB. Moreover, a significant apoptotic effect on the immature leukemia progenitors in the BM following 2 days of BL-8040 monotherapy was noted. Flow cytometric evidence of apoptosis by BL-8040 was corroborated by an increase in cleaved caspase 3 positive blasts in day 3 bone marrow biopsies. In addition, BL-8040 treatment resulted in a median decrease of 57.7% (range, -10.4% to -96.2%) in the number of BM Leukemia progenitor cells (CD45+Low/CD34+/CD117+/HLA-DR+ out of total CD45+/CD34+ normal/progenitor cells) compared with the baseline biopsy. This decrease was accompanied with a 3.1 fold increase in granulocytes in the day 3 BM biopsy supporting differentiation effect. Finally, long receptor occupancy (up to 24 hours post dosing) was confirmed by FACS analysis measuring surface CXCR4 staining. Pharmacokinetics analysis confirmed dose incremental BL-8040 exposure with a short plasma half-life. Conclusions: The current data demonstrate that sustained blockade of the CXCR4-CXCL12 axis with BL-8040 has potent anti leukemic activity and in combination with Ara-C may improve the response typically achieved in this advanced AML population. Mechanistically, BL-8040 was able to induce apoptosis of leukemic progenitor cells, overcoming the stroma protection, inducing mobilization and differentiation. Disclosures Rowe: BioLineRx Ltd.: Consultancy; Amgen: Consultancy; BioSight Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees. Uy:Novartis: Research Funding. Altman:Seattle Genetics: Consultancy; Novartis: Consultancy; Spectrum: Consultancy; Astellas: Consultancy; Ariad: Consultancy; BMS: Consultancy. Peled:Biokine Ltd.: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; BiolineRX: Consultancy, Research Funding. Pereg:BioLineRx: Employment. Vainstein:BioLineRx: Employment. Aharon:BioLineRx: Employment. Pemmaraju:Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. Cortes:Teva: Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; BerGenBio AS: Research Funding; Novartis: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy.

A 69-year-old man presents with a Dynamic International Prognostic Scoring System (DIPSS) intermediate-risk 2 post polycythemia vera myelofibrosis with significant splenomegaly, 30 pound weight loss, constitutional symptoms, and 2% peripheral blood blasts. He has no other significant past medical history and no other major comorbid conditions. You are asked by the hematology fellow you are supervising whether or not treating this patient with a Janus kinase (JAK) inhibitor will decrease major morbid events.

INTRODUCTION: Nonalcoholic fatty liver disease (NAFLD) has become the most common form of chronic liver disease. Determining the severity of NAFLD using the presence of nonalcoholic steatohepatitis (NASH) and stage of liver fibrosis is important, yet liver biopsy remains the gold standard despite limitations to its use. This study surveyed pediatric gastroenterologists across the United States to determine which guidelines are used to determine the severity of NAFLD in children, which patients undergo liver biopsy, and how these guidelines compare to each other and to clinical practice. METHODS: 140 pediatric gastroenterologists were surveyed electronically regarding current diagnostic practices for NAFLD. Responses were reviewed in Survey Monkey and compared to current North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN), American Association for the Study of Liver Diseases (AASLD) and European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) guidelines regarding liver biopsy for evaluation of NAFLD. RESULTS: 140 surveys were distributed with 54 responses, a 38.6% response rate. Participants included pediatric gastroenterologists, hepatologists and transplant hepatologists. 96.2% reported familiarity with NASPGHAN guidelines, 22.6% with ESPGHAN and 39.6% with AASLD. 88.7% of responders desired a generalized consensus regarding proper diagnosis. Pediatric gastroenterologists referred obese patients with abnormal liver enzymes suspected to have NAFLD 22% of the time, pediatric hepatologists 27.2%, and transplant hepatologists 39.9% (one-way ANOVA with P -value of 0.324). 61.5% of responders reported using Fibroscan and 59.6% used MR elastography to assess severity of NAFLD and presence of liver fibrosis when not pursuing liver biopsy. 92.5% of responders believed the presence of autoimmune antibodies was important in deciding when to proceed to liver biopsy, as well as 88.7% using abnormal screening labs and 75.5% using imaging suggestive of liver fibrosis. CONCLUSION: Comparison between the criteria that providers believed warranted a liver biopsy versus those included in society guidelines differed. The presence of autoimmune antibodies, abnormal screening labs, and liver fibrosis suggested on imaging all appeared to be important factors regardless of current guidelines. Providers also seem to rely on Fibroscan and MR elastography over liver ultrasound despite the lack of validated cutoff values in children.

INTRODUCTION: Options to treat medically refractory gastroparesis are limited. Gastric peroral endoscopic myotomy (G-POEM) is a novel minimally invasive technique in endosurgery that has shown promising results. Data is limited as to its efficacy, safety, predictive factors and its comparability to surgical pyloroplasty. The aim of our study was to synthesize and analyze the clinical outcomes of GPOEM by meta-analysis methods. METHODS: We searched multiple databases from inception through March 2019 to identify studies that reported on G-POEM and surgical pyloroplasty in gastroparesis. Our primary outcome was to analyze the pooled rates of gastroparesis cardinal symptom index (GCSI) score and 4-hr gastric emptying study (GES) results, with G-POEM. Similar outcomes with surgical pyloroplasty was used as a comparator group. RESULTS: 332 and 375 patients underwent G-POEM (11studies) and pyloroplasty (7studies), respectively. The pooled rate of clinical success, based on the GCSI score, with G-POEM was 75.8% (95% CI 68.1-82.1, I 2 = 50) and with pyloroplasty was 77.3% (95% CI 66.4-85.4, I 2 = 0), with no significance, P = 0.81. The pooled rate of clinical success, based on the 4-hour GES results, with GPOEM was 85.1% (95% CI 68.9-93.7, I 2 = 74) and with pyloroplasty was 84% (95% CI 64.4-93.8, I 2 = 81), with no significance, P = 0.91. The pooled rate of mean pre-G-POEM GCSI score was 3.4 (95% CI 3.1-3.7, I 2 = 89) and post-G-POEM GCSI score was 1.8 (95% CI 1.4-2.1, I 2 = 89), with statistical significance ( P = 0.001). The pooled pre-G-POEM 4-hr GES was 49.9% (95% CI 41.6-58.3, I 2 = 94) and post-G-POEM 4-hr GES was 20.6% (95% CI 12.3-28.8, I 2 = 77), with statistical significance ( P = 0.001). The pre and post pyloroplasty 4-hr GES results were 36% (95% CI 32.7-39.3, I 2 = 88) and 3.9% (95% CI 2.3-5.5, I 2 = 43), respectively ( P = 0.001). The pre and post pyloroplasty GCSI score was not analyzed due to paucity in data. The overall adverse events were comparable (11%, 5.9-19.8, I 2 = 66 vs 11.4%, 5-24, I 2 = 69, P = 0.95). Based on meta-regression analysis, idiopathic-gastroparesis, prior treatment with botulinum toxin and gastric-stimulator seemed to predict clinical success with G-POEM. CONCLUSION: G-POEM demonstrates clinical success in treating refractory gastroparesis with comparable outcomes to pyloroplasty. Idiopathic gastroparesis, prior treatment with botulinum injection and gastric stimulator appear to have positive predictive effects on the 4-hr GES results after G-POEM.