Abstract: Context: Kisspeptin, the endogenous ligand of the G protein-coupled receptor 54, is a key regulator of the hypothalamo-pituitary-gonadal (HPG) axis. GPR54-null mice exhibit reproductive dysfunction, and exogenous kisspeptin potently stimulates the HPG axis in rodents, primates, and human males. The effects of kisspeptin administration to human females are unknown. Objective: Our objective was to investigate the effects of kisspeptin on LH release during the menstrual cycle in female volunteers. Design: Bolus sc kisspeptin-54 was administered to female volunteers, and plasma gonadotropins were measured. Setting: The study took place at a hospital clinical research facility. Volunteers: Subjects were healthy female volunteers with regular menstrual cycles. Intervention: 1) Volunteers received a sc bolus injection of kisspeptin-54 (0, 0.2, 0.4, 0.8, 1.6, 3.2, and 6.4 nmol/kg; n = 3–4 per dose) in the follicular phase; and 2) volunteers (n = 8) received a sc bolus injection of either kisspeptin-54 (0.4 nmol/kg) or saline in random order during each phase of the menstrual cycle. Main Outcome Measures: Plasma gonadotropins were measured. Results: 1) Kisspeptin-54 caused a dose-dependent increase in mean LH over time at doses from 0.2–6.4 nmol/kg. 2) Kisspeptin-54 increased plasma LH compared with saline injection in all phases of the cycle. The effect of kisspeptin was greatest in the preovulatory phase and least in the follicular phase of the cycle [mean increase in LH over baseline (IU/liter) ± sem for follicular phase was 0.12 ± 0.17; preovulatory phase, 20.64 ± 2.91 (P & lt; 0.001 vs. follicular phase); luteal phase, 2.17 ± 0.79 (P & lt; 0.01 vs. follicular phase)]. Conclusion: Elevation of plasma kisspeptin in human females potently stimulates LH release in the preovulatory phase and provides a novel mechanism for manipulation of the HPG axis in women.

Abstract: Introduction: Hepatic VOD/SOS is a potentially life-threatening complication of HCT. VOD/SOS with multiorgan dysfunction/multiorgan failure (MOD/MOF) is associated with a mortality rate & gt;80% if untreated. DF is approved for VOD/SOS with renal or pulmonary dysfunction post-HCT in the US and for severe VOD/SOS post-HCT in pts aged & gt;1 month in the EU. A recent meta-analysis of & gt;1000 pts, including a phase 3 trial in high-risk pediatric pts, reported a significantly lower risk of VOD/SOS with prophylactic DF vs controls. This phase 3 study compared the efficacy and safety of DF vs BSC for prevention of VOD/SOS in pts undergoing HCT and at high risk of developing VOD/SOS. Methods: This study (NCT02851407) enrolled pts aged & gt;1 month, who were scheduled to undergo allogeneic (adult/pediatric pts) or autologous HCT (pediatric pts) and at high risk of developing VOD/SOS. High-risk pts underwent myeloablative conditioning (MAC) and had ≥1 hepatic-related EBMT risk factor or advanced-stage neuroblastoma. Very high-risk pts had osteopetrosis or hemophagocytic lymphohistiocytosis (or related disorder) and were undergoing MAC, or had received prior treatment with an ozogamicin-containing monoclonal antibody, or had class III high-risk thalassemia. Pts receiving rapamycin for GvHD prophylaxis were not included as a pre-specified high-risk group. Eligible pts were randomized 1:1 to DF prophylaxis (IV DF 25 mg/kg/day for up to 21 days + BSC) or BSC per institutional guidelines. VOD/SOS was diagnosed using modified Seattle criteria by investigators and evaluated by an Endpoint Adjudication Committee (EPAC) using a prespecified, blinded algorithm. Pts who developed VOD/SOS were treated with DF until resolution of VOD/SOS and related MOD/MOF. The primary endpoint was VOD/SOS-free survival by Day 30 post-HCT, as assessed by EPAC. Secondary endpoints included VOD/SOS-free survival by Day 100 post-HCT and incidence of VOD/SOS by Day 30. Investigator-assessed VOD/SOS-free survival by Day 30 post-HCT is also reported. Results: Overall, 372 pts were enrolled: 190 in the DF group (median age [range]: 13.0 [0, 72] years) and 182 in the BSC group (median age [range]: 15.0 [0, 69] ). Common primary diseases included acute lymphoblastic leukemia (26% vs 28%, respectively), acute myeloid leukemia (27% vs 24%) and neuroblastoma (14% vs 17%). Per EPAC, Kaplan-Meier (KM)-estimated VOD/SOS-free survival by Day 30 was similar in the DF and BSC groups (primary endpoint: 67% [95% Cl: 58, 74%] vs 73% [95% Cl: 62, 80%] , respectively; P = 0.85) and at Day 100 (50% [95% Cl: 26, 70%] vs 57% [95% Cl: 37, 73%] ; nominal P = 0.81). The KM-estimated investigator-assessed VOD/SOS-free survival by Day 30 was 85% (95% Cl: 79, 90%) in the DF group and 80% (95% Cl: 73, 86%) in the BSC group (hazard ratio = 0.760 [95% CI: 0.450, 1.29]; nominal P = 0.14). EPAC and investigators were discordant in 28% of VOD/SOS assessments. By Day 30 post-HCT, EPAC had diagnosed VOD/SOS more frequently in both groups vs investigators. There were 50 pts diagnosed with VOD/SOS by EPAC but not by investigators; 4 pts were diagnosed with VOD/SOS by investigators but not EPAC. In the DF and BSC groups, a comparable percentage of pts (99% and 100%, respectively) had adverse events (AEs); the most common ( & gt;50% of pts) were pyrexia (61% and 64%), nausea (60% and 56%), diarrhea (58% and 61%), stomatitis (58% and 67%) and vomiting (57% and 52%). Serious AEs (SAEs) occurred in 45% and 43% of pts in the DF and BSC groups, respectively; AEs/SAEs reflected HCT. Incidence of AEs of special interest (AESI) were similar between the DF and BSC groups (hypersensitivity reactions [50% and 45%, respectively] , pulmonary hemorrhage [24% and 26%] and GI bleeding [9% and 8%] ). AEs leading to death occurred in 6% of pts in each group. Conclusions: No significant difference was observed between the DF-treated and BSC groups in the primary endpoint, as assessed by EPAC; secondary endpoints were consistent with this result. A comparable percentage of pts had AEs, SAEs, and AESIs, supporting the safety of DF in this setting. No new safety signals were identified. Substantial differences between EPAC and investigators' assessment of VOD/SOS highlight the challenges in VOD/SOS diagnosis and confound interpretation of these results. Potential differences between the trial population and current clinical practice, including limited representation of some at-risk groups, may further limit interpretation of these data. Disclosures Grupp: Novartis, Adaptimmune, TCR2, Cellectis, Juno, Vertex, Allogene and Cabaletta: Other: Study steering committees or scientific advisory boards; Novartis, Roche, GSK, Humanigen, CBMG, Eureka, and Janssen/JnJ: Consultancy; Novartis, Kite, Vertex, and Servier: Research Funding; Jazz Pharmaceuticals: Consultancy, Other: Steering committee, Research Funding. Corbacioglu: Gentium/Jazz Pharmaceuticals: Consultancy, Honoraria. Kang: Amgen Korea: Membership on an entity's Board of Directors or advisory committees, Research Funding; Cartexell: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Korea: Membership on an entity's Board of Directors or advisory committees, Research Funding. Teshima: Merck Sharp & Dohme: Membership on an entity's Board of Directors or advisory committees; CHUGAI PHARMACEUTICAL CO., LTD.: Research Funding; Novartis International AG: Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Pfizer Inc.: Honoraria; Takeda Pharmaceutical Company: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kyowa Kirin Co.,Ltd.: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; Janssen Pharmaceutical K.K.: Other; Gentium/Jazz Pharmaceuticals: Consultancy; Fuji pharma CO.,Ltd: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Astellas Pharma Inc.: Research Funding; TEIJIN PHARMA Limited: Research Funding; Sanofi S.A.: Research Funding. Zanette: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Lopez: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Amber: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Pagliuca: Gentium/Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead, Pfizer, and MSD: Research Funding. Richardson: Sanofi: Consultancy; Celgene/BMS: Consultancy, Research Funding; Secura Bio: Consultancy; Oncopeptides: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; AstraZeneca: Consultancy; Protocol Intelligence: Consultancy; GlaxoSmithKline: Consultancy; Regeneron: Consultancy; Takeda: Consultancy, Research Funding; Janssen: Consultancy; AbbVie: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding. OffLabel Disclosure: Defibrotide is indicated for the treatment of VOD/SOS but not its prevention

Abstract: Introduction Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is an unpredictable, potentially life-threatening complication of chemotherapy (CT) given as conditioning for hematopoietic stem cell transplantation (HSCT), or as primary treatment. Severe hepatic VOD/SOS, traditionally defined by occurrence of multi-organ dysfunction/failure (MOD/MOF), may be associated with mortality rates 〉 80%. In the European Union, defibrotide is approved for treatment of severe VOD/SOS post-HSCT. It is not approved in the United States, but is available through an expanded-access program. Here, we report the results of an Italian therapeutic use program, defibrotide treatment protocol (TUT), in which defibrotide was provided upon physician request for treatment of patients with VOD/SOS. Methods This was a multicenter, single-arm, open-label program of defibrotide treatment in patients with hepatic VOD/SOS, with or without MOD/MOF, from 2010-2014. Patients were eligible if they were diagnosed with VOD/SOS having met ≥2 of the following criteria: bilirubin ( 〉 2 mg/dL), ascites, unexplained weight gain 〉 5% above baseline (weight on day 1 of HSCT conditioning or CT), or hepatomegaly. Patients with biopsy-proven VOD/SOS were also eligible. Exclusion criteria were use of anticoagulants (beyond those for IV line maintenance), significant uncontrolled acute bleeding (transfusions after dialysis were allowed), pregnancy, and hemodynamic instability requiring 〉 2 vasopressor drugs. MOD/MOF was defined as renal (creatinine 〉 3x baseline, creatinine clearance or glomerular filtration rate 〈 40% of baseline, or dialysis dependence) or pulmonary (oxygen saturation 〈 90% on room air, requiring oxygen supplementation, or ventilator dependence) dysfunction. Patients were treated with defibrotide 25 mg/kg/d in 4 divided doses given intravenously over 2 hours each. Outcomes included survival at day +100 post-HSCT or post-CT and adverse events (AEs). VOD/SOS and MOD/MOF were not reported as AEs unless the event was considered serious. Demographics and AEs were analyzed using descriptive statistics; efficacy was estimated by the SAS/STAT LifeTest Procedure. Results A total of 98 patients had hepatic VOD/SOS (92% had VOD/SOS post-HSCT [81% allogeneic, 10% autologous, 1% unknown], 8% post-CT); of these, 21% had MOD/MOF and 79% did not. Median age was 13.4 years (range 0-68; 57 [58%] aged 〈 18 years and 41 [42%] ≥18 years), 55% were male, and 65% were white. The most common primary diseases were acute myelogenous leukemia (25%) and acute lymphoblastic leukemia (19%). The most common prophylaxis regimens for graft-vs-host disease (GvHD) were reported as cyclosporine + methotrexate (38%), cyclosporine (12%), and cyclosporine + methotrexate + other (12%); tacrolimus- and sirolimus-containing regimens, which have been associated with development of VOD/SOS, were received by 5% and 4% of patients, respectively. The median defibrotide dose was 25 mg/kg/d (range, 6.15-40.0) and median duration of treatment was 14 days (range: 1-84). The estimated day +100 survival for all patients was 68.4% (95% CI, 58.0%-76.7%). Day +100 survival in post-HSCT patients was 67.0% (95% CI, 56.2%-75.8%) and for post-CT patients was 85.7% (95% CI, 33.4%-97.9%). Across the entire study, 38 deaths were reported; primary causes were progression of VOD/SOS and MOD/MOF (44.7%), infection (21.1%), GvHD (15.8%), and disease progression (13.2%). Treatment-emergent AEs were reported in 21% of patients in this therapeutic use program; the most common (reported in ≥2 patients) were MOD/MOF (9%), VOD/SOS (6%), and cytomegalovirus infection and acute respiratory distress syndrome (2% each). Treatment-related AEs were reported by 5% of patients, and included hemorrhagic cystitis, urinary tract hemorrhage, hemorrhages (unspecified), hemorrhagic diathesis, and pulmonary hemorrhage (1 patient each). Serious AEs were reported in 15% of patients, most commonly MOD/MOF (7%), VOD/SOS (4%), and acute respiratory distress syndrome (2%). Conclusion In the Italian therapeutic use program, defibrotide treatment protocol (TUT), approximately one-fifth of the patients with hepatic VOD/SOS had MOD/MOF. The estimated survival rate of 68.4% at day +100, and the AE profile, was consistent with efficacy and safety data reported in previous studies in similar VOD/SOS patient populations. Support: Jazz Pharmaceuticals. Disclosures Off Label Use: Defibrotide is an investigational treatment for hepatic veno-occlusive disease/sinusoidal obstruction syndrome in the United States.. Amber:Jazz Pharmaceuticals: Employment, Equity Ownership. Banerjee:Jazz Pharmaceuticals: Employment, Equity Ownership. Finetto:Gentium S.p.A.: Employment; Jazz Pharmaceuticals: Equity Ownership.

Abstract: Chimeric antigen receptor T-cell (CAR-T) therapy is one of the most noteworthy advances in cancer immunotherapy; however, it can be associated with life-threatening neurotoxicity linked to blood-brain barrier disruption and endothelial activation. Defibrotide has been shown to reduce endothelial cell activation in vitro and is approved in the US for treatment of veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) in patients with renal or pulmonary dysfunction post-HCT, and in the EU for treatment of severe VOD/SOS post-HCT in patients aged & gt;1 month. It was hypothesized that defibrotide may stabilize the endothelium during CAR-T therapy and reduce the rate of CAR-T-associated neurotoxicity. This open-label, single-arm, phase 2 study evaluated safety and efficacy of defibrotide for prevention of CAR-T-associated neurotoxicity in patients with relapsed/refractory large B-cell lymphoma receiving axicabtagene ciloleucel. In Part 1, the recommended phase 2 dose (RP2D; 6.25 mg/kg) was established. Overall, 20 patients (from Parts 1 and 2) receiving the RP2D were evaluable for efficacy. The rate of CAR-T-associated neurotoxicity by day 30 (primary endpoint) was ~50%, lower than the 64% reported in ZUMA-1. The median event duration of grade ≥3 neurotoxicity was 7 days. There were no unexpected defibrotide-related safety findings, and no defibrotide-related treatment-emergent adverse events or deaths. Results showed a modest reduction in the rate of CAR-T-associated neurotoxicity and high-grade neurotoxicity event duration relative to historical data; however, the reduction was unlikely to meet the primary endpoint, so the study was terminated early. Nevertheless, results contribute valuable data for potential therapeutic insight on the management of CAR-T-associated neurotoxicity. Trial registration: ClinicalTrials.gov identifier: NCT03954106.