Verification of the Prediction Accuracy of a Biomarker-Based Prognostic for Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome (VOD/SOS) After Hematopoietic Cell Transplantation (HCT).

BACKGROUND: Veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of hematopoietic cell transplantation (HCT), especially in severe cases. Patient outcomes are improved with prompt treatment; however, diagnosing this disease is challenging as many clinical symptoms of VOD/SOS overlap with other post-HCT complications. A biomarker-based prognostic test for the assessment of VOD/SOS risk, termed "VODCheck" was developed in a previous study but has not yet been validated. OBJECTIVE: This study aimed to validate the accuracy of VODCheck as a prognostic test for VOD/SOS in an independent cohort of patients. STUDY DESIGN: VODCheck incorporates hyaluronan (HA), angiopoietin-2 (ANG-2), and thrombomodulin (TM) based on their association with VOD/SOS, their analytical characteristics, and their ability to complement each other in a multivariate prognostic model. To validate VODCheck we measured plasma biomarker levels from a subset of patients enrolled in the control arm of a phase 3 study that tested VOD/SOS prophylaxis. We used a hierarchical design with prespecified primary (day 7), secondary A (day 15), and secondary B (day 1) hypotheses to verify the prognostic accuracy of VODCheck post-HCT. The cases of VOD/SOS (n = 22) were age-matched ∼1:3 with controls (n = 65). RESULTS: VODCheck was prognostic of VOD/SOS risk at all 3 time points with an area under the curve (AUC) of .815 (P < .001) for day 7, .836 (P < .001) for day 15, and .706 (P = .002) for day 1 post-HCT. A multivariate analysis confirmed the prognostic accuracy of VODCheck after adjustment for confounders such as age, VOD/SOS risk status, primary disease, and ozogamicin treatment. CONCLUSION: VODCheck was validated as an independent predictor of risk for VOD/SOS within 15 days post-HCT and appears to provide clinicians with actionable information to improve patient care.

A phase 2 trial of defibrotide for the prevention of chimeric antigen receptor T-cell-associated neurotoxicity syndrome.

Chimeric antigen receptor T-cell (CAR-T) therapy represents a major advance in cancer immunotherapy; however, it can be associated with life-threatening neurotoxicity linked to blood-brain barrier disruption and endothelial activation. Defibrotide was shown to reduce endothelial cell activation in vitro and is approved in the United States for treatment of veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) in patients with renal or pulmonary dysfunction after hematopoietic cell transplantation (HCT), and in the European Union for severe VOD/SOS after HCT in patients aged >1 month. Defibrotide may stabilize the endothelium during CAR-T therapy and reduce the rate of CAR-T-associated neurotoxicity. This phase 2 study evaluated the safety and efficacy of defibrotide for prevention of CAR-T-associated neurotoxicity in patients with relapsed/refractory large B-cell lymphoma receiving axicabtagene ciloleucel. Part 1 established the recommended phase 2 dose (RP2D; 6.25 mg/kg); 20 patients (from parts 1 and 2) receiving the RP2D were evaluable for efficacy. Rate of CAR-T-associated neurotoxicity by day 30 (primary end point) was ∼50%, lower than reported in the ZUMA-1 trial (64%). Median event duration of grade ≥3 neurotoxicity was 7 days. No unexpected defibrotide-related safety findings and defibrotide-related treatment-emergent adverse events or deaths were reported. Results showed modest reduction in rate of CAR-T-associated neurotoxicity and high-grade neurotoxicity event duration relative to historical data; however, reduction was unlikely to meet the primary end point, so the study was terminated early. Nevertheless, results contribute valuable data for potential therapeutic insight on the management of CAR-T-associated neurotoxicity. This trial was registered at www.clinicaltrials.gov as #NCT03954106.

Defibrotide plus best standard of care compared with best standard of care alone for the prevention of sinusoidal obstruction syndrome (HARMONY): a randomised, multicentre, phase 3 trial.

BACKGROUND: Sinusoidal obstruction syndrome, also known as veno-occlusive disease, is a potentially life-threatening complication of haematopoietic stem-cell transplantation (HSCT). We aimed to compare defibrotide prophylaxis plus best supportive care versus best supportive care alone for sinusoidal obstruction syndrome prevention after HSCT. METHODS: This open-label, randomised, multicentre, phase 3 trial was done in 104 centres in 14 countries. Patients who were at least 1 month old, were scheduled to receive allogeneic HSCT (adult [aged >16 years] or paediatric [aged >1 month to ≤16 years] patients) or autologous HSCT (paediatric patients only), and were at high risk or very high risk of developing sinusoidal obstruction syndrome were eligible for inclusion. Patients were randomly assigned (1:1) by an interactive web response system to receive intravenous defibrotide 25 mg/kg per day (four equal doses [6·25 mg/kg per dose]) and best supportive care (determined by individual institutional guidelines; defibrotide prophylaxis group) or best supportive care only (best supportive care group). Randomisation was stratified by sinusoidal obstruction syndrome risk, age, and country. The primary endpoint, sinusoidal obstruction syndrome-free survival at day 30 after HSCT, was assessed by an independent Endpoint Adjudication Committee in the intention-to-treat (ITT) population. Safety was assessed in all patients who received protocol treatment. The trial is registered with ClinicalTrials.gov, NCT02851407. FINDINGS: Between Jan 11, 2017, and Oct 20, 2020, 372 patients (172 [46%] women and 200 [54%] men; median age 14·0 years [IQR 4·0-41·0] were randomly assigned to the defibrotide prophylaxis group (n=190) or best supportive care group (n=182; ITT population). On the basis of recommendations from the Independent Data Monitoring Committee following completion of the planned interim analysis in the first 280 recruited patients on April 29, 2020, enrolment was prematurely stopped for presumed futility. At the final analysis, sinusoidal obstruction syndrome-free survival by day 30 after HSCT was 67% (95% CI 58-74) in the defibrotide prophylaxis group and 73% (62-80) in the best supportive care group (HR 1·27 [95% CI 0·84-1·93]; p=0·85). Treatment-emergent adverse events were similar between groups during the randomised prophylaxis phase; most treatment-emergent adverse events were related to the transplantation rather than to study drug. The most common grade 3 or 4 treatment-emergent adverse events were stomatitis (grade 3, 52 [29%] of 181 patients in the defibrotide prophylaxis group and 56 [32%] of 174 patients in the best supportive care group; grade 4, two [1%] in the defibrotide prophylaxis group and two [1%] in the best supportive care group) and febrile neutropaenia (grade 3, 51 [28%] in the defibrotide prophylaxis group and 52 [30%] in the best supportive care group; grade 4, no patients in the defibrotide prophylaxis group and three [2%] in the best supportive care group). Serious treatment-emergent adverse events occurred in 74 (41%) of 181 patients in the defibrotide prophylaxis group and 61 (35%) of 174 patients in the best supportive care group. In the rescue phase, when patients in both treatment groups received defibrotide as rescue treatment, fatal treatment-related adverse events occurred in one (4%) of 25 patients in the defibrotide prophylaxis group (intracranial haemorrhage) and one (3%) of 31 patients in the best supportive care group (sinusoidal obstruction syndrome). INTERPRETATION: Defibrotide did not show a benefit in the prophylaxis of sinusoidal obstruction syndrome. Additional studies of carefully selected patients at high risk of sinusoidal obstruction syndrome after HSCT are warranted. FUNDING: Jazz Pharmaceuticals.

A multicentre, multinational, prospective, observational registry study of defibrotide in patients diagnosed with veno-occlusive disease/sinusoidal obstruction syndrome after haematopoietic cell transplantation: an EBMT study.

Severe hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of haematopoietic cell transplantation (HCT). This multinational, prospective, observational study (NCT03032016), performed by the EBMT, enrolled patients treated with defibrotide from April 2015 to July 2018. This analysis focused on defibrotide-treated patients with VOD/SOS post-HCT. The primary endpoint was incidence of serious adverse events (SAEs) of interest up to 12 months post-HCT in patients with severe VOD/SOS. Overall, 104 defibrotide-treated patients with VOD/SOS post-HCT were enrolled: 62 had severe VOD/SOS and comprised the primary study population, including 36 with multi-organ dysfunction/failure (MOD/MOF). SAEs of interest occurred in 20 of 62 (32%) severe VOD/SOS patients; the most common by category were infection (24%) and bleeding (13%). In patients with severe VOD/SOS, the Kaplan-Meier-estimated Day 100 survival rate was 73% (95% CI: 60%, 82%) with VOD/SOS resolution by Day 100 in 45 of 62 (73%) patients. MOD/MOF resolved in 19 of 36 (53%) patients with MOD/MOF at VOD/SOS diagnosis. Results from this multicentre registry study build on prior defibrotide studies supporting the utility of defibrotide for the treatment of VOD/SOS post-HCT. These results provide additional real-world evidence of the effectiveness and safety of defibrotide in patients with VOD/SOS post-HCT.

Observational study of ezetimibe discontinuation in primary care practices in the UK.

OBJECTIVE: We investigated the circumstances of ezetimibe discontinuation as its prescribing had been discouraged in some publications. RESEARCH DESIGN AND METHODS: Adults on stable lipid-modifying therapy (LMT) including ezetimibe, who then had >8 weeks cessation in their prescribed ezetimibe regimen (2010-2011) were identified from THIN UK primary care database. Lipid values and parallel changes to other LMT were described overall and in a sub-group with a history of diabetes, cardiovascular disease or familial hypercholesterolaemia (high-risk group). RESULTS: Ezetimibe therapy stopped in 7087 patients after a mean of 38 months; 67.0% were in the high-risk group. No lipid readings were recorded for 16.1% of patients in the year before and 26.2% in the year after ezetimibe stopped; 11.0% and 12.4% in the high-risk group respectively. In the prior year, 60.2% patients with any lipid reading had a total cholesterol (T-cholesterol) <5 mmol/l and 59.2% had a T-cholesterol <5 mmol/l and LDL-cholesterol <3 mmol/l. In the high-risk group, 66.8% had a T-cholesterol <5 mmol/l, 38.9% had either a T-cholesterol <4 or a LDL-cholesterol <2 mmol/l and 29.4% had reached both targets. In both populations, 42% patients had 6 months' follow-up after ezetimibe stopped with no change to other LMT. An LMT change within 8 weeks (19%) was usually a new statin while 27% overall had a further ezetimibe prescription after 8-26 weeks. LIMITATIONS: Only absolute lipid values were included, as percentage change from baseline level may not be reliable. The study included a larger proportion of patients in Scotland relative to the UK population. CONCLUSIONS: Prescribed ezetimibe often stopped without either a recent lipid value or attainment of optimal, or sometimes minimum, lipid targets. Patients did not always receive parallel intensification of other LMT or a further ezetimibe prescription within 6 months.

Total lipid management and cardiovascular disease in the dyslipidemia international study.

OBJECTIVES: Despite statin use, many patients with cardiovascular disease (CVD) are not achieving treatment goals. An international observational study was performed to estimate the prevalence of residual lipid abnormalities in statin-treated patients with CVD to assess whether lipid management requires improvement. METHODS: Fasting plasma concentrations of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides were recorded in 11,104 patients with atherosclerotic CVD and ≥3 months of statin therapy. RESULTS: LDL-C and total cholesterol were not at goal levels in 41 and 46% of all patients, respectively; for patients with peripheral artery disease (PAD) only, 59 and 65%, respectively, were not at goal, and in those with coronary heart disease only, 38 and 42%, respectively, were not at goal. Patients with cerebrovascular disease only were least frequently observed to have low HDL-C (24%) and elevated triglycerides (36%). Overall, elevated LDL-C was the most frequent lipid anomaly observed, and preexisting heart failure was strongly and positively associated with dyslipidemia. CONCLUSIONS: Approximately two fifths of statin-treated patients with CVD are not reaching lipid goals or have abnormal lipid levels, while patients with PAD could particularly benefit from improved lipid management. In addition to targeting LDL-C, new evidence-based approaches are needed to target low HDL-C and elevated triglycerides.

PYY3-36 and oxyntomodulin can be additive in their effect on food intake in overweight and obese humans.

OBJECTIVE: Peptide YY(3-36) (PYY(3-36)), a Y2 receptor agonist, and oxyntomodulin, a glucagon-like peptide 1 (GLP-1) receptor agonist, are cosecreted by intestinal L-cells after each meal. Separately each hormone acts as an endogenous satiety signal and reduces appetite in humans when infused intravenously. The aim of the current study was to investigate whether the anorectic effects of PYY(3-36) and oxyntomodulin can be additive. RESEARCH DESIGN AND METHODS: Twelve overweight or obese human volunteers underwent a randomized, double-blinded, placebo-controlled study. An ad libitum test meal was used to measure energy intake during intravenous infusions of either PYY(3-36) or oxyntomodulin or combined PYY(3-36)/oxyntomodulin. RESULTS: Energy intake during coadministration of PYY(3-36) and oxyntomodulin was reduced by 42.7% in comparison with the saline control and was significantly lower than that during infusions of either hormone alone. CONCLUSIONS: The anorectic effects of PYY(3-36) and oxyntomodulin can be additive in overweight and obese humans. Coadministration of Y2 receptor agonists and GLP-1 receptor agonists may be a useful treatment strategy for obesity.

Serum molecular signatures of weight change during early breast cancer chemotherapy.

PURPOSE: Weight gain in women receiving chemotherapy for breast cancer is associated with a higher risk of recurrence but its mechanisms are poorly understood. EXPERIMENTAL DESIGN: To investigate this, we assessed the metabolic, cytokine, and appetite-related peptide alterations during adjuvant chemotherapy for early breast cancer in postmenopausal women, and correlated these with body mass measurements. Specifically, we performed global metabolic profiling using (1)H-nuclear magnetic resonance spectroscopy of sequential sera, examined ghrelin immunoreactivity, RIAs for GLP-1 and peptide YY, and electrochemiluminescent cytokine analyses (tumor necrosis factor-alpha and interleukin-6) on sequential samples. RESULTS: In those who gained >1.5 kg, several metabolite levels were positively associated with weight gain, specifically lactate, which was 63.5% greater in patients with increased body weight during chemotherapy compared with those with no weight gain (P < 0.01; the prespecified primary end point). A strong correlation (r = 0.7, P < 0.001) was detected between the rate of weight change and serum lactate levels, and on average, lactate levels exhibited the greatest metabolic response to chemotherapy, increasing by up to 75%. Normalized levels of peptide YY were also observed to be elevated in patients not gaining weight posttreatment (+30% compared with -7% for the weight gain group; P < 10(-4)). Baseline lactate, alanine, and body fat were all prognostic for weight gain (area under the receiver operator characteristic curves, >0.77; P < 0.05). No associations were observed between any other parameter and weight gain, including cytokine levels. CONCLUSIONS: Metabonomics identifies excess energy expenditure pathways perturbed during chemotherapy for breast cancer, and establishes a significant association between serum lactate, body fat, and substantive weight gain during chemotherapy.

Kisspeptin-54 stimulates gonadotropin release most potently during the preovulatory phase of the menstrual cycle in women.

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 < 0.001 vs. follicular phase); luteal phase, 2.17 +/- 0.79 (P < 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.

Pioglitazone added to conventional lipid-lowering treatment in familial combined hyperlipidaemia improves parameters of metabolic control: relation to liver, muscle and regional body fat content.

Familial combined hyperlipidaemia (FCHL) is a complex genetic disorder conferring high risk of premature atherosclerosis, characterized by high cholesterol and/or triglyceride, low high density lipoprotein (HDL) cholesterol and insulin resistance. We examined whether pioglitazone, added to conventional lipid-lowering therapy, would favourably affect metabolic parameters and alter body fat content. We undertook a randomized, double blind, placebo-controlled study in 22 male patients with FCHL treated with pioglitazone or matching placebo 30 mg daily for 4 weeks, increasing to 45 mg for 12 weeks. Magnetic resonance imaging and proton magnetic resonance spectroscopy were performed to measure adipose tissue (AT) body content as well as intrahepatocellular lipids (IHCL) and intramyocellular lipids (IMCL) at baseline and after treatment. Significantly improved in the pioglitazone group were: triglyceride/HDL (atherogenic index of plasma) -32.3% (p=0.002), plasma glucose -4.4% (p=0.03), alanine-aminotransferase (ALT) -7.7% (p=0.005) and adiponectin 130.1% (p=0.001). Pioglitazone treatment resulted in a significant increase in total (5.3%, p=0.02) and subcutaneous (7.1%, p=0.003) adipose tissue as well as in soleus-IMCL levels (47.4%, p=0.02) without alteration in intra-abdominal AT or IHCL. Changes in ALT and AST and IHCL were strongly correlated (r=0.72, p<0.01; r=.0.86, p<0.01, respectively). In patients with FCHL on conventional lipid-lowering therapy, the addition of pioglitazone acts favourably on several metabolic parameters.

Kisspeptin-54 stimulates the hypothalamic-pituitary gonadal axis in human males.

CONTEXT: Mutation of the G protein-coupled receptor 54 is associated with a failure of reproductive function. The endogenous neuropeptide agonist for G protein-coupled receptor 54, kisspeptin, potently stimulates the hypothalamic-pituitary-gonadal axis in rodents and primates. OBJECTIVE: The present study was designed to determine the effects of elevating circulating kisspeptin levels on LH, FSH, and testosterone in male volunteers. DESIGN: This was a double-blind, placebo-controlled, crossover study. SETTING: This was a hospital-based study. PARTICIPANTS: Male volunteers (n = 6) were recruited. INTERVENTIONS: Each volunteer received a 90-min i.v. infusion of kisspeptin-54 (4 pmol/kg x min) and a control infusion of saline (0.9%) in random order. MAIN OUTCOME MEASURE: Plasma LH, FSH, and testosterone concentrations were measured. RESULTS: Kisspeptin-54 infusion significantly increased plasma LH, FSH, and testosterone concentrations compared with saline infusion (mean 90-min LH: kisspeptin, 10.8 +/- 1.5 vs. saline, 4.2 +/- 0.5 U/liter, P < 0.001; mean 90-min FSH: kisspeptin, 3.9 +/- 0.7 vs. saline, 3.2 +/- 0.6 U/liter, P < 0.001; mean 180-min testosterone: kisspeptin, 24.9 +/- 1.7 vs. saline, 21.7 +/- 2.2 nmol/liter, P < 0.001). The plasma half-life of kisspeptin-54 was calculated to be 27.6 +/- 1.1 min. The mean metabolic clearance rate was 3.2 +/- 0.2 ml/kg x min, and the volume of distribution was 128.9 +/- 12.5 ml/kg. CONCLUSION: Elevation of plasma concentrations of kisspeptin in human males significantly increases circulating LH, FSH, and testosterone levels. Kisspeptin infusion provides a novel mechanism for hypothalamic-pituitary-gonadal axis manipulation in disorders of the reproductive system.