Imetelstat in patients with lower-risk myelodysplastic syndromes who have relapsed or are refractory to erythropoiesis-stimulating agents (IMerge): a multinational, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Unmet medical needs remain in patients with red blood cell transfusion-dependent (RBC-TD) lower-risk myelodysplastic syndromes (LR-MDS) who are not responding to or are ineligible for erythropoiesis-stimulating agents (ESAs). Imetelstat, a competitive telomerase inhibitor, showed promising results in a phase 2 trial. We aimed to compare the RBC transfusion independence (RBC-TI) rate with imetelstat versus placebo in patients with RBC-TD LR-MDS. METHODS: In phase 3 of IMerge, a double-blind, placebo-controlled trial conducted in 118 sites including university hospitals, cancer centres, and outpatient clinics in 17 countries, patients (aged ≥18 years) with ESA-relapsed, ESA-refractory, or ESA-ineligible LR-MDS (low or intermediate-1 risk disease as per International Prognostic Scoring System [IPSS] criteria) were randomly assigned via a computer-generated schedule (2:1) to receive imetelstat 7·5 mg/kg or placebo, administered as a 2-h intravenous infusion, every 4 weeks until disease progression, unacceptable toxic effects, or withdrawal of consent. Randomisation was stratified by previous RBC transfusion burden and IPSS risk group. Patients, investigators, and those analysing the data were masked to group assignment. The primary endpoint was 8-week RBC-TI, defined as the proportion of patients without RBC transfusions for at least 8 consecutive weeks starting on the day of randomisation until subsequent anti-cancer therapy, if any. Primary efficacy analyses were performed in the intention-to-treat population, and safety analyses were conducted in patients who received at least one dose of trial medication or placebo. This trial is registered with ClinicalTrials.gov (NCT02598661; substudy active and recruiting). FINDINGS: Between Sept 11, 2019, and Oct 13, 2021, 178 patients were enrolled and randomly assigned (118 to imetelstat and 60 to placebo). 111 (62%) were male and 67 (38%) were female. 91 (77%) of 118 patients had discontinued treatment by data cutoff in the imetelstat group versus 45 (75%) in the placebo group; a further one patient in the placebo group did not receive treatment. Median follow-up was 19·5 months (IQR 12·0-23·4) in the imetelstat group and 17·5 months (12·1-22·7) in the placebo group. In the imetelstat group, 47 (40% [95% CI 30·9-49·3]) patients had an RBC-TI of at least 8 weeks versus nine (15% [7·1-26·6]) in the placebo group (rate difference 25% [9·9 to 36·9]; p=0·0008). Overall, 107 (91%) of 118 patients receiving imetelstat and 28 (47%) of 59 patients receiving placebo had grade 3-4 treatment-emergent adverse events. The most common treatment-emergent grade 3-4 adverse events in patients taking imetelstat were neutropenia (80 [68%] patients who received imetelstat vs two [3%] who received placebo) and thrombocytopenia (73 [62%] vs five [8%]). No treatment-related deaths were reported. INTERPRETATION: Imetelstat offers a novel mechanism of action with durable transfusion independence (approximately 1 year) and disease-modifying activity for heavily transfused patients with LR-MDS who are not responding to or are ineligible for ESAs. FUNDING: Janssen Research & Development before April 18, 2019, and Geron Corporation thereafter.

Spiroindolines identify the vesicular acetylcholine transporter as a novel target for insecticide action.

The efficacy of all major insecticide classes continues to be eroded by the development of resistance mediated, in part, by selection of alleles encoding insecticide insensitive target proteins. The discovery of new insecticide classes acting at novel protein binding sites is therefore important for the continued protection of the food supply from insect predators, and of human and animal health from insect borne disease. Here we describe a novel class of insecticides (Spiroindolines) encompassing molecules that combine excellent activity against major agricultural pest species with low mammalian toxicity. We confidently assign the vesicular acetylcholine transporter as the molecular target of Spiroindolines through the combination of molecular genetics in model organisms with a pharmacological approach in insect tissues. The vesicular acetylcholine transporter can now be added to the list of validated insecticide targets in the acetylcholine signalling pathway and we anticipate that this will lead to the discovery of novel molecules useful in sustaining agriculture. In addition to their potential as insecticides and nematocides, Spiroindolines represent the only other class of chemical ligands for the vesicular acetylcholine transporter since those based on the discovery of vesamicol over 40 years ago, and as such, have potential to provide more selective tools for PET imaging in the diagnosis of neurodegenerative disease. They also provide novel biochemical tools for studies of the function of this protein family.

Insecticide detoxification indicator strains as tools for enhancing chemical discovery screens.

BACKGROUND: Insecticide discovery screens carried out on whole organisms screen for potency resulting from chemical activity at the target site. However, many potentially insecticidal compounds are naturally detoxified in vivo and do not make it to the target site. It is hypothesised that insect strains with their xenobiotic detoxification machinery compromised could be used to identify such compounds that normally fail to show up in screens; these compounds could then be more rationally designed to increase their bioavailability. This strategy was tested with transgenic Drosophila lines with altered expression of Cyp6g1 and Dhr96. RESULTS: It was observed that Cyp6g1 knockdown transgenic lines have increased susceptibility to the test compound imidacloprid, while Dhr96 knockdown transgenic lines are resistant. Evidence was found for a systemic response to xenobiotic exposure, uncovered by piperonyl butoxide treatment and by gene expression profiling. Sex-specific gene expression regulated by DHR96 was also observed. CONCLUSION: The results confirm that this approach to chemical discovery could identify compounds that escape traditional screens. The complexity of the system means that a panel of single and multiple gene knockdown transgenic lines may be required.

Final results of a multicenter phase 1 study of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia.

Based on clinical activity in phase 2 studies, lenalidomide was evaluated in a phase 2/3 study in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). Following tumor lysis syndrome (TLS) complications, the protocol was amended to a phase 1 study to identify the maximum tolerated dose-escalation level (MTDEL). Fifty-two heavily pretreated patients, 69% with bulky disease and 48% with high-risk genomic abnormalities, initiated lenalidomide at 2.5 mg/day, with dose escalation until the MTDEL or the maximum assigned dose was attained. Lenalidomide was safely titrated to 20 mg/day; the MTDEL was not reached. Most common grade 3-4 adverse events were neutropenia and thrombocytopenia; TLS was mild and rare. The low starting dose and conservative dose escalation strategy resulted in six partial responders and 30 patients obtaining stable disease. In summary, lenalidomide 2.5 mg/day is a safe starting dose that can be titrated up to 20 mg/day in patients with CLL.

Predicting dry weight in patients with ascites and liver cirrhosis using computed tomography imaging.

BACKGROUND/AIMS: In cirrhotic patients, ascites may increase weight and adversely impact liver transplant candidacy. METHODOLOGY: In this study we used linear and volume measurements from abdominal CT imaging to estimate dry weight of transplant candidates using multivariable linear regressions. We reviewed 200 scans. For males there were 81, 26, and 41 scans with no/small, moderate, and large ascites, respectively, and 41, 6, and 5 scans of females with no/small/moderate, and large ascites respectively. RESULTS: In males without ascites, subxiphoid subcutaneous fat volume had the strongest correlation with weight (r = 0.826); the best prediction utilized four variables including height, subcutaneous subxiphoid fat volume, and intraabdominal and subcutaneous umbilicus fat volumes (r = 0.923, r2 = 0.852, SEE = 15.15, p < 0.001). In females, subcutaneous fat volume above the umbilicus had the best correlation (r = 0.815); incorporating height and anterior subxiphoid fat thickness increased predictive accuracy (r = 0.892, r2 = 0.796, SEE = 15.37, p < 0.001). These regressions consistently under-predicted scale weight in patients with moderate and large ascites (5.92 +/- 25.50 pounds and 11.21 +/- 19.34 pounds in males, and 2.29 +/- 23.76 and 8.37 +/- 11.44 in females). CONCLUSIONS: Equations to estimate patient weight regardless of ascites may offer a more accurate representation of size than scale weight in transplant candidates with ascites.

Effect of chronic glucocorticoid therapy and the gender difference on bone mineral density in liver transplant patients.

BACKGROUND: Chronic glucocorticoid therapy (CGT) has been shown to result in bone density loss causing osteoporosis. Patients undergoing liver transplantation (LT) are on CGT and are at increased risk for bone disease. To further study the relationship between CGT and bone loss, we analyzed the bone mineral density (BMD) in relation to the cumulative dose of CGT in patients who had undergone LT. MATERIALS AND METHODS: We retrospectively collected information on 57 patients who underwent LT more than 1 year ago, which included demographics, cumulative CGT dose, BMD and t-scores of the femur/lumbar vertebra as measured by dual-energy X-ray absorptiometry (DEXA) for 1 and 2 years post-transplant. Patients receiving CGT >3500 mg/1st year were compared with CGT <3500 mg the first year. The group consisted of 75% males and 25% females. RESULTS: Data showed that all patients on CGT had a moderately increased risk of fracture one year post-transplant. In the high dose group, females had significantly worse femur BMD and t-scores that persisted through the second year. This difference was not seen in the low dose group. CONCLUSION: We found that all liver transplant patients on CGT have an increased risk of bone disease and that female patients receiving CGT >3500 mg the first year have a much higher risk of bone disease than males and that this risk persists during the second year. Because most of the steroids are given during the 1st month post-transplant, the amount of steroids given in this time period dictates the patients' risk for the subsequent 2 years.

Locus-specific requirements for Spt5 in transcriptional activation and repression in Drosophila.

Segmental patterning in Drosophila relies on a cascade of transcription factors that subdivide the embryo into successively more precise domains. We have identified a missense mutation (W049) in the gene encoding the transcriptional elongation factor Spt5 (reviewed in ) which, when homozygous in the maternal germ line, leads to defects in segmental patterning of the embryo. W049 alters the C-terminal domain of Spt5 and affects its activity in vitro, impairing its abilities to confer sensitivity to the transcriptional inhibitor DRB and to stimulate transcription at limiting nucleotide concentrations. In vivo, W049 shows locus-specific effects on transcription: expression of gap genes remains wild-type, but striped patterning of the primary pair-rule genes even-skipped and runt is disrupted. even-skipped stripes are broadened in the mutant embryos indicating that Spt5 is likely to be a direct, negative regulator of this target gene. Our results suggest control of transcriptional elongation by repressors contributes to striped gene expression in the embryo. By contrast, expression of heat shock-induced proteins is reduced in the mutant embryos. These results provide genetic evidence for Spt5 function during heat shock induction and demonstrate that Spt5 acts both positively and negatively on transcription in vivo depending on context.