NEJM original articles

Background. Patients with muscle-invasive bladder cancer who are ineligible for cisplatin-based chemotherapy proceed directly to radical cystectomy with pelvic lymph-node dissection. Perioperative therapy may improve outcomes in this population.

Methods. In this phase 3, open-label trial, participants with muscle-invasive bladder cancer who were ineligible for or declined cisplatin-based chemotherapy were randomly assigned to perioperative (neoadjuvant and adjuvant) enfortumab vedotin, an antibody-drug conjugate directed at nectin-4, plus pembrolizumab and surgery (9 total cycles of enfortumab vedotin [1.25 mg per kilogram of body weight on days 1 and 8] plus 17 total cycles of pembrolizumab [200 mg on day 1 every 3 weeks], with surgery after 3 cycles) or surgery alone (control). The primary end point was event-free survival. Key secondary end points were overall survival and pathological complete response (absence of viable tumor after surgical resection). Other secondary end points included safety.

Results. A total of 344 participants underwent randomization (170 in the enfortumab vedotin-pembrolizumab group and 174 in the control group). At data cutoff, median follow-up was 25.6 months (range, 11.8 to 53.7). Surgery was performed in 87.6% of participants in the enfortumab vedotin-pembrolizumab group and in 89.7% in the control group. At 2 years, estimated event-free survival was 74.7% in the enfortumab vedotin-pembrolizumab group and 39.4% in the control group (hazard ratio for an event or death, 0.40; 95% confidence interval [CI], 0.28 to 0.57; two-sided P<0.001); estimated overall survival was 79.7% and 63.1% (hazard ratio for death, 0.50; 95% CI, 0.33 to 0.74; two-sided P<0.001). A pathological complete response had occurred in 57.1% and 8.6% of the participants (estimated difference, 48.3 percentage points; 95% CI, 39.5 to 56.5; two-sided P<0.001). Adverse events occurred in all participants in the enfortumab vedotin-pembrolizumab group (grade ≥3, 71.3%; grade ≥3 drug-related, 45.5%) and in 64.8% in the control group (grade ≥3, 45.9%).

Conclusions. Perioperative enfortumab vedotin plus pembrolizumab and surgery led to significantly better event-free and overall survival outcomes and a greater percentage of participants with pathological complete response than surgery alone in a predominantly cisplatin-ineligible population with muscle-invasive bladder cancer. Safety was also assessed. (Funded by Merck Sharp and Dohme, a subsidiary of Merck [Rahway, NJ]; KEYNOTE-905 ClinicalTrials.gov number, NCT03924895.).

Background. Catheter-based closure of the left atrial appendage is an alternative to oral anticoagulation for stroke prevention in patients with atrial fibrillation. The effectiveness of this strategy, as compared with physician-directed best medical care, in patients at high risk for stroke and bleeding is unknown.

Methods. In this multicenter randomized trial conducted in Germany, we assigned patients with atrial fibrillation and a high risk of stroke and bleeding to undergo left atrial appendage closure or to receive physician-directed best medical care (including direct oral anticoagulants, if eligible). The primary end point, tested for noninferiority, was a composite of stroke (ischemic or hemorrhagic), systemic embolism, major bleeding, or cardiovascular or unexplained death, assessed in a time-to-event analysis. The noninferiority margin was a hazard ratio of 1.3.

Results. A total of 912 adult patients underwent randomization. The primary end-point analysis included 446 patients who were assigned to undergo left atrial appendage closure (device group) and 442 who were assigned to physician-directed best medical care (medical-therapy group). The mean (±SD) age was 77.9±7.1 years; 38.6% of the patients were women, the mean CHA₂DS₂-VASc score was 5.2±1.5 (range, 0 to 9, with higher scores indicating a greater risk of stroke), and the mean HAS-BLED score was 3.0±0.9 (range, 0 to 9, with higher scores indicating higher risk of bleeding). After a median follow-up of 3 years (interquartile range, 1.7 to 4.7), a first primary end-point event had occurred in 155 patients (incidence per 100 patient-years, 16.8) in the device group and in 127 patients (incidence per 100 patient-years, 13.3) in the medical-therapy group (difference in restricted mean survival time, -0.36 years; 95% confidence interval, -0.70 to -0.01; P = 0.44 for noninferiority). Serious adverse events occurred in 368 patients (82.5%) in the device group and 342 (77.4%) in the medical-therapy group.

Conclusions. Among patients with atrial fibrillation at high risk for stroke and bleeding, left atrial appendage closure was not noninferior to physician-directed best medical care with regard to a composite end point of stroke, systemic embolism, major bleeding, or cardiovascular or unexplained death. (Funded by the German Center for Cardiovascular Research; CLOSURE-AF ClinicalTrials.gov number, NCT03463317.).

Background. Renizgamglogene autogedtemcel (reni-cel) is an investigational clustered regularly interspaced short palindromic repeats (CRISPR)-Cas12a gene-edited autologous hematopoietic stem-cell therapy. The therapy was designed to disrupt the BCL11A binding sites in the HBG1 and HBG2 promoters to reactivate fetal hemoglobin production for the treatment of sickle cell disease.

Methods. We conducted a phase 1-2, multicenter, open-label, single-group study involving patients with severe sickle cell disease who were 12 to 50 years of age and had had at least two severe vaso-occlusive events per year in the previous 2 years. The patients received a single infusion of reni-cel after myeloablative conditioning with busulfan. The patients were monitored for engraftment, hemoglobin-related measures, allelic editing levels, vaso-occlusive events, and adverse events over a 24-month period. The study was terminated early on the basis of the sponsor's reassessment of clinical development priorities. Results of an analysis that was not prespecified are reported.

Results. As of October 29, 2024, a total of 28 patients with severe sickle cell disease had been treated with reni-cel. The median duration of follow-up was 9.5 months (range, 0.7 to 25.2). Among 27 patients who had neutrophil and platelet engraftment by the data-cutoff date, neutrophil engraftment occurred after a median of 23 days (range, 14 to 29), and platelet engraftment occurred after a median of 25 days (range, 17 to 51). At month 6, among 18 patients with at least 6 months of available data, the mean (±SD) total hemoglobin level (9.8±1.7 g per deciliter at baseline) had increased to 13.8±1.9 g per deciliter, and the mean percentage of fetal hemoglobin (2.5±2.5% at baseline) had increased to 48.1±3.2%; both measures were maintained at or above these values thereafter. One patient had two severe vaso-occlusive events after infusion. Adverse events were consistent with those that occur after myeloablative busulfan-based conditioning and autologous hematopoietic stem-cell transplantation.

Conclusions. Treatment with reni-cel led to normalization of the total hemoglobin level and an increase in the percentage of fetal hemoglobin, with no vaso-occlusive events occurring in 27 of 28 patients after infusion. These results support further investigation of this gene-editing approach in the treatment of severe sickle cell disease. (Funded by Editas Medicine; RUBY ClinicalTrials.gov number, NCT04853576.).

Background. Renizgamglogene autogedtemcel (reni-cel) is an investigational clustered regularly interspaced short palindromic repeats (CRISPR)-Cas12a gene-edited autologous hematopoietic stem-cell therapy. The therapy was designed to disrupt the BCL11A binding sites in the HBG1 and HBG2 promoters to reactivate fetal hemoglobin production for the treatment of transfusion-dependent β-thalassemia.

Methods. We conducted a phase 1-2, multicenter, open-label, single-group study of reni-cel in participants 18 to 35 years of age with transfusion-dependent β-thalassemia. The participants received myeloablative conditioning with busulfan before reni-cel infusion. The primary end points were neutrophil engraftment by 42 days after infusion and frequency and severity of adverse events. Participants were monitored for hemoglobin-related measures and transfusion independence. The study was terminated early on the basis of the sponsor's reassessment of clinical development priorities. Results of an analysis that was not prespecified are reported.

Results. Nine participants with transfusion-dependent β-thalassemia (four β⁰/β⁰ or β⁰/β⁰-like and five non-β⁰/β⁰ genotypes) received reni-cel and were included in the analysis. The median duration of postinfusion follow-up was 17.5 months (range, 3.8 to 23.4), and six participants could be evaluated for transfusion independence at 12 months or more. All the participants had neutrophil and platelet engraftment by 42 days after infusion. Rapid increases in total and fetal hemoglobin levels resulted in each of the nine participants being transfusion-free at their last follow-up visit. The six participants who could be evaluated at 12 months or later were transfusion-independent. The mean total and fetal hemoglobin levels were greater than 12 g per deciliter and greater than 11 g per deciliter, respectively, between months 6 and 18. A total of 69 grade 3 or 4 adverse events with onset or worsening during or after reni-cel infusion were reported in the nine participants. Six serious adverse events (infections, pyrexia, or pneumonitis) were reported in four participants. Adverse events were generally consistent with myeloablative conditioning. One patient had decreased lymphocyte counts attributed to reni-cel.

Conclusions. Treatment with reni-cel resulted in rapid neutrophil engraftment, an increase in fetal hemoglobin expression, and transfusion independence. These data support further investigation of Cas12a gene editing of the promoters of HBG1 and HBG2 in the treatment of transfusion-dependent β-thalassemia. (Funded by Editas Medicine; EdiThal ClinicalTrials.gov number, NCT05444894.).

Background. The role of long-term beta-blocker therapy after a myocardial infarction in patients without left ventricular systolic dysfunction or heart failure is unclear in the era of contemporary coronary-artery reperfusion and secondary prevention interventions.

Methods. We conducted an open-label, randomized, noninferiority trial at 25 centers in South Korea. Patients whose condition remained stable after a myocardial infarction, who had a left ventricular ejection fraction of at least 40% and no heart failure, and who had received beta-blocker therapy for at least 1 year after the myocardial infarction were randomly assigned in a 1:1 ratio to discontinue or to continue beta-blocker therapy. The primary end point was a composite of death from any cause, recurrent myocardial infarction, or hospitalization for heart failure. The prespecified noninferiority margin was an upper limit of the 95% confidence interval for the hazard ratio of 1.4.

Results. A total of 2540 patients underwent randomization; 1246 were assigned to beta-blocker discontinuation and 1294 to beta-blocker continuation. The mean age of the patients was 63.2 years, and 12.8% were women. At a median follow-up of 3.1 years (interquartile range, 2.5 to 3.5), a primary end-point event had occurred in 58 patients (4-year Kaplan-Meier estimate, 7.2%) in the discontinuation group and in 74 patients (4-year Kaplan-Meier estimate, 9.0%) in the continuation group (hazard ratio, 0.80; 95% confidence interval, 0.57 to 1.13; P = 0.001 for noninferiority). The incidence of serious adverse events was similar in the two groups.

Conclusions. Among patients who received beta-blocker therapy beyond the first year after a myocardial infarction, discontinuation of beta-blocker therapy was noninferior to continuation with respect to a composite of death from any cause, recurrent myocardial infarction, or hospitalization for heart failure. (Funded by Patient-Centered Clinical Research Coordinating Center in the Ministry of Health and Welfare, South Korea; SMART-DECISION ClinicalTrials.gov number, NCT04769362.).