NEJM original articles

Background. Limited data are available on survival outcomes after sentinel-lymph-node biopsy alone as compared with lymphadenectomy in cervical cancer.

Methods. In this multicenter, randomized, noninferiority trial, we enrolled patients with cervical cancer that was stage IA1 (with lymphovascular invasion), IA2, IB1, or IIA1 according to 2009 International Federation of Gynecology and Obstetrics criteria. Sentinel-lymph-node biopsy was performed at the time of surgery and was followed by examination of frozen sections. Patients who had negative sentinel lymph nodes were intraoperatively assigned in a 1:1 ratio not to undergo pelvic lymphadenectomy (the biopsy-only group) or to undergo lymphadenectomy (the lymphadenectomy group). All the patients underwent hysterectomy, and adjuvant therapy was provided according to a unified protocol. The primary end point was disease-free survival at 3 years, with a prespecified noninferiority margin of 5 percentage points in the upper limit of the confidence interval for the difference between the lymphadenectomy group and the biopsy-only group. Secondary end points included retroperitoneal nodal recurrence, cancer-specific survival, and surgical complications.

Results. A total of 838 patients underwent randomization: 420 patients were assigned to the biopsy-only group and 418 to the lymphadenectomy group. The median follow-up was 62.8 months. The 3-year disease-free survival was 94.6% in the lymphadenectomy group and 96.9% in the biopsy-only group (difference, -2.3 percentage points; 95% confidence interval [CI], -5.0 to 0.5; P<0.001 for noninferiority); the 3-year cancer-specific survival was 99.2% in the biopsy-only group and 97.8% in the lymphadenectomy group (hazard ratio for death from cancer in competing-risks analysis, 0.37; 95% CI, 0.15 to 0.95). Retroperitoneal nodal recurrences occurred in no patients in the biopsy-only group and in 9 patients (2.2%) in the lymphadenectomy group. The biopsy-only group had a lower incidence of lymphocyst than the lymphadenectomy group (8.3% vs. 22.0%; P<0.001), as well as a lower incidence of lymphedema (5.2% vs. 19.1%; P<0.001), paresthesia (4.0% vs. 8.4%; P = 0.009), and pain (2.6% vs. 7.9%; P = 0.001).

Conclusions. In patients with early-stage cervical cancer, sentinel-lymph-node biopsy alone was noninferior to lymphadenectomy with respect to disease-free survival and was associated with fewer complications. (Funded by Guangzhou Municipal Science and Technology and others; PHENIX ClinicalTrials.gov number, NCT02642471.).

Background. Telitacicept, a new dual inhibitor of the cytokines B-lymphocyte stimulator (BLyS) and APRIL (a proliferation-inducing ligand), showed efficacy in adults with active systemic lupus erythematosus (SLE) in a phase 2b trial when added to standard therapy.

Methods. We conducted a phase 3 trial in China in which participants with active SLE were randomly assigned (in a 1:1 ratio) to receive telitacicept (160 mg) or placebo subcutaneously once weekly for 52 weeks, in addition to standard therapy. The primary end point at week 52 was a response on the modified SLE Responder Index 4 (SRI-4), with a response on this composite measure defined as a reduction of at least 4 points in the Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) score (ranging from 0 to 105, with higher scores indicating greater disease activity), no new disease activity as measured on the British Isles Lupus Assessment Group index, and no worsening in the Physician's Global Assessment score.

Results. Of 433 adults screened, 335 underwent randomization (167 to the telitacicept group and 168 to the placebo group). At week 52, significantly more participants receiving telitacicept had a response on the modified SRI-4 than those receiving placebo (67.1% vs. 32.7%; adjusted difference, 34.5 percentage points; 95% confidence interval [CI], 24.3 to 44.7; P<0.001). A reduction of at least 4 points from baseline in the SELENA-SLEDAI score had occurred in 70.1% of the telitacicept group and in 40.5% of the placebo group (difference, 29.6 percentage points; 95% CI, 13.1 to 46.1). Adverse events that were considered by the investigator to be related to the trial regimen were more common with telitacicept than with placebo (74.9% vs. 50.0%). Such events that occurred more frequently in the telitacicept group than in the placebo group included upper respiratory tract infection (31.7% vs. 19.0%), a reduced serum IgG level (15.6% vs. 1.2%), a reduced serum IgM level (15.0% vs. 0.6%), and injection-site reactions (12.6% vs. 0.6%).

Conclusions. In this 52-week trial involving participants with active SLE who were receiving background therapy, the incidence of a clinical response was higher with telitacicept than with placebo. However, the incidence of upper respiratory infections, reduced immunoglobulin levels, and injection-site reactions was also higher with telitacicept. (Funded by RemeGen; 18C010 ClinicalTrials.gov number, NCT04082416.).

Background. Severe combined immunodeficiency (SCID) due to adenosine deaminase (ADA) deficiency (ADA-SCID) is a life-threatening inborn error of immunity for which lentiviral gene therapy has been investigated in clinical trials.

Methods. Between 2012 and 2019, we treated patients who had ADA-SCID with busulfan nonmyeloablative conditioning followed by transplantation with autologous CD34+ hematopoietic stem cells transduced ex vivo with a lentiviral vector encoding human ADA. The primary efficacy end points were overall survival and event-free survival (defined as survival free from rescue allogeneic hematopoietic stem-cell transplantation, reinitiation of enzyme-replacement therapy, and additional gene therapy). Secondary end points included no receipt of immunoglobulin-replacement therapy, the presence of protective titers to tetanus or pneumococcal vaccines, and sustained discontinuation of fungal or viral prophylaxis. We now report the long-term results from this cohort representing 474 patient-years of follow-up, with a median follow-up of 7.5 years.

Results. We treated 62 patients with ADA-SCID in the United States (33 patients) and the United Kingdom (29 patients). Overall survival was 100%, and event-free survival was 95% (59 of 62 patients). All 59 patients who had successful gene-marked engraftment at 6 months have continued not to receive enzyme-replacement therapy and have had stable gene marking, ADA enzyme activity, metabolic detoxification, and immune reconstitution through the last follow-up; 58 of these patients (98%) discontinued IgG replacement therapy and have evidence of a robust response to vaccinations. None of the patients had a leukoproliferative event or clonal expansion.

Conclusions. These long-term findings in a large patient cohort show the sustained clinical efficacy and safety of autologous CD34+ hematopoietic stem-cell lentiviral gene therapy for ADA-SCID, indicating that it is a curative treatment. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov number, NCT04049084.).

Background. Mass administration of azithromycin to children 1 to 59 months of age has been shown to reduce mortality among infants and children in this age group in some areas of sub-Saharan Africa. The largest effects have appeared to be among infants younger than 12 months of age, within 3 months after treatment; this observation motivated the design of the current trial.

Methods. In this trial, we randomly assigned villages in Mali, West Africa, in a 3:4:2 ratio to receive distributions of placebo, azithromycin two times a year, or azithromycin four times a year. Infants 1 to 11 months of age received, in doses of 20 mg per kilogram of body weight, placebo every 3 months (control group); azithromycin at two quarterly visits from January through June and placebo at two quarterly visits from July through December (twice-yearly azithromycin group); or azithromycin every 3 months (quarterly azithromycin group). The primary outcome was death within 3 months after eligibility had been confirmed, analyzed in the intention-to-treat population.

Results. From December 2020 through December 2022, a total of 1151 villages were enrolled in the trial; 386 villages were randomly assigned to the control group, 511 to the twice-yearly azithromycin group, and 254 to the quarterly azithromycin group. Among all the villages, 149,090 infants received at least one dose of placebo or azithromycin, with a total of 82,600 person-years of follow-up; 968 deaths were recorded. Mortality was 11.9 deaths per 1000 person-years at risk in the control group, 11.8 deaths per 1000 person-years in the twice-yearly azithromycin group (incidence rate ratio, 1.00; 95% confidence interval [CI], 0.83 to 1.19), and 11.3 deaths per 1000 person-years in the quarterly azithromycin group (incidence rate ratio, 0.93; 95% CI, 0.75 to 1.15). Adverse events were rare, and the percentages of infants with adverse events were similar in the three groups. Mortality among untreated children 12 to 59 months of age was similar across groups.

Conclusions. Mass administration of azithromycin in Mali, limited to infants 1 to 11 months of age, did not result in lower infant or child mortality than placebo, regardless of whether azithromycin was delivered twice yearly or quarterly. (Funded by the Gates Foundation; LAKANA ClinicalTrials.gov number, NCT04424511.).