Hackensack University Medical Center

BACKGROUND:Sickle cell disease is characterized by chronic hemolytic anemia and recurrent severe vaso-occlusive crises. Ristoglogene autogetemcel (risto-cel) includes autologous CD34+ hematopoietic stem and progenitor cells that have been base-edited to target the HBG1 and HBG2 promoters and inhibit BCL11A binding without altering BCL11A expression, yielding a switch in hemoglobin production from sickle hemoglobin (HbS) to antisickling fetal hemoglobin (HbF). METHODS:In this phase 1-2 study, we enrolled patients 12 to 35 years of age with sickle cell disease who had had at least four severe vaso-occlusive crises in the 2 years before enrollment. After myeloablative conditioning with pharmacokinetically guided administration of busulfan, patients received a single infusion of risto-cel (at a dose of ≥3.0×106 viable CD34+ cells per kilogram of body weight). The primary efficacy end point was freedom from severe vaso-occlusive crises for 12 consecutive months, starting later than 60 days after the last red-cell transfusion. This interim analysis was unplanned; here, we describe safety, editing, engraftment, and hemoglobin production and the number of severe vaso-occlusive crises starting later than 60 days after the last red-cell transfusion. RESULTS:A total of 31 patients received risto-cel and were followed for a mean of 6.6 months (range, 0.3 to 20.4). A median of one cycle (range, one to five) was required for stem-cell collection. Neutrophil engraftment occurred at a median of 17.5 days, and platelet engraftment at a median of 19 days. One patient died from idiopathic pneumonia syndrome. All 31 patients had at least one adverse event, 27 (87%) had an adverse event of grade 3 or higher, and 12 (39%) had a serious adverse event. At 6 months, the mean fraction of on-target edited alleles in peripheral blood was 67.4%, the mean HbF as a fraction of total hemoglobin was more than 60%, and the HbS as a fraction of total hemoglobin was less than 40% (among 13 patients); these levels were maintained throughout follow-up. No investigator-reported severe vaso-occlusive crises occurred later than 60 days after the last red-cell transfusion. CONCLUSIONS:Treatment with risto-cel was followed by rapid engraftment and durable expression of HbF and reduction in HbS. These data support further investigation of risto-cel to treat sickle cell disease. (Funded by Beam Therapeutics; BEACON ClinicalTrials.gov number, NCT05456880.).

ABSTRACT:Circadian rhythms orchestrate immune activation and effector function, yet whether within-day timing influences chimeric antigen receptor (CAR) T-cell therapy outcomes remains unknown. We conducted an international, multicenter retrospective study of 1052 adults with relapsed or refractory large B-cell lymphoma treated with CD19-directed CAR T-cell therapy across 7 centers (2017-2025). The median infusion time was 11:48 am (interquartile range, 11:06 am to 12:45 pm). Each hour later in infusion time was associated with an increased risk of progression, relapse, or death (hazard ratio, 1.11; 95% confidence interval, 1.03-1.20; P = .004) after adjustment for center, product, and key clinical variables. One-year progression-free survival (PFS) was 51.4% for early (before 12:00 noon) infusion vs 35.2% for late (at or after 12:00 noon) infusion, whereas overall survival was similar between groups. The PFS benefit was driven by lower relapse and higher complete response rates in the early infusion group. Although no differences were observed in immune toxicities, late infusion correlated with higher peak inflammatory markers and reduced day 7 CAR T-cell expansion. Together, these findings suggest that the timing of CAR T-cell infusion may influence therapeutic efficacy and support prospective evaluation of circadian-informed delivery strategies.

Introduction Liso-cel and axi-cel are CAR T cell therapies approved for 2L treatment of R/R LBCL. While both pivotal trials established superior efficacy versus standard of care, the absence of direct comparisons underscores the importance of RW comparative data to support informed treatment selection, toxicity management, and site-of-care planning. Objectives This study investigated the RW effectiveness, safety, and HCRU of liso-cel and axi-cel in the 2L treatment setting. Methods Patients with LBCL who received 2L liso-cel or axi-cel (April 2022–April 2025) were selected from the US Flatiron Health Research Database, an oncology-specific platform combining electronic health records and other RW data. RW OS and PFS were evaluated using Kaplan-Meier method. Descriptive statistics were used to describe safety endpoints (cytokine release syndrome [CRS], immune effector cell–associated neurotoxicity syndrome [ICANS], cytopenia) and HCRU (tocilizumab/steroid use, hospitalization). Further analyses adjusting for demographic and clinical covariates will be included in the presentation. Results The study included 473 patients with LBCL who received 2L CAR T cell therapy, with 198 receiving liso-cel versus 275 receiving axi-cel (median [IQR] age, 72 y [63–77] vs 63 y [54–70]; elevated LDH, 39% vs 33%; high-grade B-cell lymphoma, 41% vs 40%; receipt of bridging therapy, 78% vs 71%; bulky disease, 68% vs 74%; relapsed within 1 y of first-line treatment, 72% vs 86%; and median [IQR] follow-up time, 8 months [4–14] vs 12 months [5–22]).Early survival outcomes among patients in liso-cel versus axi-cel groups were similar at 6 months with no statistically significant differences observed (OS, 89% [95% CI, 84%–94%] vs 89% [85%–93%]; PFS, 69% [63%–77%] vs 71% [66%–77%]). CRS and ICANS of any grade were less frequent with liso-cel than axi-cel (CRS, 31% vs 64%; ICANS, 15% vs 34%), as were grade ≥ 3 CRS/ICANS (CRS, 1% vs 3%; ICANS, 3% vs 18%; Figure 1). Grade ≥3 cytopenia between day 30 to 89 after CAR T cell therapy infusion was less common with liso-cel than axi-cel (19% vs 28%). Patients in the liso-cel group were less likely to receive treatment for CRS/ICANS versus the axi-cel group (Table 1). Infusion in an outpatient setting was more common with liso-cel than axi-cel (21% vs 6%) and was associated with a lower rate of hospitalization after infusion (47% vs 62%; Table 2). For patients infused at an inpatient setting, liso-cel was associated with shorter length of stay (8 days vs 12 days) and lower rates of rehospitalization (33% vs 40%) compared with axi-cel. Conclusion In this retrospective RW analysis, liso-cel demonstrated similar effectiveness and a more favorable safety and HCRU profile versus axi-cel as a 2L therapy for R/R LBCL. Despite limited follow-up, these RW findings suggest liso-cel could deliver safety advantages without compromising efficacy in a broad population of patients with 2L LBCL.

BACKGROUND:Ifinatamab deruxtecan is a novel B7-H3-directed antibody-drug conjugate that leverages the clinically validated deruxtecan technology. We report dose-escalation results from a trial of ifinatamab deruxtecan in patients with solid tumours. METHODS:In this two-part, multicentre, open-label, first-in-human, phase 1/2 study of ifinatamab deruxtecan conducted at clinics in ten hospitals and cancer centres in the USA and Japan, we recruited patients aged 18 years or older who had advanced treatment-refractory solid tumours (small-cell lung cancer, oesophageal squamous cell carcinoma, castration-resistant prostate cancer, squamous non-small-cell lung cancer, head and neck squamous cell carcinoma, bladder cancer, sarcoma, endometrial cancer, melanoma, or breast cancer), and Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received ifinatamab deruxtecan at doses of 0·8-16·0 mg/kg intravenously every 3 weeks. The primary outcome of dose escalation was the safety profile, which was evaluated in patients who received one or more dose of ifinatamab deruxtecan. Antitumour activity (per Response Evaluation Criteria in Solid Tumours version 1.1; secondary outcome) was evaluated in patients receiving ifinatamab deruxtecan at doses of 4·8 mg/kg or higher. The data cutoff was Jan 31, 2023. This trial is registered with ClinicalTrials.gov (NCT04145622) and is ongoing. FINDINGS:Between Oct 25, 2019, and July 13, 2022, 97 patients were enrolled and treated. 77 (79%) patients were male and 20 (21%) were female, 56 (58%) patients were White, and 31 (32%) were Asian. Three patients (3%) had dose-limiting toxicities; however, on the basis of protocol-defined criteria, the maximum tolerated dose was not reached. The most common grade 3 or worse treatment-emergent adverse events (TEAEs) were anaemia (17 [18%] patients), neutropenia (four [4%]), lymphocyte count decreased (three [3%]), and neutrophil count decreased (three [3%]). Serious TEAEs occurred in 31 (32%) patients. TEAEs associated with death were reported in five patients (5%; pneumonia, pneumonia aspiration, COVID-19 pneumonia, interstitial lung disease, and one death of undesignated cause); death due to interstitial lung disease was considered related to study medication by the investigator. After a median follow-up of 8·6 months (IQR 4·1-12·9), the confirmed objective response rate across tumour types was 34% (95% CI 23-47; 24 of 70 evaluable patients). INTERPRETATION:The maximum tolerated dose was not reached with ifinatamab deruxtecan; however, one death due to treatment-related interstitial lung disease highlights the importance of prompt evaluation and careful management of patients who develop interstitial lung disease. Promising antitumour activity was observed across various solid tumours. These findings support further evaluation of ifinatamab deruxtecan in randomised controlled trials. FUNDING:Funding for this study was provided by Daiichi Sankyo Company (Daiichi Sankyo) and Merck Sharp & Dohme, a subsidiary of Merck, Rahway, NJ, USA.

As robotic total knee arthroplasty (TKA) adoption grows, the learning curve for new users remains a concern for both physicians and staff. Previous studies have reported on clinical outcomes for TKA with a novel implant-agnostic, handheld, wireless robotic TKA system (rTKA). This study investigates the rTKA adoption learning curve relevant to multiple clinical stakeholders. This multicenter, multi-surgeon observational study includes up to the first 25 rTKA procedures by 7 surgeons. Observers noted timing and workflow at 8/25 rTKA cases and 2 standard-of-care benchmark TKAs (prior manual or robotic use by user), and analyzed logs for all rTKA cases. Learning curves were assessed via benchmark TKA time neutrality, statistical comparison between early and later cases, and cumulative sum (CUSUM) analysis. Surgeon and staff surveys followed each observed rTKA case. Each analysis type demonstrated a different learning curve duration: surgeons averaged approximately 10 cases to time neutrality, with 2 not reaching time neutrality within the observed case series. Cases 3 and onward were significantly faster than cases 1–2 (p = 0.0454), indicating early operative time improvement after initial system exposure. Average observed skin-to-skin time was 68 min. Surgeons and staff rated the system easy to use and were familiar with the system after 4 cases. Use of the handheld surgical robot for rTKA demonstrated a short learning curve and high reported ease of adoption by surgeons and staff. This study demonstrates the rTKA system exhibits a short learning curve and high reported ease of adoption, and may compare favorably with previously reported learning curves for other robotic TKA systems. Level of evidence: IV.