Rainbow Babies & Children''s Hospital,University Hospitals of Cleveland

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.).

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/Objectives: Sinusoidal obstruction syndrome (SOS), also known as veno-occlusive disease, is a serious complication of hematopoietic stem cell transplantation (HSCT), particularly in high and very high-risk pediatric patients. Despite known risk factors, U.S. data remain limited. The benefit of prophylactic defibrotide is uncertain, with prior trials yielding inconclusive results. This study evaluates its use and association with SOS incidence, healthcare burden, and outcomes. Methods: We performed a retrospective cohort study of 10,250 pediatric HSCT encounters using the Pediatric Health Information System. Patients were stratified as high-risk (n = 9584) or very high-risk (n = 666) per HARMONY criteria. Prophylactic defibrotide was used in 344 encounters; 9906 received none (therapeutic use allowed after SOS diagnosis). Outcomes included SOS incidence, length of stay (LOS), ICU admission, mortality, acute GVHD, and costs. Mixed-effects logistic regression models with patients as a random intercept were used (p < 0.05). Results: SOS incidence differences between the defibrotide prophylaxis and non-prophylaxis groups were not statistically significant in either risk category (high-risk: 26% [n = 79/302] vs. 7.1% [n = 663/9282] p = 0.495, OR 1.457, 95% CI 0.494-4.296; very high-risk: 31.0% [n = 13/42] vs. 21.6% [n = 135/624], p = 0.970, OR 1.081, 95% CI 0.019-60.769). The extremely wide confidence intervals indicate that the data are consistent with both benefit and harm of prophylaxis. Median LOS was longer in the prophylactic group (40 vs. 33 days, p < 0.001; 56 vs. 49 days, p = 0.296, respectively). ICU admissions (50.7% vs. 32.8%; 69.0% vs. 50.8%), mortality (7.9% vs. 3.5%; 23.8% vs. 10.9%), and costs ($443,537 vs. $205,325; p < 0.001) were also higher in the prophylaxis group. Acute GVHD incidence differences were not statistically significant, with contradictory directions between risk subgroups. Conclusions: Prophylactic defibrotide was not associated with reduced SOS incidence and was associated with higher ICU use, longer LOS, increased mortality, and greater costs. These findings represent associations, not causation, and likely reflect residual confounding by indication-as defibrotide prophylaxis was preferentially administered to patients perceived to be at highest clinical risk. Prospective studies with appropriate confounding adjustment are needed to clarify the role of defibrotide in SOS prevention.

BACKGROUND:Appropriate terminology and definitions of neonatal encephalopathy (NE), hypoxic-ischemic encephalopathy (HIE), and perinatal asphyxia (PA) remain controversial. Participant criteria used in therapeutic hypothermia (TH) trials are frequently used as case definitions for NE/HIE/PA but studies are inconsistent. This review aims to assess variations in terminology and case participant criteria between trials for NE/HIE/PA. METHODS:Search strategy retrieved articles from databases (Embase, MEDLINE, CENTRAL, CDSR and WHO) for randomized controlled trials (RCTs) of interventions for NE/HIE/PA using any definition for NE/HIE/PA. Outcomes were a description of the terminology, definitions, and participant criteria. Two reviewers independently screened results. Qualitative results were synthesized in a narrative summary. RESULTS:The search provided 6768 results. 67 were included in the qualitative synthesis. HIE was the most frequently used term (56/67). NE was the least frequent (16/67). Some of the common inclusion criteria were Apgar scores (63/67), metabolic acidosis (58/67), and reduced level of consciousness (57/67). Most frequently employed exclusion criteria were prematurity (63/67), major congenital abnormalities (62/67), and identification beyond 6 h from birth (62/67). DISCUSSION:This review identified variations in terminology and in-trial participant criteria between studies. These results will inform a consensus process for developing a definition and case definition of NE/HIE/PA. IMPACT:Our article demonstrated significant variations in the terminology used to describe the condition of NE/HIE/PA, which demonstrates a need for more consistent definitions in terminology. A broad but meaningful definition of the condition would provide an inclusive approach while permitting subclassifications within the condition, and permitting comparisons and benchmarking across different settings. Developing consistency across these areas, as far as possible, would allow improved interpretation of interventions on long-term prognosis and greater generalizability of trial results.