Background: Exagamglogene autotemcel (exa-cel) is a non-viral cell therapy designed to reactivate fetal hemoglobin via ex vivo CRISPR-Cas9 gene-editing of autologous CD34+ hematopoietic stem and ...progenitor cells (HSPCs) at the erythroid-specific enhancer region of the BCL11A gene in patients (pts) with severe sickle cell disease (SCD). We report that in a pre-specified interim analysis, the pivotal CLIMB SCD-121 trial of exa-cel met primary and key secondary endpoints. Methods: CLIMB SCD-121 is an ongoing, 24-mo, phase 3 trial of exa-cel in pts age 12-35y with SCD and a history of ≥2 VOCs/y in 2y prior to screening. Primary efficacy endpoint is proportion of pts free of severe VOCs for ≥12 consecutive months (mos) (VF12); key secondary efficacy endpoints are proportion of pts free from inpatient hospitalization for severe VOCs for ≥12 consecutive mos (HF12) and proportion of pts free from severe VOCs for ≥9 consecutive mos (VF9). Evaluable pts for VF12 and HF12 had ≥16 mos follow-up after exa-cel infusion; pts evaluable for VF9 had ≥12 mos follow-up after infusion. Evaluation of primary and key secondary endpoints began 60 days after last RBC transfusion for post-transplant support or SCD management. Pts completing trial enrolled in long-term follow-up Study 131. Mean (SD) are shown except where noted. Results: As of 10 Feb 2023, 42 pts with SCD (age 21.2range 12-34y; 1228.6% age ≥12 to <18y; 4.2 VOCs/y at baseline) received exa-cel. Following infusion, all pts engrafted neutrophils and platelets (median 27 and 34.5 days, respectively). 19/20 (95.0%) pts evaluable for primary endpoint were free of VOCs for ≥12 consecutive mos (VF12; 95% CI, 75.1% to 99.9%; P<0.0001), 20/20 (100%) were free from hospitalizations for VOCs for ≥12 consecutive mos (HF12; 95% CI, 83.2 to 100.0; P<0.0001), and 29/30 (96.7%) were free of VOCs for ≥9 consecutive mos (VF9; 95% CI, 82.8 to 99.9; P<0.0001). In pts achieving VF12, VOC free duration was 21.8 (range 12.3-41.4) mos; 18 pts remained VOC free through follow-up and 1 pt had an adjudicated VOC in the setting of parvovirus infection ~22.8 mos after exa-cel; pt recovered fully and has since been VOC free (Fig). For all pts, total Hb was 12.1 g/dL at Month 3 and was maintained at ≥11.0 g/dL from Month 6 onward; HbF was 36.0% at Month 3 and was generally maintained at ≥ 40.0% from Month 6 onward with pancellular distribution (≥95% RBCs expressing HbF). Proportion of edited BCL11A alleles was stable over time in bone marrow CD34 + and peripheral blood nucleated cells. 36/39 pts with ≥60 days follow-up after last RBC transfusion (including those not yet evaluable) remained VOC free (up to 41.4 mos; Fig). Quality-of-life (QOL) measures showed clinically significant improvements from baseline. All pts had ≥1 adverse event (AE), most were Grade 1 or 2; 40 (95.2%) pts had AEs of Grade 3 or 4 severity. Most common AEs were nausea (66.7%), stomatitis (61.9%), febrile neutropenia (52.4%), headache (52.4%), and vomiting (52.4%). Most AEs and serious AEs (SAEs) occurred within first 6 mos after infusion. No pts had SAEs considered related to exa-cel. As previously reported, 1 pt died from respiratory failure due to COVID-19 unrelated to exa-cel. There were no study discontinuations or malignancies. Conclusions: The CLIMB SCD-121 trial met primary and key secondary endpoints, with exa-cel treatment resulting in early and sustained increases in Hb and HbF leading to elimination of VOCs in 95% of pts, elimination of inpatient hospitalization for VOCs in 100% of pts and improved QOL. Safety profile of exa-cel was generally consistent with myeloablative busulfan conditioning and autologous transplantation. These results show exa-cel has the potential to deliver a one-time functional cure to pts with severe SCD.
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IJS, IMTLJ, KILJ, NLZOH, NUK, SAZU, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Of 30 patients with severe sickle cell disease who were treated with gene-edited autologous hematopoietic stem and progenitor cells, 29 were free from vaso-occlusive crises for at least 12 ...consecutive months.
The Primary Immune Deficiency Treatment Consortium (PIDTC) enrolled children in the United States and Canada onto a retrospective multicenter natural history study of hematopoietic cell ...transplantation (HCT).
We investigated outcomes of HCT for severe combined immunodeficiency (SCID).
We evaluated the chronic and late effects (CLE) after HCT for SCID in 399 patients transplanted from 1982 to 2012 at 32 PIDTC centers. Eligibility criteria included survival to at least 2 years after HCT without need for subsequent cellular therapy. CLE were defined as either conditions present at any time before 2 years from HCT that remained unresolved (chronic), or new conditions that developed beyond 2 years after HCT (late).
The cumulative incidence of CLE was 25% in those alive at 2 years, increasing to 41% at 15 years after HCT. CLE were most prevalent in the neurologic (9%), neurodevelopmental (8%), and dental (8%) categories. Chemotherapy-based conditioning was associated with decreased-height z score at 2 to 5 years after HCT (P < .001), and with endocrine (P < .001) and dental (P = .05) CLE. CD4 count of ≤500 cells/μL and/or continued need for immunoglobulin replacement therapy >2 years after transplantation were associated with lower-height z scores. Continued survival from 2 to 15 years after HCT was 90%. The presence of any CLE was associated with increased risk of late death (hazard ratio, 7.21; 95% confidence interval, 2.71-19.18; P < .001).
Late morbidity after HCT for SCID was substantial, with an adverse impact on overall survival. This study provides evidence for development of survivorship guidelines based on disease characteristics and treatment exposure for patients after HCT for SCID.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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