Exagamglogene Autotemcel for Transfusion-Dependent β-Thalassemia
Notice bibliographique
Résumé
Background: Exagamglogene autotemcel (exa-cel) is a non-viral cell therapy designed to reactivate fetal hemoglobin (HbF) via ex vivo CRISPR-Cas9 gene-editing of autologous CD34+ hematopoietic stem and progenitor cells (HSPCs) at the erythroid-specific enhancer region of BCL11A in patients (pts) with transfusion-dependent β-thalassemia (TDT). Here we report that in a pre-specified interim analysis, the pivotal CLIMB THAL-111 trial of exa-cel met primary and key secondary endpoints. Methods: CLIMB THAL-111 is an ongoing, 24-month (mo), phase 3 trial of exa-cel in pts age 12-35y with TDT and a history of ≥100 mL/kg/y or ≥10 U/y packed red blood cell (RBC) transfusions in the 2y before screening. Primary endpoint is transfusion independence defined as proportion of pts maintaining a weighted average hemoglobin (Hb) ≥9 g/dL without RBC transfusion for ≥12 consecutive mos (TI12). Key secondary endpoint is proportion of pts maintaining a weighted average Hb ≥9 g/dL without RBC transfusion for ≥6 consecutive mos (TI6). Evaluable pts had ≥16 mos of follow-up after exa-cel infusion. Evaluation of TI12 and TI6 started 60 days after last RBC transfusion for post-transplant support or TDT management. Pts completing trial enrolled in long-term follow-up Study 131. Mean (SD) shown except where noted. Results: As of 16 Jan 2023, 52 pts (mean age 21.5[range 12-35]y; 18[34.6%] age ≥12 to <18y; 31[59.6%] with severe genotypes [β 0/β 0 or β 0/β 0-like], median annualized transfusion volume 201.0 mL/kg) received exa-cel; median follow-up 20.4 (range 2.1-48.1) mos. Following infusion, all pts engrafted neutrophils and platelets (median 29 and 44 days, respectively). Of the 35 pts evaluable for primary and key secondary endpoints, 32 (91.4%) achieved TI12 and TI6 (95% CI: 76.9%, 98.2%; P<0.0001). Pts achieving TI12 stopped transfusions 35.2 (SD, 18.5) days after exa-cel infusion and remained transfusion independent for 22.5 (range, 13.3, 45.1) mos (Fig). For 3 pts not achieving TI12, one had reductions in annualized RBC transfusion volume of 83.9%, while the others have been transfusion-free for 7.3 mos and 4.0 mos starting 60 days after the last transfusion. For all pts, total Hb was 11.4 g/dL at Month 3 (≥12g/dL Month 6 onward) and HbF was 7.7 g/dL at Month 3 (≥ 10 g/dL Month 6 onward) with pancellular distribution (≥95% RBCs expressing HbF Month 6 onward). Proportion of edited BCL11A alleles was stable over time in bone marrow CD34 + and peripheral blood nucleated cells. Pts not yet evaluable and with sufficient follow-up were also transfusion-free. Quality-of-life (QOL) measures showed clinically significant improvements. All pts had ≥1 adverse event (AE), most were Grade 1 or 2; 46 (88.5%) pts had AEs of Grade 3 or 4 severity. Most common AEs were febrile neutropenia (61.5%), headache (53.8%), and stomatitis (50.0%). Most AEs and serious AEs (SAEs) occurred within first 6 mos after infusion. Two pts had SAEs considered related to exa-cel: headache, hemophagocytic lymphohistiocytosis (HLH), acute respiratory distress syndrome and idiopathic pneumonia syndrome (latter also considered related to busulfan) all in the context of HLH (n=1) and delayed engraftment and thrombocytopenia (both also considered related to busulfan) (n=1), which all resolved. There were no deaths, discontinuations, or malignancies. Conclusions: The CLIMB THAL-111 trial met primary and key secondary endpoints, with exa-cel treatment resulting in early and sustained increases in Hb and HbF leading to transfusion independence in >90% of pts with TDT 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 TDT.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,005 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».