S270: TRANSFUSION INDEPENDENCE AFTER EXAGAMGLOGENE AUTOTEMCEL IN PATIENTS WITH TRANSFUSION-DEPENDENT ΒETA-THALASSEMIA
Notice bibliographique
Résumé
Topic: 27. Thalassemias Background: Exagamglogene autotemcel (exa-cel) is a one-time, non-viral cell therapy designed to reactivate fetal hemoglobin (HbF) via ex vivo CRISPR/Cas9 gene-editing at the erythroid enhancer region of BCL11A in autologous CD34+ hematopoietic stem and progenitor cells. Aims: Evaluate efficacy and safety of exa-cel in patients (pts) with transfusion-dependent β-thalassemia (TDT) in a pre-specified interim analysis of the pivotal CLIMB THAL-111 trial. Methods: CLIMB THAL-111 is an ongoing, 24-mo, phase 3 trial of a single dose of exa-cel in pts age 12-35y with TDT and a history of ≥100 mL/kg/y or ≥10 U/y of packed red blood cell (RBC) transfusions 2y before screening. Primary and key secondary efficacy endpoints are proportion of pts who maintained a weighted average hemoglobin (Hb) ≥9 g/dL without RBC transfusion for ≥12 mos (TI12; primary endpoint) and ≥6 mos (TI6; key secondary endpoint). Evaluable pts included those followed for ≥16 mos 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. Results: As of 06 Sept 2022, 48 pts (median age 20 [range 12-35] y; 16 [33.3%] age ≥12 to <18y; 28 [58.3%] with severe genotypes [β0/β0 or β0/β0-like]) received exa-cel. Of the 27 pts evaluable for primary and key secondary endpoints, 24 (88.9%) achieved TI12 and TI6 (95% CI: 70.8%, 97.6%; P<0.0001). Pts achieving TI12 had a mean time to last transfusion of 37 (SD, 20.6) days after exa-cel infusion and remained transfusion independent (mean [range] duration 20.5 [12.1, 40.7] mos; Fig). The 3 pts not achieving TI12 had substantial reductions (70.3%, 79.6% and 95.5%) in transfusion volume from baseline. For all pts, mean total Hb was ≥11g/dL at Month 3 (≥12g/dL Month 6 onward) and mean HbF was ≥6 g/dL at Month 3 (≥ 9g/dL Month 6 onward) with pancellular distribution. Mean 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 improvement from baseline: mean EQ VAS, FACT-G and BMTS scores increased by 21.0, 17.0, and 7.8 points at Month 24. All pts with sufficient follow-up achieved neutrophil and platelet engraftment (median 29 and 44 days, respectively). All pts had ≥1 adverse event (AE), most were Grade 1 or 2; 41 (85.4%) pts had AEs of Grade 3 or 4 severity. The most common AEs were febrile neutropenia (58.3%), headache (54.2%), and stomatitis (50.0%). Most AEs and serious AEs (SAEs) occurred within first 3 mos after infusion. Two pts had SAEs considered related to exa-cel: one pt had SAEs of headache, hemophagocytic lymphohistiocytosis (HLH), acute respiratory distress syndrome and idiopathic pneumonia syndrome (latter also considered related to busulfan) all in the context of HLH, and another pt had SAEs of delayed engraftment and thrombocytopenia (both also considered related to busulfan). All SAEs resolved. There were no deaths, discontinuations, or malignancies. Summary/Conclusion: In this pre-specified interim analysis of the pivotal trial of exa-cel in TDT, almost all pts achieved transfusion independence, with early and sustained Hb and HbF increases, durable allelic editing, and improved QOL. Safety profile of exa-cel was generally consistent with myeloablative busulfan conditioning and autologous transplantation. These results show exa-cel can deliver a one-time functional cure for pts with TDT.Keywords: beta thalassemia, Hemoglobinopathy, Gene therapy, Clinical trial
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Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| 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 | 0,001 |
| 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 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 0,000 |
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 tête enseignante, 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 ».