Health-Related Quality-of-Life Improvements after Exagamglogene Autotemcel in Patients with Severe Sickle Cell Disease
Notice bibliographique
Résumé
Background: Severe sickle cell disease (SCD) is characterized by recurrent vaso-occlusive crises (VOCs), which negatively impact health-related quality of life (HRQoL). Exagamglogene autotemcel (exa-cel), a one-time, ex vivo, CRISPR/Cas9 gene-edited, autologous cell therapy shown to eliminate VOCs is approved for the treatment of severe SCD in patients ≥12 years of age. We report long-term HRQoL measures for participants with SCD in the ongoing phase 3 CLIMB SCD-121 and CLIMB-131 studies. Methods: CLIMB SCD-121 is a 2-year, pivotal phase 3 study of a single dose of exa-cel in participants (12-35 years) with SCD and a history of ≥2 VOCs/year in each of the 2 years before screening. Participants who completed CLIMB SCD-121 may enroll in the 13-year, long-term extension study, CLIMB-131. Changes from baseline over time for patient-reported outcomes were assessed as a secondary endpoint in both studies: EuroQol Scale 5 dimensions 5 levels of severity (EQ-5D-5L; includes descriptive system and visual analog scale [VAS]), Functional Assessment of Cancer Therapy Bone Marrow Transplant (FACT-BMT; includes FACT-General [FACT-G] and bone marrow transplant subscale [BMTS]), Adult Sickle Cell Quality of Life Measurement Information System (ASCQ-Me), 11-point pain Numerical Rating Scale (NRS) for adults; EuroQol Scale 5 dimensions youth (EQ-5D-Y), Pediatric Quality of Life Inventory (PedsQL), and 11-point pain NRS for adolescents. Minimal clinically important difference (MCID) thresholds and population norms are provided to contextualize clinical meaningfulness of HRQoL change scores, as applicable. Data are presented for participants who were followed for ≥16 months and were included in the efficacy evaluable population. Results: As of May 2024, a total of 29 adults (mean: 23.6 years; range: 18, 34) and 11 adolescents (mean: 14.5 years; range: 12, 17) in the efficacy evaluable population were followed for up to 4.9 years (median 2.6 years, range: 1.4, 4.9) after exa-cel infusion. Clinically meaningful improvements were observed in all HRQoL instruments and met or exceeded MCID thresholds, where applicable. For adults, baseline EQ-5D-5L US index (mean [SD]: 0.77 [0.26]) and EQ VAS (mean [SD]: 70.3 [22.4]) scores were lower than that of the general US population norm (EQ-5D-5L US index mean [SD]: 0.85 [0.21]; EQ VAS mean [SD]: 80.4 [15.6]) and similar to baseline scores for adults with recurrent VOCs. By Month 6, substantial improvements that were maintained through Month 36 were observed in EQ-5D-5L health utility US index (n=14; mean [SD]: 0.12 [0.16]; MCID: 0.078) and EQ VAS (n=14; mean [SD]: 26.8 [22.0]; MCID: 7-10). Mean FACT-G total scores improved from baseline at Month 36 (n=14; 24.3 [23.4], MCID: 3 to 7) with improvements seen in all 4 subscales (physical, social/family, emotional, functional well-being). Mean BMTS scores improved by Month 6 and were maintained through Month 36 (n=14; 5.1 [6.4], MCID: 2 to 3). All subscales of the ASCQ-Me except stiffness (emotional impact, pain impact, social functioning impact, sleep impact, pain episode frequency, pain episode severity) showed clinically meaningful improvements from baseline through month 36 exceeding MCID; for the pain-related subscales, the largest numerical improvement was pain episode frequency (n=14; mean [SD]: -21.1 [6.4], MCID: -5). Improvements in pain NRS were observed by Month 6 and maintained through Month 36 (n=14; mean [SD]: -1.9 [2.2], MCID: -1). For adolescents, improvements in the EQ-5D-Y VAS were observed by Month 12 and maintained through Month 24 (n=6; mean [SD]: 11.2 [26.6]). Mean PedsQL total score improved by Month 3 and was maintained through Month 24 (n=5; 27.4 [16.8], MCID: 4.36), with consistent improvements in domains and sub-domains, including physical functioning and psychosocial health (social, emotional, school functioning). For adolescents, improvements in pain NRS were maintained through Month 24 (n=7; mean [SD]: -0.9 [0.7], MCID: -1). Conclusion: These results demonstrate that exa-cel provides substantial and durable clinical benefit to adults and adolescents with SCD in HRQoL including physical, social/family, emotional, functional well-being, pain experience, and overall health status.
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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 | 0,001 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,001 |
| 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) | 0,002 | 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 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 ».