CORRELATIVE ANALYSES OF CYTOKINE RELEASE SYNDROME AND NEUROLOGICAL EVENTS IN TISAGENLECLEUCEL‐TREATED RELAPSED/REFRACTORY DIFFUSE LARGE B‐CELL LYMPHOMA PATIENTS
Notice bibliographique
Résumé
Background: Tisagenlecleucel (anti-CD19 CAR-T cell therapy) has shown durable responses and a manageable safety profile in adult patients (pts) with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL). We report a 24 mo clinical update and correlative analyses between cytokine release syndrome (CRS)/neurological events (NE) and inflammatory/lab analyte markers. Methods: JULIET (NCT02445248) is a single-arm, pivotal, phase 2 trial of tisagenlecleucel in adult pts with r/r DLBCL. The primary endpoint was overall response rate (ORR: complete [CR] + partial response). Peak (within 1 mo of infusion) serum cytokine levels/lab parameters were correlated with rate/grade (gr) of CRS (by Penn) and NE (by CTCAE v4.03) within 8 wk of infusion. Results: As of 11 Dec 2018, 115 pts were infused (99 evaluable for efficacy). ORR remained 54% (95% CI: 43, 64), CR rate was 40%, and median duration of response was not reached (NR; 95% CI: 10, –) at a max follow-up of almost 24 mo from onset of response. Of 31 pts with CR at 6 mo, 3 relapsed between 6-12 mo and 1 relapsed beyond 12 mo. Median overall survival for all 115 pts was 10.3 mo (NR for pts in CR). Severe (gr 3/4) CRS and NE occurred in 23% and 11%, respectively. 83% of pts with any gr NE also had CRS; 62% of pts with severe NE had severe CRS. Median time to onset of CRS and NE was 3 and 6 d, respectively. Peak cytokine levels within 1 mo of infusion were increased in pts with CRS/NE and the trend was more noticeable in pts with severe CRS and severe NE. Higher CRP, ferritin, interferon-ɣ (IFNG), IL2, IL6, and IL10 were observed in pts with severe CRS; severe NE showed similar trends of a lesser degree, except for IFNG. In pts with CRS, cytokines peaked on d 6-9, with early increase of IL2, IL6, and IFNG in the first 2 d post-infusion with severe CRS. Low platelet count, elevated lactate dehydrogenase, and below-normal albumin levels were seen after lymphodepleting chemotherapy; these trends continued post-infusion in pts with severe CRS. As CRS progressed, hepatic and kidney dysfunction-related analytes trended toward an increase, peaking 2 wk post-infusion in pts with severe CRS. Additional univariate/multivariate analyses using pts’ disease and clinical characteristics in an attempt to predict CRS/NE severity are ongoing. Conclusions: With almost 24 mo max follow-up, tisagenlecleucel continued to demonstrate durable efficacy. Severe NE appeared to correlate with severe CRS. Trends in peak levels of several markers were noted with severe CRS and – to a lesser extent – severe NE. Keywords: CD19; cytokines; diffuse large B-cell lymphoma (DLBCL). Disclosures: Bachanova, V: Consultant Advisory Role: Novartis; Research Funding: GAMIDA Cell, UNUM, Novartis, GT Biopharm. Westin, J: Consultant Advisory Role: Novartis, Kite Pharma, Juno, Celgene, Janssen, Genentech. Tam, C: Honoraria: Novartis. Borchmann, P: Honoraria: Novartis. Jaeger, U: Honoraria: AbbVie, Bioverativ, Celgene, Gilead, Janssen, MSD, Novartis, Roche, Takeda Millenium, Amgen, AOP Orphan, BMS, Sandoz; Research Funding: Bioverativ, Celgene, Gilead, Janssen, MSD, Novartis, Roche; Other Remuneration: AbbVie, Celgene, Gilead, Janssen, MAD, Novartis, Roche, Takeda Millenium, Amgen, AOP Orphan, BMS, Sandoz. McGuirk, J: Honoraria: Kite Pharma; Research Funding: Novartis, Kite Pharma, Fresenius Biotech, Astellas Pharma, Bellicum Pharmaceuticals, Gamida Cell, Pluristem Ltd. Holte, H: Consultant Advisory Role: Novartis; Honoraria: Novartis. Waller, E: Employment Leadership Position: Cambium Medical Technologies; Consultant Advisory Role: Kalytera, Novartis; Stock Ownership: Cerus Corporation, Chimerix; Honoraria: Cambrium Medical Technologies, Kalytera, Novartis; Research Funding: Celldex, Novartis, Pharmacyclics. Jaglowski, S: Honoraria: Kite Pharma, Juno; Research Funding: Novarits. Bishop, M: Employment Leadership Position: United Healthcare; Honoraria: Celgene, Jeneau Therapeutics, Novartis. Andreadis, C: Honoraria: Novartis, Genentech, Seattle Genetics, Gilead, Astellas; Research Funding: Novartis, Cellerant Therapeutics, Incyte, Pharmacyclics, Amgen, Genentech. Fleury, I: Honoraria: Gilead, Novartis, Roche, Seattle Genetics, Janssen, AbbVie. Teshima, T: Honoraria: Novartis; Research Funding: Novartis. Mielke, S: Consultant Advisory Role: Celgene, KIADIS Pharma, Miltenyi Biotec, DGHO, EHA. Salles, G: Consultant Advisory Role: Novartis; Honoraria: Novartis. Ho, P: Other Remuneration: Novartis, Celgene, La Jolla Pharmaceuticals. Izutsu, K: Honoraria: Novartis, Eisal, Kyowa Hakko Kirin, MSD, Takeda, Janssen, Bristol Myers Squib, Dainihon Sumitomo, Mundipharma, Nihon Mediphysics, Chugai, AstraZeneca, AbbVie, Bayer, Ono, Celgene; Research Funding: Novartis, Eisal, MSD, Takeda, Janssen, Mundipharma, Chugai, AbbVie, Bayer, Ono, Gilead, Zenyaku, Celgene, Solasia, Symbio, Astellas, Astellas Amgen, Diichi Sankyo. Maziarz, R: Consultant Advisory Role: Novartis, Incyte, Juno Therapeutics; Honoraria: Novartis, Incyte, Juno Therapeutics, Kite Therapeutics; Research Funding: Novartis; Other Remuneration: Athersys, Inc. Van Besien, K: Research Funding: Novartis. Kersten, M: Consultant Advisory Role: Roche, Celgene, Takeda, Novartis, Kite, BMS; Honoraria: Roche, Celgene, Takeda, Novartis, Kite; Research Funding: Roche, Celgene, Takeda. Wagner-Johnston, N: Consultant Advisory Role: Juno, ADC Therapeutics, Janssen. Corradini, P: Consultant Advisory Role: Celgene, AbbVie, Amgen, Daiichi Sankyo, Gilead, Janssen, Kiowakirin, Novartis, Roche, Sanofi, Servier, Takeda. Han, X: Employment Leadership Position: Novartis. Agoulnik, S: Employment Leadership Position: Novartis. Chu, J: Employment Leadership Position: Novartis. Eldjerou, L: Employment Leadership Position: Novarits. Pacaud, L: Employment Leadership Position: Novartis. Schuster, S: Honoraria: Celgene, Genentech, Merck, Pharmacyclics, Novartis, Nordic Nanovector, Acerta, Pfizer, Gilead; Research Funding: Celgene, Genentech, Merck, Pharmacyclics, Novartis, Gilead.
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 | 0,001 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 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 | 0,000 |
| 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 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 ».