S1636 FRACTIONATED DOSING OF ARI‐0001 CELLS (A3B1:CD8:4–1BB:CD3Z CAR19) AND EARLY TOCILIZUMAB ADMINISTRATION MAY REDUCE THE INCIDENCE OF SEVERE CYTOKINE RELEASE SYNDROME IN PATIENTS WITH CD19+ MALIGNANCIES
Notice bibliographique
Résumé
Background: Cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS) are major adverse events in patients receiving CART cell therapy. Forecasting the in vivo toxicity of “living drugs” like CART cells is complex and multifactorial. Some of these factors might be disease burden and CART cell dose, so adjusting dose to disease burden might be a plausible strategy to minimize toxicity. Nevertheless, reliably assessing disease burden is a tricky task due to technical issues and even hour‐changing disease dynamics. Aims: To characterize the impact of ARI‐0001 cell dose fractioning on CRS and ICANS in two cohorts (fractioned vs single‐full dose) of adult and pediatric patients with relapsed/refractory (R/R) CD19+ malignancies. Methods: Eligibility criteria included patients with R/R CD19+ acute lymphoblastic leukemia (ALL), non‐Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL) who had failed standard available therapy. All patients were conditioned with fludarabine (90 mg/m 2 ) and cyclophosphamide (900 mg/m 2 ) before receiving ARI‐0001 cells (0.5–5 x10 6 cells/kg). Originally, patients received the entire ARI‐0001 cell dose in a single infusion (day 0) (single dose [SD] cohort), but after 3 fatal toxic events (two of them CRS) a major amendment to the protocol was implemented. After the amendment, patients received 10%, 30% and 60% of the total ARI‐0001 cell dose on days 0, +1 and +2 (fractionated dose [FC] cohort), with administration of fractions 2 and 3 contingent on the absence of CRS signs or symptoms. Also, before the amendment tocilizumab was administered to patients with grade ≥ 3 CRS and after amendment to patients with grade ≥ 2 CRS. Results: As of February 2019, a total of 30 patients (23 adults/7 pediatrics) have received ARI‐0001 cells (19 SD and 11 FD). Diagnoses were ALL (25), NHL (4) and CLL (1). Median age was 24 years (3–54), and 56% were men. 21/25 of ALL patients relapsed after alloHCT, and 3/4 of NHL patients relapsed after autoHCT. At screening, active disease (≥ 5% lymphoblasts in the bone marrow, or tumor masses by PET‐CT) was documented in 62% of SD patients and 33% in FD patients. The remaining patients were in complete remission at screening. CRS was observed in 16/19 (84%) of SD patients and 5/11 (45%) of FD patients. Indeed, fraction 3 was omitted in 2/11 (18%) FD patients due to early onset of CRS. Moreover, grade ≥ 3 CRS occurred in 5/19 (26%) of SD patients, including 2 fatal events, whilst 0/11 (0%) cases of grade ≥ 3 CRS were observed in FD patients. Finally, tocilizumab was administered to 26% (5/19) of SD patients and to 18% (2/11) of FD patients. Grade 1–2 ICANS was documented in 3/19 (16%) of SD patients and in 3/11 (27%) of FD patients. The only 2 cases of grade 2 ICANS occurred in patients with known active CSF infiltration at the time of ARI‐0001 cell infusion. No cases of grade ≥ 3 ICANS were seen neither in SD nor FD patients, and no specific treatment was required. Summary/Conclusion: The fractionated administration of ARI‐0001 cells may improve their safety profile by reducing the incidence of grade ≥ 3 CRS. The incidence of ICANS appeared equally low with both approaches. Based on these preliminary results, FD has been selected for a phase 2 multicenter trial on the use of ARI‐0001 cells in patients with R/R ALL.
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 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 | 0,000 |
| 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 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 ».