Dose-Dense Chemoimmunotherapy Including Early CNS Prophylaxis for High-Risk DLBCL. -Final Analysis from a Nordic Phase II Study (the CHIC trial)
Notice bibliographique
Résumé
Abstract Introduction: Survival of patients with high-risk diffuse large B-cell lymphoma (DLBCL) is suboptimal, and the risk of early central nervous system (CNS) progression is high. Here we present the final results from a Nordic phase II study, where dose-dense chemoimmunotherapy including early systemic CNS prophylaxis with high dose methotrexate (HD-Mtx), further intensified by intrathecally (IT) administered liposomal cytosine arabinoside (AraC), was given. Patients and methods: Inclusion criteria were age 18-65 years, de novo DLBCL or grade 3B follicular lymphoma without clinical, radiological or cytological signs of CNS involvement, age adjusted IPI 2-3, WHO performance score 0-3, and/or anatomical sites related to increased risk for CNS recurrence (e.g. testis, facial sinuses, orbita). Treatment consisted of two courses of HD-Mtx in combination with R-CHOP14, followed by four courses of R-CHOEP14 and one course of R-HD-AraC. Liposomal AraC was administered IT at courses 1, 3 and 5 (omitted during a period of production halt). Primary end points were failure free survival (FFS; disease progression, discontinuation of protocolled therapy due to toxicity, death from any cause) and CNS progression rate at 18 months. Among the secondary endpoints were the identification of biological risk factors for high risk disease and prognostic role of cerebrospinal fluid (CSF) cytology-/flow cytometry (FC)+for CNS recurrence. Results: Of the accrued 143 patients, 140 met the inclusion criteria and were evaluable for baseline characteristics and primary endpoints. Of these, 132 had a complete set of treatment data. The male/female ratio was 1.7 and the median age 56 years (range 20-64). The majority of the patients had DLBCL (96%), advanced clinical stage (93%), elevated LDH (91%), more than one extranodal site (73%), and B-symptoms (64%). A bulky lesion (>10 cm) was present in 37% of the patients and 11 CSF samples (8%) were FC+. Most patients (n=127, 96%) received a full treatment schedule. Liposomal AraC was given to 81 (61%) and radiotherapy to 39 (30%) patients. Grade 4 infections were observed in 12% of the patients. The frequency of grade 3-4 mucositis as well as gastrointestinal toxicity was 20%, and of grade 3 arachnoiditis 2,5%. Three toxic deaths were observed. In addition, three patients developed AML/MDS and one PML. At the end of treatment, CR/CRu, PR and PD rates were 79%, 17% and 3%, respectively. Of the 120 patients who underwent PET-CT, 92 (77%) achieved a metabolic CR (Deauville score (DS) 1-3). Three patients had primary refractory disease. At a median follow-up of 30 months, additional 14 patients had relapsed, three of them in the CNS (only one had a pre-therapeutic FC+ CSF), and 15 had died. FFS, PFS, OS and CNS progression rates at 30 months were 80%, 83%, 90%, and 2.4%, respectively. PET positivity (DS 4-5) at the end of treatment (p=0.019) and BCL2 expression (p=0.049) were associated with increased risk of progression, whereas other factors, such as molecular subtype (GC versus non-GC), Ki-67 score (≥70%), aaIPI group (2 versus 3), number of extranodal sites, FC-based CSF positivity, and treatment with liposomal AraC did not seem to have significant impact on outcome. Conclusions: Safety profile and final outcome results of the Nordic CHIC trial indicate high response rates, favorable survival, low number of CNS recurrences and manageable toxicity as a result of this CNS targeted intensive therapy schedule. PET response at the end of therapy and selected biological factors identify patients at high risk of progression. Disclosures Leppa: Roche: Honoraria, Other: Travel expenses, Research Funding; Janssen: Research Funding; Bayer: Research Funding; Mundipharma: Research Funding; Amgen: Research Funding; Takeda: Honoraria, Other: Travel expenses; CTI Life Sciences: Honoraria; Merck: Other: Travel expenses. Joergensen:Amgen: Research Funding; Mundipharma: Research Funding. Mannisto:SOBI: Honoraria; Pfizer: Honoraria; Gilead: Other: Travel expenses; Celgene: Other: Travel expenses; Novartis: Other: Travel expenses; Amgen: Other: Travel expenses; Takeda: Honoraria, Other: Travel expenses; Roche: Honoraria, Other: Travel expenses. Jerkeman:Gilead: Research Funding; Celgene: Research Funding; Mundipharma: Research Funding; Amgen: Research Funding; Janssen: Research Funding. Holte:Amgen: Research Funding; Mundipharma: Research Funding.
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 | 0,003 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,002 | 0,002 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,001 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,001 |
| 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 ».