A phase 2 randomized study of chemoimmunotherapy with or without eflornithine (DFMO) in relapsed/refractory neuroblastoma: A Children’s Oncology Group (COG) report.
Notice bibliographique
Résumé
10001 Background: Dinutuximab, irinotecan, temozolomide and GM-CSF (DIT) is widely used in first relapsed/ refractory high-risk neuroblastoma (r/r HRNB), however <50% of patients (pts) respond. ODC1 is a key enzyme important for NB cell survival. Difluoromethylornithine (DFMO) irreversibly inhibits ODC1, suppressing polyamine biosynthesis and driving anti-NB activity. DFMO also inhibits arginase and may enhance immunotherapy in r/r NB. COG ANBL1821 was a randomized phase 2 study for pts with r/r NB that evaluated response to DIT with or without DFMO (NCT03794349). Methods: Patients with first episode of r/r NB were randomized 1:1 to DIT (Arm A) or DIT with DFMO (6750 mg/m 2 divided TID; Arm B). They were stratified by measurable/evaluable disease, MYCN status, prior anti-GD2 therapy, and prior DFMO therapy. Cycles were 21 days. On Arm B, DFMO was initially given continuously; discontinuous DFMO dosing (days 1-7 and 15-21) was instituted due to ototoxicity in the initial cohort. Objective Response Rate [(ORR); sum of complete (CR), partial (PR), and minor (MR) responses per the 2017 International Neuroblastoma Response Criteria (INRC)] was determined based on central review of imaging. Toxicities were graded per CTCAE v5.0. Results: 91 eligible and evaluable pts (44 Arm A, 47 Arm B) were randomized May 2019-Jan 2024. 28/44 (63.6%) of Arm A pts and 32/47 (68.1%) of Arm B pts had relapsed or progressive disease (RPD); the remaining pts had refractory disease. The ORR was 61.4% (27/44) for Arm A and 57.4% (27/47) for Arm B (p=0.566). On Arm A, 22/44 (50%) achieved CR or PR compared to 23/27 (48.9%) on Arm B. Response rates for pts with RPD were similar to those with refractory disease in both arms. The 1-year progression-free survival (PFS) for Arm A was 70.0±8.0% and 56.8±8.2% for Arm B. Overall survival was 87.0±5.7% and 81.4±6.3% for Arms A and B, respectively. The most common toxicities reported on both arms were hematologic and gastrointestinal. Fewer pts on Arm B (n=7) had Grade 3+ pain than on Arm A (n=15) (p=0.0326). Hearing loss was a toxicity of interest; with continuous dosing, 55.6% (5/9) of Arm B pts developed hearing loss requiring DFMO dose hold. With discontinuous dosing, hearing loss was 15.8% (6/38) on Arm B compared to 6.3% (2/32) on Arm A (p=0.275). 14/16 (87.5%) NB+ marrows were GD2+ at enrollment; loss of GD2 was not detected on persisting NB cells in on therapy marrows analyzed. Conclusions: The addition of DFMO to DIT did not improve response rates in pts with first r/r HRNB, though the response rates in both arms confirmed DIT activity in this population. The ORR to DIT is higher than previously reported, likely due to use of the 2017 INRC that includes MR in calculation of ORR. Rates of CR+PR in this trial were similar to those previously reported. DFMO was associated with an increased incidence of hearing loss which was partially mitigated by discontinuous dosing. Clinical trial information: NCT03794349 .
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 | 0,002 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,002 | 0,001 |
| Méta-épidémiologie (sens large) | 0,002 | 0,001 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,001 |
| Communication savante | 0,001 | 0,001 |
| Science ouverte | 0,001 | 0,000 |
| Intégrité de la recherche | 0,002 | 0,003 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,006 | 0,001 |
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 ».