220 | HIGH EFFICACY OF BRIEF BRAF AND MEK COINHIBITION, ALONE AND COMBINED WITH ANTI‐CD20 IMMUNOTHERAPY, IN RELAPSED/REFRACTORY HAIRY CELL LEUKEMIA: A PHASE‐2 TRIAL
Notice bibliographique
Résumé
Introduction: ∼50% of HCL patients (pts) relapse after purine analogs (PA) chemotherapy. Vemurafenib (VEM), an oral inhibitor of the BRAF-V600E kinase mutation (genetic cause of HCL; Tiacci et al. NEJM, 2011), proved active when given for a few months to R/R pts (∼35% complete remissions/CR—Tiacci, Park et al. NEJM, 2015). Still, minimal residual disease/MRD persisted in the bone marrow (BM) even in CR pts and the median progression-free survival (PFS) was ∼1 year. Moreover, BM HCL cells often showed ERK phosphorylation (pERK+) despite ongoing BRAF inhibition by VEM, suggesting bypass MEK/ERK reactivation downstream of BRAF as resistance mechanism. BRAF+MEK coinhibition with dabrafenib + trametinib, given to BRAF inhibitor-naïve pts for an indefinite duration (median ∼3 years), led to 66% CR but still rare MRD-negativity (16%; Kreitman et al. Blood, 2023); such a continuous therapy sustained a high PFS at 2 years (94%) but led to frequent serious toxicities (35% of pts). Adding rituximab/RTX (8 doses) to a short VEM course (8 weeks) yielded 87% CR, frequent MRD-negativity (60%), 78% PFS at ∼3 years of median follow-up, and few clinically relevant toxicities (3% of pts) (Tiacci et al. NEJM, 2021). To improve these results, we tested in R/R HCL a brief BRAF+MEK coinhibition (with VEM + cobimetinib/COB) combined to obinutuzumab/OBI (potentially more active than RTX), after establishing the currently unknown efficacy and safety of VEM+COB in HCL. Methods: We enrolled 19 R/R pts (median age 58 years; median of 3 previous therapies, including BRAF inhibitor ± RTX in 4 pts [21%]) in a phase-2 multicenter trial testing VEM (960 mg bid) + COB (60 mg daily, 21 days on/7days off) for 2–3 cycles (28 days each), followed at disease progression (PD) by another brief course of VEM+COB combined to OBI (8 doses over 6 cycles, starting together with VEM+COB). Results: VEM+COB toxicity was as expected and manageable. Clinical events (i.e., not laboratory-only abnormalities) were mostly grade 1–2, consisting mainly in rash due to either drug; arthralgia and photosensitivity due to VEM; and diarrhoea, oral aphthosis and serous retinopathy due to COB. 17/19 pts responded (89%), and 13 of 18 evaluable pts had a CR (72%; 1/13 MRD-). BM pERK+ HCL cells were detected in only 1/9 (11%) evaluable pts. Median PFS was long, 42 months, and a sizable pts subset (4/19, 21%) is free from PD at > 5 years. Of 12 pts with PD, 5 have not (or not yet) received VEM+COBI+OBI for various reasons, while 7 were treated with this short regimen 22–79 months after VEM+COB. All 7 pts (100%) obtained MRD- CR, and are free from cytopenia recurrence at 4–51 months (n = 6 pts) or had a cytopenia relapse at 44 months (n = 1 pt); only 2 clinically relevant toxicities were recorded. Conclusions: Brief BRAF+MEK coinhibition with VEM+COB, especially if boosted by anti-CD20 immunotherapy through OBI, is very effective in R/R HCL (see Figure), and compares well with other strategies tested in this setting. Encore Abstract: EHA 2025 Keywords: molecular targeted therapies; combination therapies; indolent non-Hodgkin lymphoma No potential sources of conflict of interest.
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 | 0,001 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,002 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,001 |
| Communication savante | 0,000 | 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) | 0,000 | 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 ».