Bleximenib in combination with intensive chemotherapy: A phase 1b study in newly diagnosed Acute Myeloid Leukemia with KMT2A or NPM1 alterations
Notice bibliographique
Résumé
Abstract Objective Bleximenib is a potent, selective menin inhibitor with activity in NPM1-mutated (NPM1m)or KMT2A-rearranged (KMT2Ar) acute myeloid leukemia (AML), now in Phase 3 development in combination with AML-directed therapies. Previous data have shown an acceptable safety and efficacy profile in participants (pts) with newly diagnosed (ND) NPM1m or KMT2Ar AML treated with bleximenib in combination with intensive chemotherapy (IC) (Recher C, ASH 2024). We now report updated safety and efficacy data (clinical cut-off: July 2025) from this combination treatment in IC-eligible ND AML pts (Cohort C1). Methods In the ALE1002 Phase 1b, multicenter, dose-finding study (NCT05453903), pts in Cohort C1 received a standard '7+3' regimen of cytarabine 200 mg/m2/day and daunorubicin 60 mg/m2/day intravenous (IV) or idarubicin 12 mg/m2/day IV in combination with bleximenib. Bleximenib was administered by mouth at 30–100 mg twice daily (BID) continuously starting on Day 4 of induction, including during count recovery. Pts who achieved a complete remission (CR) received consolidation therapy with up to 4 cycles of intermediate-dose cytarabine plus bleximenib. Those not proceeding to allogeneic hematopoietic stem cell transplant could receive bleximenib in continuation for up to 12 months. The safety dataset includes all dosed pts receiving bleximenib 30–100 mg BID in combination with '7+3'. Relative dose intensity (RDI) is the total bleximenib dose received divided by total planned doses of bleximenib for a 28-day cycle. The intention-to-treat efficacy dataset comprises pts with NPM1m or KMT2Ar who received bleximenib 100 mg BID in combination with '7+3', including those who discontinued prior to first disease evaluation. Response criteria was assessed by each investigator according to European LeukemiaNet (ELN) recommendations. Results The safety analysis set included 44 ND AML pts (median age, 57.0 years [range, 19–71]; 52.3% female; 56.8% NPM1m, 43.2% KMT2A; 15.9% FLT3 co-mutations; ELN risk classification: 44.2% favorable, 27.9% intermediate, 27.9% adverse). The median duration of follow-up was 6.3 months (range, 1.31–22.51). All 44 pts had ≥1treatment-emergent adverse event (TEAE, all grades), with the most common being thrombocytopenia (35/44; 79.5%), neutropenia (32/44; 72.7%), diarrhea (31/44; 70.5%), nausea (30/44; 68.2%), anemia, and febrile neutropenia (both 28/44; 63.6%). The majority of cytopenia TEAEs were Grade 3/4, consistent with an IC backbone. Of the 44 pts dosed, the 30- and 60-day mortality was 0/44 (0%) and 1/44 (2.3%), respectively. There was no differentiation syndrome (DS) observed. Three TEAEs of QT prolongation were reported, all of which were Grade 1/2 and resolved without bleximenib interruption. Among 37 pts achieving composite CR (cCR=CR + CR with partial hematologic recovery [CRh] + CR with incomplete hematologic recovery [CRi]), the median time from Day 1 of induction to platelet count recovery (50x109/L) was 32.0 days (range, 22.0–82.0), and the median time to neutrophil count recovery (0.5x109/L) was 30.0 days (range, 21.0–71.0). During induction, the median RDI of bleximenib was 100% (range, 16–100), with no required dose reductions of co-agents. Of 24 pts (NPM1m, n=15; KMT2Ar, n=9) in the intention-to-treat efficacy dataset receiving bleximenib 100 mg BID in combination with '7+3', overall response rate (ORR; ≥partial response) was 95.8%, cCR was 87.5%, and CR/CRh was 75%. Responses were similar across mutational subtypes. Median time to CR in the 100 mg BID group was 28 days (range, 21–36) and this was similar to the median time to first response. Median duration of response was not reached. Four pts receiving bleximenib 100 mg BID in combination with '7+3' proceeded to allogenic transplant. ConclusionsIn ND NPM1m or KMT2Ar AML, the safety profile of bleximenib + '7+3', including count recovery, was consistent with a '7+3' IC backbone, with no DS adverse events and no QTc prolongation signal observed. Combined with early efficacy, the clinical data are supportive of a planned Phase 3 study of bleximenib + '7+3' in IC-eligible ND AML pts harboring KMT2Ar or NPM1m.
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) | 0,001 | 0,000 |
| 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 | 0,001 | 0,002 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 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 ».