FLAG-IDA Plus Venetoclax in High-Risk Newly Diagnosed and Relapsed or Refractory Acute Myeloid Leukemia: The Princess Margaret Cancer Center Experience
Notice bibliographique
Résumé
Introduction: Intensive induction chemotherapy (IC) is the main therapeutic modality for achieving complete remission (CR) with curative intent in patients (pts) with acute myeloid leukemia (AML). However, pts with newly diagnosed (ND) high-risk, or relapsed/refractory (R/R) AML have lower rates of CR with IC, and those who achieve CR rarely maintain durable remissions, frequently leading to death from progressive disease. Venetoclax combined with FLAG-IDA has been studied with promising results in pts with ND or R/R AML in a single-center phase Ib/II clinical trial, but data on its efficacy and safety in other centers outside of clinical trials are limited. Method: We studied retrospectively the safety and outcomes of fludarabine, cytarabine, G-CSF, and idarubicin plus venetoclax (FLAG-IDA + VEN) in pts with high-risk ND or R/R AML treated with at the Princess Margaret Cancer Centre (Toronto, Canada). VEN was given during induction at a 400 mg equivalent dose for 14 days. The primary endpoint was overall response rate (ORR), including CR with complete, partial, or incomplete hematologic recovery (CR/CRh/CRi), morphologic leukemia-free state (MLFS), and partial response, as per the ELN 2022 AML response criteria. Measurable residual disease (MRD) was assessed by flow cytometry at the end of induction. Secondary endpoints were overall survival (OS), relapse-free survival (RFS), frequency of adverse events, and time to hematologic recovery. Results: Forty-four pts with AML were treated with FLAG-IDA + VEN between November 2021 and April 2024 were included (17 ND, 27 R/R). The median age was 59 years (range 22-75) and 20 (46%) were aged ≥60 years (no difference between ND and R/R pts). Among pts with ND AML, almost all had very high-risk genetics (complex/monosomal karyotype, n=7 [41%]; TP53 mutation, n=9 [53%]; MECOM-rearrangement, n=3 [18%]). Twelve (70%) pts had secondary AML, 1 (6%) had therapy-related AML, and 2 (12%) had mixed-phenotype acute leukemia (MPAL). Among pts with R/R AML, 14 (52%) were in first salvage, including 1 (4%) with TP53, 7 (26%) with ASXL1, and 4 (15%) with RUNX1 mutations. Seven (27%) pts had undergone prior allogeneic stem cell transplantation (alloSCT) and 13 (30%) had previous VEN exposure. In ND high-risk pts, the ORR was 71%, with 75% achieving MRD negativity. Six (35%) pts proceeded to alloSCT. The median OS and RFS were 9 months (range 4.3 - NA) and 8 months (range 4 - 10), respectively. In R/R pts, the ORR was 67%, with 67% achieving MRD negativity. Twelve (44%) pts proceeded to alloSCT. The median OS and RFS were 26 months (range 15.0 - NA) and 15 months (range 6 - NA), respectively. Ten pts experienced disease relapse after achieving remission with FLAG-IDA+VEN (3/12 [25%] ND; 7/18 R/R [39%]; including 3 relapses post-alloSCT, 1 ND and 2 R/R). Eighteen (41%) pts died (9/17 ND; 9/27 R/R); the primary causes of death were disease- (n=14) and infection-related (n=4). Common non-hematological adverse events included febrile neutropenia (n=16; 36%), pneumonia (n=20; 45%), and bacteremia (n=15; 34%). The median time to neutrophil recovery >0.5x109/L and >1.0x109/L was 33 and 38 days, respectively, with no difference observed between ND and R/R pts. The median time to platelet recovery >50x109/L was 31 days (ND, 28 days vs R/R 36.5 days, p=0.01), and >100x109/L was 34 days (ND, 31 days vs R/R 38 days, p=0.049). There was no induction mortality, and the 60-day mortality rate was 0%. Conclusion: FLAG-IDA plus venetoclax (FLAG-IDA+VEN) demonstrated promising efficacy in both high-risk ND and R/R AML pts, similar to previous reports, with notable overall response and MRD negativity rates. This regimen allowed a significant number of pts with R/R AML to proceed to alloSCT. Our data confirm the applicability of this regimen for high-risk ND and R/R AML. Relapse and treatment-related adverse events remain challenges. Further studies are warranted to further optimize this regimen and improve long-term patient outcomes.
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) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,001 |
| Études des sciences et des technologies | 0,001 | 0,000 |
| Communication savante | 0,001 | 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 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 ».