Morphologic leukemia-free state (MLFS) is associated with inferior outcomes in patients with Acute Myeloid Leukemia (AML) treated with front-line azacitidine plus venetoclax
Notice bibliographique
Résumé
Abstract Background Azacitidine plus venetoclax (Aza-Ven) is now standard of care for newly diagnosed acute myeloid leukemia (AML) in patients (pts) ineligible for intensive chemotherapy. Whilst this is better tolerated than intensive induction therapy, myelosuppression is common and can be severe. In this study, we sought to investigate the impact of incomplete hematological recovery after Aza-Ven on long-term survival. Methods We conducted a retrospective study of pts diagnosed with AML, who received front-line treatment with Aza-Ven at the Princess Margaret Cancer Centre between 2017 and 2024. Reponses were categorised based on the 2022 European Leukemia Network (ELN) recommendations for AML. We defined composite complete remission (CRc) rate as a combination of complete remission (CR) and CR with incomplete hematological recovery (CRi). We defined morphologic composite remission (mCR) as achievement of < 5% bone marrow blasts including CR, CRi and morphologic leukemia-free state (MLFS). The primary outcome was overall survival (OS). Results Our cohort consisted of 132 cases, with 82 (62%) male pts. The median age was 74 years (range, 34 – 90). Based on the International Consensus Classification (ICC), 127 (96%) pts met the diagnostic criterion for AML; five (4%) pts were classified as myelodysplastic syndrome/AML (MDS/AML). In this real-world cohort, 83 (63%) pts met VIALE-A eligibility criteria. Most pts received 28 days of venetoclax (n=106, 80%) with cycle 1. Bone marrow assessments (BMA) were performed in 117 (89%) pts after cycle 1. In evaluable pts with BMA after cycle 1, 59 (50%) achieved CRc, including 31 (26%) in CR and 28 (24%) in CRi. A total of 82 (70%) achieved mCR, including pts in CRc plus 23 (20%) pts in MLFS. Nine (8%) pts had partial response (PR) and 24 (21%) pts had no response (NR). From initiation of cycle one, 30-day and 60-day mortality were 2% and 8%, respectively. The median OS in our whole cohort was 13 months (95% CI: 11 – 16 months). To better characterise the heterogeneity within pts achieving mCR (n=82), subgroup analysis was performed. Pts who achieved MLFS were more likely to have had previous exposure to hypomethylating agents (HMA) (13% vs 0%, p<0.01) as well as mutations in ASXL1 (42.9% vs 19%, p=0.03), STAG2 (23.8% vs 3.4%, p<0.01) and TET2 (38.1% vs 15.5%, p=0.03). Pts achieving CR/CRi also more commonly had favourable risk disease as per ELN 2024 (49.2% vs 26.1%, p=0.03), compared to those who achieved MLFS. There was no significant association between achievement of MLFS, and prior history of MDS or MDS/MPN (p=0.11) or previous cytotoxic therapy (p=0.12). Mutations in FLT3-TKD (p=0.04) and STAG2 (p=0.03) were more common among pts with delayed neutrophil recovery (≥42 days from cycle 1 day 1). Conversely, mutations in FLT3-ITD (p=0.02), RUNX1 (p=0.03), and STAG2 (p=0.03) were more frequent in pts with delayed platelet recovery (≥28 days from cycle 1 day 1). There was no significant difference in measurable residual disease (MRD) positivity assessed by flow cytometry between pts who achieved CRc versus MLFS (38% vs 53%, p=0.26) and MRD status was not associated with OS (HR 0.89, 95% CI 0.42-1.89, p=0.77) among pts achieving mCR. There was no significant relationship between reduced duration of venetoclax (<25 days), MLFS, neutrophil or platelet recovery. However, due to the relatively small number of pts who received the shorter course (n=22/132), definitive conclusions cannot be drawn. Pts achieving CRc (n=59) after cycle 1 had significantly longer median OS at 22.5 months, compared to those who achieved MLFS (n=23) at 6.6 months (HR 0.45, 95% CI: 0.24 – 0.85, p=0.01). The 2-year OS rates in pts achieving CRc and MLFS were 46% and 27%, respectively. Median relapse-free survival (RFS) in pts achieving CRc and MLFS were 25.0 months and 7.9 months respectively (HR 0.62, 95% CI: 0.29 – 1.32, p=0.22). The 2-year RFS in pts achieving CRc and MLFS were 52% and 38%, respectively.Conclusion: Patients who achieve MLFS after Aza-Ven have significantly worse OS compared with those who achieve CRc. There was no significant difference in MRD positivity between pts achieving CRc or MLFS, but mutational profile may identify pts at risk of delayed or deficient hematological recovery. Future research should focus on identifying strategies to improve bone marrow failure beyond the achievement of bone marrow blast reduction.
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 | 0,000 | 0,002 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| 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 | 0,000 | 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 ».