P735: EFFICACY AND SAFETY OF ORAL DECITABINE/CEDAZURIDINE (ASTX727) IN THE CMML SUBPOPULATION FROM PHASE 2 AND ASCERTAIN PHASE 3 STUDIES
Notice bibliographique
Résumé
Topic: 16. Myeloproliferative neoplasms - Clinical Background: Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disease characterized by persistent monocytosis, splenomegaly, and both dysplastic and myeloproliferative changes in the bone marrow. Hypomethylating agents are approved for CMML treatment as they have historically been included in pivotal studies, however only account for ~10% of trial patients. ASTX727, an orally available fixed dose combination (FDC) of 35 mg decitabine (DEC) and 100 mg cedazuridine (CED), a cytidine deaminase inhibitor, produces comparable PK AUC exposure compared to intravenous decitabine (Garcia-Manero, et al, 2019). Aims: We present the combined clinical experience of patients with CMML in the critical studies leading to FDA approval of oral DEC/CED (ClinicalTrilas.gov NCT02103478 and NCT03306264, respectively) with additional analysis of genetic profiles for the subset. Methods: 33 CMML patients (16 from phase 2, and 17 from phase 3) who were candidates for parenteral decitabine with PS 0-2 were enrolled and received standard oral decitabine/cedazuridine FDC for 5 days. Clinical endpoints were best response according to International Working Group (IWG) 2006 response criteria, transfusion independence for at least 8 or 16 consecutive weeks, leukemia free survival (LFS), overall survival (OS), and safety. Peripheral blood collected prior to treatment was used for DNA isolation from leukocytes, and molecular abnormalities identified using a NGS hematologic malignancy panel, including 8 genes frequently associated with CMML. Cox-regression analysis on the various factors (eg binary mutational status, CR, etc.) was used for analyses of risk-factors for OS. Results: Median age was 71 years, with 55% patients with ECOG PS of 1. One-third of patients were RBC transfusion-dependent at baseline. 70% of patients were subtyped as CMML-1 based on the 2022 WHO classification, and 76% patients had MD-CMML. The median number of mutations in CMML patients was 3 (range 0-5) among 8 commonly mutated genes (see Figure 1). 85% of patients had received no prior anticancer therapy for CMML. Patients received a median of 10 cycles of therapy (range 2-36). Seven patients (21.2%) had Complete Responses (CR), 14 (42.4%) had marrow CR (mCR), including 5 (15.2%) who also had hematologic improvement (HI). Overall response rate (ORR) [CR + PR+ mCR + HI] was 75.8%. 63.6% of those dependent on red blood cell (RBC) transfusions at baseline became transfusion independent (TI) for at least 8 weeks and 45.5% for 16 weeks. Median LFS was 28.3 months and median OS was 35.7 months. Safety profile is consistent with decitabine, with most grade 3 or higher events related to myelosuppression; Treatment-emergent adverse events of CTCAE Grade 3 or higher in > 10% of patients, independent of relationship to ASTX727, were cytopenias (neutropenia [61%], thrombocytopenia [55%], anemia [36%], febrile neutropenia [27%], and leukopenia [24%]). Given the advanced age of the CMML cohort, only 3 (9%) went on to Hematopoietic Stem Cell Transplant. Cox regression analysis suggested that post-treatment RBC TI seemed to be associated with survival; no apparent effect on OS was observed for other baseline or response-related factors, including baseline genetic variants, such as ASXL1 among others (Figure 1) though the sensitivity of such analysis is limited by the number of patients. Summary/Conclusion: DEC/CED has a well-tolerated safety profile with clinical benefit in CMML patients. Preliminary analysis suggests an association between TI and longer survival.Keywords: Oral, Chronic myelomonocytic leukemia, CMML, Hypomethylating agents
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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 | 0,001 |
| 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 | 0,000 | 0,000 |
| Communication savante | 0,000 | 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) | 0,000 | 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 ».