Optimized treatment for pediatric patients with low-risk Acute Myeloid Leukemia: A report from the Children's oncology group study AAML1831
Notice bibliographique
Résumé
Abstract Introduction: Prior comparison of low risk (LR) pediatric acute myeloid leukemia (AML) patients enrolled on Children’s Oncology Group (COG) Phase 3 trials AAML0531 and AAML1031 determined that removal of the 5th high-dose cytarabine cycle results in an increased relapse rate (RR) and inferior disease-free survival (DFS) for most patients except those with favorable genetics and negative (<0.05% by flow cytometry) end of induction 1 (EOI1) minimal residual disease (MRD). COG AAML1831 implemented 4 cycles for this favorable group (LR1) and 5 cycles for LR2 patients (not LR1, not high risk [HR]). AAML1831 also decreased anthracycline exposure for LR1 patients by replacing mitoxantrone/cytarabine (MA) in Cycle 4 with high-dose cytarabine/asparaginase (Capizzi). Here, we report the impact of these changes on outcomes of LR1 and LR2 patients enrolled on AAML1831. Methods: AAML1831 risk stratification criteria were applied retrospectively to AAML0531 Arm B and AAML1031 Arms A and B. To validate the necessity of a 5th cycle, we compared 2-year RR, DFS and overall survival (OS) of LR2 patients on AAML1831 (n=99, 5 cycles), AAML0531 (n=115, 5 cycles) and AAML1031 (n=319, 4 cycles). Similarly, we compared 2-year outcomes between LR1 patients on AAML0531 (n=116, 5 cycles)and AAML1831 (n=88, 4 cycles), and evaluated the impact of substitution of MA (AAML1031 [n=243, 4 cycles]) with Capizzi (AAML1831, 60% cumulative anthracycline reduction). Patients with activating FLT3 point mutations or internal tandem duplication with allelic ratio > 0.1 were not included in this analysis. Time dependent variable (TDV) analysis was used to evaluate the impact of a 5th chemotherapy course. Results: LR2 patients treated with 5 cycles on AAML1831 had a lower 2-year RR than those receiving 4 cycles on AAML1031 (24% vs 44%, p<0.001). Similarly, LR2 DFS was improved on AAML1831 compared to AAML1031 (74% vs 54%, p=0.001). There was no significant difference in OS for LR2 patients treated on AAML1831 vs AAML1031 (87% vs 81%, p=0.21) suggesting that the survival impact of omitting a 5th cycle could be partially mitigated with relapse therapy, including hematopoietic stem cell transplant. As expected, there was no significant difference in RR, DFS or OS for LR2 patients on AAML0531 and AAML1831 as these patients received 5 similar cycles on both studies. Multivariable analysis with cycle 5 as a TDV confirmed the importance of the 5th treatment cycle, with a significant difference in RR (p=0.032), DFS (0.004) and OS (p<0.001). For the most favorable LR1 group, RR and DFS were not significantly different when treated with 4 cycles on AAML1831 compared to 5 cycles on AAML0531 (RR 19% vs 15%, p=0.7; DFS 81% vs 78%, p=0.34). Omission of cycle 5 did not decrease OS, and those treated on AAML1831 had superior OS compared to those treated on AAML0531 (99% vs 90%, p=0.01). Importantly, we found that anthracycline could be safely removed from post-induction therapy for the favorable LR1 group. The 2-year RR and DFS were similar for those treated on AAML1831 and AAML1031 (RR: 19% vs 22%, p=0.33, DFS: 81% vs 75%, p=0.11). LR1 patients receiving high-dose cytarabine without anthracycline on AAML1831 also had superior OS compared to those receiving MA on AAML1031 (99% vs 92%, p=0.031). Multivariable analysis using cycle 5 as a TDV confirmed no survival benefit of a 5th cycle in the LR1 cohort given lack of significant difference in RR, DFS or OS across the 3 trials. Conclusion: Comparison of data from the most recent COG AML phase 3 studies demonstrates that a subgroup of pediatric AML patients (LR2) had superior outcomes with 5 chemotherapy cycles when compared to 4 cycles. The lowest-risk patients with favorable genetics and good disease response (LR1) had no significant difference in RR or DFS with 4 chemotherapy cycles on AAML1831 compared to 5 cycles on AAML0531. Furthermore, this study demonstrates that in LR1 patients, substantial therapy reduction, including a 60% decrease in anthracycline exposure, can be achieved with outstanding survival. These results set a new precedent for risk-adapted treatment to minimize short- and long-term toxicity for pediatric patients with LR AML. Acknowledgment: Astellas Pharma Inc. is a collaborator for AAML 1831, including study funding and clinical supply. Jazz Pharmaceuticals provided funding for AAML1831 and performed a courtesy medical review of the abstract.
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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 | 0,002 | 0,002 |
| 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) | 0,001 | 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 ».