Treatment Intensification Does Not Improve Outcome for Children with Myeloid Leukemia of Down Syndrome (ML-DS) Who Are MRD-Positive after Induction Therapy: A Report from the Children's Oncology Group
Notice bibliographique
Résumé
Background . Myeloid leukemia of Down syndrome (ML-DS) is a distinct form of pediatric AML that is treated with DS-specific reduced intensity chemotherapy with a resulting favorable prognosis (5-year EFS 89.9%). In contrast, non-responders and patients with relapsed ML-DS have a dismal outcome. The aim of Children's Oncology Group (COG) study AAML1531 was introduce risk stratification of chemotherapy intensity for patients with ML-DS based on measurable residual disease by multi-parameter flow cytometry at the end of the first course of induction (EOI-1 MRD), which is used to risk stratify treatment intensity for non-DS pediatric AML patients and was prognostic in the preceding ML-DS trial, AAML0431. Methods . AAML1531 enrolled 280 patients with ML-DS between November 2015 and April 2022. All patients received the same first course of induction therapy (Induction I): daunorubicin, cytarabine, 6-thioguanine (DAT). Those with EOI-1 MRD <0.05% were classified as Standard Risk (SR, Arm A) and treated with reduced-intensity chemotherapy based on the historical control, AAML0431, but with elimination of the second induction course of AAML0431 therapy, which consisted of high-dose cytarabine/asparaginase, to reduce infectious events. Patients with EOI-1 MRD >0.05% were classified as High Risk (HR, Arm B) and had their subsequent treatment intensified to a level consistent with that of pediatric non-DS AML (Induction II: mitoxantrone/high-dose cytarabine; Intensification I: cytarabine/etoposide; Intensification II: high-dose cytarabine/asparaginase) with the aim of reducing the number of relapse events. Cytogenetic results were centrally reviewed and MRD was measured by multidimensional flow cytometry in a reference laboratory (Hematologics, Inc., Seattle, WA). Results.We previously reported outcomes for the SR group (n=114) (Hitzler et al. Blood 2021). We now report outcomes of patients in the ML-DS HR group (n=41). Efficacy: Intensification of chemotherapy for EOI-1 MRD-positive patients did not significantly improve the 2-year EFS compared to that of the AAML0431 EOI-1 MRD-positive cohort (AAML1531: 80.5 + 12.4% vs. AAML0431: 76%, p=0.247). OS also did not differ significantly (AAML1531: 80.5 + 12.4% vs. AAML0431: 76.2 + 18.6%, p=0.819). There were 7 relapses and 1 death as first event. Of the 7 patients with relapse, 6 did not survive (2-year-OS 14.3 + 26.5% after relapse). Adverse events: Febrile neutropenia (FN) occurred in 25.4% of all AAML1531 patients during the common Induction I phase. During intensified post-induction therapy on the HR arm, the course-specific proportions of FN were 31.7% of 41 patients (Induction II), 27.5% of 40 patients (Intensification I) and 26.3% of 38 patients (Intensification II). The corresponding proportions on the reduced-intensity SR arm were significantly lower than on the HR arm: 3.7% of 108 patients (Induction II, p<0.001), 6.9% of 101 patients (Induction III, no corresponding HR course), 6.1% of 98 patients (Intensification I, p=0.001) and 8.6% of 93 patients (Intensification II, p=0.008). Sepsis grade 3 or greater was reported in 9.8% of 41 patients (Induction II, p=0.005) treated on HR arm compared to none treated on the SR (Ind II, n=108), and in 3.3% in the common Induction phase (Induction I). Conclusions. Intensification of chemotherapy for patients with ML-DS with positive EOI-1 MRD neither improved EFS nor OS and resulted in more FN and a greater number of sepsis events. While EOI-1 flow cytometric MRD detected ML-DS patients whose outcomes were poorer than those without MRD (Taub et al. Blood 2017), intensification of chemotherapy was not beneficial to the MRD-positive group. Overall, results of AAML1531 demonstrate that stratification of treatment intensity according to flow cytometric EOI-1 MRD did not did not improve outcomes for patients with ML-DS. Alternative approaches such as mutational profiling of ML-DS blasts should be evaluated with regard to prognostication, risk stratification and identification of targets for novel agents to improve the overall outcome for this disease.
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Prédiction machine sur la base complète
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Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,002 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,001 |
| Bibliométrie | 0,000 | 0,000 |
| 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 ».