Factors associated with central nervous system relapse after b-acute lymphoblastic leukemia: A Children's oncology group report
Notice bibliographique
Résumé
Abstract Introduction: While advancements in treatment of pediatric B-cell acute lymphoblastic leukemia (B-ALL), through incorporation of novel agents such as blinatumomab, have resulted in remarkable improvements in disease-free survival (Gupta, NEJM 2024), central nervous system (CNS) relapses remain a barrier. As immunotherapies which provide excellent medullary disease control but lack CNS penetration are incorporated into frontline treatment, there is a need to identify patients at risk of CNS relapse in whom deintensification of CNS directed therapy may be inappropriate, and whether these patients differ from those at risk of bone marrow (BM) relapse. Methods: Data from Children's Oncology Group (COG) trials for patients with de novo B-ALL (AALL0331, AALL0232, AALL0932 and AALL1131) were analyzed to examine factors associated with isolated CNS (iCNS), isolated BM (iBM) relapse and any CNS-involved relapse (CNS with any other site). Demographic and clinical characteristics were examined. Cumulative incidence of iCNS, iBM and any CNS-involved relapse was evaluated, treating death, induction failure, subsequent neoplasm and other relapses as competing events. Proportional cause-specific hazards models were used to estimate the association of covariates with the hazard of iCNS, iBM and any CNS relapse. Results: Among the 21,830 patients enrolled across the four trials between 01/2004 and 08/2019 (54.6% male; median age: 4 years [y] [range, 1-30y]), 2,238 (10.3%) patients relapsed (473 [21.2%] iCNS, 1,341 [60.1%] iBM, and 671 [30.0%] any CNS). The 5-year cumulative incidence of relapse among all patients was 9.5%±0.2% and for iCNS, iBM and any CNS-involved relapse was 2.2%±0.1%, 5.6%±0.2% and 3.2%±0.1%, respectively. Median time to relapse was earlier for iCNS compared to iBM: 24.6 vs. 38 months. Multivariable analysis demonstrated that age at diagnosis was not associated with iCNS relapse (10-15y: Hazard ratio [HR]=1.2, 95% confidence interval [CI]=0.9-1.5; ≥16y: HR=1.3, 95%CI=0.9-1.7; ref=1-9y) but was associated with iBM relapse (10-15y: HR=1.6, 95%CI=1.4-1.8; ≥16y: HR=1.7, 95%CI=1.5-2.1; ref=1-9y). Compared to males, females were at a lower hazard of iCNS relapse (HR=0.5, 95%CI=0.4-0.6) but greater hazard of iBM relapse (HR=1.2, 95%CI=1.0-1.3). Compared to Non-Hispanic White patients, Non-Hispanic Black race/ethnicity was associated with greater hazard of both iCNS (HR=1.8, 95%CI=1.3-2.5) and iBM relapse (HR=1.7, 95%CI=1.4-2.1) with similar magnitudes of risk, whereas Hispanic ethnicity was associated with greater hazard of iBM relapse only (HR=1.2, 95%CI=1.0-1.3). The findings for any CNS-involved relapse were similar to iCNS relapse, with the addition of Hispanic ethnicity associated with higher risk (HR=1.2, 95%CI=1.0-1.5). Favorable blast genetics were associated with reduced hazard of both iCNS and iBM relapse. Unfavorable blast genetics were associated with greater hazard of iBM relapse (hypodiploidy: HR=4.6, 95%CI=3.6-5.7; BCR::ABL1: HR=1.9, 95%CI=1.5-2.5; ref=neutral cytogenetics) but not iCNS relapse (hypodiploidy: HR=0.3, 95%CI=0.1-1.1; BCR::ABL1: HR=1.3, 95%CI=0.8-2.2; ref=neutral cytogenetics), with the exception of intrachromosomal amplification of chromosome 21 (iAMP21), which was associated with both (iBM relapse: HR=1.8, 95%CI=1.5-2.3; iCNS relapse: HR=1.8, 95%CI=1.2-2.7). CNS status at diagnosis was associated with greater hazard of iCNS relapse (CNS2: HR=2.2, 95%CI=1.7-2.7; CNS3: HR=2.5, 95%CI=1.5-4.0; ref=CNS1) as well as any CNS relapse but not iBM relapse (CNS2: HR=1.1, 95%CI=0.9-1.2; CNS3: HR=1.1, 95%CI=0.8-1.7; ref=CNS1). EOI MRD was also associated with both, however magnitude of association was substantially higher for iBM relapse (0.01%-0.099%: HR=3.0, 95%CI=2.6-3.5; 0.1%-0.99%: HR=4.2, 95%CI=3.6-4.8; ≥1.0%: HR=4.5, 95%CI=3.7-5.4; ref=<0.01%) than iCNS relapse (0.01%-0.099%: HR=1.5, 95%CI=1.2-2.0; 0.1%-0.99%: HR=1.5, 95%CI=1.1-2.0; ≥1.0%: HR=1.6, 95%CI=1.0-2.3; ref=<0.01%). The findings for any CNS-involved relapse were similar to iCNS. Conclusions: To our knowledge, this is the largest analysis of factors associated with CNS relapse to date. We find that predictors of CNS relapse differ from those of BM relapse, with implications for future trials testing treatment strategies which rely on immunotherapy to de-intensify traditional chemotherapy. Novel and more powerful predictors of CNS relapses and more effective CNS-directed therapies are needed to fully optimize the potential of immunotherapy.
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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 | 0,001 | 0,003 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,001 | 0,002 |
| 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 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 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 ».