Genetic and Response-Based Risk Classification Identifies a Subgroup of NCI High Risk Childhood B-Lymphoblastic Leukemia (HR B-ALL) with Outstanding Outcomes: A Report from the Children's Oncology Group (COG)
Notice bibliographique
Résumé
Overall improvements in ALL outcomes have been attributed in part to refinements in risk classification that affect treatment intensity. The COGdeveloped a real-time disease classification protocol utilizing clinical, biologic and early disease response measures from local and central reference laboratories. Patients between 1-30 years were enrolled on the COG AALL03B1 classification study at the time of B-ALL diagnosis and subsequently initiated a 3-drug (standard risk; SR) or 4-drug induction (HR) based on NCI risk group. All patients underwent standardized testing at approved or central laboratories to detect favorable (triple trisomies of chromosomes 4, 10 and 17 [TT] or ETV6-RUNX1 fusion) and unfavorable (hypodiploidy [DNA index <0.81 or chromosomes < 44], MLL rearrangements, BCR-ABL1 or iAMP21) cytogenetic abnormalities. At the end of induction therapy, patients > 1 year of age with B-ALL were classified into low, standard, high or very high risk groups for treatment allocation. Variables used for risk classification included age, initial WBC, extramedullary disease status, blast cytogenetics and early treatment response based on bone marrow morphology and day 29 marrow minimal residual disease (MRD). Rapid early response (RER) was defined as M1 (<5% blasts) bone marrow by day 15 plus flow cytometry-based MRD < 0.1% on day 29 of induction. Those with either M2/M3 (≥ 5% blasts) day 15 marrow or MRD ≥ 0.1% at day 29 were deemed slow early responders (SER). From December 2003 - September 2011, 11,196 (11,144 eligible) patients enrolled on AALL03B1; 89% enrolled on a frontline ALL therapeutic trial, 96% of whom were evaluable for post-induction treatment assignment. Among these patients, 5104 and 2791 respectively, were treated on companion clinical trials for NCI SR (AALL0331, 65%) or HR (AALL0232, 35%) B-ALL. Patients with very high risk features (BCR-ABL1, hypodiploidy, induction failure, or poor response at day 43) did not continue on AALL0232/AALL0331 post induction, but did have outcome data captured for analysis. The distribution of induction response was 84% RER and 16% SER with 5-year event-free (EFS) and overall survival (OS) rates of 89.3% and 95.2%, respectively for RERs and 67.9% and 84.3%, respectively for SERs. Five-year EFS and OS rates for SR and HR patients combined according to cytogenetic subtype are summarized in the Table. The overall frequencies for the genetic subsets were: ETV6-RUNX1 26%; TT 21%; hypodiploidy 1.5%; MLL 2%; BCR-ABL1 2.6% and iAMP21 2%. Five-year EFS varied according to cytogenetic subset ranging from 70% (unfavorable) to 95% (favorable). Notably, 5-year OS was over 98% for the favorable cytogenetic subsets of combined SR and HR patients that accounted for almost half of all patients. In a subsequent analysis using current COG MRD response measures (RER=day 8 blood MRD <1% and day 29 marrow MRD <0.01%), HR patients with favorable cytogenetics who were CNS1 had 5-yr EFS and OS of 94.9% and 98.1% (n=243), respectively. In conclusion, real-time classification was feasible in close to 10,000 patients enrolled on COG ALL trials and identified patients with varying outcomes for risk-based treatment allocation. While the COG has not previously utilized favorable cytogenetic features to risk classify NCI HR B-ALL patients, outcomes for this subgroup who also have rapid MRD responses during induction are excellent and suggest that these patients will not benefit from further chemotherapy intensification. Table. Favorable 5-year EFS (SE)* 5-year 0S (SE)* ETV6-RUNX1 Positive (n=1928) 93.2% (0.7%) 98.3% (0.3%) Negative (n=5578) 83.5% (0.6%) 92% (0.4%) Triple Trisomy 4/10/17 Positive (n=1483) 94.7% (0.7%) 98.7% (0.3%) Negative (n=5603) 83.6% (0.6%) 92.2% (0.4%) Unfavorable MLL rearrangement Positive (n=145) 73.9% (4.2%) 83.1% (3.6%) Negative (n=6649) 85.9% (0.5%) 93.6% (0.3%) iAMP21 Positive (n=156) 69.5% (4.3%) 90.1% (2.8%) Negative (n=7739) 86.1% (0.5%) 93.4% (0.3%) *P < 0.0001 for all EFS and OS comparisons between positive and negative cytogenetic subsets except P = 0.0026 for the OS comparison for iAMP21. Disclosures Borowitz: Becton Dickinson Biosciences, Medimmune: Research Funding. Hunger:Spectrum Pharmaceuticals: Consultancy; Jazz Pharmaceuticals: Consultancy; Merck: Equity Ownership; Sigma Tau: Consultancy.
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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 | 0,001 |
| 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) | 0,000 | 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 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 ».