Inferior Survival in Double Refractory Large B-Cell Lymphoma Eligible for Third-Line CD19 Chimeric Antigen T-Cell Therapy
Notice bibliographique
Résumé
Background: Outcomes following CD19 chimeric antigen T-cell (CAR-T) therapy for patients (pts) with large B-cell lymphoma (LBCL) refractory (rf) to both an anthracycline and platinum-based therapy, referred to as double refractory (DR), are not well described. It is also unclear if these patients may be less likely to proceed to CAR-T infusion. We reviewed the outcomes of pts referred for CAR-T at our centre. Methods: Retrospective review of the CAR-T database at the Princess Margaret Cancer Centre from April 2020 - December 2023. Anthracycline-refractoriness was defined as pts progressing/stable disease (PD/SD) on therapy or relapsing <3 months of completing treatment (typically R-CHOP). Platinum-refractoriness was defined as PD/SD while receiving platinum-based therapy (typically R-GDP). Inclusion criteria: adults >18 years from Ontario, Canada with LBCL referred for consideration of >3-line standard of care CD19 CAR-T therapy. Outcomes included progression free survival (PFS) defined from date of cell infusion to PD/death. Overall survival (OS) defined from date of initial CAR-T consultation to death. DR cohort outcomes were compared against non-double refractory (NDR) pts (defined as pts not relapsing <3 months or no PD/SD on anthracycline-based and no PD/SD on platinum-based treatment. Kaplan-Meier estimator was used to generate OS curves. Turnbull estimator was used to generate PFS curves. Results: A total of 174 pts were identified that met inclusion criteria (59: DR, 115: NDR). There were no difference in baseline characteristics (median age, sex, ECOG, stage, disease bulk, presence of MYC and BCL2/BCL6 translocation, extra-nodal involvement including CNS disease) between the 2 cohorts. Median age 61-years (range 20-83), 63% male, median prior lines 2 (range 1-3) for LBCL and 29% had an intake ECOG of >2. Histologic subtypes: de novo diffuse large B-cell lymphoma (DLBCL) (67%), transformed DLBCL (28%), primary mediastinal B-cell lymphoma (5%). MYC and BCL2/BCL6 translocations were detected by FISH in 41/114 pts tested (35.9%). The majority had stage IV disease (53%) with extra-nodal involvement in 58%, a history of central nervous system (CNS) involvement in 6% and bulky disease (>7cm) in 43%. While no patients in the DR cohort had a prior autologous stem cell transplantation (ASCT), 43% of the NDR cohort had a prior ASCT. Bridging therapy (BT) was administered in 71% (n=122): radiotherapy (RT) (23%, n=39), chemotherapy (CT) (21%, n=36), RT and steroids (ST) (9%, n=16), ST only (9%, n=15), CT and ST (4%, n=7), CT, RT and ST (3%, n=5), CT and RT (2%, n=4), p=0.21. CAR-T product: axicabtagene ciloleucel 76%, tisagenlecleucel 24%. Of all 174 pts, 36 (20.6%) were unable to proceed with the intended CAR-T infusion due to ineligibility (poor ECOG or PD) (48%), pt decline (22%), active CNS disease (12%), manufacturing failure (8%) or death (6%) [missing data 4%]. The failure rate to proceed with CAR-T infusion in the DR and NDR cohorts were 30.5% versus 15.6%, p=0.036. Median follow-up for all pts was 17.5 months (range 14.7-21.1). In all pts the 12-month OS was 57% (95% CI 49-66.2%); DR 41.7% (95% CI 29.9-58%) versus NDR 65.2% (95% CI 55.6-76.6%), p=0.0046. In pts proceeding to CAR-T infusion, 12-month OS was 66.7% (95% CI 58-76.6); DR 57.2% (95% CI 42.9-76.4%) versus NDR 71% (95% CI 60.8-82.9%), p=0.23. In pts that proceeded to CAR-T infusion, 6-month PFS was 49.8% (95% CI 28.7-86.2%); DR 50.4% (95% CI 24.8-100%) versus NDR 51.7% (95% CI 29.2-91.8%), p=0.43. In pts that did not proceed to CAR-T infusion (DR: 18, NDR: 18) median OS was 2.56 months (95% CI 1.94-3.42); DR 1.94 months (95% CI 1.61-3.35) versus NDR 3.42 months (95% CI 2.56-NR), p=0.032. Univariable and multivariable analysis found DR status a predictor of inferior OS (adjusted p=0.034). Conclusion: In our analysis, DR pts had inferior OS to NDR pts, driven by higher failure rates to proceed with CAR-T infusion. The OS of DR and NDR pts proceeding to CAR-T infusion appears similar but may be influenced by sample size. Identifying DR status at time of referral as a determinate of outcome would be clinically beneficial. Approaches to bridge DR pts to CAR-T therapy and assessing outcomes of DR pts (those progressing on platinum-based BT) in second line CAR-T therapy need to be prospectively investigated.
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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 | 0,000 | 0,002 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| 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) | 0,002 | 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 ».