BCL2 Expression Identifies a Population with Unmet Medical Need in Previously Untreated (1L) Patients with DLBCL
Notice bibliographique
Résumé
Introduction .High BCL2 protein expression has been associated with inferior outcome in multiple studies in diffuse large B-cell lymphoma (DLBCL) (Gascoyne et al. 1997; Salles et al. 2011; Horn et al. 2013; Tsuyama et al. 2017). Patients with high levels of BCL2 expression may benefit from treatment with venetoclax, a first-in-class, highly selective BCL2 inhibitor with demonstrated activity in cell lines and xenograft models (Souers et al. 2013, Punnoose et al. 2016). The evaluation of BCL2 as a prognostic marker has been complicated by the variability in recognized immunohistochemistry (IHC) thresholds (de Jong et al. 2007; Tsuyama et al. 2017) and the impact of cell-of-origin (COO) (Iqbal et al. 2011). Using a BCL2 IHC scoring algorithm that was developed to identify cell lines that are sensitive to BCL2 inhibition, and that could potentially identify patients likely to benefit from venetoclax, we evaluated the prognostic capability of BCL2 IHC in three independent cohorts of 1L DLBCL patients. Cohorts included two Phase 3 studies (MAIN [NCT00486759] and GOYA [NCT01287741]), and a representative cohort from the British Columbia Cancer Agency (BCCA) registry-based population, in which subjects received chemoimmunotherapy (either rituximab or obinutuzumab, combined with cyclophosphamide, doxorubicin, vincristine and prednisone [CHOP]). Patients and Methods . Pretreatment tumor samples were tested for BCL2 IHC using an algorithm that assesses both the percent of tumor cells stained and the intensity of staining, similar to the BCL2 algorithm proposed by Tsuyama et al. (Table 1).Whole-tissue slides from184 patients from MAIN were tested at Genentech , whole tissue slides from 366 patients from GOYA were tested at Hematogenex (Ventana assay) and tissue microarray slides from 310 patients from BCCA were tested at Ventana (Ventana assay). The NanoString Lymphoma Subtyping gene expression assay was used for classification of COO into germinal center B-cell (GCB), activated B-cell (ABC) or unclassified subtypes in MAIN (n=159), GOYA (n=353) and BCCA (n=302). Multivariate Cox regression analysis of progression-free survival (PFS) was performed in each study with the International Prognostic Index (IPI; The International NHL Prognostic Factors Project 1993) and/or COO as covariates. Given the similar treatment effect, patient data from both treatment arms in each study were merged for this analysis. Results . Baseline characteristics were similar for the BCL2 IHC evaluable and intent-to-treat (ITT) populations of these three cohorts. Prevalence of BCL2 positive patients was 48% in MAIN, 49% in GOYA and 58% in the BCCA cohort. The prevalence of BCL2 positive samples within the ABC subtype was 64%, 75% and 60% in the MAIN, GOYA and BCCA cohorts, respectively, and 40%, 38% and 56% within the GCB subtype, respectively. In univariate analysis, BCL2 positivity was associated with shorter PFS in all three cohorts (Figure 1, A-C). In the MAIN study, the prognostic effect of BCL2 appeared to be in the GCB subgroup, not ABC, as previously reported (Punnoose et al. ASH 2015). In the two largest studies of GOYA and BCCA cohorts, the prognostic effect of BCL2 was similar in ABC and GCB (not shown), and was independent of IPI (Table 2). Conclusions . Using a newly developed BCL2 IHC scoring algorithm, we demonstrate that DLBCL patients positive for BCL2 have a consistently inferior prognosis compared with patients negative for BCL2. The prognostic value of BCL2 IHC is independent of IPI and COO in GOYA and BCCA. The Ventana assay is currently being used in a Phase 2 study of venetoclax in combination with R-CHOP to evaluate the correlation (if any) of BCL2 expression with venetoclax + R-CHOP treatment (CAVALLI - NCT02055820). Disclosures Szafer-Glusman: Genentech: Employment. Peale: Genentech / Roche: Employment, Equity Ownership. Lei: Roche: Employment. Ray: Genentech/Roche: Employment. Farazi: Genentech: Employment. Kornacker: Roche: Equity Ownership; F. Hoffmann-La Roche: Employment. Oestergaard: F. Hoffmann-La Roche Ltd: Employment. Liu: F. Hoffmann-La Roche: Employment. Punnoose: Genentech: Employment.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
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 | 0,001 |
| 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 | 0,001 | 0,000 |
| Communication savante | 0,001 | 0,000 |
| Science ouverte | 0,000 | 0,001 |
| 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 ».