CD20 Mutations at the Rituximab Binding Site Are Rare and Are Not a Significant Cause of R-CHOP Resistance in Patients with De Novo Diffuse Large B-Cell Lymphoma.
Notice bibliographique
Résumé
Abstract Background: Diffuse Large B Cell Lymphoma (DLBCL) is the most common non-Hodgkin’s lymphoma and is not cured in 40% of patients who receive combined Rituximab + CHOP (R-CHOP) immunochemotherapy. The mechanisms of resistance to R-CHOP therapy are poorly understood. Rituximab is a humanized monoclonal antibody directed against the CD20 antigen on B lymphocytes. Since its addition to CHOP chemotherapy in 2001, it has reduced the mortality of patients with DLBCL by 50% in British Columbia (BC). Given this significant improvement in survival, rituximab must contribute an important role in the neoplastic B cell death. Its precise binding site on the CD20 antigen has recently been elucidated (Binder et al. Blood 2006). We hypothesized that mutations at this site could be a cause of failure to cure the DLBCL with R-CHOP. If so, detection of CD20 mutations could help risk-stratify patients and identify a group who may not benefit from the addition of rituximab to their chemotherapy regimen. Methods: We extracted DNA from 282 frozen DLBCL specimens (including 21 patients with Primary Mediastinal B cell lymphoma) at the BC Cancer Agency performed after March 2001, the date when the provincial treatment policy for advanced DLBCL was changed to R-CHOP. We amplified exon 6 of the CD20 gene which contains the rituximab epitope with the following primers: 5′-TGTAAAACGACGGCCAGTTTGGAATTCCCTCCCAGATT-3′ and 5′-CAGGAAACAGCTATGACGGATCCAGAGTTCATGCTCA-3′. In italics are the sequencing primers -21M13F and M13R. The purified 431 base pair product was bi-directionally sequenced using BigDye® Terminator v3.1 Cycle Sequencing Kit and a 3730 XL Applied Biosystems sequencer. The sequence reads where then analyzed using Polyphred/Consed. Results: 264 patients had successful sequences for this analysis. The clinical characteristics were available on only 241 pts and were as follows: median age 63 yrs (range 16–101); 129 (62%) were male; 64% IPI 0–2, 36% IPI 3–5. 197 pts received R-CHOP chemotherapy and were evaluated for outcome. The remaining patients were recorded as not receiving rituximab either because, the information was not available; they had limited-stage disease (in 2001), or were too frail to receive chemotherapy. 20% of patients relapsed or progressed after R-CHOP after a median follow-up time of 2 years (range 0.1–6.3 years). The sequencing analysis revealed 2/264 (0.008%) cases of CD20 mutations in exon 6, both in R-CHOP treated pts. One indicates a heterozygous 4 base pair (bp) deletion in nucleotides 353–356, upstream of the epitope. Clinically, this patient progressed on R-CHOP therapy. The other indicates a heterozygous 13 bp deletion at position 722 which is downstream of the epitope. This patient achieved a complete remission with R-CHOP. Interestingly, there were no Single Nucleotide Polymorphisms (SNPs) in this 431 base pair sequence which could also potentially impact rituximab binding at this site. Conclusions: The incidence of CD20 mutations at the rituximab binding site in 264 pts with de novo DLBCL is extremely low. Mutations at this site are therefore not a significant cause of R-CHOP resistance in this group of pts.
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 | 0,002 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,001 | 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 | 0,001 | 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 ».