High Cereblon Protein Expression Correlates with Improved Response and Survival in Myeloma Patients Treated with Lenalidomide
Notice bibliographique
Résumé
Abstract Abstract 931 Background: Cereblon (CRBN), an adaptor protein of the Cul4A-DDB1-ROC1 ubiquitin E3 ligase complex was recently identified as a primary target of thalidomide teratogenicity and as essential requirement for IMiDs mediated cytotoxicity in multiple myeloma (MM) cells in vitro (Zhu YX et al, 2011). We have undertaken the current study to confirm the association between cereblon protein expression and the clinical response to lenalidomide. Methods: We constructed tissue microarrays (TMA) using bone marrow biopsies collected immediately prior to initiating therapy with lenalidomide. Fluorescence immunohistochemistry was performed using a polyclonal anti-CRBN antibody (HDA045910, Sigma-Aldrich) at a dilution of 1:4000, with 3 minutes of antigen retrieval at 121°C in a decloaking chamber in a pH=9 Tris/EDTA-based buffer (S2367, Dako). Tissue microarray slides were scanned on a HistoRx PM-2000 and digital images where analyzed with AQUA analysis software to determine the CRBN AQUA scores (protein expression = AQUA scores defined as the average CRBN pixel intensity within CD138 positive cells). CRBN AQUA scores where standardized on the Z-distribution (Z= X-μ/σ). The clinical parameters, response criteria and survival outcomes (PFS and OS) of these patients were defined according to the international uniform response criteria. The Kaplan-Meier method was used to estimate OS and PFS. Multivariate analysis was performed using the Cox regression method. Results: 42 patients with newly diagnosed (71.4%) or relapsed / refractory (28.6%) MM patients treated with lenalidomide and dexamethasone (MM009, MM016 or MM020 trials) and available pre-treatment bone marrow biopsies were included in this analysis. In this cohort, median age was 68 (range 46–88), median Hb 114 g/L (range 77–145), median Calcium 2.35 mmol/L (range 1.62–2.82), median creatinine 91.5 μmoles/L (range 44–500), high LDH in 21.4%, median albumin 35.5 g/L (range 23–47), β2 microglobulin 4.66 mg/L (range 1.2–35.19), ISS I 19%, II 35.7% and III 45.3% and high-risk cytogenetics (del17p13, t(4;14) by FISH) in 26.6%. Response CR/nCR was observed in 13/42 (31 %), PR in 21/42 (50%), MR in 4/42 (9.5%) and PD in 4/42 (9.5%). With a median follow-up of 22.4 months (range 0.72–65.6), 28/42 (67%) progressed with mPFS 19.53 months (95% CI 8.57–30.496) and mOS 28.733 months (95% CI 24.061–33.406). Cereblon expression or AQUA normalized Z scores ranged from -1.419 to 3.895. Kaplan Meier log-rank survival analysis were generated based on CRBN normalized AQUA Z scores with the bottom (Q4) and top quartiles (Q1-3) defined as CRBN-low or CRBN-high groups respectively. PFS was significantly shorter in CRBN-low (5.633 months) versus CRBN-high (19.733 months; p= 0.008). Similarly, OS was also reduced in CRBN-low patients (11.4 versus 30.467 months; p=0.033). In univariate Cox regression analysis, cereblon protein expression was significantly associated with PFS (HR 0.322; 95% CI 0.133–0.780; p=0.012) and OS (HR 0.323; 95% CI 0.108–0.970; p=0.044). Cereblon expression remained an independent predictor of PFS (HR 0.161; p=0.01) but not for OS when ISS and cytogenetics were included in multivariate regression analysis. In the CRBN-high group only 5/31 patients (16.1%), compared to 54.5% (6/11) in the CRBN-low group, failed to respond (≤MR) to lenalidomide. Similar to the protein tissue array analysis, low CRBN mRNA was also significantly associated with shorter PFS (p=0.008) in a chip microarray analysis of CRBN expression (Affymetrix probe 222533_at) in a cohort of 32 MM patients treated with lenalidomide and dexamethasone. Cereblon protein expression (AQUA normalized Z score) significantly correlated with CRBN mRNA microarray values (Affymetrix probe 222533_at) in 17 patients with matching protein and mRNA samples (Spearman's rho 0.417; p= 0.048). In contrast, and confirming the specificity of cereblon for response to IMiDs, no association between cereblon protein expression and response to therapy or survival outcomes (PFS/OS) was observed in a independent cohort of newly diagnosed MM patients (n=37) treated with bortezomib induction therapy and ASCT. Conclusion: Using an automated, observer-independent and fully quantitative approach, our studies confirm the association between cereblon protein expression and response to lenalidomide in MM. Disclosures: Neri: Johnson ans Johnson: Research Funding. Bahlis:Johnson and Johnson: Honoraria, Research Funding; Celgene: Honoraria.
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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 | 0,001 |
| 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 | 0,000 | 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 ».