RESUMO
Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is a type of mature B lymphocyte clonal proliferative tumor with a specific immunophenotype. Bruton tyrosine kinase inhibitors (BTKi) have been approved for the treatment of CLL/SLL. However, the efficacy and safety of new-generation BTKi-based regimens have not been systematically studied. In this systematic review, we evaluated the efficacy and safety of new-generation BTKi-based regimens for the treatment of patients with CLL/SLL. A comprehensive search on PubMed, Embase, Cochrane Library, and ClinicalTrials.gov. up to January 31, 2023, was conducted by us. Studies reporting data on CLL/SLL patients treated with new-generation BTKi were included. We assessed the overall response rate (ORR), complete response (CR) rate, and 24-month OS/PFS rates for efficacy analysis. For safety analysis, we evaluated the incidence of grade ≥ 3 adverse events (AEs). The meta-analysis included twenty studies. The pooled ORR for new-generation BTKi was 92% (95% CI, 89-95%, I2 = 80.68%, P = 0.00), while the pooled CR rate was 10% (95% CI, 6-14%, I2 = 88.11%, P = 0.00). Research has found that the new-generation BTKi-based therapy had higher efficacy under the following treatment conditions: < 65 years old, treatment-naive (TN)-CLL, and BTKi combination therapy. The ORR/CR rates and 24-month OS/PFS rates of BTKi combination therapy were higher than that of BTKi monotherapy. Compared to acalabrutinib monotherapy, zanubrutinib monotherapy demonstrated higher ORR/CR rates and 24-month OS/PFS rates. Common grade ≥ 3 AEs included cytopenia and hypertension. The new-generation BTKi-based therapy has good tolerance and provides incremental benefits for CLL/SLL patients. Despite the superior efficacy of BTKi combination therapy compared to monotherapy, its AEs rates are relatively high. Compared to acalabrutinib, Zanubrutinib may be the preferred monotherapy for CLL. However, randomized-controlled studies are still needed.
RESUMO
Decellularized extracellular matrix (dECM) is a valuable tool for generating three-dimensional in vitro tumor models that effectively recapitulate tumor-extracellular matrix (ECM) interactions. However, in current culture models, the components and structures of dECM are enzymatically disrupted to form hydrogels, making it difficult to recapitulate the native ECM. Additionally, when studying ECM-cell interactions, large-volume tumor culture models are incompatible with traditional experimental techniques and the nutrient-oxygen concentration gradient, which is a significant confounding factor. To address these issues, we developed a decellularized brain extracellular matrix slice (dBECMS) glioblastoma (GBM) culture model. This model possesses good light transmittance and substance diffusivity, making it compatible with traditional experimental techniques without forming nutrient-oxygen concentration gradients. Through transcriptomic analysis, we found that native brain ECM has a broad impact on glioma cells; the impact involves the ECM-ECM receptor interactions and the ECM and metabolic reprogramming. Further experiments demonstrated that dBECMS promoted glucose consumption and lactate production in GBM cells. Silver staining experiments revealed abundant proteins in the media of dBECMS, suggesting the degradation of the brain ECM by GBM cells. Transcriptome analysis also showed that the dBECMS-GBM culture model more accurately recapitulated the transcriptional profile of GBM than the two-dimensional culture. We experimentally demonstrated that the dBECMS-GBM model enhanced the resistance of GBM cells to temozolomide and increased the stemness of GBM cells. Additionally, we demonstrated the feasibility of the dBECMS-GBM model as a platform for drug response modeling. STATEMENT OF SIGNIFICANCE: The decellularized brain extracellular matrix (ECM) slice glioblastoma culture model mimics the interaction between native brain ECM and glioblastoma when glioblastoma infiltrates the brain and reveals the effects of native brain ECM on glioblastoma metabolism, ECM reprogramming, drug responsiveness, and stemness.