apatinib and Lymphoma--Large-B-Cell--Diffuse

Treatment options for relapsed or refractory diffuse large B-cell lymphoma (RR DLBCL) represent an unmet medical need. Apatinib is a new oral tyrosine kinase inhibitor mainly targeting vascular endothelial growth factor receptor-2 (VEGFR-2) to inhibit tumour angiogenesis. In the present study, we evaluated the efficacy and safety of apatinib for patients with RR DLBCL.. In this phase II, open-label, single-arm, prospective study, we enrolled patients aged 14-70 years with treatment failure of at least two chemotherapeutic regimens using Simon's two-stage design. All patients were administered apatinib at an initial dose of 500 mg on a 4-week cycle at home and visited the outpatient clinic every two cycles to evaluate efficacy and to record adverse events. We considered objective response rate (ORR) as the primary end point, and progression-free survival (PFS), and overall survival (OS) plus duration of response (DoR) as the secondary end point. (This trial was registered at ClinicalTrials.gov, identifier: NCT03376958.).. From January 2017 to February 2019, we screened 35 patients and enrolled 32 eligible patients. At the cutoff point (April 2019), we noted 2 (6.3%) complete responses, 12 (37.5%) partial responses, and 9 (28.1%) stable diseases, attributing to an ORR of 43.8% and a disease control rate of 71.9%. The median PFS and OS were 6.9 (95% confidence interval [CI], 5.8-7.9) and 7.9 months (95% CI, 7.0-8.7), respectively. The median DoR was 5.0 months (95% CI, 3.5-6.5) for patients who achieved PR. The most common grade 3-4 adverse events (AE) were hypertension (12.6%), hand-foot syndrome (9.4%), and leucopenia (6.3%). No apatinib-related deaths were noted.. Home administration of apatinib shows promising efficacy and manageable AEs in patients with RR DLBCL.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Prospective Studies; Protein Kinase Inhibitors; Pyridines; Vascular Endothelial Growth Factor Receptor-2; Young Adult

To investigate the effect of Apatinib (an inhibitor targeting VEGFR-2) enhances chemosensitivity of ABT-199 on diffuse large B-cell lymphoma (DLBCL). Viability assay and flow cytometric assay for determining apoptosis, cell cycle, mitochondrial membrane potential, reactive oxygen species and immunoblotting were used to explore the combination effect in DLBCL cell lines, DLBCL patient samples, and DLBCL mouse models. RNA sequencing assay helped identify mechanisms of ABT-199 plus Apatinib. The results show that ABT-199 combined with Apatinib inhibited cell proliferation, reduced colony-forming capacity, and induced apoptosis and cell cycle arrest in DLBCL cells. Mechanistically, the combination therapy inhibited tumour cell growth and promoted tumour cell death by regulating EDN1 and MAPK-related pathways and activating the intrinsic apoptotic pathway. The effect of the combination therapy was also validated in primary DLBCL blasts and xenograft mouse models. Our findings indicate that Apatinib enhances the chemosensitivity of ABT-199 and might serve as a promising therapeutic strategy for DLBCL.

Topics: Animals; Apoptosis; Cell Line, Tumor; Cell Proliferation; Humans; Lymphoma, Large B-Cell, Diffuse; Mice; Reactive Oxygen Species; Vascular Endothelial Growth Factor Receptor-2; Xenograft Model Antitumor Assays