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Introduction: Advanced MZL is generally incurable, with periods of remission and relapse. Zanubrutinib (BGB-3111), a potent and highly specific next-generation Bruton tyrosine kinase (BTK) inhibitor, was approved in the US and Canada for R/R MZL based on the MAGNOLIA primary analysis (BGB- 3111-214;NCT03846427);here, the final MAGNOLIA analysis is presented. Method(s): This was a phase 2, multicenter, single-arm study of adult patients (pts) with R/R MZL (>=1 prior CD20-directed therapy). Zanubrutinib (160 mg twice daily) was given until disease progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR) by independent review committee (IRC) per Lugano classification. Secondary endpoints were investigator-assessed ORR, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Efficacy was assessed by positron emission tomography (PET)-based Lugano criteria for IRC-confirmed fluorodeoxyglucose (FDG)-avid disease at baseline;non-avid disease was assessed by computed tomography (CT)-based criteria. Result(s): As of May 4, 2022, 68 pts were treated (median age=70 y [range 37-95];>=75 y=27.9%). MZL subtypes included extranodal (38.2%), nodal (38.2%), splenic (17.6%), and unknown (5.9%). The median number of prior therapies was 2 (range 1-6);32.4% of pts had disease refractory to last therapy, most (89.7%) had prior chemoimmunotherapy, and 7 (10.3%) had rituximab monotherapy as their only prior treatment. Sixty-one pts (89.7%) had FDG-avid disease. After a median follow-up of 28.0 mos (range 1.6-32.9) and a median treatment duration of 24.2 mos (range 0.9-32.9), 66 pts were efficacy- evaluable. IRC-assessed ORR (complete response [CR]+partial response [PR]) was 68.2% (CR=25.8%). By subtype, (Figure Presented)(Figure Presented)ORR/CR rates were 64.0%/40.0% (extranodal), 76.0%/20.0% (nodal), 66.7%/8.3% (splenic), and 50.0%/25.0% (unknown). Median DOR, PFS, and OS were not reached. Over 70.0% of pts were alive or progression-free after 2 years (Figure). Sensitivity analysis using only CT-based criteria (n=66) showed an ORR of 66.7% and CR of 24.2%. The most common treatment-emergent AEs were bruising (23.5%), diarrhea (22.1%), and constipation (17.6%). Neutropenia (8.8%) and COVID-19 pneumonia (5.9%) were the most common Grade >=3 AEs. Five pts (7.4%) died due to unrelated AEs: COVID-19 pneumonia=2, acute myeloid leukemia=1, myocardial infarction=1, septic encephalopathy=1. Hypertension occurred in 3 pts (4.4%), atrial fibrillation and atrial flutter in 1 pt (1.5%) each;none led to treatment withdrawal. One pt (1.5%) had a Grade 3 gastrointestinal hemorrhage while receiving rivaroxaban. None of the pts required dose reduction. Conclusion(s): In this final analysis with over 2 years of median follow-up, zanubrutinib continues to demonstrate durable disease control and was generally well tolerated, with no new safety signals observedCopyright © 2023 American Society for Transplantation and Cellular Therapy
ABSTRACT
Phytochemical-based drug discovery against the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has been the focus of the current scenario. In this context, we aimed to perform the phytochemical profiling of Magnolia champaka, an evergreen tree from the Magnoliaceae family, in order to perform a virtual screening of its phytoconstituents against different biological targets of SARS-CoV-2. The phytochemicals identified from the ethanol extract of M. champaka leaves using liquid chromatography-mass spectroscopy (LC-MS) technique were screened against SARS-CoV-2 spike glycoprotein (PDB ID: 6M0J), main protease/Mpro (PDB ID: 6LU7), and papain-like protease/PLpro (PDB ID: 7CMD) through computational tools. The experimentation design included molecular docking simulation, molecular dynamics simulation, and binding free energy calculations. Through molecular docking simulation, we identified poncirin as a common potential inhibitor of all the above-mentioned target proteins. In addition, molecular dynamics simulations, binding free energy calculations, and PCA analysis also supported the outcomes of the virtual screening. By the virtue of all the in silico results obtained, poncirin could be taken for in vitro and in vivo studies in near future.Communicated by Ramaswamy H. Sarma.
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Background: MZL is the second most common lymphoma in older pts. Choosing an optimal treatment can be challenging because of patient-or disease-related risk factors and treatment-related toxicities (Curr Opin Oncol. 2019;31(5):386-393). Zanubrutinib is a potent, irreversible next-generation Bruton tyrosine kinase (BTK) inhibitor designed to maximize BTK occupancy and minimize off-target kinase inhibition, which may improve efficacy outcomes and minimize toxicities, such as cardiac arrythmias and bleeding events. Zanubrutinib received accelerated approval from the United States FDA for the treatment of pts with R/R MZL (Haematologica . 2022;107(1):35-43). Aims: We aim to present a subgroup analysis of efficacy and safety of zanubrutinib in pts aged ≥65 years with R/R MZL enrolled in MAGNOLIA (BGB-3111-214;NCT03846427). Methods: MAGNOLIA is a phase 2, multicenter, single-arm study of adults with R/R MZL who had received ≥1 line of therapy including ≥1 CD20-directed regimen. All were treated with zanubrutinib 160 mg twice daily until disease progression or unacceptable toxicity. Use of long-term antiplatelet and anticoagulation agents was permitted. The primary endpoint was overall response rate (ORR;complete response [CR] and partial response [PR]) determined by an independent review committee (IRC) in accordance with the Lugano classification. Secondary endpoints include ORR by investigator assessment (INV), duration of response (DOR), progression-free survival (PFS), and safety. All pts gave informed consent. Results: As of 18 January 2021, a total of 68 pts were enrolled (Table). Forty (61%) pts were ≥65 years old with a median age of 73 (range, 65-85);18 pts were ≥75 years old. Median number of prior therapies was 2 (range, 1-6) and 10 (25%) pts were refractory to last therapy. Most pts received prior rituximab + cyclophosphamide + vincristine + prednisone (48%) or bendamustine + rituximab (30%), while 5 (13%) pts received rituximab monotherapy. MZL subtypes included extranodal (n=17, 43%), nodal (n=14, 35%), and splenic (n=8, 20%). Median duration of treatment was 14.4 months (mo;range, 0.9-19.6). At a median follow-up of 15.8 mo (range, 2.8-21.8), ORR by IRC was 75% (CR 25%, PR 50%;Table). Responses were observed in all subtypes, with an ORR of 71%, 86%, and 75% in extranodal, nodal, and splenic subtypes, respectively (CR 41%, 21%, and 0%, respectively). Median DOR and PFS were not reached;15-month PFS was 87% and 12-month DOR was 93%. Most (63%) pts are continuing zanubrutinib. Treatment discontinuation due to disease progression was 28% by INV. Most common treatmentemergent adverse events (AEs) observed in ≥20% of pts include contusion (28%), diarrhea (25%), and constipation (20%). Grade ≥3 neutropenia occurred in 5% of pts. The most common infection was upper respiratory tract infection (10%). Two (5%) pts discontinued zanubrutinib due to unrelated fatal AEs (COVID-19 pneumonia and myocardial infarction in a patient with pre-existing coronary artery disease). Atrial fibrillation/flutter and hypertension occurred in 2 (5%) pts each and did not lead to treatment discontinuation. No pts required dose reductions, or experienced major or serious hemorrhage. Image: Summary/Conclusion: The safety profile of zanubrutinib observed in older pts was consistent with previously published results (Clin Cancer Res . 2021;27(23):6323-6332). Zanubrutinib was well tolerated and effective, as demonstrated by a high response rate and durable disease control in older pts with R/R MZL.
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Objective: To explore the network regulation mechanism of Huoxiang Zhengqi Oral Liquid(HXZQ) in the treatment of coronavirus disease 19 (COVID-19).