Brukinsa (zanubrutinib)

P3, N=500, Recruiting, BeiGene | Enrolling by invitation --> Recruiting

P2, N=50, Recruiting, Weill Medical College of Cornell University | Trial completion date: May 2028 --> Dec 2027 | Trial primary completion date: Mar 2027 --> Jan 2025

P1/2, N=51, Recruiting, Zhejiang Genfleet Therapeutics Co., Ltd.

P2, N=66, Not yet recruiting, Institute of Hematology & Blood Diseases Hospital, China

Moreover, combination of dasatinib with BTK inhibitors (BTKi) (ibrutinib, acalabrutinib or zanubrutinib) significantly decreased E2A-PBX1+/preBCR+ human and murine cell proliferation, reduced PLCG2 and BTK phosphorylation and total protein levels and increased disease-free survival of mice in secondary transplantation assays, reducing particularly CNS-leukemic infiltration. Hence, dasatinib with ibrutinib reduced pPLCG2 and pBTK in primary ALL patient samples, including E2A-PBX1+ ALLs. In summary, genetic depletion and pharmacological inhibition of BTK increase dasatinib effects in human and mouse E2A-PBX1+/preBCR+ ALL in most of performed assays, and the combination of dasatinib and BTKi is very effective in reducing CNS-infiltration of E2A-PBX1+/preBCR+ ALL cells in vivo.

P2, N=43, Recruiting, H. Lee Moffitt Cancer Center and Research Institute

P1, N=66, Completed, BeiGene | Recruiting --> Completed

P2, N=52, Recruiting, Fudan University

P3, N=652, Completed, BeiGene | Active, not recruiting --> Completed

The estimated 1-year PFS was 72.3% (95% confidence interval [CI], 51.9-85.1) for FL and 56.3% (95% CI, 28.9-76.7) for MCL (median follow-up: 16.5 and 10.9 months respectively). Zandelisib plus zanubrutinib was associated with high response rates and no increased toxicity compared to either agent alone.

P2, N=20, Recruiting, RenJi Hospital | Not yet recruiting --> Recruiting

P3, N=750, Recruiting, BeiGene | Trial completion date: Jun 2029 --> Jun 2030

P2, N=76, Not yet recruiting, University Health Network, Toronto | Initiation date: Jan 2024 --> Aug 2024

P1/2, N=55, Active, not recruiting, BeiGene | Trial primary completion date: Sep 2024 --> May 2023

In TP53MUT, compared to ibrutinib, zanubrutinib-treated patients had higher VGPR+CR (34.6% vs 13.6%, P<0.05), numerically improved MRR (80.8% vs 63.6%, P=0.11), and longer PFS (not reached vs 44.2 months, HR=0.66, P=0.37). Collectively, WM patients with CXCR4MUT or TP53MUT had worse prognosis compared to patients with WT alleles and zanubrutinib led to better clinical outcomes.

The cBTK-i zanubrutinib shows greater response activity and/or improved PFS in wild-type MYD88, mutated CXCR4, or altered TP53 patients...For patients with acquired resistance to c-BTKi, newer options include the non-covalent BTK-inhibitor pirtobrutinib or the BCL2 antagonist venetoclax. Combinations of BTK-inhibitors with chemoimmunotherapy, CXCR4 and BCL2 antagonists have advanced and are discussed. Algorithms for positioning BTK-inhibitors in treatment-naïve and previously treated WM patients based on genomics, disease characteristics, and co-morbidities are presented.

P3, N=640, Recruiting, BeiGene | Not yet recruiting --> Recruiting

P3, N=510, Active, not recruiting, BeiGene | Recruiting --> Active, not recruiting

The patient was initially treated with ibrutinib, before transitioning to zanubrutinib. However, she developed disease progression necessitating radiotherapy with lenalidomide and rituximab maintenance therapy, which achieved remission. This case sheds light on the diagnosis and management of a very rare complication of a rare disease.

Our empirical observations demonstrated that the combination of zanubrutinib with HD-MTX yielded a marked clinical response and tolerability among newly diagnosed PCNSL patients. Non-invasive CSF liquid biopsy profiling may be feasible for evaluating treatment response and tumor burden.

P2, N=10, Recruiting, Matthew C. Baker

P2, N=78, Recruiting, Gruppo Italiano Malattie EMatologiche dell'Adulto

P1, N=537, Recruiting, BeiGene | Phase classification: P1a/1b --> P1

P2, N=76, Not yet recruiting, University Health Network, Toronto

Moreover, 18 patients (85.7%) had grade 1-2 cytokine-release syndrome, and two patients (9.5%) had grade 1 immune effector cell-associated neurotoxicity syndrome. Zanubrutinib-based combination bridging regimen of CAR-T therapy for r/r DLBCL has high efficacy and demonstrated a good safety profile.

P=N/A, N=400, Recruiting, iOMEDICO AG | N=300 --> 400

Background: We aimed to compare the cost-effectiveness of bruton tyrosine kinase inhibors (BTKis) versus bendamustine-rituximab (R-bendamustine) as a first-line treatment for Chinese patients with relapsed or refractory chronic lymphocytic leukemia. While ibrutinib had a higher ICER relative to R-bendamustine. Zanubrutinib was cost-effective for patients with relapsed or refractory chronic lymphocytic leukemia in China.

With the worldwide approval of the oral covalent Bruton tyrosine kinase (BTK) inhibitors ibrutinib and zanubrutinib for treating patients with Waldenström macroglobulinemia (WM), targeted agents have certainly taken center stage in the therapeutic landscape of WM. Novel targeted agents of interest include BCL2 antagonists (e.g., venetoclax and sonrotoclax) and non-covalent BTK inhibitors (e.g., pirtobrutinib and nemtabrutinib), among others. The therapeutic landscape of patients with WM will benefit from the robust participation of patients in clinical trials.

P3, N=421, Recruiting, Alliance for Clinical Trials in Oncology | Not yet recruiting --> Recruiting

"Adaptive Biotechnologies Corporation (Nasdaq: ADPT), a commercial stage biotechnology company that aims to translate the genetics of the adaptive immune system into clinical products to diagnose and treat disease, together with its collaborators will present data from more than 30 abstracts demonstrating the actionability of Adaptive’s next-generation sequencing (NGS)-based clonoSEQ^® test in assessing minimal residual disease (MRD) in blood cancer patients at the 65th Annual Meeting of the American Society of Hematology (ASH), December 9-12 in San Diego, California."

The zanubrutinib combined regimens are zanubrutinib with IMIDs, chemotherapy and/or rituximab. Zanubrutinib-combined regimens are effective and safe as bridging therapy in CD19 CAR-T therapy. More prospective studies are further command.

Inhibitors of BCL2 (venetoclax) and Bruton Tyrosine Kinase (BTK) (ibrutinib, acalabrutinib and zanubrutinib) are novel agents that have revolutionized outcomes in CLL patients in the newly diagnosed and relapsed/refractory settings. Fasting's risks and benefits must be discussed with patients . Further prospective clinical trials, including exploration of different forms of IF, are needed to better elucidate the effect of IF on FLNAs treatment -related outcomes in CLL patients .

After 8 cycles, patients with VGPR remission receive Chlorambucil 6mg D1-4,15-18, dexamethasone 20mg D1-4,15-18, cyclophosphamide 300mg, D1-4,15-18 for 4cycles, others receive Zanubrutinib as maintenance. These results demonstrate that zanubrutinib, dexamethasone and or not cyclophosphamide are quickly effective in the treatment of WM, with more deeper response and less toxicity, maybe treatment discontinued by combining with cyclophosphamide after deep remission. Comments*The regimen of ZD: Zanubrutinib 240mg d1-28, dexamethasone 20mg D1-4,15-18. Patients more than 75 years old, Zanubrutinib 160mg d1-28, dexamethasone 10mg D1-4,15-18.

The aim of this study was to further investigate the effect of CXCR4 S338X on BTK inhibitors (ibrutinib and zanubrutinib) and a BCL-2 inhibitor (venetoclax) resistance. The above data demonstrate the role of CXCR4 S338X mutation in drug resistance and suggest the necessity to develop therapeutic strategies to address this issue and overcome this therapeutic barrier in WM. Data on more cell lines and downstream signaling will be presented at the meeting.

2 cells did not respond to the BTK-inhibitors ibrutinib, zanubrutinib or pirtobrutinib but were sensitive to the BCL2 inhibitor venetoclax. BCWM. 2 represents a novel, BTK-inhibitor resistant, BCL2 inhibitor sensitive WM cell line that demonstrates MYD88 (S243N) and LYN (I297N) somatic activating mutations, and deletions of 6q. BCWM.

Using the TME system, we have demonstrated that modeled drug response correlates well with patient clinical response to BTK inhibitor ibrutinib and BCL2 inhibitor venetoclax...To test the hypothesis, we exposed CLL cells in the TME model system to covalent and noncovalent BTKi including ibrutinib, zanubrutinib, and pirtobrutinib at clinically achievable concentrations...Furthermore, plerixafor blocks ibrutinib-driven CIC in cell lines as well as in primary CLL cells...B. One CLL cell was captured halfway in.

Patients received therapies: R-CHOP intravenously Rituximab (375mg/m2 on Day0), Cyclophosphamide (750mg/m2on Day1), Doxorubicin (50mg/m2 on Day1), Vincristine(1. 4mg/m2 on Day1), and oral Prednisone(50mg/day Day1-5) with Zanubrutinib (160mg bid Day1-21) regimen...CONCLUSIONSOur results showed that Zanubrutinib plus R-CHOP(ZR-CHOP) is a safe and effective scheme for DLBCL patients with extranodal involvement. It indicate that the addition of zanubrutinib to the standard first-line treatment can enable these patients to achieve remission in the early stage of treatment and without significantly increasing toxicity.

It is recently available in China and approved in combination with Bendamustine and Rituximab for r/r DLBCL. gov (NCT05940051) . We illustrated the flowchart of our study in Figure 2.

The study is open to enrollment and registered at ClinicalTrials. gov (NCT05665530).

This is the first study to describe the genomic landscape of patients with B-cell malignancies who were intolerant to ibrutinib and/or acalabrutinib. Here we show that the gene mutational profile of these patients at baseline or at/after disease progression is comparable with patients with relapse/refractory disease who tolerate ibrutinib and, consistent with other studies, patients with mutations in TP53, SF3B1 or ATM genes had less favorable prognosis on BTKi. Further, intolerant patients who progressed on zanubrutinib acquired new BTK mutations and/or had an increase in the frequency of BTK mutations.

The combination of 4 cycles of R-CHOP regimen with zanubrutinib in the induction treatment of DLBCL patients with high-risk factors, such as extranodal involvement or MYC/BCL2 double expression, has shown promising clinical outcomes especially in older or unfit/frail patients. This approach allows for a reduction in the number of cytotoxic drug cycles, thereby improving the patients' tolerance to the treatment. Moreover, the efficacy of this regimen is superior to the traditional 6-8 cycles of R-CHOP induction therapy.