Brukinsa (zanubrutinib) / BeOne Medicines, Medison - LARVOL DELTA

BOSon: Zanubrutinib, Obinutuzumab, and Sonrotoclax in Previously Untreated Patients With CLL or SLL (clinicaltrials.gov) - P2 | N=40 | Recruiting | Sponsor: Massachusetts General Hospital | Not yet recruiting ➔ Recruiting

Enrollment open • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma

Chronic lymphocytic leukemia: criteria for first-line therapeutic choice-an opinion paper. (PubMed, Med Oncol) - "Recent advancements in Bruton's tyrosine kinase (BTK) inhibitors like acalabrutinib and zanubrutinib offer improved efficacy and safety profiles, impacting treatment choice for all patients namely elderly patients with comorbidities. Targeted therapy is preferred for most patients, with geriatric assessment pivotal for treatment decisions. Second-generation drugs aim to improve outcomes both in efficacy and safety, advocating for a patient-centered approach in clinical studies."

Journal • Review • Cardiovascular • Chronic Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • IGH • TP53

Targeting BTKi-Resistant CLL Using the Dual Irreversible/Reversible 4th Generation BTK Inhibitor Rocbrutinib (IWCLL 2025) - P1 | "Using FPCBA, rocbrutinib was the only BTKi—among ibrutinib, acalabrutinib, zanubrutinib, nemtabrutinib, and pirtobrutinib—to retain nanomolar potency against WT BTK as well as clinically relevant resistance mutations, including C481S, V416L, M437R, and L528W. Collectively, our findings demonstrate rocbrutinib is a potent and selective inhibitor of BTK with activity even in the presence of mutations that mediate resistance to cBTKi and ncBTKi. These data support the continued investigation of rocbrutinib, which is currently being studied in the phase 1 setting of CLL and NHL (NCT04775745 and NCT04993690)."

IO biomarker • Chronic Lymphocytic Leukemia • Hematological Malignancies • BCL2 • BCL2A1 • BCL2L1 • CCL3 • CD40 • PLCG2

New Immunotherapeutic Horizons in Richter's Transformation: Synergistic Approaches with Targeted Agents (SOHO 2025) - "BTK inhibitors, such as ibrutinib and zanubrutinib, have been shown to modulate immune function, reducing regulatory T-cell activity and altering cytokine profiles...Pembrolizumab and nivolumab achieved response rates of approximately 13% to 20%, with a median OS of less than 6 months...The landscape shifted with the RT1 trial, which evaluated the combination of tislelizumab, a PD-1 inhibitor, with zanubrutinib in 48 patients with RT...The MOLTO trial adopted a triplet strategy, combining atezolizumab, a PD-L1 inhibitor, with venetoclax and obinutuzumab...Support for combination strategies comes from a recent case series by Smith et al, in which six RT patients were treated with lisocabtagene maraleucel (liso-cel)...9,10 Given these encouraging results, epcoritamab is being tested in combination with venetoclax, R-CHOP, and other immune modulators...Other bispecific constructs under investigation include glofitamab and mosunetuzumab, each with distinct pharmacokinetic..."

IO biomarker • B Cell Lymphoma • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Richter's Syndrome • HAVCR2 • LAG3 • NOTCH1 • PD-L2 • TP53

Targeting BTKi-Resistant CLL Using the Dual Irreversible/Reversible 4th Generation BTK Inhibitor Rocbrutinib (IWCLL 2025) - P1 | "Using FPCBA, rocbrutinib was the only BTKi—among ibrutinib, acalabrutinib, zanubrutinib, nemtabrutinib, and pirtobrutinib—to retain nanomolar potency against WT BTK as well as clinically relevant resistance mutations, including C481S, V416L, M437R, and L528W. Collectively, our findings demonstrate rocbrutinib is a potent and selective inhibitor of BTK with activity even in the presence of mutations that mediate resistance to cBTKi and ncBTKi. These data support the continued investigation of rocbrutinib, which is currently being studied in the phase 1 setting of CLL and NHL (NCT04775745 and NCT04993690)."

IO biomarker • Chronic Lymphocytic Leukemia • Hematological Malignancies • BCL2 • BCL2A1 • BCL2L1 • CCL3 • CD40 • PLCG2

Autoimmune complications of lymphoproliferative diseases (ICML 2025) - "Moreover, several drugs may be responsible for immune-mediated cytopenias, including several antibiotics (ceftriaxone, piperacillin, rifampin, nafcillin, erythromycin, ticarcillin, trimethoprim, sulfamethoxazole), and various other drugs (procainamide, quinine, phenacetin, diclofenac, cimetidine, hydrochlorothiazide, chlorpropamide) [8]...Ibrutinib, through the inhibition of autoantibodies producing B-cells and restoration of T-cell homeostasis seems safe, while some case reports of autoimmune diseases have been reported for idelalisib (autoimmune hepatitis, colitis) and venetoclax (AIHA) [5, 6]...They included nivolumab, followed by pembrolizumab, ipilimumab, and atezolizumab...In particular, in CLL several therapies have been reported effective in refractory cytopenias: alemtuzumab single agent, the combinations ibrutinib-rituximab, bendamustine-rituximab, and rituximab–cyclophosphamide-dexamethasone [34-37]. Notably, some of the new/experimental treatments for primary..."

IO biomarker • B Cell Lymphoma • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Hodgkin Lymphoma • Leukemia • Lymphoma • Lymphoplasmacytic Lymphoma • Marginal Zone Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology • T Cell Non-Hodgkin Lymphoma • Waldenstrom Macroglobulinemia • CTLA4 • HP • IL10 • PD-1 • TGFB1

Advances in the Management of Relapsed/Refractory CLL and Richter Transformation (ICML 2025) - P=N/A, P2, P3 | "BRUIN CLL-321 is a phase 3, registrational study that evaluated pirtobrutinib compared to the investigator's choice of idelalisib plus rituximab (IdelaR) or bendamustine plus rituximab (BR) [23]...Nemtabrutinib is now being evaluated in the registrational, phase 3 BELLWAVE-010 trial (NCT05947851) for patients with R/R CLL, comparing nemtabrutinib plus venetoclax to venetoclax plus rituximab...An ongoing, open-label, first-in-human phase 1/2 study is evaluating the BTK degrader BGB-16673 as monotherapy in patients with R/R CLL [27, 28]...NX-2127 is an investigational, first-in-class BTK degrader currently being evaluated in a phase 1 trial for patients with relapsed or refractory B-cell malignancies, CLL [29, 30]...NX-5948 is another investigational and more selective BTK degrader in an ongoing Phase 1a/1b clinical trial...This trial aims to establish lisaftoclax plus acalabrutinib as a potential alternative to venetoclax-based BTKi combination..."

IO biomarker • Acute Myelogenous Leukemia • B Cell Lymphoma • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Leukemia • Non-Hodgkin’s Lymphoma • Oncology • Richter's Syndrome • Small Lymphocytic Lymphoma • BCL2L1 • TP53

Zanubrutinib for Treatment of Patients with Recurrent Neuromyelitis Optica Spectrum Disorders. (ECTRIMS 2025) - P2 | " Five patients were enrolled, three of whom relapsed after rituximab treatment. In this small study, zanubrutinib has the potential to be a safe and effective treatment for patients with recurrent NMOSD, especially for those who have failed B cell depletion therapy. A multicenter randomized controlled study with a larger sample is needed to further assess its safety and efficacy."

Clinical • CNS Disorders • Immunology • Neuromyelitis Optica Spectrum Disorder • Rare Diseases

PRT2527-02: A Study of PRT2527 as Monotherapy and in Combination With Zanubrutinib or Venetoclax in Participants With R/R Hematologic Malignancies (clinicaltrials.gov) - P1 | N=86 | Active, not recruiting | Sponsor: Prelude Therapeutics | Trial primary completion date: Nov 2025 ➔ Jun 2025

Monotherapy • Trial primary completion date • Acute Myelogenous Leukemia • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Chronic Lymphocytic Leukemia • Chronic Myelomonocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Myelodysplastic Syndrome • Myeloproliferative Neoplasm • Non-Hodgkin’s Lymphoma • Oncology • Richter's Syndrome • Small Lymphocytic Lymphoma • T Cell Non-Hodgkin Lymphoma

Self-assembled zanubrutinib loaded lipid polymer hybrid nanoparticles for enhanced oral absorption by lymphatic uptake: in vitro, ex vivo and in vivo evaluations. (PubMed, Pharm Dev Technol) - "The AUCtotal of ZBR-LPHNPs was reduced by 60.37% in cycloheximide treated group of rats, indicating uptake by intestinal lymphatic system. Overall, this study establishes LPHNP-mediated intestinal lymphatic transport as an effective strategy to enhance oral bioavailability of ZBR."

Journal • Preclinical • CYP3A4

EUROCOVER-CLL: Reimbursement and accessibility of new treatments in relapsed/refractory chronic lymphocytic leukemia. (PubMed, Front Pharmacol) - "Ibrutinib, reimbursed in 13 countries, had the longest mean reimbursement delay (35.6 months), while venetoclax (11 countries, 26.5 months), acalabrutinib (9 countries, 16.4 months), and zanubrutinib (6 countries, 15.2 months) had shorter delays. Data on HTA outcomes and the number of treated patients were limited in several countries, and common challenges included funding constraints, administrative barriers, and the lack of centralized rare disease policies. Significant disparities in access to targeted CLL therapies persist across the analyzed countries, with the number of reimbursed therapies positively correlated with GDP per capita."

Journal • Reimbursement • US reimbursement • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • Rare Diseases • TP53

Debate: Progression on Covalent BTK Inhibitors — Change to Venetoclax-Based Therapy (SOHO 2025) - "Search terms included combinations of " CLL, "" BTKi resistance, "" ibrutinib, "" acalabrutinib, "" zanubrutinib, "" veneto-clax, " and " treatment sequencing...In the MURANO trial, 389 patients with R/R CLL were randomized to receive venetoclax plus rituximab (VenR) for 2 years versus bendamustine plus rituximab...8 Finally, a phase 1b trial tested fixed-duration pirtobrutinib plus venetoclax (PV, n = 15) or PV with rituximab (PVR, n = 10) in BTKi-experienced, venetoclax-naïve patients...For those with del(17p)/ TP53 mutation — a high-risk subgroup — preferred regimens consist of venetoclax-based therapies, with or without obinutuzumab. Additional recommended options include venetoclax combined with rituximab (category 1) or with ibrutinib (category 2B)...As newer agents, such as noncovalent BTKis and bispecific antibodies emerge, the landscape will continue to evolve. Until then, venetoclax remains a..."

IO biomarker • B Cell Lymphoma • Chronic Lymphocytic Leukemia • Leukemia • Lymphoma • Oncology • Richter's Syndrome • IGH • MCL1 • PLCG2 • TP53

Real-World Burden of Disease (BoD), Treatment Patterns, and Outcomes in Patients With Mantle Cell Lymphoma (MCL) (SOHO 2025) - "Treatment regimens were categorized into seven mutually exclusive groups: bendamustine-based chemotherapy (B-based); rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone (R-CHOP); rituximab mono-therapy (R-mono); Bruton tyrosine kinase inhibitors (BTKis), including zanubrutinib, acalabrutinib, ibrutinib, and pirtobrutinib; bortezomib-based; venetoclax-based; and other regimens. In this real-world study, trends of increasing utilization of BTKis and reduction in the use of B-based regimens in treatment-naïve and R/R settings were observed. Many patients received treatment that resulted in short TTNT and substantial HCRU, highlighting the need for novel agents to lower BoD in MCL. Previously submitted to EHA 2025 and ICML 2025."

Clinical • HEOR • Real-world • Real-world evidence • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Oncology

Diagnosis and Management of Waldenstrom's Macroglobulinemia (ICML 2025) - P2 | "New or emerging options for patients progressing on c-BTKi include pirtobrutinib, BGB-16673, venetoclax, and sonrotoclax...CXCR4 antagonists such as plerixafor or ulocuplumab can sensitize CXCR4Mut-expressing WM cells to ibrutinib [22-24]...6 BTK Mutations BTKCys481 is the binding site for covalent BTK inhibitors (cBTK-i), including ibrutinib, zanubrutinib, acalabrutinib, orelabrutinib and tirabrutinib...For symptomatic treatment-naïve patients, chemoimmunotherapy with bendamustine and rituximab (Benda-R), dexamethasone, rituximab, and cyclophosphamide (DRC), as well as cBTK-i can be considered...Additional options in second or later relapse include re-use of chemotherapy if a response lasted for > 3 years, alternative chemoimmunotherapy, nucleoside analogs, or everolimus [38]...Zanubrutinib in combination with ixazomib and dexamethasone (ZID) is being investigated in a study in China (NCT04463953) and has shown high levels of response activity and good..."

IO biomarker • Hematological Malignancies • Leukemia • Lymphoma • Lymphoplasmacytic Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Waldenstrom Macroglobulinemia • BCLAF1 • CXCL12 • FOXO3 • IL10 • IL6 • IRAK4 • MYD88 • PLCG2 • SYK • TNFAIP3 • TRAF3IP2

Combination of Zanubrutinib + Venetoclax for Treatment-naive Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: Results in SEQUOIA Arm D (IWCLL 2025) - P3 | ": BeOne Medicines Ltd Background: Zanubrutinib monotherapy demonstrated superior progression-free survival (PFS) compared with bendamustine + rituximab in patients without del(17p) at 26.2-month follow-up and sustained PFS benefit at 5-year follow-up. SEQUOIA arm D data demonstrate promising efficacy and tolerability of zanubrutinib + venetoclax combination treatment in treatment-naive CLL/SLL, regardless of del(17p) and/or TP53 mutational status. Best peripheral blood uMRD was also similar regardless of mutational status. The safety profile of zanubrutinib + venetoclax was consistent with results of prior zanubrutinib studies, and no new safety signals were identified."

B Cell Lymphoma • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Small Lymphocytic Lymphoma • BCL2 • IGH

Other Cancers in Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (IWCLL 2025) - "Among patients treated with targeted therapies, 931 (52%) received ibrutinib,357 (20%) received acalabrutinib, 157 (9%) received zanubrutinib, and 258 (15%) received venetoclax. In this large dataset of newly diagnosed patients with CLL/SLL in the past decade, approximately 10% patients developed OC at 5 years. Receipt of CLL directed therapy was associated with a 40% increased risk of development of OC compared to those patients who did not receive therapy. The risk was highest among patients who received CIT+targeted therapy compared to those who received CIT only or those who received targeted therapy alone."

Clinical • IO biomarker • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma • IGH

Triplet Therapies in Chronic Lymphocytic Leukemia. (PubMed, Hematol Oncol Clin North Am) - "Triplet therapy regimens, which we define as the combination of a BTK inhibitor (ibrutinib, acalabrutinib, zanubrutinib, or pirtobrutinib), BCL2 inhibitor (venetoclax or sonrotoclax), and a CD20 antibody (obinutuzumab), have been developed in chronic lymphocytic leukemia (CLL). Herein, we comprehensively review the available clinical data for triplet regimens in treatment-naïve CLL, including an evidence-based discussion of the role of TP53 aberrancy in patients receiving triplet therapies, and of retreatment options after frontline triplet therapy. We also review ongoing trials with potential to further define the role of triplet therapies in treatment-naïve CLL."

Journal • Review • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma • TP53

A Network Meta-Analysis (NMA) of Efficacy of Zanubrutinib versus Fixed-Duration Acalabrutinib Plus Venetoclax in Treatment-naïve (TN) Chronic Lymphocytic Leukemia (CLL) (IWCLL 2025) - P3 | "Bendamustine plus rituximab (BR) and fludarabine plus cyclophosphamide and rituximab (FCR)/BR were assumed to be treated as common control arms in the network. This NMA found a statistically significant improvement in PFS for ZANU over AV for patients with low-risk TN CLL. The observed efficacy differences should be interpreted under the limitation and assumptions of NMA, with further analysis upon trial data maturation."

Retrospective data • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • IGH • TP53

New Targets and Drugs on the Horizon in Chronic Lymphocytic Leukemia (SOHO 2025) - P1, P1/2 | "12 Treatment planning for patients with " double refractory " CLL — CLL that is resistant to a covalent BTKi and venetoclax — is a relatively novel but emerging scenario in the clinic...Noncovalent (Reversible) BTK Inhibitors In the BRUIN-321 phase 3 randomized trial of pirtobrutinib monotherapy versus the control arm of the investigator's choice between idealisib plus rituximab or bendamustine plus rituximab, pirtobrutinib had improved PFS (14 vs 8.7 months, Hazard ratio [HR] 0.54, P = 0.0002) and a superior time to next treatment or death compared to the control arm (24 vs 10.9 months, HR 0.37, P < 0.0001)...Nemtabrutinib is another noncovalent BTKi under clinical investigation, demonstrating an overall response rate (ORR) of 36.4% in CLL patients in the phase 1 study (n = 22 patients)...23,24 Thus far, data for three orally administered BTK degraders — NX-2127, NX-5948 and BGB-16673 23–25— have been presented, and there are ongoing clinical..."

IO biomarker • B Cell Lymphoma • Chronic Lymphocytic Leukemia • Leukemia • Lymphoma • Oncology • CD20 • PRKCB • PRKCH • ROR1

Comparative Safety and Efficacy of Bruton Tyrosine Kinase Inhibitors for Patients With Treatment-Naive Versus Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials (SOHO 2025) - "For TN patients, the drugs showing the best OS and PFS were acalabrutinib+venetoclax (HR = 0.25; 95% CI, 0.14-0.44) and ibrutinib (HR = 0.16; 95% CI, 0.09-0.28). For patients with TN CLL/SLL, the drug showing the best overall efficacy profile was ibrutinib. For patients with R/R CLL/SLL, the overall best drug was zanubrutinib. Considering these results and combining them with future studies, clinicians are advised to use the drugs with the best safety and efficacy in their clinical practice."

Retrospective data • Review • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma

A Network Meta-Analysis of Efficacy of Zanubrutinib vs Fixed-Duration Acalabrutinib Plus Venetoclax in Treatment-Naïve Chronic Lymphocytic Leukemia (SOHO 2025) - P3 | "Bendamustine plus rituximab (BR) and fludarabine plus cyclophosphamide and rituximab (FCR)/BR were assumed to be treated as common control arms in the network. This NMA found a statistically significant improvement in PFS for ZANU over AV for patients with low-risk TN CLL. The observed efficacy differences should be interpreted under the limitation and assumptions of NMA, with further analysis upon trial data maturation. Previously submitted to ASCO 2025, EHA 2025, and ICML 2025."

Retrospective data • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • IGH • TP53

Prevalence of BTK, PLCG2, and BCL2 mutations in CLL patients in Croatia - KROHEM study (IWCLL 2025) - "Among 41 previously treated patients, 28 had been exposed to BTKi (20 ibrutinib, 8 acalabrutinib, 2 zanubrutinib, 1 pirtobrutinib) and 13 had been exposed to venetoclax-based treatment (12 monotherapy, 3 time-limited regimens), with several patients having received multiple BTKi and/or Bcl2a-based treatments. BTK, PLCG2, and BCL2 resistance mutations are found in a significant proportion of individuals who relapsed after or were refractory to targeted agents. Although routine testing for these mutations is not currently recommended, they may provide additional information that can be considered in treatment decisions. This could become more relevant with the increasing number of drugs targeting selected pathways and different resistance patterns."

Clinical • IO biomarker • Chronic Lymphocytic Leukemia • Hematological Malignancies • BCL2 • PLCG2 • TP53

A Phase 2 study with Tafasitamab and Zanubrutinib in newly diagnosed chronic lymphocytic leukemia/small lymphocytic lymphoma – TaZa CLL Study (IWCLL 2025) - P2 | "Tafasitamab is a humanized, FC-enhanced anti-CD19 monoclonal antibody, which has demonstrated favorable response rates and toxicity profile when combined with venetoclax or idelalisib in relapsed and refractory CLL (R/R CLL) (Staber PB et al, ASH 2019). Our preliminary results suggest that the combination of tafasitamab and Zanubrutinib leads to high overall response rate, including patients with unfavorable prognostic factors. TaZa is well tolerated with no unexpected toxicity. Updated response data with additional patients and correlative MRD studies will be presented in the meeting."

IO biomarker • P2 data • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Small Lymphocytic Lymphoma • CD5 • GAS1 • TP53

Real-world Utilization of Novel Therapies and Overall Survival among U.S. Medicare Beneficiaries Initiating Frontline Chronic Lymphocytic Leukemia Treatment (IWCLL 2025) - "Novel therapies included BTKis (ibrutinib-, acalabrutinib-, or zanubrutinib-based regimens) and BCL-2is (venetoclax-based regimens); all other CLL treatments (anti-CD20 monotherapy, traditional chemotherapy, etc.) were classified as non-novel. This national real-world study of Medicare beneficiaries initiating frontline CLL therapy found that novel treatment, particularly the BCL-2i venetoclax, was associated with longer overall survival. Given these differences in survival, consideration of novel agent use, especially venetoclax combinations, is warranted in older CLL patients. Our findings highlight the importance of understanding the reasons for and addressing potential access barriers to novel therapies among Medicare beneficiaries with CLL in the U.S."

Clinical • Medicare • Real-world • Real-world evidence • Reimbursement • US reimbursement • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia

Efficacy of Continuous Zanubrutinib vs Fixed-Duration Venetoclax in Combination With Obinutuzumab in Treatment-Naive Chronic Lymphocytic Leukemia: A Matching-Adjusted Indirect Comparison (SOHO 2025) - P3 | "This unanchored MAIC investigated the relative efficacy of zanubrutinib vs VenO, suggesting zanubrutinib had longer PFS and an extended OS trend. Results should be interpreted considering MAIC model assumptions and limitations. Further studies are needed to confirm these findings."

Clinical • Combination therapy • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma • B2M • IGH