Abstract
A combination of Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib and rituximab has shown promising efficacy in mantle cell lymphoma (MCL). This phase II trial evaluated the second-generation BTK inhibitor zanubrutinib plus rituximab as induction, followed by shortened chemoimmunotherapy as frontline treatment for MCL (NCT04624958). Eligible patients had histologically confirmed stage II–IV disease requiring immediate therapy and no prior MCL-related systemic treatment. Patients received zanubrutinib-rituximab for up to 12 cycles (part A); those achieving a complete response (CR) or experiencing disease progression proceeded to four cycles of R-DHAOx (rituximab, dexamethasone, cytarabine, and oxaliplatin) (part B). Patients with CR after part B received zanubrutinib maintenance for one year. The primary endpoint was the CR rate at part A completion. Forty-two patients were enrolled. The CR rate at part A completion was 88% (95% confidence interval [CI], 74-96), and 86% (95% CI, 72-95) at part B completion. Hematologic toxicities predominated: the most common grade 3-4 adverse events were neutropenia (7%) in part A, and thrombocytopenia (77%) and neutropenia (49%) in part B. In conclusion, zanubrutinib-rituximab induction followed by shortened R-DHAOx is efficacious with manageable safety as frontline therapy for MCL. This strategy allows for a reduction in chemotherapy cycles and warrants validation in randomized controlled trials.
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Data availability
The study protocol is provided in the Supplementary Information file as a Supplementary Note. Clinical data are not publicly available due to patient privacy, but can be accessed on request from the corresponding author, Qingqing Cai, for 10 years; individual deidentified participant data will be shared. All requests for data will be reviewed by the leading site, Sun Yat-Sen University Cancer Center, to verify if the request is subject to any intellectual property or confidentiality obligations. Requests for access to the patient-level data from this study can be submitted via email to caiqq@sysucc.org.cn with a detailed proposal for approval. The raw sequence data reported in this paper have been deposited at Genome Sequence Archive43 in National Genomics Data Center44, China National Center for Bioinformation/Beijing Institute of Genomics, Chinese Academy of Sciences (GSA: HRA011494; accessible at https://ngdc.cncb.ac.cn/gsa-human/browse/HRA011494). The sequencing data are available under restricted access due to patient privacy. Access may be granted to researchers for research purposes, subject to approval by the GSA-Human Data Access Committee and the study investigators, in accordance with institutional and ethical regulations. Requests should be submitted through the GSA-Human Data Access System and by contacting the corresponding author, Qingqing Cai. Data will be made available within two weeks following approval and will remain accessible for 12 months under a data use agreement and in compliance with repository policies. The remaining data are available within the Article, Supplementary Information, or Source Data file. Source data are provided with this paper.
Code availability
No novel code/algorithm was used in this study.
References
Armitage, J. O. & Longo, D. L. Mantle-Cell Lymphoma. N. Engl. J. Med. 386, 2495–2506 (2022).
Le Gouill, S. et al. Rituximab after Autologous Stem-Cell Transplantation in Mantle-Cell Lymphoma. N. Engl. J. Med. 377, 1250–1260 (2017).
Geisler, C. H. et al. Long-term progression-free survival of mantle cell lymphoma after intensive front-line immunochemotherapy with in vivo-purged stem cell rescue: a nonrandomized phase 2 multicenter study by the Nordic Lymphoma Group. Blood 112, 2687–2693 (2008).
Dreyling, M. et al. Ibrutinib combined with immunochemotherapy with or without autologous stem-cell transplantation versus immunochemotherapy and autologous stem-cell transplantation in previously untreated patients with mantle cell lymphoma (TRIANGLE): a three-arm, randomised, open-label, phase 3 superiority trial of the European Mantle Cell Lymphoma Network. Lancet 403, 2293–2306 (2024).
Merryman, R. W. et al. Rituximab/bendamustine and rituximab/cytarabine induction therapy for transplant-eligible mantle cell lymphoma. Blood Adv. 4, 858–867 (2020).
Robak, T. et al. Frontline bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) versus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in transplantation-ineligible patients with newly diagnosed mantle cell lymphoma: final overall survival results of a randomised, open-label, phase 3 study. Lancet Oncol. 19, 1449–1458 (2018).
Rummel, M. J. et al. Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet 381, 1203–1210 (2013).
Wang, M. et al. Acalabrutinib Plus Bendamustine-Rituximab in Untreated Mantle Cell Lymphoma. J. Clin. Oncol. 43, 2276–2284 (2025).
Sarkozy, C. et al. Long-term follow-up of Rituximab maintenance in young patients with mantle-cell lymphoma included in the LYMA Trial: A LYSA Study. J. Clin. Oncol. 42, 769–773 (2024).
Eskelund, C. W. et al. 15-year follow-up of the Second Nordic Mantle Cell Lymphoma trial (MCL2): prolonged remissions without survival plateau. Br. J. Haematol. 175, 410–418 (2016).
Wang, M. L. et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N. Engl. J. Med. 369, 507–516 (2013).
Wang, M. et al. Acalabrutinib in relapsed or refractory mantle cell lymphoma (ACE-LY-004): a single-arm, multicentre, phase 2 trial. Lancet 391, 659–667 (2018).
Song, Y. et al. Zanubrutinib in relapsed/refractory mantle cell lymphoma: long-term efficacy and safety results from a phase 2 study. Blood 139, 3148–3158 (2022).
Wang, M. L. et al. Pirtobrutinib in Covalent Bruton Tyrosine Kinase Inhibitor Pretreated Mantle-Cell Lymphoma. J. Clin. Oncol. 41, 3988–3997 (2023).
Deng, L. J. et al. Orelabrutinib for the treatment of relapsed or refractory MCL: a phase 1/2, open-label, multicenter, single-arm study. Blood Adv. 7, 4349–4357 (2023).
Giné, E. et al. Ibrutinib in Combination With Rituximab for Indolent Clinical Forms of Mantle Cell Lymphoma (IMCL-2015): A Multicenter, Open-Label, Single-Arm, Phase II Trial. J. Clin. Oncol. 40, 1196–1205 (2022).
Jain, P. et al. Ibrutinib With Rituximab in first-line treatment of older patients with mantle cell lymphoma. J. Clin. Oncol. 40, 202–212 (2022).
Jain, P. et al. Acalabrutinib with Rituximab As First-Line Therapy for Older Patients with Mantle Cell Lymphoma - a Phase II Clinical Trial. Blood 142, 3036–3036 (2023).
Jerkeman, M. et al. Acalabrutinib and Rituximab in Elderly Patients with Newly Diagnosed Mantle Cell Lymphoma Including a Matched Population-Based External Comparator- the Nordic Lymphoma Group NLG-MCL8 (ALTAMIRA) Phase II Trial. Blood 144, 747 (2024).
Qu, C. et al. Zr Study: A Prospective Phase II Study of Zanubrutinib-Rituximab Chemo-Free Therapy with or without Autologous Stem Cell Transplantation in Newly Diagnosed Mantle Cell Lymphoma. Blood 142, 1658 (2023).
Wang, M. L. et al. Ibrutinib-rituximab followed by R-HCVAD as frontline treatment for young patients (≤65 years) with mantle cell lymphoma (WINDOW-1): a single-arm, phase 2 trial. Lancet Oncol. 23, 406–415 (2022).
Honigberg, L. A. et al. The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy. Proc. Natl. Acad. Sci. USA 107, 13075–13080 (2010).
Guo, Y. et al. Discovery of Zanubrutinib (BGB-3111), a Novel, Potent, and Selective Covalent Inhibitor of Bruton’s Tyrosine Kinase. J. Med. Chem. 62, 7923–7940 (2019).
Tam, C. S. et al. Phase 1 study of the selective BTK inhibitor zanubrutinib in B-cell malignancies and safety and efficacy evaluation in CLL. Blood 134, 851–859 (2019).
Brown, J. R. et al. Zanubrutinib or Ibrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia. N. Engl. J. Med. 388, 319–332 (2023).
Tam, C. S. et al. A randomized phase 3 trial of zanubrutinib vs ibrutinib in symptomatic Waldenström macroglobulinemia: the ASPEN study. Blood 136, 2038–2050 (2020).
Hermine, O. et al. Addition of high-dose cytarabine to immunochemotherapy before autologous stem-cell transplantation in patients aged 65 years or younger with mantle cell lymphoma (MCL Younger): a randomised, open-label, phase 3 trial of the European Mantle Cell Lymphoma Network. Lancet 388, 565–575 (2016).
Tessoulin, B. et al. Oxaliplatin before autologous transplantation in combination with high-dose cytarabine and rituximab provides longer disease control than cisplatin or carboplatin in patients with mantle-cell lymphoma: results from the LyMA prospective trial. Bone Marrow Transplant. 56, 1700–1709 (2021).
Pabla, N. & Dong, Z. Cisplatin nephrotoxicity: mechanisms and renoprotective strategies. Kidney Int. 73, 994–1007 (2008).
Kuter, D. J. Managing thrombocytopenia associated with cancer chemotherapy. Oncology 29, 282–294 (2015).
Romaguera, J. E. et al. High rate of durable remissions after treatment of newly diagnosed aggressive mantle-cell lymphoma with rituximab plus hyper-CVAD alternating with rituximab plus high-dose methotrexate and cytarabine. J. Clin. Oncol. 23, 7013–7023 (2005).
Cheson, B. D. et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J. Clin. Oncol. 32, 3059–3068 (2014).
Cheson, B. D. et al. Report of an international workshop to standardize response criteria for non-Hodgkin’s lymphomas. NCI Sponsored International Working Group. J. Clin. Oncol. 17, 1244 (1999).
Cheson, B. D. et al. Revised response criteria for malignant lymphoma. J. Clin. Oncol. 25, 579–586 (2007).
Wang, M. L. et al. Ibrutinib plus Bendamustine and Rituximab in Untreated Mantle-Cell Lymphoma. N. Engl. J. Med. 386, 2482–2494 (2022).
Visco, C. et al. Rituximab, bendamustine, and low-dose cytarabine as induction therapy in elderly patients with mantle cell lymphoma: a multicentre, phase 2 trial from Fondazione Italiana Linfomi. Lancet Haematol. 4, e15–e23 (2017).
Yi, S. et al. Genomic and transcriptomic profiling reveals distinct molecular subsets associated with outcomes in mantle cell lymphoma. J. Clin. Investig. 132, e153283 (2022).
Jain, P. et al. Immune-depleted tumor microenvironment is associated with poor outcomes and BTK inhibitor resistance in mantle cell lymphoma. Blood Cancer J. 13, 156 (2023).
Bolger, A. M., Lohse, M. & Usadel, B. Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinforma 30, 2114–2120 (2014).
Dobin, A. et al. STAR: ultrafast universal RNA-seq aligner. Bioinforma 29, 15–21 (2013).
Li, B. & Dewey, C. N. RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome. BMC Bioinforma. 12, 323 (2011).
Chalmers, Z. R. et al. Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med. 9, 34 (2017).
Zhang, S. et al. The GSA Family in 2025: a broadened sharing platform for multi-omics and multimodal data. Genomics Proteom. Bioinforma. 23, qzaf072 (2025).
CNCB-NGDC Members and Partners. Database Resources of the National Genomics Data Center, China National Center for Bioinformation in 2025. Nucleic Acids Res. 53, D30–d44 (2025).
Acknowledgements
This work was supported by the National Natural Science Foundation of China (82230001 and 82270199 to Q.Q.C.), Noncommunicable Chronic Diseases-National Science and Technology Major Project (2025ZD0544300 to Q.Q.C.), Guangzhou Science and Technology Program (2024B03J1291 to Q.Q.C.), National Key Research and Development Program (2022YFC2502602 to Q.Q.C.), the Sun Yat-Sen University Clinical Research 5010 Program (2020009 to Q.Q.C.), Beijing Xisike Clinical Oncology Research Foundation (Y-2024AZ(BTK)QN--0062 to M.N.), and the China National Postdoctoral Program for Innovative Talents (BX20240445 to Y.C.Z.). The authors are grateful to all patients and their families who participated in the study. The authors thank BeiGene Ltd., Beijing, China, for donating zanubrutinib. The authors thank Kehong Zhang, M.D., Ph.D., from Ivy Medical Editing (Shanghai, China) for revising the final manuscript. The authors wish to thank Geneseeq Technology Inc., and particularly Ms. Chuqiao Liang, for their technical support and assistance in the data analysis of sequencing data. Alluvial plots were created with Sangerbox.com.
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Conception and design: Q.Q.C., Y.X., H.Q.H., Y.C.Z., M.N. Provision of study materials or patients: All authors. Collection and assembly of data: All authors. Data analysis and interpretation: Y.C.Z., M.N., Y.C., Y.X., Q.Q.C. Manuscript writing: Y.C.Z., M.N., Y.C., Y.X., Q.Q.C. Final approval of manuscript: All authors
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Zhang, Y., Nie, M., Cao, Y. et al. Zanubrutinib-rituximab followed by shortened chemoimmunotherapy as frontline treatment for mantle cell lymphoma (CHESS): a phase II trial. Nat Commun (2026). https://doi.org/10.1038/s41467-026-71241-1
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DOI: https://doi.org/10.1038/s41467-026-71241-1
