Frontline Zanubrutinib-Based Therapy Shows High CR Rates in Older Patients, High-Risk MCL

This article was originally published on OncLive^®.

Zanubrutinib (Brukinsa)–based frontline regimens produced universal responses and high complete remission (CR) rates in older patients as well as younger, high-risk patients with newly diagnosed mantle cell lymphoma (MCL), according to interim data from an investigator-initiated phase 2 trial (NCT06427213) presented at the 2025 ASH Annual Meeting & Exposition.¹

The objective response rate (ORR) was 100%, with a complete response (CR) rate of 88.9% and partial response (PR) rate of 11.1% when zanubrutinib was paired with rituximab (Rituxan; n = 9). When coupled with rituximab, bendamustine, and cytarabine (R-BAC; n = 13), zanubrutinib also produced an ORR of 100%, with a CR rate of 84.6% and PR rate of 15.4%.

“In treatment-naive, elderly patients with MCL, zanubrutinib combined with rituximab demonstrated favorable efficacy and safety, warranting further investigation,” Qing Zhang, a postdoctoral researcher at the Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital in China, and coauthors wrote in the poster.

Zanubrutinib has been approved for use in adult patients with relapsed/refractory MCL since 2019.² In June 2025, the FDA approved a tablet formulation of the agent for use in all 5 approved indications of the capsule formulation, including pretreated MCL.³

Autologous stem cell transplant (ASCT) preceded by first-line chemoimmunotherapy leads to favorable outcomes in younger, fit patients with MCL, representing an optimal standard of care.¹ However, for older patients and younger patients with high-risk features such as TP53 mutations, high Ki-67, or blastoid morphology, optimal first-line therapy is not well defined.

Zanubrutinib is a selective BTK inhibitor with a proven record of improved safety and tolerability. To further delineate the activity and synergistic potential of the agent, investigators conducted an open-label, multicenter, prospective trial evaluating the agent in combination with anti-CD20 antibodies in older and younger, high-risk patients with newly diagnosed MCL.

Key Findings From the Phase 2 Trial (NCT06427213)

• Zanubrutinib plus rituximab, with or without BAC, achieved a 100% ORR and CR rate exceeds 84% in newly diagnosed MCL.
• Promising efficacy outcomes were observed in elderly patients and younger patients with high-risk features, including TP53 mutations.
• Safety profiles of both regimens were manageable, with no grade 3/4 adverse effects reported in the elderly cohort.

What was the study design?

The study was divided into 2 cohorts: an elderly cohort (n = 21) of patients 65 years or older and a younger, high-risk cohort (n = 20) of patients no older than 65 years with at least 1 of the following high-risk features: a TP53 mutation, blastoid/pleomorphic variant, or high-risk Simplified Mantle Cell Lymphoma International Prognostic Index (MIPI) score ranging from 6 to 11.

In the elderly cohort, patients received 160 mg of oral zanubrutinib twice daily plus 375 mg/m² of rituximab on day 1 for 12, 28-day cycles. In the younger cohort, patients received 6 cycles of zanubrutinib and rituximab at the same dose and schedule, plus 70 mg/m² of bendamustine on days 2 and 3 and 500 mg/m² of cytarabine on days 2 through 4 of each cycle. Transplant-eligible patients proceeded to ASCT. Transplant-ineligible patients as well as elderly patients in the former cohort went on to receive 160 mg of zanubrutinib as maintenance until progressive disease.

The primary end point was CR rate following induction therapy. Secondary end points included ORR after induction, CR rate mid-way through induction, minimal residual disease (MRD)–negativity rate after induction, progression-free survival (PFS), overall survival (OS), treatment-related adverse effects (AEs), and patient quality of life.

What were the demographics and baseline characteristics?

A total of 23 patients were enrolled between October 2023 and May 2025, and 22 were evaluable for efficacy in the older cohort (n = 9) and younger, high-risk cohort (n = 13). In the older cohort the median age was 71 years (range, 66-82) and most patients were male (n = 7; 77.8%). A MIPI score of 6 or greater, bone marrow involvement, and Ki-67 levels above 30% were each documented in 4 patients (44.4%).

In the younger, high-risk cohort the median age was 59 years (range, 43-63) and most patients were male (n = 11; 84.6%). A MIPI score of 6 or greater, bone marrow involvement, and Ki-67 levels above 30% was seen in 53.8% (n = 7), 84.6% (n = 11), and 53.8% (n = 7) of patients, respectively.

What other efficacy outcomes were shared?

PFS and OS were not statistically significant, with P values of 0.32 and 1.00, respectively.

When looking at outcomes among the two cohorts, the 1-year PFS and OS rates were 85.7% and the 100%, respectively, in the older cohort. The median follow-up was 11.5 months. In the younger, high-risk cohort the 1-year PFS and OS rates were both 100%. The median follow-up was 10.7 months.

With respect to durability in the all-comer population, the median duration of response (DOR) was not reached; the 6-month DOR rate was 81.8% (n = 18).

How did the safety profiles stack up in these 2 cohorts?

“Grade 3/4 AEs occurred mainly in the younger, high-risk cohort, including neutropenia, thrombocytopenia, anemia, and pneumonia, [and were mainly] R-BAC related and manageable. No grade 3/4 AEs occurred in elderly patients. Common grade 1/2 AEs included arrhythmia and rash,” the authors stated.

In the older cohort, AEs included leukopenia (grade 1, 11.1%), skin infection (grade 2, 11.1%), rash (grade 2, 11.1%), cardiac arrhythmia (grade 2, 11.1%), leukopenia (grade 1, 22.2%), and thrombocytopenia (grade 1, 11.1%). In the younger, high-risk cohort, AEs included leukopenia (grade 2, 7.7%; grade 4, 15.4%), pneumonia (grade 3, 23.1%), myelosuppression (grade 4, 7.7%), lymphopenia (grade 4, 38.5%), rash (grade 2, 15.4%), anemia (grade 2, 7.7%; grade 3, 23.1%), thrombocytopenia (grade 2, 15.4%; grade 3, 15.4%; grade 4, 7.7%), and neutropenia (grade 1, 7.7%; grade 2, 7.7%; grade 4, 38.5%).

“For younger, high-risk patients, zanubrutinib combined with R-BAC showed encouraging efficacy and high MRD negativity rates in a small cohort, suggesting its potential to improve prognosis and showing promise as a first-line treatment option for this population,” the authors concluded.

Disclosures: No disclosures were listed for Zhang.

References

1. Zhang Q, Wu Y, Jiao Q, et al. Efficacy and safety of zanubrutinib-containing regimens in patients with newly diagnosed mantle cell lymphoma: interim results from a phase II investigator-initiated study. Blood. 2025;146(suppl 1):1823. doi:10.1182/blood-2025-1823
2. FDA grants accelerated approval to zanubrutinib for mantle cell lymphoma. FDA. Updated November 15, 2019. Accessed January 5, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-zanubrutinib-mantle-cell-lymphoma
3. U.S. FDA approves tablet formulation of BeOne’s Brukinsa for all approved indications. News release. BeOne. June 11, 2025. Accessed January 5, 2026. https://ir.beonemedicines.com/news/us-fda-approves-tablet-formulation-of-beones-brukinsar-for-all-approved-indications/644dc063-4114-48b8-9636-c60cb6cc6bd1