Zanubrutinib combined with bendamustine and rituximab in previously untreated patients with advanced follicular lymphoma: A prospective, open-label, single-arm phase II clinical study

Abstract Background Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma (NHL), accounting for approximately 20-30% of all NHL cases. Despite advances in treatment, including chemoimmunotherapy regimens, a subset of patients experiences early relapse or refractory disease, highlighting the need for novel therapeutic strategies. Bruton's tyrosine kinase (BTK) inhibitors, such as zanubrutinib, have demonstrated efficacy in B-cell malignancies, clinical studies have also shown that combining zanubrutinib with chemoimmunotherapy could enhance efficacy in relapsed/refractory FL. Given the unmet need for more effective frontline therapies in FL, this prospective, open-label, single-arm phase II clinical study evaluates the safety and efficacy of zanubrutinib in combination with bendamustine and rituximab (ZBR) in previously untreated patients with advanced FL. Methods This phase II study (ChiCTR2500095617) planned to enroll 34 treatment-naïve patients aged 18-75 years with histologically confirmed FL (grade 1-3a, Ann Arbor stage III/IV) without prior systemic therapy. The treatment consisted of induction and maintenance phases: during induction, patients received bendamustine (90 mg/m2 IV on Days 2-3 of Cycle 1 and Days 1-2 of Cycles 2-6), rituximab (375 mg/m2IV on Day 1 of each cycle), and zanubrutinib (160 mg orally twice daily, 3 weeks on/1 week off per cycle) for six 28-day cycles; maintenance therapy included rituximab (375 mg/m2 IV every 3 months) for up to 2 years or until disease progression/unacceptable toxicity. Primary endpoints were complete response rate (CRR) per Lugano 2014 with secondary endpoints of objective response rate (ORR), safety (assessed by CTCAE v5.0 criteria), progression-free survival (PFS) and overall survival (OS). Results A total of 35 patients were enrolled in this study, among which 3 were excluded from the analysis due to loss to follow-up or withdrawal prior to the first efficacy assessment. Among the 32 participants (53.1% female), median age of 51years. Most patients (90.6%) were B symptoms absent, while 34.4% had bone marrow involvement. Normal LDH levels were observed in 78.1% of cases, though 62.5% exhibited extranodal involvement. Disease staging revealed 56.3% at Ann Arbor stage III and 43.8% at stage IV. FLIPI scores distribution was 46.9% intermediate-risk, 34.4% high-risk, and 15.6% low-risk, with 56.3% meeting GELF treatment criteria. Of the 32 patients, 31 were evaluable for response. The best responses were as follows: complete response (CR) was achieved in 80.6% (95% CI: 62–92%), partial response (PR) in 19.4% (95% CI: 8.1–38%), yielding an objective response rate (ORR) of 100%. With a median follow-up of 6.6 months (95% CI: 5.3–11 months), median PFS and OS had not been reached, with the 12-month PFS rate at 83% (95% CI: 66–100%). Disease progression occurred in 2 patients who completed induction therapy, and histologic transformation occurred in 1 patient after 2 cycles of treatment, who achieved a PR. Subgroup analysis showed that baseline elevated LDH levels, bone marrow involvement, and FLIPI score correlated with shorter PFS (p < 0.05). Patients with CR during induction therapy demonstrated significantly longer PFS compared to those with PR (p < 0.001). The most common adverse events (AEs) included leukopenia (59.4%, 19/32), neutropenia (59.4%, 19/32), elevated ALT (28.1%, 9/32). Grade 3/4 AEs occurred in 46.9% of patients (15/32), including neutropenia (25%, 8/32), leukopenia (15.6%, 5/32), and fever (6.3%, 2/32). No treatment-related deaths occurred. Conclusion The ZBR regimen demonstrated promising efficacy, with an 80.6% CRR and 100% ORR, surpassing traditional R-CHOP and BR regimens, along with a manageable safety profile in treatment-naïve advanced FL, supporting its potential as a frontline therapeutic option. While early outcomes are encouraging, extended follow-up and larger Phase III trials comparing ZBR with standard BR are warranted to validate survival benefits and long-term tolerability.