Background: Patients with untreated follicular lymphoma (FL) and intermediate-high risk FLIPI scores (≥2) face poor outcomes: 5-year PFS is ~50% with standard G-CHOP plus 2-year obinutuzumab maintenance, accompanied by significant toxicity (infection, cytopenias, secondary malignancies and quality-of-life deterioration). Bruton's tyrosine kinase (BTK) inhibition is a rational therapeutic strategy, as BTK signaling drives FL pathogenesis and tumor microenvironment interactions. Zanubrutinib-a next-generation, highly selective BTK inhibitor-synergizes with anti-CD20 therapy and demonstrates clinical activity in relapsed/refractory FL. The phase II ZAP (Zanubrutinib-Adapted Protocol) trial pioneers a response-adapted de-escalation paradigm integrating zanubrutinib into frontline therapy, aiming to maximize early molecular remissions while reducing treatment burden in this vulnerable population.

Methods: From April 2024 to December 2024, this phase II trial (NCT06474481) enrolled 32 untreated FL patients (FLIPI 2-5) receiving 4 cycles of zanubrutinib (160mg BID) + standard G-CHOP with mandatory pegfilgrastim prophylaxis. Response-adapted therapy post-cycle 4: patients achieving CR (Deauville 1-3 + MRD negativity) initiated abbreviated 12-month maintenance (zanubrutinib + obinutuzumab); others received 2 additional induction cycles. Minimal residual disease (MRD) was assessed via dual-modality tracking: tumor-informed ctDNA (PhasED-seq, 10⁻⁶ sensitivity) at baseline/C2/C4/C6/q6mo maintenance and ClonoSEQ® NGS (BM, 10⁻⁶). Correlative studies included baseline whole-exome sequencing, serial immune profiling (35-plex CyTOF on PBMCs), and patient-reported outcomes (EORTC QLQ-C30/LY20). Primary endpoint was CR rate after 4 cycles; secondary endpoints included MRD negativity, PFS, and safety.

Results: As of July 25, 2025, all 32 enrolled patients completed at least 4 cycles of zanubrutinib-enhanced G-CHOP, demonstrating striking efficacy. The primary endpoint was surpassed with a CR rate of 84.4% (27/32; 95% CI: 68.3-93.1%) after just 4 cycles. MRD negativity, assessed through dual-modality tracking, confirmed profound molecular responses: 90.6% (29/32) achieved ctDNA clearance, while 87.5% (28/32) had bone marrow MRD eradication. Notably, 84.4% of patients (27/32) showed concordant negativity in both assays, establishing a robust biomarker-defined subgroup with exceptional outcomes (97% 12-month PFS). Early molecular responders-those achieving ctDNA negativity by cycle 2 (n=24)-universally attained CR by cycle 4, compared to only 37.5% (3/8) of delayed clearers (p<0.001), validating C2 MRD as a critical decision point for de-escalation.

High-risk subgroups benefited uniformly: patients with bulky disease (>7 cm, n=14) achieved an 85.7% CR rate (12/14), while those with FLIPI 4-5 (n=11) reached 81.8% CR (9/11). Patient-reported outcomes (EORTC QLQ-C30) revealed clinically meaningful improvements, with Global Health Status scores rising from 58.2 at baseline to 83.6 post-induction (Δ25.4, p<0.001)-76% of participants rated their treatment experience as “much better” than standard regimens.

The safety profile supported the de-escalation strategy. Grade 3-4 neutropenia occurred in 21.9% (7/32), with only 6.3% (2/32) developing febrile neutropenia-attributable to mandatory pegfilgrastim prophylaxis. BTK inhibitor-related adverse events were mild (grade 1-2 bruising: 5/32; atrial fibrillation: 1/32), and no treatment-related deaths occurred.

Conclusion: The ZAP trial demonstrates that zanubrutinib-enhanced G-CHOP induces high CR (84.4%) and MRD negativity (>90%) rates in high-risk FL, enabling early chemotherapy de-escalation (omitting 33% of cycles) and shortened maintenance (12 months) without compromising efficacy (12-month PFS: 97%). This response-adapted, MRD-guided paradigm redefines frontline FL therapy by replacing fixed-duration treatment with a precision approach.

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2025
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