Ibrutinib Followed by BR (Bendamustine and Rituximab) as a Time-Limited Therapy for Waldenström Macroglobulinemia

Oral Bruton's tyrosine kinase (BTK) inhibitor administered at a fixed dose of 420 mg once daily. Capsules must be swallowed whole with water; do not open, break, or chew. If a dose is missed by ≤6 hours, take immediately; if \>6 hours, skip the dose and resume normal schedule the next day. Avoid grapefruit and Seville oranges (moderate CYP3A inhibitors). Treatment duration: 3 cycles (28 days/cycle) or until disease progression/unacceptable toxicity. Dose reduction is mandated for specific toxicities: 420 mg → 280 mg → 140 mg → discontinuation (per protocol-specified criteria). Use with caution in hepatic impairment (Child-Pugh A: reduce to 80 mg/day; Child-Pugh B/C: contraindicated).

Intravenous alkylating agent dosed via a 3+3 dose de-escalation design (70 mg/m² → 60 mg/m² → 50 mg/m²). Infused over 60-120 minutes on Days 1-2 of each 28-day cycle for 3 cycles. Starting dose: 70 mg/m² (Dose Level 1); dose reduction triggered by Dose-Limiting Toxicity (DLT) events per protocol. In the dose-expansion phase, all subjects receive the MTD/RP2D established in Part 1. Concomitant live vaccines are prohibited. Dose delays (≤4 weeks) and reductions are required for Grade ≥3 hematologic/non-hematologic toxicities.

Intravenous anti-CD20 monoclonal antibody administered at a fixed dose of 375 mg/m² on Day 0 of each 28-day cycle for 3 cycles. Initial infusion starts at 50 mg/hour; if tolerated, increase by 50 mg/hour every 30 minutes (maximum: 400 mg/hour). Subsequent infusions start at 100 mg/hour with the same escalation. Premedication with acetaminophen and an antihistamine is required prior to each infusion. Permanently discontinue for Grade 4 infusion-related reactions or severe/life-threatening toxicity.