ZR2-miniCHOP for elderly patients with newly diagnosed diffuse large B-cell lymphoma.

BACKGROUND: Very old or frail patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) frequently cannot tolerate full-dose R-CHOP, and long-term control with R-miniCHOP is suboptimal. We assessed a sequential, chemotherapy-limiting regimen using zanubrutinib, lenalidomide, and rituximab (ZR2) induction followed by response-adapted ZR2-miniCHOP. METHODS: This single-center, open-label, investigator-initiated phase 2 trial enrolled untreated patients aged ≥ 80 years, or 60–79 years with ECOG performance status ≥ 2. All patients received two 21-day cycles of chemotherapy-free ZR2 (zanubrutinib 160 mg twice daily continuously; lenalidomide 25 mg once daily on days 1–10; rituximab 375 mg/m2 on day 0), then four cycles of ZR2 plus reduced-dose miniCHOP. PET/CT after cycle 6 determined consolidation: two cycles of ZR2 maintenance for complete responders or two additional cycles of ZR2-miniCHOP for partial responders. Primary endpoints were overall response rate (ORR) and complete remission (CR) rate after six cycles; secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Forty-eight patients were treated (median age 78 years; 45.8% ≥ 80; 70.8% high-risk by R-IPI). After ZR2 induction, ORR was 100% with 33.3% CR. By the end of treatment, ORR remained 100% and CR increased to 80.5%. At a median follow-up of 28.7 months, 2-year PFS and OS were 76.1% and 81.4%, respectively, with no CNS relapses observed. Grade 3–4 toxicities were mainly hematologic (neutropenia 29.2% during induction; 34.8% with miniCHOP), and no treatment-related deaths occurred. CONCLUSIONS: Sequential ZR2 induction followed by response-adapted ZR2-miniCHOP achieved rapid, deep, and durable remissions with manageable toxicity in elderly or frail DLBCL, warrants further evaluation in randomized trials. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR2100047738), registered on 25 June 2021.