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

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. 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. 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. 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. Chinese Clinical Trial Registry (ChiCTR2100047738), registered on 25 June 2021.