Time-Limited of Zanubrutinib, Rituximab and Lenalidomide (ZR2) Regimen for the Treatment of Super-Elderly Diffuse Large B-Cell Lymphoma (DLBCL): A Prospective, Exploratory Clinical Study

Background: The prognosis of elderly patients with diffuse large B-cell lymphoma (DLBCL) is worse than that of young patients, due to expected toxicities, most elderly patients cannot receive full doses of anthracyclines. Elderly patients (age ≥75) are unfit or frail to standard regimen chemotherapy according to simplified comprehensive geriatric assessment (sGA). With the in-depth study of the biological properties of DLBCL and the emergence of highly effective, low-toxicity new drugs, combination regimens of new drugs have become the focus of current research, especially for older DLBCL patients who are unfit or frail to standard regimens of chemotherapy. Aim: Our trial is an investigator-initiated, prospective single-arm, multicenter, phase II study, aimed to explore the efficacy and safety of the time-limited ZR2 regimen in newly diagnosed elderly DLBCL. Methods: Eligible patients were newly diagnosed elderly DLBCL (Age≥75 years) patients, who were unfit or frail to the standard regimen chemotherapy according to sGA. Patients received therapies: The combination therapy phase of ZR2 regimen: rituximab 375 mg/m2 on day 1 of each cycle; lenalidomide 10 mg on days 1-14 of each cycle; and zanubrutinib 160 mg twice daily orally, this phase consists of 1 cycle every 21 days for a total of 8 cycles. After that, patients who achieve PR or higher will be given lenalidomide 10mg on day 1-14 every 21 days as maintenance therapy. The duration of maintenance therapy is not less than 12 months (ChiCTR2400079581) . Results: As of July 29 2024, 24 patients received the ZR2 regimen, and 17 completed at least 6 cycles of treatment, 14 completed 8 cycles of ZR2 therapy, 14 entered to the maintenance phase, and 4 patients finished maintenance therapy. All of the patients were from china, the median age was 81.5 years old, of which 17 were over 80 years old, 7 were male and 17 were female. 22 patients had intermediate and high risk of IPI score, 18 patients had stage Ⅲ/Ⅳ disease, 18 patients with non-GCB, 8 patients with double-expressed DLBCL, and 12 patients with extra-nodal involvement. The overall response rate (ORR) after 8 cycles of combination therapy was 100% (14/14), with 12 patients (85.7%) achieved complete remission (CR). Disease progression occurred in 6 patients after entering the lenalidomide maintenance phase, with 3 patients (11.5%) withdrew from the trial. The median duration of remission (DOR) was 12.14 months. The most common hematologic adverse events (AEs) were neutropenia (53.8%), thrombocytopenia (34.6%) and anemia (34.6%). Grade 3/4 AEs were neutropenia 19.2%, thrombocytopenia 15.4%, nausea 11.5% and infectious pneumonia 11.5%. Conclusion: Our results showed that zanubrutinib combined with lenalidomide and rituximab (ZR2) regimen is a safe and effective chemo-free treatment regimen for super-elderly DLBCL patients. As this trial was intended to be a time-limited exploration, however, we found that some patients experienced disease progression in a relatively short period of time after the end of combination therapy. This suggested: for super-elderly DLBCL, a short-cycle ZR2 regimen with lenalidomide monotherapy maintenance therapy is not sufficient to control the disease, and the time-limited chemo-free therapy suitable for super-elder DLBCL patients need to be further explored.