P1163: zanubrutinib plus rituximab and lenalidomide (zr2) for relapsed and refractory diffuse large b cell lymphoma

Topic: 19. Aggressive Non-Hodgkin lymphoma - Clinical Background: Relapsed and refractory diffuse large B cell lymphoma (R/R DLBCL) patients are difficult to obtain long term survival through traditional chemotherapy. and the young and fit usually take high-dose chemotherapy and autologous transplantation, but most patients cannot tolerate such strategy. Therefore, further study is needed to explore high efficacy and low toxicity chemo-free regimen for unfit patients with R/R DLBCL. Aims: To explore the efficacy and safety of zanubrutinib plus rituximab and lenalidomide (ZR2) in R/R DLBCL. Methods: This is an interim report of an investigator-initiated, multi-center, open, single arm, prospective clinical trial. All enrolled patients treated with zanubrutinib (160 mg bid), rituximab (375 mg/m2, d1) and lenalidomide (10-25mg, d1-21) every 28 days for six cycles in induction phase. In maintenance phase, patients received rituximab every 2 months, lenalidomide (10 mg, d1-21) every 28-day and zanubrutinib as before. The primary endpoint is objective response rate (ORR) of the induction therapy. Secondary endpoints include complete response rate, progression-free survival (PFS), overall survival (OS) and adverse reaction events (TEAS). Results: A total of 28 patients were enrolled in this clinical study between July 2021 and February 2023. The median age was 71.6 years (range, 49-84 years). 42.8% of patients were non–germinal center B-cell (non-GCB) sub-type and 57.1% were GCB. About 67.9% of them were refractory and 32.1% were relapsed. 75% patients had received ≥ 2 prior regimens. 4 patients were newly enrolled and had not been evaluated yet. Median follow-up time of 24 patients with effective evaluation was 9.1 months (range, 2.5-14.5 months) and 54.2% (13/24) patients received more than 6 months of treatment. The ORR was 79.2% (19/24), including 37.5% (9/24) complete response (CR) and 41.7% (10/24) partial response (PR). The median time of best response reached was 2.9 months. Responses rate were similar between non-GCB (81.8%, 9/11) and GCB (76.9%, 10/13) groups. The responses rate was higher in relapsed patients (100%, 8/8) than refractory patients (68.6%, 11/16). Three patients exited the study for personal reasons and 8 of the 16 responsive patients progressed again with 5.2 months of median response duration. 66.7% (6/9) CR patients were still progress-free by the end of follow-up, but one patient died of COVID-19. The median PFS (21 patients) is 5.1 months (range, 1.9-15.7 months) and the median OS has not reached. The most frequently reported TEAEs were leukopenia (9, 37.5%), rash (7, 29.2%), infection (5, 20.8%), gastrointestinal events (3, 12.5%), fatigue (2, 8.3%). Grade ≥ 3 TEAEs were seen in 20.8% (5/24) patients and 80% (4/5) was leukopenia. Only 16.7% (4/24) patients interrupted medication due to AE and none died. More than half of patients (62.5%, 15/24) received fixed doses of 25 mg lenalidomide daily since beginning and only one patient reduced dose in the subsequent treatment. Interestingly, there was no increased adverse reactions in the 25mg group, which was probably related to age (Mean age 78.6 years in 25mg group vs 68.8 years in 10mg group). The 25mg group had a better response (ORR 86.7%, 13/15) than 10mg group (ORR 66.7%, 6/9). This study was registered at www.clinicaltrials.gov as #NCT05392257. Summary/Conclusion: This prospective study showed ZR2 is an effective therapy for R/R DLBCL and is well tolerated especially in old patients. Patients who achieved CR during ZR2 treatment had much longer duration of response.Keywords: relapsed/refractory, Bruton’s tyrosine kinase inhibitor (BTKi), Diffuse large B cell lymphoma