Rituximab, Chidamide, and Zanubrutinib±CHOP Could be a Promising Regimen for Newly Diagnosed Double-Expressor DLBCL (DE DLBCL)

Background: DLBCL patients with co-expression of MYC (≥40%) and BCL2(≥50%) by immunohistochemistry are considered as double expressor lymphomas (DE DLBCL). The prognosis of DE DLBCL is usually worse than non-DE DLBCL. The Smart Start trial had explored the feasibility of chemotherapy-free targeted therapy before frontline chemotherapy. The BTK inhibitor Zanubrutinib (Z) or epigenetic drug Chidamide (C) with R-CHOP regimen has a potential synergistic effect in the treatment of DE DLBCL. Under the inspiration of Smart Start, this trial aim to explore the feasibility of RCZ±CHOP regimen in newly diagnosed DE DLBCL.

Methods: This is a multicenter, open-label, single-arm phase II study (NCT05527912) conducted in China. If patients achieve complete response (CR) after cycle-2 (C2), RCZ will be continued for up to 8 cycles. Otherwise, RCZ-CHOP will be given for another 6 cycles. The primary endpoint is CR rate at the end of treatment (CRR-EOT); secondary endpoints included ORR (overall response rate) ,2y-PFS, and 2y-OS. Plasma samples were collected at baseline, after C2 and the EOT. In evaluable samples, circulating tumor DNA (ctDNA) assays were performed.

Results: From February 2023 till now, 43 newly diagnosed DE DLBCL patients were enrolled, with 38 patients evaluable. The median age was 55y (range: 22-68), 51.2% were male, 67.4% were Non-GCB. 18 patients who achieved CR by C2 were continued with RCZ chemo-free therapy, and CHOP were added to the 16 PR and 2 SD patients. In the 38 evaluable patients, ORR after C2 of RCZ was 89.5%(CR 47.4%, PR 42.1%, SD 5.3%, PD 5.3%). Up to now, 11 patients have completed RCZ chemo-free therapy 8 cycles (C8) and all of them have achieved CR, both ORR and CR are 100% (11/11). 17 patients have completed RCZ chemo-free therapy 2 cycles and RCZ-CHOP therapy 6 cycles, with a remarkable CR rate of 82.4% and 2 patients withdrew due to PD. For safety information in the trial, the majority of G-3/4 AEs is hematological events, including leukopenia(46.9%), neutropenia(21.9%) and thrombocytopenia(50%), mostly occurred in RCZ-CHOP period. The CR rate at C2 was 66.7% in patients with negative baseline plasma test results (n=32). The patients with BCL6 fusion of ctDNA at baseline were more prone to PD. C2 plasma ctDNA levels decreased significantly from baseline. 29 patients were evaluable for ctDNA after C2, 100%(12/12) of C2-CR patients and 58.8%(10/17) of non-C2-CR patients were negative, P=0.023. The number of detected mutations and the average VAF in plasma were also decreased in Non-C2-CR patients.

Conclusions: This trial demonstrates the RCZ±CHOP therapy could be a promising regimen with an active antitumor effect and acceptable toxicity in newly diagnosed DE DLBCL patients.

No relevant conflicts of interest to declare.