Preliminary Results of a Retrospective Study on a Regimen Based on Orelabrutinib Combined with Anti-CD20 Monoclonal Antibody in Patients with Marginal Zone Lymphoma
Authors: Peng Hongling , Xiang Xixi , Rao Jun , Yan Wenzhe , Cui Yajuan , Li Ji , Jiang Yafeng , Zhang Xi 
Published: December 2024

Background: Marginal zone lymphoma (MZL) is the second most prevalent form of indolent lymphoma and the optimal strategy for symptomatic, advanced MZL is CD20-based monoclonal therapy. Orelabrutinib, a novel and irreversible Bruton's tyrosine kinase (BTK) inhibitor, exhibited a high overall response rate of 58.9% in relapsed/refractory (r/r) MZL patients. The combination of Orelabrutinib with anti-CD20 monoclonal antibody has been shown to preserve natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC) and in vitro studies demonstrated that the combination of the two drugs enhanced tumor cell apoptosis. The overall response rate (ORR) reached 90% in a small sample study of MZL treated with the combination of Orelabrutinib and rituximab. The presence of minimal residual disease (MRD) has been correlated with patient prognosis, with negative MRD status linked to improved survival. This study aims to evaluate the efficacy and remission depth of a regimen combining Orelabrutinib with CD20 monoclonal antibodies, with a focus on guiding treatment discontinuation based on ultra-minimal residual disease (uMRD) and complete response (CR) criteria.

Methods: This study employed a single-arm, multicenter, retrospective design. Patients diagnosed with MZL were enrolled from two clinical centers. The treatment protocol involved initial therapy with anti-CD20 monoclonal antibodies (rituximab, obinutuzumab, and zuberitamab), with or without bendamustine to control the tumor load. Subsequently, patients received a combination of Orelabrutinib and anti-CD20 monoclonal antibodies, with or without bendamustine, and continued Orelabrutinib as monotherapy maintenance. The main clinical outcomes included ORR, CR, and the rate of uMRD negativity at the conclusion of combination therapy, as well as adverse events, progression-free survival (PFS), and overall survival (OS).

Results: From August 2023 to July 2024, a total of 12 eligible patients were accrued at two centers. The median patient age was 58.5 years (range 29-79), with an equal gender distribution (6 males and 6 females). 33.3%（4/12） patients were refractory recurrence and 66.7%（8/12） patients were initial treatment .Mucosa-associated lymphoid tissue (MALT) lymphoma constituted 72.7% (8/12), nodal MZL (NMZL) 9.1% (1/12), and splenic MZL (SMZL) 18.2% (2/12). Disease sites predominantly included lymph nodes, the gastrointestinal tract, spleen, abdominal cavity, lung, parotid gland, bone, and eye. According to the Lugano stage, 58.3% (7/12) of patients were staged as IV, with two patients exhibiting bone marrow involvement. MRD was detected by next-generation sequencing (NGS) in 3 patients, and MRD reached 28×102 in 1 patient. Of the 12 patients, 66.7% (8/12) received anti-CD20 monoclonal antibody monotherapy, while 33.3% (4/12) were treated with a combination of anti-CD20 monoclonal antibodies and bendamustine, and combined therapy with Orelabrutinib after tumor control for a total of 6 cycles. Orelabrutinib monotherapy was continued after the end of combination therapy for maintance. The median follow-up duration was 4.5 months. Among the seven evaluable patients, the best CR and ORR were 42.5% (3/7) and 71.4% (5/7), respectively. No significant adverse events (AEs) led to drug discontinuation or dose reduction, with AEs including bone marrow suppression, herpes zoster, sleep disturbances, gastrointestinal disorders, and fever.

Conclusion: The combination of Orelabrutinib with anti-CD20 monoclonal antibodies, with or without bendamustine, has demonstrated promising efficacy and safety in the treatment of MZL. The follow-up time of this study is short, and the dynamic changes of MRD will be updated later, and the timing of drug withdrawal will be monitored by uMRD and CR.