Orelabrutinib in Combination with Rituximab and Chemotherapy for Newly Diagnosed Aggressive B-Cell Lymphoma: A Multicenter, Single-Arm, Prospective Study

Abstract

Keywords: Orelabrutinib, B-cell lymphoma, overall response rate Introduction Dysregulated B-cell receptor (BCR) signaling has been identified as an important feature of B-cell lymphomas. Inhibition of Bruton's tyrosine kinase (BTK), downstream of BCR, has demonstrated promising efficacy profiles in B-cell malignancies. Orelabrutinib is a newly developed BTK inhibitor with high selectivity for B-cell malignancies. This study was conducted to evaluate the preliminary efficacy and safety of orelabrutinib in combination with rituximab and chemotherapy for newly diagnosed aggressive B-cell lymphoma. Methods This was a single-arm, multicenter, prospective study in patients with clinical and histopathological confirmed aggressive B-cell lymphoma. The primary endpoints were investigator-assessed overall response rate (ORR) and complete response (CR) rate. Adverse events (AEs) were assessed in accordance with NCI CTCAE v4.03. Results A total of 42 patients with newly diagnosed aggressive B-cell lymphoma were enrolled from October 2020 to May 2022, including 28 diffuse large B-cell lymphoma (DLBCL), 12 primary central nervous system lymphoma (PCNSL), and 2 patients with high-grade B-cell lymphoma. The median age was 66.5 years (range, 35-86 years), and 23 (54.7%) were male. 66.7% of enrolled patients had stage III-IV disease. The median follow-up was 8.0 months (2.0-20.0 months). All the patients received orelabrutinib combined with rituximab and chemotherapy regimens. At data cutoff, 28 patients completed 6 cycles of treatment and were evaluated for therapeutic efficacy. Next-generation sequencing was performed and the genetic mutations included MYD88, BCL6, BCL2, CD79b, KMT2D, etc. All 42 patients were evaluable for toxicity. The toxic reactions were relatively mild, including grade 3 febrile neutropenia in 2 cases (4.8%), grade 3 neutropenia (2.4%), grade 3 thrombocytopenia (2.4%), and grade 3 leukopenia (2.4%). No other grade 3-4 non-hematologic AEs were reported. There was no dose modification due to AEs. The therapeutic responses were assessed. Among the 30 patients with DLBCL or high-grade B-cell lymphoma, 21 patients completed 6 cycles of treatment at data cutoff, with an ORR of 100%, and 15 (71.4%) patients achieved CR. The estimated 1-year overall survival (OS) and 1-year progression-free survival (PFS) rates were 100% and 94.1%, respectively. In addition, subgroup analyses were performed. Seventeen patients were non-GCB subtype, with a CR rate of 84.5%. Among the included DLBCL patients, 13 patients had MYC/BCL2 protein dual expression (DE), and the ORR and CR rate were 100% and 90.9%, respectively. Twenty-two patients were extra-nodal DLBCL, with a CR rate of 86.7%. The estimated 1-year PFS rate was 93.8%. Among them, 13 patients were non-GCB subtype, and 11 of them received 6 courses of treatment, with a CR rate of 81.8%. We further analyzed the treatment response of PCNSL patients. A total of 12 patients with newly diagnosed PCNSL were included in this study, with a median age of 57 years (range, 35-75 years) and 7 (58.2%) patients were male. Ten (83.3%) patients were non-GCB subtype. Seven patients completed 6 courses of treatment, with an ORR of 100%, and 4 patients achieved CR. Conclusions The preliminary results of this study suggested that orelabrutinib in combination with rituximab and chemotherapy may be a well-tolerated and effective regimen in newly diagnosed aggressive B-cell lymphoma patients. A larger sample size and longer follow-up time are needed in the future to validate this conclusion. Next-generation sequencing results are expected to provide additional explanations for differential treatment responses. Disclosure: No relevant conflicts of interest to declare.