3009 - Orelabrutinib combined with bendamustine and obinutuzumab as the first-line treatment for chronic lymphocytic leukemia/small lymphocytic leukemia: a phase II multicenter exploratory study

Introduction: Targeted therapy with Bruton's tyrosine kinase inhibitors (BTKis) has emerged as a standardized treatment for patients with previously untreated or relapsed/refractory chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL; William G et al. J Natl Compr Canc Netw 2022). Recently, given the increase in adverse events, high dropout rates and drug resistance with long-term continuous administration of BTKi, there has been an increased focus on time-limited BTKi-based regimens and undetectable minimal residual disease (uMRD; Hampel et al. Am J Hematol 2023; Jiang et al. Curr Med Sci 2021; Wierda et al. J Clin Oncol 2021). Ibrutinib or zanubrutinib combined with bendamustine (B) and rituximab therapy has been confirmed to be associated with promising activity for CLL/SLL through fixed-duration therapy (Zhu et al. Blood 2021). Compared with rituximab, Obinutuzumab (G) is a type II anti-CD20 antibody with enhanced direct cell killing and antibody-dependent cellular cytotoxicity (ADCC; Sehn et al. J Hematol Oncol 2020). Orelabrutinib is a novel BTKi with excellent target selectivity for B‐cell lymphoma, combined with rituximab could preserve natural killer-cell-mediated ADCC induced by rituximab and produces synergistic anti-tumor responses (Yu et al. Mol Ther-Oncolytics 2021). Recent accumulating evidence has demonstrated that orelabrutinib has shown an encouraging anti-tumor activity and favorable safety profile in CLL/SLL (Xu et al. Am J Hematol 2023). Additionally, taking the CR/CRi with uMRD rate as the primary endpoint would avoid the lack of stability (return to positivity within a short time) and inadequate assessment (residual lesions at other sites) by MRD negativity alone. Here, we present this phase II, multicenter, single-arm trial to investigate the new time-limited orelabrutinib combined with BG regimen in patients with CLL/SLL who are ineligible for intensive chemotherapy and to explore the influence of this time-limited therapy as well as complete response (CR) with MRD negativity on MRD stability by dynamic MRD monitoring.

Methods: Eligible patients will be aged 18-65 years with severe disease (non-CLL Cumulative Illness Rating Scale score ≥6) or >65 years, with histologically/pathologically confirmed CD20 positive CLL/SLL per International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria, and have not received prior systemic therapy for CLL/SLL. Patients are also required to have an Eastern Cooperative Oncology Group performance status score of 0-2, at least one treatment indication according to IWCLL 2008 criteria or Guidelines for the diagnosis and treatment of CLL/SLL in China version 2022, and adequate hematologic, hepatic, and renal function. Patients with chromosome 17p deletion or TP53 mutations are excluded. Patients will receive BG therapy for the first 28-day cycle, followed by orelabrutinib combined with BG for cycle 2-6, and orelabrutinib monotherapy for cycle 7 thereafter (Figure 1). The primary endpoint is CR/CRi with uMRD rate at the end of cycle 7. Secondary endpoints include CR/unconfirmed CR (CRu) with uMRD rate, objective response rate, uMRD rate, progression-free survival, overall survival, duration of response, quality of life, and safety. CRi was defined as CR with incomplete recovery of bone marrow. CRu was defined as CR/CRi with spleen size≤16 cm. Exploratory endpoints are dynamic monitoring of MRD in the patient's bone marrow (baseline, cycle 7) and peripheral blood (baseline, cycle 4, cycle 7, month 13, month 19, and month 25) using next-generation sequencing assays. This study plans to enroll 24 patients and the clinicaltrials(NCT) registration is ongoing.

Conclusions: This phase II study is expected to provide a treatment option for patients with CLL/SLL who are ineligible for intensive chemotherapy.