Spruce-TN CLL/SLL (Cwcll-002 Study): an Ongoing Study of MRD-Guided Sonrotoclax Plus Zanubrutinib in Treatment-Naïve Chronic Lymphocytic Leukemia /small Lymphocytic Lymphoma (CLL/SLL)

Background: The combination of venetoclax (a first-generation of BCL2 inhibitor) and ibrutinib (a first-generation BTK inhibitor) has demonstrated efficacy in the first-line treatment of CLL/SLL. However, the efficacy and safety profile of this regimen indicates a need for a more potent and tolerable combination of BTK and BCL2 inhibitors. Additionally, questions remain regarding the optimal duration of therapy. Minimal residual disease (MRD) is at the center of this exploration. Previous studies suggest the potential for finite treatment according to MRD status in patients with treatment-naïve (TN) CLL/SLL. Sonrotoclax, a next-generation BCL2 inhibitor, is a more selective and more pharmacologically potent inhibitor of BCL2 than venetoclax (Liu et al. Blood. 2024). Zanubrutinib, a next-generation BTK inhibitor, significantly improved PFS and had a more tolerable safety profile, including fewer cardiac adverse events, vs ibrutinib in a randomized, head-to-head study of patients with CLL/SLL (Brown et al. N Engl J Med. 2023). In an ongoing phase 1 study in B-cell malignancies, patients in TN CLL cohorts treated with sonrotoclax plus zanubrutinib achieved high objective response rate (ORR) and high blood uMRD4 rates measured by flow cytometry (FC) with a trend of deepening over time; no tumor lysis syndrome or cardiac toxicity was observed. Higher uMRD rate was achieved in the 320 mg dose cohort (Tam et al. Blood. 2023). To explore a novel BTK and BCL2 inhibitors combination, as well as the role of MRD-guided finite therapy duration, we design the SPRUCE-TN CLL/SLL trial, a prospective, multicenter, single-arm, phase 2 study, to evaluate the efficacy of sonrotoclax plus zanubrutinib with MRD-guided treatment duration as frontline therapy for patients with CLL/SLL (cwCLL-002 study, BDH-CLL-004, NCT06367374). Methods: Eligible patients must have previously untreated CLL/SLL that requires treatment per 2018 iwCLL criteria, ≤75 years old, an ECOG performance score of 0 to 2, and adequate hematologic and organ function. Approximately 66 patients will be enrolled to receive 3 cycles of zanubrutinib lead-in (160mg BID, the approved dosage in China; every 28 days per cycle) to mitigate risk of tumor lysis syndrome (TLS). After the zanubrutinib lead-in, sonrotoclax will be added with a ramp-up schedule to the intended target dosage of 320 mg QD at a 28-day cycle. The combination of sonrotoclax and zanubrutinib will be continued for up to 2 years, unless the stopping rules are reached, or until disease progression or unacceptable toxic effects occurred. Patients will be assessed at two timepoints to determine if they meet the stopping rules: at the end of cycle 12 (EOT1) and the end of cycle 24 (EOT2) of sonrotoclax and zanubrutinib combination treatment. The stopping rules are defined as uMRD4 (undetectable MRD at <10-4 sensitivity) in both peripheral blood (PB) and bone marrow (BM) as assessed by FC at EOT1 or EOT2, along with clinical response of at least PR. For subjects who do not meet the stopping rules till EOT2, zanubrutinib monotherapy will be administered till PD or intolerance. The primary endpoint is 4-yr PFS rate, assessed by investigator. Secondary endpoints include complete response rate (CRR), defined as CR or CR with incomplete hematopoietic recovery (CRi); ORR; duration of response; rates of uMRD4 in BM and PB by EOT1 and EOT2 as assessed by FC; PFS; overall survival; time to next therapy; safety and tolerability. Exploratory endpoints include relationship between various baseline markers and clinical outcome parameters; rates of uMRD4 based on next-generation sequencing (NGS); correlation between MRD status and PFS; correlation between MRD status in BM and PB; correlation between MRD status based on FC and NGS; potential drug resistance biomarkers and mechanisms. Recruitment is ongoing.