Zanubrutinib and venetoclax as initial therapy for CLL/SLL with obinutuzumab triplet consolidation in patients with detectable minimal residual disease (BruVenG).

Abstract Introduction Bruton's tyrosine kinase inhibitors (BTKi), anti-CD20 antibodies, and B cell lymphoma 2 inhibitors (BCL-2i) are essential therapeutic drug classes in the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Synergy has been observed between BTKi and BCL-2i, which can offer a safe, effective, and all oral fixed duration regimen (Tam et al., 2022). Triplet regimens combining BTKi, BCL2i, and anti-CD20 demonstrate improvement in undetectable minimal residual disease (uMRD), with comparable response rates, similar survival outcomes, but with increased hematologic toxicity and infections as compared to BTKi/BCL2i doublets (Brown et al., 2025). Thus, anti-CD20 therapy may best be utilized within a response-adapted approach in order to maximize efficacy while minimizing toxicity. Here we report interim efficacy and safety data utilizing a response adapted approach for initial treatment of CLL/SLL pts (BruVenG). Methods Eligible patients (pts) had untreated CLL/SLL with treatment indications per International Workshop on CLL (IWCLL) 2018 guidelines. Enrolled pts had adequate organ, bone marrow, and performance status. All pts were treated with an initial 3 cycle (C) lead-in of 320mg, oral, once daily zanubrutinib (Z). Starting at C4, venetoclax (V) was escalated to an effective dose of 400mg, oral, once daily. Escalation followed standard prescriber guidelines based on tumor lysis syndrome (TLS) risk evaluated prior to C4. Pts continued on Z and V until C17. At C16, radiographic, peripheral blood (PB), and bone marrow (BM) assessments were performed. If pts were MRD4 in both the PB and BM at C16, defined as MRD levels <1x10-4 via clonoSEQ® (Adaptive Biotechnologies) they stopped Z and V at C17. If pts were MRD+ in either PB or BM, then obinutuzumab (O) was introduced at C17 following standard CLL dosing guidelines, continuing with Z and V for an additional 6 cycles. At C23, pts receiving consolidation repeated radiographic, PB, and BM assessments and stopped treatment regardless of response. The coprimary endpoints are C16 PB, BM, and overall best MRD4 rates. Key secondary endpoints include C16 response rates, 36-month progression free survival (PFS), 36-month overall survival (OS), 36-month time to next treatment (TTNT), 24- and 36-month PB MRD negativity rates, tumor lysis syndrome (TLS) reduction rates, and safety. Responses were graded per IWCLL 2018 guidelines. Results Between 5/2023 and 4/2025, 45 pts enrolled. The median age was 61 (range 33-83), 31 (69%) were male, 37 (82%) were white, 5 (11%) were black. At entry, 26 (57%) had Rai stage III/IV disease, 16 (36%) had nodes ≥5cm, and 13 (29%) were high risk for TLS defined per V prescribing information. Twenty (44%) had an unmutated IGHV gene, 26 (58%) had del13q, 14 (31%) had trisomy 12, 7 (16%) had del11q, 7 (17%) had del17p, 8 (18%) had del17p or TP53 mutations, and 18 (40%) had complex karyotype defined as ≥3 abnormalities, with 9 (20%) having ≥5 abnormalities. Median follow-up time on study was 13.1 months. At time of data cutoff, 37 pts were evaluable for a best response at C4 or later, and 20 pts completed at least C16. The best overall response rate was 97%. Twenty pts were evaluable for complete response (CR) and MRD after at least 16 cycles, 7 (35%) achieved a CR and 6 (30%) were MRD4 or better in the PB while 3 (15%) were MRD4 or better in both PB/BM. Nine pts completed triplet consolidation, 6 (67%) were in CR at C23 with 7 (78%) converting to at least MRD4 in the PB and 6 (67%) converting to at least MRD4 in both PB/BM. At time of data cutoff, no pts progressed or had died. Forty three pts recorded an adverse event (AE). The most common any grade AE that occurred in 20% or more pts were fatigue (56%), diarrhea (53%), hypertension (31%), nausea (27%), upper respiratory infection (27%), arthralgia (27%), bruising (24%), neutropenia (22%), thrombocytopenia (22%), and rash (20%). No atrial fibrillation was recorded. One pt discontinued study due to a grade 4 intracranial hemorrhage prior to V escalation and 1 pt discontinued V due to recurrent Grade 4 neutropenia but continue on study with Z. Conclusions Response adapted therapy as initial treatment for CLL/SLL is feasible, effective, and safe. Despite initial low rates of MRD4 with the oral doublet, consolidation with O based triplet therapy leads to high rates of uMRD. Updated results on efficacy and safety will be reported.