1115 - Venetoclax Consolidation after BTKi Based Therapy for Patients with CLL

Background: Bruton Tyrosine Kinase Inhibitors (BTKi) can yield long-term disease control for patients (pts) with chronic lymphocytic leukemia (CLL) but requires indefinite therapy that can lead to cumulative side effects, especially cardiovascular (Barr et al. 2022). Venetoclax (Ven) is a BCL-2 inhibitor that produces deep responses with high rates of undetectable minimal residual disease (uMRD) for pts with CLL, thus allowing for fixed duration therapy (Al-Sawaf et al. 2020). We performed a single institution retrospective analysis of pts treated ven regimen following BTKi evaluating feasibility, efficacy, and safety.

Methods: 19 Pts treated between the years of 2015 and 2023 were evaluated. Pts were initially treated with a BTKi but stopped therapy either due to intolerance or personal preference. Pts who had progression on BTKi were excluded. Ven based treatment consisted of single agent ven or in combination with obinutuzumab, with standard ven dose ramp up to a maximum dose of 400mg daily. Obinutuzumab was administered per FDA standard dosing. Response assessment was performed using iwCLL criteria. Minimal residual disease (MRD) was assessed by multi- parametric peripheral blood flow cytometry with a sensitivity of 10-4.

Results: The pts had a median age of 64 years (range; 41-82). Rai stage at time of treatment (Tx) initiation with BTKi: I 10.5%; II 47.4%; III 5.3%; Stage IV 26.3%. 73.6% of Pts were previously treated. The median number of previous Txs was 1 (range; 0-5). One patient was previously treated with ven. Pts harbored the following cytogenetic abnormalities: del(13q) 52.6%; del(11q) 36.8%; trisomy 12 21.1%; normal 15.8%; del(17p) 10.5%; and complex in 10.5%. 61.5% of pts harbored an unmutated immunoglobulin heavy chain. 78.9% of pts were treated with ibrutinib and 21.1% of patients were treated with acalabrutinib. Reasons for stopping BTKi included: atrial fibrillation 26.3%; desired for fixed duration therapy 21.1%; diarrhea 15.8%; completion of planned treatment 15.8%; infection 10.5%; arthralgia 5.3%; and hemorrhage 5.3%. Tumor lysis risk (TLS) prior to starting BTKi was low 63.2%; intermediate 26.3%; and high 10.5%.

The median number of months on BTKi therapy prior to ven was 29.3 (range; 1.3-70.3). 15.8% of pts underwent dose reduction of BTKi prior to switching to ven. Response to BTKi therapy was partial response (PR) in 89.5% of pts and stable disease (SD) in 10.5% of pts. Tumor lysis risk prior to starting ven was low 94.7% and intermediate 5.3%. 68.4% of pts received ven monotherapy, and 31.6% of pts received ven plus obinutuzumab. The median number of months of ven based treatment was 13 (range; 0.2-63.2). 42% of pts currently remain on ven based therapy. 13 pts we assessable for MRD. The best peripheral blood MRD response was: uMRD 76.9% and low MRD 23.1%. The best MRD response for pts on ven monotherapy was uMRD 77.8% and low MRD 22.2%. The best MRD response for pts on ven plus obinutuzumab was uMRD 75% and low MRD 25%. One pt had progression after ven based therapy. Four pts required dose reductions of ven, secondary to neutropenia and diarrhea. Eight pts currently remain on ven. The median progression free survival (PFS) and time to next treatment (TTNT) after ven was 67.3 months and 50.7 months, respectively.

Conclusions: We found that CLL pts treated with ven after BTKi discontinuation due to intolerance/patient preference is a feasible treatment strategy, with high uMRD rates. There has been increasing focus on investigating the combination BTKi and ven. However, combination therapy does increase the risk of hematologic and gastrointestinal side effects, which can lead to dose reduction or drug discontinuation (Tam et al. 2022). In our analysis we found high rates of uMRD irrespective of the type of ven based therapy. Thus, initial BTKi administration may facilitate sufficient debulking of CLL to facilitate administration of single agent ven, avoiding the use of an anti-CD20 monoclonal antibody which can increase toxicity. This was evident in our cohort, as all but one pt had low-risk TLS prior to initiation of ven. Moreover, sequential therapy of a BTKi followed by single agent ven may lower the incidence of adverse events related to combination therapy. Our analysis demonstrates that sequential ven after BTKi is a feasible and effective treatment strategy for pts with CLL that deserves further evaluation in prospective clinical trials.