1158 - A retrospective study evaluating the sequence of BTKi and venetoclax, with a focus on toxicity

Introduction
The Bruton’s Tyrosine Kinase inhibitors (BTKi), ibrutinib, acalabrutinib, and zanubrutinib, and the BCL2 inhibitor (BCL2i), venetoclax (VEN), are FDA approved, and considered standard of care for the treatment of treatment-naïve (TN) and relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Although the current treatment paradigm promotes the use of BTKi followed by BCL2i or vice versa, data behind the efficacy of this sequence is limited to real-world retrospective studies. As such, safety of second line BCL2i or BTKi after front-line BCL2i or BTKi has not been well-studied.

Methods
We performed a single-center, retrospective cohort study to evaluate therapy-related toxicities in patients who received venetoclax after BTKi for the treatment of CLL/SLL. We aimed to also evaluate and compare efficacy/safety of patients who received BTKi after venetoclax, but we had an insufficient number of patients. Clinical data was collected for adult patients who received treatment for CLL/SLL with a BTKi then venetoclax between December 31, 2009 and October 20, 2022. We assessed toxicities by assessing grade 3 or higher toxicities, dose reductions, and treatment discontinuations. Efficacy was assessed by determining progression-free survival (PFS), and overall survival (OS). Descriptive statistics were used to summarize safety data. Survival outcomes were estimated using Kaplan-Meier methods from the initiation date of venetoclax.

Results
We identified 215 patients treated with a BTKi and venetoclax in the electronic medical record. 60 patients were included in the final analysis, having received a BTKi then venetoclax in sequence. The study population was comprised of primarily white (n=56, 93.3%) males (n=40, 66.7%) with a median age of 58 years (range: 40-81) at diagnosis. 15 patients (25%) were treated with a BTKi then venetoclax for TN disease, and 45 patients (75%) were treated with this sequence for R/R disease. Median prior lines of therapy were 2 (range: 0-9) for the entire cohort, and 3 (range: 1-9) for patients who had R/R disease. 45 patients (75%) received venetoclax without concurrent anti-CD20 monoclonal antibody therapy. With a median exposure to therapy of 15 months (range: 1-48), patients experienced a grade 3 or higher toxicity rate of 76.7%. The most common grade 3 or higher toxicity was neutropenia, which occurred in 31 patients (54.4%), followed by thrombocytopenia in 19 patients (32.2%). Tumor lysis syndrome (TLS) occurred in 9 patients (15%), in which 4 patients (6.7%) experienced clinical TLS. The high rate of TLS may be related to high baseline TLS risk or dose escalation over a shorter timeframe than the licensed schedule in CLL, however these variables were not collected. Venetoclax dose reduction occurred in 13 patients (22.8%) and seven patients (11.7%) discontinued venetoclax secondary to adverse drug events. After a median follow-up of 23 months (range: 1-91), utilizing the initiation date of venetoclax, median PFS was 31.9 months (95% CI, 20.2-40.3) and median OS was 44.8 months (95% CI, 31.9-Not reached (NR)). Patients that were TN prior to the BTKi/VEN sequence had a median PFS of 59.0 months (95% CI, 8.1-NR) and a median OS of NR (95% CI, 16.7-NR). Patients who were R/R prior to the BTKi/VEN sequence had a median PFS of 27.3 months (95% CI, 19.4-39.6) and a median OS of 36.9 months (95% CI, 31.8-NR) (figure 1).

Conclusion
In this real-world retrospective cohort study of patients with R/R CLL/SLL who received treatment with a BTKi then venetoclax, the rate of grade 3 or higher toxicities during venetoclax therapy was similar to previously published clinical trials (Seymour, N Engl J Med, 2018). The current study adds real-world survival data with a median PFS that compares similarly with clinical trial data from the MURANO trial, which demonstrated a four-year PFS estimate of 57.3% (Kater, J Clin Onc, 2020) and a trial by Jones JA, et al., demonstrating a median PFS of 24.7 months (Jones, Lancet Oncol, 2019) in a largely R/R population who received the BTKi/VEN sequence. Additionally, due to recent publications supporting the use of a BTKi plus venetoclax, future retrospective studies comparing the sequence of BTKi then venetoclax with BTKi plus venetoclax are warranted.