# Venetoclax–Rituximab and Emerging Treatment Strategies After c-BTKi Exposure in Relapsed/Refractory CLL: A Real-World Cohort and Literature Overview

## TL;DR

This study shows that venetoclax plus rituximab is effective and safe for treating chronic lymphocytic leukemia patients who previously failed covalent BTK inhibitors.

## Contribution

Provides real-world evidence on venetoclax-rituximab efficacy in CLL patients after covalent BTKi exposure, a previously understudied group.

## Key findings

- VR achieved 91.7% overall response rate and 66.7% complete remission in R/R CLL patients.
- Among c-BTKi-pretreated patients, VR showed 87.5% ORR and 62.5% CR with high MRD negativity rates.
- VR demonstrated >90% 30-month PFS and OS in both overall and c-BTKi-pretreated cohorts.

## Abstract

Patients with chronic lymphocytic leukemia (CLL) who relapse after treatment with covalent Bruton tyrosine kinase inhibitors (c-BTKis) represent a growing and clinically challenging group, for whom evidence-based treatment options are still limited. Venetoclax combined with rituximab (VR) is an established fixed-duration therapy, but data on its use in c-BTKi-pretreated patients are scarce. In this retrospective study, we present real-world outcomes of VR in relapsed/refractory CLL, including patients previously exposed to c-BTKi. In parallel, we provide a systematic overview of available evidence from real-world studies and clinical trials of emerging therapies. Notably, most published real-world data on VR after c-BTKi exposure are still restricted to small cohorts or meeting abstracts. Our findings show that VR remains effective and safe even in this difficult-to-treat population and help place VR in context with novel agents such as non-covalent BTK inhibitors, thereby informing therapeutic decisions in daily practice.

Background: Fixed-duration venetoclax plus rituximab (VR) is a standard therapy for relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). However, evidence supporting its use after covalent BTK inhibitor (c-BTKi) therapy is scarce in clinical trials and limited in real-world settings. Objectives: To assess the efficacy and safety of VR in a real-world cohort of patients with R/R CLL, including cBTKi-pretreated individuals, and to contextualize outcomes alongside published real-world studies and registrational trials of alternative therapies. Methods: We retrospectively analyzed 37 patients with R/R CLL treated with VR at our center between April 2018 and November 2024. Baseline characteristics, treatment responses, minimal residual disease (MRD), and adverse events were recorded. Survival was estimated using the Kaplan–Meier method. A structured review of relevant real-world evidence and pirtobrutinib clinical trials was also conducted. Results: Median age was 67 years; 35.1% had prior cBTKi exposure. The overall response rate (ORR) was 91.7% (22/24 evaluable patients), with 66.7% achieving complete remission (CR). Among evaluable c-BTKi-pretreated patients, the ORR was 87.5% (7/8) and the CR rate was 62.5%. Undetectable MRD (uMRD) rates were 78.6% in peripheral blood and 71.4% in bone marrow. Thirty-month progression-free survival (PFS), time to next treatment (TTNT), and overall survival (OS) were >90% for the whole cohort and for c-BTKi-pretreated patients. The most frequent adverse event was neutropenia grade ≥ 3, especially during combination therapy, which is easily managed with GCSF support. Conclusions: Our real-world evidence shows that VR is an effective and well-tolerated option even after c-BTKi therapy in R/R CLL. These data complement evidence from emerging therapies and inform post-c-BTKi treatment selection in clinical practice.