Activity of Venetoclax in Patients with Relapsed or Refractory Chronic Lymphocytic Leukaemia: Analysis of the VENICE-1 Multicentre, Open-Label, Single-Arm, Phase 3b Trial

Background Most patients with chronic lymphocytic leukaemia progress after treatment or retreatment with targeted therapy or chemoimmunotherapy and have limited subsequent treatment options. Response levels to the singleagent venetoclax in the relapsed setting is unknown. We aimed to assess venetoclax activity in patients with or without previous B -cell receptor -associated kinase inhibitor (BCRi) treatment. Methods This multicentre, open -label, single -arm, phase 3b trial (VENICE -1) assessed activity and safety of venetoclax monotherapy in adults with relapsed or refractory chronic lymphocytic leukaemia, stratified by previous exposure to a BCRi. Eligible participants were aged 18 years or older with previously treated relapsed or refractory chronic lymphocytic leukaemia. Presence of del(17p) or TP53 aberrations and previous BCRi treatment were permitted. Patients received 5 -week ramp -up to 400 mg of oral venetoclax once daily and were treated for up to 108 weeks, with 2 years follow-up after discontinuation, or optional extended access. The primary activity endpoint was complete remission rate (complete remission or complete remission with incomplete marrow recovery) in BCRi-naive patients. Analyses used the intent -to -treat (ie, all enrolled patients, which coincided with those who received at least one dose of venetoclax). This study was registered with ClinicalTrials.gov, NCT02756611, and is complete. Findings Between June 22, 2016, and March 11, 2022, we enrolled 258 patients with relapsed or refractory chronic lymphocytic leukaemia (180 [70%] were male; 252 [98%] were White; 191 were BCRi-naive and 67 were BCRipretreated). Median follow-up in the overall cohort was 495 months (IQR 472-541), 492 months (472-532) in the BCRi-naive group, and 497 months (474-543) in the BCRi-pretreated group. Of 191 BCRi-naive patients, 66 (35%; 95% CI 278-418) had complete remission or complete remission with incomplete marrow recovery. 18 (27%; 95% CI 168-391) of 67 patients in the BCRi-pretreated group had complete remission or complete remission with incomplete marrow recovery. Grade 3 or worse treatment -emergent adverse events were reported in 203 (79%) and serious adverse events were reported in 136 (53%) of 258 patients in the overall cohort. The most common treatment -emergent adverse event was neutropenia (96 [37%]) and the most common and serious adverse event was pneumonia (21 [8%]). There were 13 (5%) deaths reported due to adverse events; one of these deaths (autoimmune haemolytic anaemia) was possibly related to venetoclax. No new safety signals were identified. Interpretation These data demonstrate deep and durable responses with venetoclax monotherapy in patients with relapsed or refractory chronic lymphocytic leukaemia, including BCRi-pretreated patients, suggesting that venetoclax monotherapy is an effective strategy for treating BCRi-naive and BCRi-pretreated patients.