Real-World Efficacy and Safety of Venetoclax Alone and in Combination with Rituximab in Patients with Chronic Lymphocytic Leukemia: Interim Results of the Verone Study

Introduction: The efficacy and tolerability of venetoclax (VEN), a first-in-class selective oral B-cell lymphoma 2 (BCL-2) inhibitor, in patients with chronic lymphocytic leukemia (CLL) have been demonstrated in several clinical trials. This French observational ongoing study aims to describe the effectiveness and tolerability of VEN in routine clinical practice, either as monotherapy or in combination with rituximab.

Methods: VERONE is an ongoing prospective non-interventional study conducted in adult CLL patients having started VEN alone until progression or in combination with rituximab as 2-year fixed treatment duration, with a planned follow-up period of 48 months. This interim analysis was performed 4 years after the first inclusion in the study. In each group of patients [monotherapy (VEN) or combination with rituximab (VEN+R)] with at least one follow-up visit (evaluable populations), the best overall response rate (BORR) [proportion of responders, i.e., complete response (CR), CR with incomplete bone marrow recovery, nodular partial response, clinical complete response, or partial response, according to physician's assessment] was estimated at 1 and 2 years after initiation of VEN therapy, as well as progression-free survival (PFS) and overall survival (OS).The primary objective of this study is to describe the effectiveness of venetoclax in terms of best response to treatment up to 12 months.

Results: From March 2018 to March 2022, among the 345 analyzed patients included in 64 centres, 227 were retained in the VEN safety population, 94 in the VEN+R safety population, and 13 patients received an other combination than VEN+R. Among the 227 VEN and 94 VEN+R patients, 225 and 94, respectively met all the selection criteria (analyzed populations), and 121 and 70, respectively entered the evaluable populations. In the analyzed populations, respective baseline patient characteristics were as follows: median age, 74.0 (41.0; 91.0) and 73.0 (50.0; 90.0) years; male, 68.6% and 67.0%; ECOG ≥2, 15.6% and 15.5%; del(17p) and/or TP53 mutation, 40.9% and 42.4%; median CLL duration, 8.4 and 8.8 years; median prior lines of therapy, 2 [1;9] and 1 [1;8]; prior B-cell receptor inhibitors 68.0% and 44.7%. In the 121 patients of the VEN evaluable population, the median follow-up duration was 28.4 months at the time of this analysis. It was 24.3 months in the 70 patients of the VEN+R evaluable population.

BORR for VEN and VEN+R cohorts are presented in Table 1. In VEN and VEN+R evaluable patients, 1-year PFS were estimated at 84.6% (95% CI [76.3; 90.1]) and 87.2% [76.0; 93.4], respectively; PFS estimates were 71.7% [60.6; 80.2] and 77.9% [64.9; 86.6] at 2 years. Respective 1-year OS were estimated at 88.8% [81.5; 93.4] and 92.9% [83.7; 97.0]; 2-year OS estimates were 79.6% [70.2; 86.3] and 80.6% [68.0; 88.7].

Among both safety populations, 202 VEN patients (89.0%) and 94 VEN+R patients (100%) completed the ramp-up period, and 76.2% and 90.4%, respectively reached the recommended daily dose of 400 mg at the time of analysis. Median durations of treatment were 17.1 and 21.1 months, respectively. Overall, 80.6% and 92.6% of patients, respectively experienced adverse events (AEs), 62.1% and 67.0% ≥grade 3 AEs, 45.8% and 45.7% serious AEs (SAEs), and 18.5% and 17.0% venetoclax-related SAEs (neutropenia 7.0% and 5.3%). Four fatal venetoclax-related AEs were reported in 3 VEN patients (deterioration of the general status, ascites and hepatic failure, death with no precision). Over the ramp-up period, 20 VEN patients (8.8%) and 9 VEN+R patients (9.6%) experienced tumor lysis syndrome which led to treatment discontinuation in 4 (1.8%) and 1 (1.1%) patients.

Conclusion: Our interim real-life data tend to confirm that venetoclax used as monotherapy or combination with rituximab is effective in non-selected pre-treated CLL patients, as previously shown in clinical trials. Safety data are reassuring, with no new safety signals identified. BORR seem to be equivalent between each groups of patients and further results are expected next year once survival outcomes are more mature.

Table 1: BORR at 1 year and 2 years for VEN and VEN+R cohorts

Ysebaert:Abbvie, Astra-Zeneca, Janssen, Roche, Beigene, BMS/Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Troussard:AstraZeneca, Innate Pharma, Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Le Calloch:AbbVie, Gilead, Janssen, Takeda: Honoraria. Guieze:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astrazeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie, Beigene, Janssen, Gilead, Roche, AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Laribi:AbbVie, AstraZeneca, Beigene, Iqone, Janssen, Novartis, Takeda: Honoraria. Lepretre:AbbVie, Roche, Amgen, AstraZeneca, Janssen, Beigene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Leblond:Abbvie, Beigene, Roche, Amgen, Lilly AstraZeneca, Janssen, Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Feugier:AstraZeneca, Janssen, Abbvie, Beigene, Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Congress Invitations. Lahjibi:AbbVie: Current Employment. Ramier:AbbVie: Current Employment. Delmer:Abbvie, AstraZeneca, Janssen, Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees.