Venetoclax Elicits Enduring Responses in R/R Chronic Lymphocytic Leukemia

“To our knowledge, this is the largest study of venetoclax monotherapy to be carried out in this setting and is consistent with the data previously reported, supporting early use of venetoclax within [CLL]," according to the study authors.

Treatment with venetoclax (Venclexta) yielded lasting responses among patients with relapsed/refractory chronic lymphocytic leukemia (CLL), including those previously treated with B-cell receptor–associated kinase inhibitor (BCRi) treatment, according to findings from the phase 3b VENICE-1 trial (NCT02756611) published in The Lancet Oncology.

Among all evaluable patients (n = 258), 29% had a complete remission (CR), and 45% had a partial remission (PR). Additionally, the rate of CR or CR with incomplete marrow recovery was 33% (95% CI, 26.9%-38.6%). Treatment with venetoclax produced a nodular PR or PR rate of 47% (95% CI, 41.1%-53.6%) and an overall response rate (ORR) of 80% (95% CI, 74.4%-84.6%).

Following treatment with venetoclax, the CR rate and PR rate was 31% and 48%, respectively, in patients who were naïve to treatment with BCRi therapy (n = 191). The CR or CR with incomplete marrow recovery rate was 35% (95% CI, 27.8%-41.8%), and the nodular PR or PR rate was 51% (95% CI, 43.5%-58.1%). Additionally, the ORR in this cohort was 85% (95% CI, 79.5%-90.0%).

Among those who previously received treatment with BCRi therapy (n = 67), venetoclax elicited a CR rate of 25% and a PR rate of 37%. Additionally, the rate of CR or CR with incomplete marrow recovery was 27% (95% CI, 16.8%-39.1%) in this cohort, and the nodular PR or PR rate was 37% (95% CI, 25.8%-50.0%). Data highlighted an ORR of 64% (95% CI, 51.5%-75.5%).

The median duration of response (DOR) was 25.1 months (95% CI, 19.4-28.6) in the overall population, 24.4 months (95% CI, 18.1-27.9) in the BCRi-naïve cohort, and 28.6 months (95% CI, 16.8-45.3) among those previously treated with BCRi therapy. The median time to progression was 28.3 months (95% CI, 23.4-32.6), 24.6 months (95% CI, 21.9-30.6), and 33.8 months (95% CI, 23.4-not estimable [NE]) in each respective group.

“This phase 3b trial VENICE-1 indicates venetoclax monotherapy can have deep and durable responses in patients with relapsed or refractory [CLL], including BCRi-pretreated patients; high rates of [CR] or [CR] with incomplete marrow recovery were observed over long-term follow-up, with no new safety signals identified,” Arnon P. Kater, MD, PhD, a professor in the Department of Hematology, Cancer Center Amsterdam, Lymphoma and Myeloma Center Amsterdam, Amsterdam UMC, University of Amsterdam, in The Netherlands, and coauthors wrote. “To our knowledge, this is the largest study of venetoclax monotherapy to be carried out in this setting and is consistent with the data previously reported, supporting early use of venetoclax within [CLL].”

In this trial, patients received venetoclax orally once daily as part of a ramp-up dosing schedule to a target dose of 400 mg. Treatment continued for a maximum of 108 weeks or until unacceptable toxicity, disease progression, or intolerability.

The trial’s primary end point was the rate of patients with a CR or CR with incomplete marrow recovery as their best response based on 2008 modified International Workshop on CLL criteria in patients naïve to treatment with BCRi therapy. Secondary end points included progression-free survival (PFS), ORR, DOR, time to progression, and overall survival (OS).

Patients 18 years and older with previously treated relapsed/refractory CLL and a creatine clearance rate of at least 50 mL/minute were eligible for enrollment on the trial. Those with del(17p) or TP53 aberrations were also eligible for enrollment.

The median age across the overall population was 68 years (IQR, 61-72), with 64% being 65 years or older. Additionally, most patients were male (70%), White (98%), not Hispanic (96%), had an ECOG performance status of 0 (55%), and 1 prior line of therapy for CLL (41%).

The median PFS was 28.3 months (95% CI, 22.2-30.5) in the overall population, 28.8 months (95% CI, 22.2-31.8) in the BCRi-naïve group, and 23.4 months (95% CI, 16.8-33.8) in the BCRi-pretreated cohort. Additionally, venetoclax produced estimated 5-year OS rates of 71% (95% CI, 65.0%-76.5%), 75% (95% CI, 67.5%-80.6%), and 61% (95% CI, 47.7%-71.6%) across each respective group.

Overall, 79% of patients in the overall population had grade 3 or higher treatment-emergent adverse effects (TEAEs), the most common of which included neutropenia (37%), anemia (13%), and thrombocytopenia (13%). Additionally, serious TEAEs affected 53% of patients and consisted of pneumonia (8%) and febrile neutropenia (6%).

A lower proportion of patients without prior BCRi treatment experienced TEAEs compared with the BCRi-pretreated group, which included grade 4 TEAEs (30% vs 57%), serious AEs (50% vs 60%), and death (24% vs 37%). Additionally, 6% and 3% of patients from each respective group had grade 5 TEAEs. The rates of dose interruption, reduction, or discontinuation following TEAEs were comparable between patients with and those without prior exposure to BCRi therapy.

Reference

Kater AP, Arslan O, Demirkan F, et al. 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. Lancet Oncol. 2024;25(4):463-473. doi:10.1016/S1470-2045(24)00070-6