Venetoclax Results in Durable Efficacy for Relapsed/Refractory CLL


Venetoclax provided long-lasting responses in patients with relapsed/refractory chronic lymphocytic leukemia.

Venetoclax Results in Durable Efficacy for Relapsed/Refractory CLL

Venetoclax Results in Durable Efficacy for Relapsed/Refractory CLL

Patients with relapsed/refractory chronic lymphocytic leukemia (CLL) experienced deep and durable responses when treated with venetoclax (Venclexta) monotherapy, as demonstrated by findings from the phase 3b VENICE-1 trial (NCT02756611) published in The Lancet Oncology.

Data from the primary activity analysis demonstrated that, at a median follow-up of 49.2 months (IQR, 47.2-53.2) in the B-cell receptor-associated kinase inhibitor (BCRi)-naive cohort (n = 191) and 49.7 months (IQR, 47.4-54.3) in the BCRi-pretreated cohort (n = 67), patients who received venetoclax experienced complete remission (CR) or CR with incomplete marrow recovery at rates of 35% (95% CI, 27.8%-41.8%) and 27% (95% CI, 16.8%-39.1%), respectively. Additionally, the 48-week CR/CR with incomplete marrow recovery rate in the overall population (n = 258) was 33% (95% CI, 26.9%-38.6%).

“These data demonstrate deep and durable responses with venetoclax monotherapy in patients with relapsed or refractory CLL, including BCRi-pretreated patients, suggesting that venetoclax monotherapy is an effective strategy for treating BCRi-naive and BCRi-pretreated patients,” study authors wrote.

VENICE-1 was an open-label, single-arm trial conducted at 59 sites across 21 countries in Europe and North America. The study enrolled adult patients with previously treated relapsed/refractory CLL with a minimum creatinine clearance of 50 mL/min requiring treatment per the 2008 modified International Workshop on Chronic Lymphocytic Leukaemia criteria. Those who had developed Richter transformation or prolymphocytic leukemia and/or had received prior venetoclax were ineligible. Prior to starting venetoclax therapy, patients could not have received antineoplastic biological agents for 30 days or less; anticancer therapy, excluding BCRi, or radiotherapy within 5 half-lives or 14 days; steroids or strong or moderate cytochrome P450 3A (CYP3A) inducers for 1 week or less; or strong or moderate CYP3A inhibitors or BCRi for 3 days or less.

Following enrollment, the starting dose of oral venetoclax was 20 mg once daily, increasing weekly to 50 mg, 100 mg, and 200 mg, up to the target dose of 400 mg once daily. Patients received venetoclax at the target dose for up to 108 weeks, barring discontinuation or reduction due to unacceptable toxicity, disease progression, or intolerability.

The primary end point was CR rate in BCRi-naive patients. Secondary end points included CR/CR with incomplete marrow recovery in BCRi-pretreated patients, progression-free survival (PFS), overall response rate (ORR), duration of response (DOR), time to progression, and overall survival (OS).

At baseline, patients in the overall population had a median age of 68 years (IQR, 61-72), with 64% being at least 65 years old. Most patients were male (70%), White (98%), not Hispanic or Latino (96%), had an ECOG performance status of 0 (55%), had a largest lymph node diameter of less than 5 cm (64%), and did not have 17p deletion (53%) or a TP53 mutation (51%).

The median number of prior lines of anticancer therapy was 2 (IQR, 1-3), with patients receiving 1 (41%), 2 (25%), or at least 3 (34%) prior lines. Most patients (61%) received previous fludarabine; 19% and 10% of patients experienced previous ibrutinib (Imbruvica) or idelalisib (Zydelig) failure.

Additional findings from VENICE-1 showed that the ORR in the overall, BCRi-naive, and BCRi-pretreated cohorts was 80%, 85%, and 64%, respectively. The median DOR was 25.1 months (95% CI, 19.4-28.6), 24.4 months (95% CI, 18.1-27.9), and 28.6 months (95% CI, 16.8-45.3), respectively. 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), respectively.

Regarding survival, in the overall, BCRi-naive, and BCRi-pretreated cohorts, 27%, 24%, and 37% of patients died, respectively. The median OS was not reached in any group; the estimated 5-year OS rates were 71% (95% CI, 65.0%-76.5%), 75% (95% CI, 67.5%-80.6%), and 61% (95% CI, 47.7%-71.6%), respectively. The median PFS was 28.3 months (95% CI, 22.2-30.5), 28.8 months (95% CI, 22.2-31.8), and 23.4 months (95% CI, 16.8-33.8), respectively.

In terms of adverse effects (AEs), any-grade treatment-emergent AEs (TEAEs) occurred at a rate of 98%. The most common any-grade TEAEs consisted of neutropenia (43%), diarrhea (39%), and nausea (27%). Grade 3 or higher TEAEs were reported at a rate of 79% and included neutropenia (37%), anemia (13%), and thrombocytopenia (13%). Fifty-three percent of patients experienced a serious TEAE, including pneumonia (8%) and febrile neutropenia (6%). Overall, 70 patients died during the study; 8% of deaths occurred within 30 days of the last dose of venetoclax and 5% were attributed to AEs.

The median duration of treatment exposure in the overall, BCRi-naive, and BCRi-pretreated cohort was 108 weeks (IQR, 73.7-190.0), 110 weeks (IQR, 85.9-202.1), and 107 weeks (IQR, 24.3-119.6), respectively. In the overall cohort, 186 patients discontinued venetoclax treatment, due to continuing to the extension portion (n = 48), disease progression (n = 48), AEs (n = 39), transferring to commercial venetoclax (n = 21), physician decision (n = 9), patient withdrawal (n = 2), COVID-19 logistical restriction (n = 1), being lost to follow-up (n = 1), study termination (n = 1), and other reasons (n = 16). Seventy-two patients completed treatment, with 61 doing so at 108 weeks and 11 doing so beyond week 108.

“The safety profile reported here was consistent with previously published venetoclax data in relapsed or refractory CLL. No clinical tumor lysis syndrome adverse events were observed, and no patients discontinued venetoclax due to tumor lysis syndrome. Although common, neutropenia was managed with brief interruptions or reductions in venetoclax dosing. 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,” study authors wrote in conclusion.


Kater AP, Arslan Ö, 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. Published online March 8, 2024. doi:10.1016/S1470-2045(24)00070-6

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