Venetoclax Monotherapy Leads to Durable Responses in Relapsed, Refractory CLL

Venetoclax (Venclexta; Abbvie/Genentech) monotherapy leads to deep, durable responses in many patients with relapsed or refractory chronic lymphocytic leukemia (CLL), according to a new report.

The phase 3b VENICE-1 trial found the therapy was effective in patients without prior B-cell receptor–associated kinase inhibitor (BCRi) therapy, but also among those with previous exposure to the therapy. The report, which is believed to be the largest and longest study of venetoclax monotherapy in this patient population, was published in The Lancet Oncology.

The investigators of this study enrolled 258 patients with relapsed or refractory CLL between June 2016 and March 2022 in the open-label, multicenter, single-arm phase 3b VENICE-1 trial | Image Credit: OmNomNom - stock.adobe.com

The study was initiated in 2016, at a time when venetoclax was being developed as a combination regimen with CD20 antibodies, explained the study authors. Their goal was to provide data on venetoclax monotherapy in patients with diverse molecular features and previous treatment exposure, they said.

The investigators enrolled 258 patients with relapsed or refractory CLL between June 2016 and March 2022 in the open-label, multicenter, single-arm trial. Patients with del(17p) and TP53 aberrations were permitted to enroll, the authors said. Most of the patients (70%) were male, 98% of participants were White, and a majority of enrollees were BCRi-naïve.

Of the 67 patients with previous BCRi treatment, the most common prior therapy was ibrutinib (Imbruvica; Pharmacyclics/Johnson & Johnson), which 75% of the BRCi-exposed patients had received.

Participants were given a 5-week ramp-up to a 400-mg daily dose of oral venetoclax, and then were treated for up to 108 weeks. Patients who discontinued the therapy were followed for 2 years, and those who continued the therapy were given the option of extended access. The overall median (IQR) follow-up was 49.5 (47.2-54.1) months, and the median duration of treatment exposure was 108 (74.7-190.0) weeks.

The study authors found that 66 of the BRCi-naïve patients (35%; 95% CI, 27.8%-41.8%) achieved complete remission (CR) or complete remission with incomplete marrow recovery. In the BRCi-pretreated group, 18 patients (27%; 95% CI, 16.8%-39.1%) achieved that status.

The overall response rate (ORR) was 80%, including 85% in the BCRi-naïve group and 64% in the BCRi-pretreated group.

The investigators said they were particularly encouraged with the results in the pretreated group.

“Previous exposure to BCRis and number of previous therapies have been associated with reduced response rates in previous clinical trials and real-world studies and suggest that early use of venetoclax should be the preferred choice,” they noted. “However, the current overall response rate was 64% in the BCRi-pretreated group, suggesting that patients still benefit after BCRi discontinuation.”

Seventy-nine percent of patients reported grade 3 or worse treatment-emergent adverse events (AE), the authors said; 53% of patients experienced a serious AE. The most common serious AE was pneumonia, which was reported in 21 patients. Overall, the most common treatment-emergent AE was neutropenia, which occurred in 96 patients. No instances of clinical tumor lysis syndrome were observed, the authors said.

Thirteen patients died due to AEs, but only 1 of those cases—a patient with autoimmune hemolytic anemia—was believed to be possibly related to venetoclax therapy, the authors said. The investigators said they did not identify any new safety signals.

They concluded that these new data bolster the case for venetoclax monotherapy in patients with relapsed or refractory CLL.

“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 chronic lymphocytic leukemia,” they wrote.

Reference

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. 2024;25(4):463-473. doi:10.1016/S1470-2045(24)00070-6