Venetoclax Produces Enduring Real-World Responses in Pretreated CLL/SLL

“These results support that venetoclax-based therapy is associated with durable remission following covalent BTK inhibitor discontinuation, even with prior chemotherapy or chemoimmunotherapy exposure," according to Nilanjan Ghosh, MD, PhD.

Regimens including venetoclax (Venclexta) yielded high response rates, even when administered in the second- or third-line setting, among patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who discontinued prior therapy with covalent Bruton tyrosine kinase (BTK) inhibitors, according to findings from a real-world study presented at the 2023 American Society of Hematology (ASH) Annual Meeting and Exposition.

The overall response rate (ORR) in the overall study population (n = 184) was 78.0%, which included partial responses (PRs) in 34.6% of patients and complete responses (CRs) in 43.3%. Additionally, the median time to next treatment or death (TTNT-D) was 39.5 months (95% CI, 30.4-not reached [NR]); the TTNT-D rate was 82.3% at 12 months and 72.4% at 18 months. Investigators also highlighted a median progression-free survival (PFS) of 43.2 months (95% CI, 31.9%-NR), a 12-month PFS rate of 82.8%, and an 18-month PFS rate of 75.1%.

Among patients who initiated second-line venetoclax-based treatment following covalent BTK inhibitor therapy in the first line (n = 65), the ORR was 84.1%, the PR rate was 29.5%, and the CR rate was 54.5%. The median TTNT-D in this group was NR (95% CI, 31.9 months to-NR), with 12-month and 18-month rates of 85.0% and 73.9%, respectively. Venetoclax-based treatment produced a median PFS of 43.2 months (95% CI, 39.5-NR), a 12-month rate of 86.4%, and an 18-month rate of 81.8%.

For those who received venetoclax in the third line after discontinuing second-line covalent BTK inhibitors (n = 67), investigators reported an ORR of 78.3%, a PR rate of 37.0%, and a CR rate of 41.3%. Additionally, the median TTNT-D was 44.2 months (95% CI, 37.0-NR), the 12-month rate was 83.1%, and the 18-month rate was 76.5%. The median PFS was 44.1 months (95% CI, 31.8-NR), and the PFS rates at 12 and 18 months were 85.2% and 80.4%, respectively. In a subset of patients who were previously treated with chemotherapy or chemoimmunotherapy prior to initiating covalent BTK inhibitors (n = 57), the ORR was 75.7%, the median TTNT-D was 44.2 months (95% CI, 37.0-NR), and the median PFS was 44.1 months (95% CI, 31.8-NR).

“This multi-center real-world study demonstrates that venetoclax-based therapy is an effective therapy with high response rates, both overall as well as second- or third-line therapy following covalent BTK inhibitor discontinuation,” presenting author Nilanjan Ghosh, MD, PhD, said. “These results support that venetoclax-based therapy is associated with durable remission following covalent BTK inhibitor discontinuation, even with prior chemotherapy or chemoimmunotherapy exposure.”

Ghosh is a chair of the Department of Hematologic Oncology and Blood Disorders at Atrium Health Levine Cancer Institute in Charlotte, North Carolina.

Investigators gathered data as part of the multi-center CLL Collaborative Study of Real-World Evidence (CORE) study and assessed outcomes in adult patients with CLL/SLL who received a venetoclax-based regimen after they discontinued treatment with a covalent BTK inhibitor. Clinical outcomes included ORR, TTNT-D, and PFS. Patients were stratified by when they initiated venetoclax-based therapy as well as whether they received prior chemotherapy or chemoimmunotherapy for those who began venetoclax in the third line.

The study included a total of 2020 patients, 1287 of whom received a covalent BTK inhibitor for at least 1 line of treatment. Of those patients, 184 discontinued treatment with a covalent BTK inhibitor and subsequently received therapy including venetoclax.

The median patient age was 68.2 years. Most patients were male (69.0%), had an ECOG performance status of 1 to 4 (66.0%), a low risk of tumor lysis syndrome (49.3%), unmutated IGHV (67.2%), and insurance with Medicare (40.8%). An equal proportion of patients had Rai stage 0 to II (50.0%) and stage III to IV disease (50.0%).

Patients received venetoclax-based treatment for a median of 14.5 months. Additionally, most received venetoclax monotherapy (62.5%) followed by combination treatment (37.5%); of those who received a venetoclax-based combination, most received the agent plus rituximab (Rituxan; 81.2%).

Venetoclax-based treatment doses were maintained for 81.0% of patients, and 16.8% required a dose reduction. Most patients discontinued prior covalent BTK inhibitors due to intolerance (45.1%) or disease progression (42.4%).

“As the CLL paradigm continues to evolve in terms of breadth of available treatment options, clinicians can use these timely results to inform their clinical practice. Further analysis of the study with larger cohorts and longer follow-up will be undertaken as part of future work to grow this body of evidence,” Ghosh concluded.

Reference

Ghosh N, Lamanna N, Eyre TA, et al. Treatment effectiveness with venetoclax-based therapy after Bruton tyrosine kinase inhibitors in chronic lymphocytic leukemia: an international real-world study. Presented at the 2023 American Society of Hematology (ASH) Annual Meeting and Exposition; December 9-12; San Diego, CA; abstract 1908.