Venetoclax Safe, Active in Relapsed CLL, SLL With Poor Prognostic Features

Selective targeting of BCL2, a key protein involved in the survival of chronic lymphocytic leukemia (CLL) cells, with venetoclax had a manageable safety profile and induced substantial responses in patients with relapsed CLL or small lymphocytic leukemia (SLL), including those with poor prognostic features.¹

Although new treatments have improved outcomes for patients with relapsed CLL, achieving a complete remission continues to be uncommon. Therefore, researchers sought to evaluate the safety and activity of venetoclax in a phase 1 dose-escalation study. The findings were published in The New England Journal of Medicine.¹

In the dose-escalation phase, researchers enrolled 56 patients and assigned them to receive venetoclax 150 to 1200 mg per day. Then, 60 additional patients were treated with venetoclax in a weekly stepwise ramp-up dosing schema up to 400 mg per day. Most participants had received multiple prior therapies, and 89% had poor prognostic clinical or genetic features.

Results showed that venetoclax was active at all dose levels, with an overall response rate of 79% among the 116 patients who received venetoclax.

Researchers found that response rates ranged from 71% to 79% among patients with an adverse prognosis, including those with resistance to fludarabine, those with chromosome 17p deletions, and those with unmutated IGHV.

A total of 20% of patients achieved complete remissions, including 5% who had no minimal residual disease on flow cytometry. Furthermore, the researchers estimated the 15-month progression-free survival to be 69% in the 400-mg dose group.

In terms of safety, clinical tumor lysis syndrome occurred in 3 of the 56 patients in the dose-escalation cohort, with 1 death. After the investigators made adjustments to the dose-escalation schedule, clinical tumor lysis syndrome did not occur in any patients in the expansion cohort.

Other notable toxicities included mild diarrhea in 52% of patients, upper respiratory tract infection in 48%, nausea in 47%, and grade 3 or 4 neutropenia in 41%.

Researchers were ultimately not able to identify a maximum tolerated dose.

Reference

1. Roberts AW, Davids MS, Pagel JM, et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016; 374(4):311-322.