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.

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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.

RELATED: Venetoclax Granted New Drug Application, Priority Review for CLL

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.


  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.