FDA Approves Venetoclax for CLL

The FDA approved the BCL-2 inhibitor venetoclax (Venclexta) for patients with chronic lymphocytic leukemia (CLL) who have a 17p deletion (del[17p]), following at least 1 prior therapy.

Richard Pazdur, MD

The FDA has granted an accelerated approval to the BCL-2 inhibitor venetoclax (Venclexta) for patients with chronic lymphocytic leukemia (CLL) who have a 17p deletion (del[17p]), following at least 1 prior therapy.

The FDA approval was primarily based on data from the phase II M13-982 study, in which venetoclax elicited responses in nearly 80% of patients with relapsed/refractory del(17p) CLL.1 The Vysis CLL FISH probe kit was also approved as a companion diagnostic to venetoclax for detection of the del(17p).

“These patients now have a new, targeted therapy that inhibits a protein involved in keeping tumor cells alive,” said Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “For certain patients with CLL who have not had favorable outcomes with other therapies, Venclexta may provide a new option for their specific condition.”

The open-label, single-arm, multicenter M13-982 study included 106 patients with relapsed/refractory del(17p) CLL. The median age was 67 years (range, 37-85 years) and patients had received a median of 2.5 prior regimens (range, 1-10). Many of the patients were refractory to fludarabine and bendamustine therapy.

Patients received venetoclax once daily with a weekly dose ramp-up schedule (20, 50, 100, 200, 400 mg) over a period of 5 weeks with tumor lysis syndrome prophylaxis. Patients were treated with 400 mg of venetoclax daily dosed continuously until disease progression or discontinuation. As of the interim data cutoff (April 30, 2015), the median time on study was 12.1 months (range, 0.3-21.5 months).

Overall, 79.4% (95% CI, 71%-87%) of the 106 patients evaluated in the clinical trial responded to venetoclax monotherapy according to the independent review committee evaluation, including 8 patients (7.5%) with a complete remission (CR) or a CR with incomplete marrow recovery (CRi). Of 45 patients evaluated for minimal residual disease (MRD), 18 attained MRD-negative status in their peripheral blood.

When presenting the data at the 2015 ASH Annual Meeting, lead study author Stephan Stilgenbauer, MD, of the University of Ulm, Germany, said one of the most noteworthy outcomes of the study was the impact of venetoclax on the change in absolute lymphocyte count among participants. Only 4 of the 87 patients with baseline lymphocytosis did not normalize to <4x10.9 In addition, the median time to normalization was 22 days (range, 2-122 days).

The median time to first response was 0.8 months (range, 0.1-8.1 months) and the median time to CR/CRi was 8.2 months (range, 3.0-16.3 months). At 12 months' median follow-up, the median duration of response had not been reached (range, 2.9-19 months).

In the realm of adverse events (AEs), Stilgenbauer said patients treated with venetoclax during the trial experienced AEs that were comparable to or less prevalent than those experienced by individuals receiving frontline chemotherapy.

Ninety-six percent of 103 evaluable patients experienced a treatment-emergent AE of any grade, including 76% with grade 3/4 events. The most common all-grade AEs included neutropenia (43%), diarrhea (29%), and nausea (29%).

Infections occurred in a total of 77 patients (72%), but there were only 16 patients (15%) who had upper respiratory tract infections of any grade including only 2 patients (2%) with grade 3/4 infections. Stilgenbauer said it was “reassuring” that respiratory infections were uncommon and that the overall infection rate was “lower than expected in this high-risk population.”

Simultaneous with the presentation of the phase II data at ASH, results of a phase I dose-escalation study of venetoclax among patients with CLL were published in The New England Journal of Medicine.2 In this study, the ORR was 79% with venetoclax among 116 patients treated during the study, including a CR in 20% of participants. The 15-month progression-free survival estimate for patients who received the highest dose of 400 mg per day was 69%.

All participants in that study had relapsed CLL and more than one-third were refractory to their last treatment, but the study was not restricted to patients with a 17p deletion.

Today’s regulatory approval follows an FDA breakthrough therapy designation granted to venetoclax in April 2015 for previously treated patients with del(17p) CLL.

“Up to half of people whose CLL progressed have 17p deletion, a genetic marker that makes the disease difficult-to-treat,” Sandra Horning, MD, chief medical officer and head of Global Product Development at Genentech, which codevelops venetoclax along with AbbVie, said in statement. “Venclexta is the first approved medicine designed to trigger a natural process that helps cells self-destruct, and is a new way to help people who have been previously treated and have this high-risk form of the disease.”

Also commenting on the approval, Richard Gonzalez, chairman and CEO of AbbVie, said, “This FDA approval marks a major milestone for our company, and more importantly for the patients diagnosed with relapsed/refractory CLL who harbor the 17p deletion. BCL-2 inhibition is a novel mechanism which brings a new treatment option to patients who need additional therapies.”

Under the accelerated program, full approval for venetoclax is contingent upon findings from a confirmatory study. At this time, there are currently two phase III trials assessing venetoclax in combination with anti-CD20 antibodies for patients with CLL.


  1. Stilgenbauer S, Eichhorst BF, Schetelig JS, et al. Venetoclax (ABT-199/GDC-0199) monotherapy induces deep remissions, including complete remission and undetectable MRD, in ultra-high risk relapsed/refractory chronic lymphocytic leukemia with 17p deletion: results of the pivotal international phase II study. Presented at: 57th American Society of Hematology Annual Meeting; Orlando, Florida; December 5-8, 2015. Abstract LBA6.
  2. Roberts AW, Davids MS, Pagel JM, et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Eng J Med. doi:10.1056/NEJMoa1513257. 2016;374(4):311-322.

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