FDA Issues Venetoclax Priority Review as Second-Line Treatment in CLL

Venetoclax has been granted priority review status by the FDA for use in adults with chronic lymphocytic leukemia (CLL) following at least 1 prior therapy. This patient population includes those with a 17p deletion (del[17p]), according to codevelopers of the BCL-2 inhibitor AbbVie and Genentech.

Stephan Stilgenbauer, MD

Venetoclax has been granted priority review status by the FDA for use in adults with chronic lymphocytic leukemia (CLL) following at least 1 prior therapy. This patient population includes those with a 17p deletion (del[17p]), according to codevelopers of the BCL-2 inhibitor AbbVie and Genentech.

The FDA plans to take action on the application within 6 months, as opposed to the standard 10 months under regular review.

"Venetoclax is a potential new way to treat this difficult type of chronic lymphocytic leukemia,” Sandra Horning, MD, chief medical officer and head of Global Product Development at Genentech, said in a statement. “We look forward to working with AbbVie and health authorities to bring this first-of-its-kind medicine to people who need more options.”

In a separate development, the European Medicines Agency (EMA) has validated a Marketing Authorization Application for venetoclax for patients with CLL harboring a 17p deletion or TP53 mutation. The FDA and EMA reviews will both be based on data from the phase II M13-982 study, where venetoclax obtained responses in nearly 80% of patients with relapsed/refractory del(17p) CLL.1

The open-label, single-arm, multicenter M13-982 study included 107 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 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% of the 107 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 response (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 <4x109. In addition, the median time to normalization was 22 days (range, 2-122 days).

Stilgenbauer also said that responses are still evolving. 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).

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.2In 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 developments follow an FDA breakthrough therapy designation granted to venetoclax in April 2015 for previously treated patients with del(17p) CLL.

"Patients are always our number one priority and we accelerated our efforts to bring venetoclax, the first BCL-2 inhibitor, to patients with CLL in need of new therapies, including those with 17p deletion who typically have a poor prognosis,” Michael Severino, MD, executive vice president of Research and Development and chief scientific officer at AbbVie, said in a statement.


  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 [published online December 6, 2015].N Eng J Med. doi:10.1056/NEJMoa1513257.