FDA Grants Venetoclax Combination Breakthrough Designation in CLL

Venetoclax has received an FDA breakthrough therapy designation for use in combination with rituximab to treat patients with relapsed/refractory chronic lymphocytic leukemia.

Michael Severino, MD

Venetoclax has received an FDA breakthrough therapy designation for use in combination with rituximab (Rituxan) to treat patients with relapsed/refractory chronic lymphocytic leukemia (CLL), according to AbbVie, which is codeveloping the BCL-2 inhibitor with Genentech.

The designation, which will expedite the development and review of the combination in CLL, is based on data from the phase Ib M13-365 study. In the trial, the venetoclax/rituximab combination had an overall response rate (ORR) of 86%, with deep and durable responses in patients with relapsed/refractory CLL.1

“This second breakthrough therapy designation for venetoclax granted by the FDA underscores the significant potential of this therapy in treating relapsed/refractory CLL patients, and reflects AbbVie's commitment to providing breakthrough therapies for cancer patients,” Michael Severino, MD, executive vice president of research and development and chief scientific officer at AbbVie, said in a statement.

Venetoclax’s previous breakthrough designation was for single-agent use in previously treated patients with CLL who have a 17p deletion (del[17p]). AbbVie and Genentech filed a new drug application under this designation and the FDA recently granted single-agent venetoclax a priority review for use in adults with CLL, including del[17p] patients, after at least 1 prior therapy.

Results from the phase Ib M13-365 study were presented at the 2015 ASH Annual Meeting. The trial included 48 patients with CLL and 1 patient with small lymphocytic lymphoma.

Forty-one patients were enrolled in 1 of 5 dose escalation cohorts. Patients received continuous venetoclax starting at 20 or 50 mg daily and then were escalated to their cohort dose of 200 to 600 mg daily, followed by rituximab, given every 4 weeks for a total of 6 doses.

There was also a safety expansion cohort comprising 8 patients for which the venetoclax dose was 400 mg daily. The recommended phase II dose for venetoclax established by the study was 400 mg daily.

For the overall study population, the median age was 68 years (range, 50-88) and patients had received a median of 2 prior regimens (range, 1-5). Among the 45 (92%) patients who received prior rituximab, 14 (29%) were rituximab-refractory. Among the 29 patients (59%) who received prior fludarabine, 18% (n = 9) were fludarabine-refractory. Nine of 46 (20%) evaluable patients had a del[17p] and 19 of 27 (70%) evaluable patients expressed unmutated IGHV.

The investigators assessed responses by iwCLL criteria at 7 months using CT scan and bone marrow biopsy. Assessment of minimal residual disease (MRD) was conducted on bone marrow aspirates in local laboratories with ≥4 color flow cytometry (minimum sensitivity, 0.01%).

By investigator assessment, responses were observed in 42 of 49 (86%) of patients, including 20 (41%) complete responses (CR) or CRs with incomplete marrow recovery (CRi). MRD-negative status was achieved in 26 (53%) patients overall, including 15 (75%) of the patients who reached CR/CRi.

There was 1 (2%) nodular partial remission and 21 (43%) partial responses (PR). Four patients had stable disease (SD), 2 patients had progressive disease, and 1 patient died of tumor lysis syndrome (TLS) prior to assessment. Nine patients with PR or SD on the combination at the 7-month analysis achieved CR after a median of 6 months (range, 2-9) of single-agent venetoclax.

Five (12%) of the 42 responders have progressed. The median progression-free survival (PFS) has not been reached. At a median follow-up of 17.5 months (range, 0.03-32), the 12- and 24-month PFS rates were 87% and 84%, respectively. Ninety-four percent of patients were alive at 12 months. The median overall survival has not been reached.

The response and survival rates remained consistent among high-risk subgroups, including patients aged ≥70 years and the del[17p], unmutated IGHV, and fludarabine-refractory cohorts.

At the time of the data analysis, 12 patients had discontinued the study: 6 had PD, 3 due to adverse events (AEs; neuropathy, TLS, and myelodysplasia), and 3 withdrew consent (1 following an MRD-negative CR).

The most common AEs in the study included neutropenia (55%), diarrhea (53%), nausea (49%), upper respiratory tract infection (45%), fatigue and pyrexia (37% each), cough (35%), and headache (33%). The most frequently occurring grade 3/4 AEs were neutropenia (53%), thrombocytopenia (16%), anemia (14%), febrile neutropenia (12%), and leukopenia (10%). There were 2 deaths that occurred following PD.

The FDA’s ongoing priority review of single-agent venetoclax is based on data from the open-label, single-arm, M13-982 study, which included 107 patients with relapsed/refractory del(17p) CLL.2 Overall, 79.4% of the patients responded to venetoclax monotherapy, including 8 (7.5%) patients with a CR/CRi. Of 45 patients evaluated for MRD,18 attained MRD-negative status in their peripheral blood.

The venetoclax/rituximab combination is being compared head-to-head with bendamustine plus rituximab in patients with relapsed/refractory CLL in the phase III MURANO trial (NCT02005471).


  1. Ma S, Brander DM, Seymour JM, et al. Deep and durable responses following venetoclax (ABT-199/GDC-0199) combined with rituximab in patients with relapsed/refractory chronic lymphocytic leukemia: results from a phase 1b study. Presented at: 2015 ASH Annual Meeting; December 5-8, 2015; Orlando, Florida. Abstract 830.
  2. 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: 2015 ASH Annual Meeting; December 5-8, 2015; Orlando, Florida. Abstract LBA6.