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FDA Grants Venetoclax Breakthrough Designation in AML

Jason M. Broderick @jasoncology
Published: Thursday, Jan 28, 2016

Michael Severino, MD

Michael Severino, MD

Venetoclax has received an FDA breakthrough therapy designation for use in combination with hypomethylating agents in treatment-naïve patients with acute myeloid leukemia (AML) who are not eligible for standard high-dose induction treatment, 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 AML, is based on data from a small early-stage trial in which over 70% of untreated patients with AML had clinical responses to combination venetoclax therapy.

“Acute myeloid leukemia is an aggressive and life-threatening cancer. Unfortunately, for many AML patients, intensive therapy is not an option, causing a high need for new, effective, and alternative treatments,” Michael Severino, MD, executive vice president of research and development and chief scientific officer at AbbVie, said in a statement.

Data were presented at the 2015 ASH Annual Meeting for an ongoing phase Ib trial examining venetoclax, in combination with the hypomethylating agents decitabine or azacitidine, in 22 treatment-naïve patients with AML. In the nonrandomized, dose-escalation study, thirty-six percent of the patients were male and the median age was 74 years (range, 65-85).

Among patients receiving decitabine plus venetoclax, 6 patients received venetoclax at 400 mg and 6 patients received the drug at 800 mg. In the azacitidine plus venetoclax arm, 4 and 6 patients received the 400- and 800-mg venetoclax doses, respectively. As of June 11, 2015, the median time on study was 95.5 days (range, 6-205).

Overall, 19 of 22 patients were evaluable for response. The overall response rate (ORR) was 75% (n = 9) among patients who received venetoclax plus decitabine. At the 400-mg venetoclax dose, 2 patients achieved complete remission (CR) and 1 patient had a CR with incomplete marrow recovery (CRi). There were 5 CRi’s and 1 partial response at the 800-mg venetoclax dose.

In the venetoclax plus azacitidine arm, the ORR was 70% (n =7). There was 1 CR and 2 CRi’s with 400 mg of venetoclax. At the higher dose, there were 2 CRs, 1 CRi, and 1 PR.

Of the patients experiencing an objective response, none had a relapse of AML. Also of note, 3 patients who did not have an ORR by the International Working Group criteria used for the study had decreases in bone marrow blast counts at the end of their first cycle of treatment.

As of the data cutoff, 75% (n = 9) of the patients in the decitabine/venetoclax arm and 50% (n = 5) of the patients in the azacitidine arm remained active in the trial. Three and 5 patients in the two arms, respectively, had discontinued treatment.

The researchers reported safety data on adverse events (AEs) that occurred in ≥30% of both primary study arms. In the decitabine arm, at the lower venetoclax dose, the rates of febrile neutropenia, nausea, constipation, and cough were 67%, 50%, 33%, and 33%, respectively. At the 800-mg dose, the rates were 50%, 67%, 17%, and 17%, respectively.

Among patients receiving azacitidine, the rates with the 400 mg venetoclax dose were 50%, 75%, 25%, and 0 for febrile neutropenia, nausea, constipation, and cough, respectively. The rates for the higher dose were 33% each for all 4 toxicities.

The most frequently reported grade 4 AEs across the 2 primary study arms were decreased platelet count (8% with decitabine/venetoclax, 30% with azacitidine/venetoclax), neutrophil count (8%, 20%), and white blood cell count (8%, 20%). The most common serious AE across the 2 arms was febrile neutropenia (33%, 30%).

Across the entire study population, most patients (n = 15) had grade 1/2 cytopenias at baseline. Five and 4 patients in the decitabine and azacitidine arms, respectively, progressed to grade 3/4 cytopenia.

Overall, 55% of patients (n = 12) required study drug interruption. There were 4 deaths in the decitabine arm and 1 in the azacitidine arm.

Venetoclax’s previous 2 breakthrough designations were in chronic lymphocytic leukemia (CLL), for single-agent use in previously treated patients with CLL who have a 17p deletion (del[17p]) and for use in combination with rituximab (Rituxan) in patients with relapsed/refractory CLL. The FDA is currently considering the single-agent indication for approval under its priority review program.

“This third breakthrough therapy designation for venetoclax highlights our efforts to pursue the significant and broad potential of this therapy,” Severino said in his statement.


DiNardo C, Pollyea D, Pratz K, et al. A phase 1b study of venetoclax (ABT-199/GDC-0199) in combination with decitabine or azacitidine in treatment-naive patients with acute myelogenous leukemia who are ≥ to 65 years and not eligible for standard induction therapy. Presented at: 2015 ASH Annual Meeting; December 5-8, 2015; Orlando, Florida. Abstract 327.



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