The Backstory
On April 11, 2016 the FDA approved venetoclax (Venclexta) for the treatment of patients with chronic lymphocytic leukemia (CLL) with the 17p deletion who have been treated with at least one prior therapy. This is the first FDA approval for venetoclax.
In addition to this recent FDA approval, venetoclax has been granted priority review for its new drug application (NDA) of venetoclax as a single agent in CLL, as well as FDA breakthrough therapy designation for use in combination with rituximab (Rituxan) to treat patients with relapsed/refractory chronic lymphocytic leukemia (CLL).
What is venetoclax?
Venetoclax, previously known as ABT-199 is the first FDA-approved treatment that targets the B-cell lymphoma 2 (BCL-2) protein. The BCL-2 protein plays an important role in enabling CLL cells to survive. CLL cells and other lymphomas overexpress and are more dependent upon BCL-2 protein than normal cells. Therefore, when venetoclax inhibits the protein, the CLL cells die, while the normal cells continue unharmed.
What is the 17p deletion and how does it affect CLL?
17p deletion occurs when part of chromosome 17 in the CLL cells is deleted in the CLL cells. This abnormality only occurs in the CLL cells, and not normal cells, and results in losing the p53 protein. The p53 protein plays an important role in enabling a cell to undergo suicide, and prevent itself from growing out of control. In CLL cells with a 17p deletion, the second genetic copy is often mutated, and as a result, these cells can grow more aggressively and are less responsive to chemotherapy. This results in worse clinical outcomes. Agents like venetoclax work independent of p53, and therefore are still effective in these cases. The 17p deletion is found in approximately 3-7% of newly diagnosed CLL patients, but increases to 30-40% in relapsed and refractory cases.
Why was venetoclax granted FDA approval?
Venetoclax was granted FDA approval based on the results from the M13-982 trial investigating venetoclax in patients with 17p deletion who had received at least one prior therapy. Venetoclax demonstrated an overall response rate of 80%, which included 8% complete response rates. Almost three quarters of patients were free from progression at one year.
Were there any side effects?
The most worrisome side effect of venetoclax is life-threatening tumor lysis syndrome. In the initial studies, when a full dose was administered on day one, two patients died as a result of tumor lysis. Since a modified weekly ramp-up starting at 20 mg and increasing weekly to 50 mg, 100 mg, 200 mg, and finally 400 mg once daily, no cases of clinically significant tumor lysis were seen. Common, less serious side effects included low white blood cell count, diarrhea, nausea, anemia, upper respiratory tract infection, low platelet count, and fatigue. More serious side effects included pneumonia, fever, autoimmune hemolytic anemia, anemia, and tumor lysis syndrome.
How can you access venetoclax now?
Venetoclax is commercially available. Clinical trials investigating the use of venetoclax in patients who are progressed after B-cell receptor (BCR) inhibitors, namely ibrutinib and idelalisib, are ongoing.
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