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Venetoclax Approved for Some Patients with Chronic Lymphocytic Leukemia

May 4, 2016, by NCI Staff

Blood smear containing chronic lymphocytic leukemia cells (with purple stained nuclei and scant cytoplasm) and blood samples in test tubes.

Credit: Wikimedia/National Cancer Institute

The Food and Drug Administration (FDA) approved venetoclax (Venclexta®) on April 11 for patients with chronic lymphocytic leukemia (CLL) whose tumors have a specific genetic alteration.

The accelerated approval is for patients with CLL whose tumor cells are missing a portion of chromosome 17, commonly referred to as a 17p deletion, and who have received at least one prior therapy for their cancer.

The 17p deletion—which leads to the loss of the tumor-suppressor gene TP53—is present in about 10 percent of untreated patients and 20 percent of patients whose cancers return after treatment. Patients whose tumors develop a 17p deletion are considered to be at high risk of disease progression and have an expected survival of only a few years.

In concert with the venetoclax approval, the agency also cleared a companion diagnostic test, the Vysis CLL FISH probe kit, which must be used to test patient tumors for the 17p deletion.

Venetoclax is the first FDA-approved drug that targets the BCL2 protein in cancer cells. BCL2, which is part of the p53 signaling pathway and regulates a form of cell death called apoptosis, is overexpressed in many patients with CLL. BCL2 overexpression is associated with increased drug resistance and tumor cell survival.

"Targeting BCL2 represents a distinct therapeutic mechanism in CLL," said Kieron Dunleavy, M.D., of the Lymphoid Malignancies Branch in NCI’s Center for Cancer Research.

Venetoclax was tested in a single-arm, dose-escalation trial of more than 100 patients with CLL whose tumors had a 17p deletion. All of the patients enrolled in the study had received previous treatment; many had received multiple therapies.

Nearly 80 percent of patients in the trial responded to the venetoclax and, in about 85 percent of those patients, the responses lasted for a year or more. The drug was particularly effective among patients with a poor prognosis, including patients whose tumors do not respond to treatment with the chemotherapy drug fludarabine, Dr. Dunleavy explained.

The most toxic side effect was clinical tumor lysis syndrome, which occurred in 3 of the first 56 patients treated, one of whom died. The dosing schedule in the trial was subsequently altered, with venetoclax administered in a stepped-up dosing schedule, which mitigated the risk of tumor lysis syndrome.

The most common side effects were diarrhea, upper respiratory infection, nausea, and neutropenia. Neutropenia is likely to be a class effect of drugs that target BCL2, Dr. Dunleavy said.

Venetoclax is being studied as a treatment for other B-cell cancers, including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, and mantle cell lymphoma, Dr. Dunleavy added.

"In DLBCL, for example, tumors that overexpress the c-MYC and BCL2 proteins are associated with poorer outcomes following standard therapy, and novel treatment strategies for this cancer that incorporate venetoclax are currently being developed," he said.

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