Venetoclax Approved in US for Certain CLL Patients

Zosia Chustecka

April 11, 2016

A new drug has been approved by the US Food and Drug Administration (FDA) for use in certain patients with chronic lymphocytic leukemia (CLL).

Venetoclax (Venclexta, AbbVie and Genentech) is indicted for use in CLL patients with the chromosomal abnormality 17p deletion who have been treated with at least one previous therapy.

CLL is one of the most common types of leukemia in adults, with approximately 15,000 new cases diagnosed in the United States each year, according to the National Cancer Institute. Approximately 10% of patients with untreated CLL and 20% of patients with relapsed CLL carry the 17p deletion, according to the FDA in its approval announcement.

However, the manufacturer gives a higher estimate of the proportion of patients affected. "Up to half of people whose CLL progressed have 17p deletion, a genetic marker that makes the disease difficult to treat," said Sandra Horning, MD, chief medical officer at Genentech said in a statement.

"Venetoclax is the first approved medicine designed to trigger a natural process that helps cells self-destruct, and is a new way to help people who have been previously treated and have this high-risk form of the disease," she added.

Patients with this deletion can be identified by the FDA-approved companion diagnostic Vysis CLL FISH probe kit.

Patients Have Poor Prognosis

Patients with relapsed CLL and this 17p deletion are resistant to conventional therapy and have a poor prognosis, but venetoclax has shown high rates of responses in such cases, as previously reported by Medscape Medical News.

Data from a pivotal single-group phase 2 trial — which were cited by the FDA in the approval announcement — were reported at the 2015 annual meeting of the American Society of Hematology (ASH).

In this trial, conducted in 107 CLL patients harboring the 17p deletion, who have the worst prognoses, the new drug achieved an overall response rate of 79.4%. A year later, response was maintained in most patients (84.7%). "This is a very special population with the most dismal outcome," lead author Stephan Stilgenbauer, MD, from the University of Ulm, Germany, reported at the meeting.

Among those responding were eight patients (7.5%) who achieved a complete response or a complete response with incomplete blood count recovery (determined by an independent review committee).

Among 45 patients who were tested for minimal residual disease (MRD), 18 attained MRD-negative status in peripheral blood, and about half (n = 25) of 48 patients who were assessed also had no CLL in the bone marrow, as determined by immunohistochemistry.

"Based on these data, venetoclax may be an attractive component to incorporate into novel combinations or to sequence in patients with this very-high-risk disease characterized by 17p deletion," Dr Stilgenbauer said at the time.

In addition, results of a phase 1 dose-escalation study of venetoclax monotherapy in patients with relapsed/refractory CLL, of whom 89% had poor prognostic clinical or genetic features, were published in the New England Journal of Medicine to coincide with the ASH meeting. In this study, the overall response rate was also 79%. Complete remissions occurred in 20% of the patients, including 5% who had no MRD in evidence on flow cytometry. The 15-month progression-free survival estimate for the groups receiving the 400 mg dose was 69%.

"What we are seeing in the phase 2 study and the one just published in the New England Journal of Medicine is that about 80% of patients in these very refractory groups have had a good response, and for some of those patients, it's potentially a very durable response," commented Tait D. Shanafelt, MD, professor of medicine at the Mayo Clinic, in Rochester, Minnesota, who was not involved in the studies.

"Some patients can even get down to MRD-negative states, which in these refractory patients are depths of remission that we couldn't typically achieve with our traditional treatments," Dr Shanafelt told Medscape Medical News.

"This is another medicine that really has the potential to add to our armamentarium for patients who previously didn't have good treatment options," Dr Shanafelt added.

Adverse Effects Include Tumor Lysis Syndrome

The FDA noted in its approval announcement that the most common adverse effects of venetoclax include neutropenia, diarrhea, nausea, anemia, upper respiratory tract infection, thrombocytopenia and fatigue. Serious complications can include pneumonia, neutropenia with fever, fever, autoimmune hemolytic anemia, anemia, and metabolic abnormalities known as tumor lysis syndrome.

This adverse effect of tumor lysis syndrome is a potentially life-threatening oncologic emergency that is caused by massive tumor cell lysis, which is associated with the release of large amounts of potassium, phosphate, and nucleic acids into the systemic circulation.

It can occur with venetoclax because "this agent has been shown to induce very rapid and very deep remissions...[and] the rapid destruction of these cells can potentially do harm," explained Dr Stilgenbauer.

Therefore, a step-wise, ramped-up dosing schedule was introduced in the phase 2 trial. "The starting dose was 20 mg, which is only 5% of the target dose of 400 mg," he explained. "And with this 5% dose, we were already seeing the destruction of tumor cells. This highlights the highly dramatic efficacy of this agent."

There are not many therapeutic agents that can achieve a tumor response at only 5% of the target dose, Dr Stilgenbauer added.

Despite the risk, Ephraim P. Hochberg, MD, assistant professor of medicine, Harvard Medical School, and instructor in hematology/oncology, Massachusetts General Hospital, Boston, does not think tumor lysis syndrome will be a major deterrent to using this new agent.

The outcomes are very exciting and promising in this difficult-to-treat population, he commented. "In this study, they titrated the dose up slowly.

"Tumor lysis syndrome occurs with the rapid killing of tumor cells," Dr Hochberg told Medscape Medical News last year. "It's too much of a good thing, so the goal is to slow it down."

Whenever this drug is given, it will have to be ramped up slowly, he explained. "My guess is that when it does come on the market, we will have a highly specific algorithm to use so that it can be given safely out in the community setting."


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