Venclexta (Venetoclax) for Hard-to-Treat Leukemia

Helping malignant cells listen to self-destruct signals

Leukaemia blood cell, illustration
Kateryna Kon/Science Photo Library/Getty Images

CLL is the most common type of adult leukemia. Like other types of leukemia, CLL is a malignancy of the blood and blood-forming cells. In CLL, the leukemia cells often build up slowly over time. People who develop CLL may have very different experiences, but often they are diagnosed and continue to live without any symptoms at all, for at least a few years. Typically it is a routine blood count showing high levels lymphocyte white blood cells — and not leukemia symptoms — that tips a doctor off and eventually leads to a diagnosis.


Different types of CLL behave differently. Some grow more quickly than others. The leukemia cells from faster-growing and more slowly growing CLL types look alike on the surface, but lab tests can help tell the difference between them. For instance, cells that contain low amounts of proteins called ZAP-70 and CD38 are thought to grow more slowly, according to the American Cancer Society.

In certain cases of CLL, a part of chromosome 17 is lost — and along with it, an important gene that controls apoptosis (programmed cell death) called p53. The 17p deletion is found in 3 to 10 percent of previously untreated people, but up to 30 to 50 percent of relapsed or refractory cases. In other words, the 17p deletion may be an indicator of more hard-to-treat CLL.


In 2016, there will be an estimated 4,660 deaths from the disease in the United States. Although signs of CLL may disappear for a period of time after initial treatment, the disease is considered incurable and many people will require additional treatment, due to the return of cancerous cells.

Venclexta FDA Approval

Venclexta (venetoclax) is the first medicine of its kind to be approved — it is designed to help restore a cell’s ability to self-destruct (apoptosis) by selectively blocking the BCL-2 protein.

As noted above, CLL is an incurable disease and relapse is common, with up to 30 to 50 percent of people whose CLL progressed having the 17p deletion, a genetic marker associated with a hard-to-treat disease.

This FDA approval means that Venclexta is indicated for the treatment of patients with CLL with 17p deletion, as detected by an FDA approved test, who have received at least one prior therapy. The approval was based on findings from a clinical study called M13-982 that showed an 80 percent overall response rate with Venclexta.

Significance for Patients With CLL

“Up to half of people whose CLL progressed have 17p deletion, a genetic marker that makes the disease difficult-to-treat,” said Sandra Horning, M.D., chief medical officer and head of Global Product Development. “Venclexta 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.”

Venclexta was given the Breakthrough Therapy Designation by the FDA for the treatment of people with previously treated (relapsed or refractory) CLL with 17p deletion. Breakthrough Therapy Designation is designed to expedite the development and review of medicines intended to treat serious or life-threatening diseases and to help ensure people have access to them through FDA approval as soon as possible. The New Drug Application for Venclexta was granted Priority Review, a designation for medicines that the FDA has determined to have the potential to provide significant improvements in the treatment, prevention or diagnosis of a disease.

Safety Profile

Possible serious side effects with Venclexta include pneumonia, low white blood cell count with fever, fever, abnormal immune response that results in low red blood cell count, low red blood cell count and tumor lysis syndrome (TLS). The most common side effects of Venclexta include low white blood cell count, diarrhea, nausea, low red blood cell count, upper respiratory tract infection, low platelet count and tiredness. A pooled safety analysis of 240 patients with previously treated CLL from three clinical trials showed serious side effects were reported in 43.8 percent of patients. Side effects are graded based on severity, with increasing severity is you go from 1 to 4. The most common Grade 3 or 4 side effects were low white blood cell count, low red blood cell count and low platelet count.

According to Pheobe Starr in the February 2016 issue of "American Health and Drug Benefits," venetoclax has such strong antitumor activity that tumor lysis syndrome emerged as a major concern in preliminary studies, however this led AbbVie (one of the study's sponsors) and the investigators to adjust the dosing schedule of venetoclax, initiating treatment at 20 mg daily and increasing the dose slowly over 4 weeks to a target dose of 400 mg daily. The TLS rate with the new dosing schedule was 6 percent in the pivotal trial, with no clinical TLS.

The FDA's Accelerated Approval Program allows conditional approval of a medicine that fills an unmet medical need for a serious condition based on early evidence suggesting clinical benefit. This indication is approved under accelerated approval based on the overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Venclexta and BCL-2

Venclexta is a small molecule designed to selectively bind and inhibit the BCL-2 protein, which plays an important role in a process called apoptosis, or programmed cell death — essentially apoptosis is a cellular self-destruct sequence. Bcl-2 is an anti-apoptotic protein. By inhibiting Bcl-2, Venetoclax, has a pro-apoptotic effect on cancer cells — it induces programmed cell death. 

BCL-2 got its name from research done years ago on B-cell lymphomas. B-lymphocytes, or B-cells, are a type of white blood. Scientists learned that changes to the chromosomes in B cells caused the Bcl-2 gene to become activated, allowing the cells to survive and grow as cancer. Since that time, involvement of BCL-2 has also been discovered in a number of other cancers. In addition to CLL, BCL-2 is involved in melanoma, breast, prostate and lung cancers.

As noted, above, BCL-2 has also been linked cancer cells that resist treatment. CLL that mass-produces BCL-2 protein has been linked to resistance to certain drugs. It is believed that blocking BCL-2 may restore the signaling system that tells cells, including cancer cells, to self-destruct.

Venclexta is being developed by AbbVie and Genentech, a member of the Roche Group. Together, the companies are committed to research with Venclexta, which is currently being evaluated in Phase III clinical trials for the treatment of relapsed, refractory and previously untreated CLL, along with studies in several other cancers.

Emerging Therapies for CLL

Venclexta is also being studied in combination with other drugs used to fight CLL. Venclexta is the first approved medicine designed to restore apoptosis by selectively blocking the BCL-2 protein — and it's Genentech’s 10th new medicine approved in the past seven years.

Thus far, 3 other new drugs have been approved by the FDA for the treatment of patients with CLL, including the Bruton's kinase inhibitor ibrutinib (Imbruvica), the PI3K inhibitor idelalisib (Zydelig), and the anti-CD20 obinutuzumab (Gazyva).

Because Venetoclax has a different mechanism, it has the potential to be very useful in combination with other CLL drugs that have a complementary mechanism of action.