Venetoclax Shows Positive Results for CLL with 17p Deletion

A stethoscope on a laboratory bench. Clinical trial of venetoclax yields positive results.

Sometimes, cancer medicines are huge proteins. Other times, a very small molecule is able to throw a monkey wrench into the biological machinery of cancer.

Venetoclax, formerly known as ABT-199, is one such small molecule that has recently shown positive results in what is referred to as a pivotal trial.

A clinically meaningful overall response rate -- that is, a reduction in the number of cancer cells -- was demonstrated in a proportion of people with a difficult-to-treat form of chronic lymphocytic leukemia, or CLL.

This particular type of leukemia is known as 17p deletion CLL.

About CLL

CLL is one of the most common forms of blood cancer and the most common leukemia in adults. According to the American Cancer Society’s estimates, 14,620 new cases of CLL are expected in 2015. About 4,650 deaths from CLL will occur over this same year.

About 17p Deletion CLL

17p deletion CLL is a form of the disease that is harder to treat. Tests are done to detect specific genes or parts of genes to identify this condition. In general, people with 17p deletion CLL tend not to respond as well to conventional chemotherapy, but this is not always the case, and the percentage of cancer cells that have the 17p deletion is also important.

What's behind the name? 17p deletion CLL is so named because a piece of a specific chromosome, chromosome 17, is lost -- and, most of the time, along with it goes an important gene called p53 that controls apoptosis, or programmed cell death.

The 17p deletion is found in about 3 to 10 percent of people with CLL, overall. If you look those who are no longer responding to chemotherapy -- that is, those with relapsed or refractory disease -- the percentage having the 17p deletion increases to about 30 to 50 percent.

P53 isn’t the only protein that controls the cellular self-destruct sequence, however.

BCL-2 is a another one, and researchers are developing inhibitors of the BCL-2 protein to fight cancer. Venetoclax is a small molecule designed to bind and inhibit the BCL-2 protein.

About Venetoclax

On August 12, 2015, Genentech, a leading biopharmaceutical company and a member of the Roche Group, announced positive results from a clinical study of venetoclax, an investigational medicine being developed in partnership with AbbVie. The clinical study, called M13-982, evaluates the efficacy and safety of venetoclax in patients with relapsed or refractory CLL with the 17p deletion.

How Venetoclax Works

Blocking BCL-2 may restore the signaling system that tells cancer cells to self-destruct. The BCL-2 protein is made, or expressed, by CLL cells as well as certain non-Hodgkin’s lymphoma cells. The BCL-2 protein has been linked to drug resistance in certain cancers, and the hope is that blocking BCL-2 might also increase the drug-sensitivity of these cancers.

More About BCL-2

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 them 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 associated with resistance to cancer treatments.

About the Venetoclax Study (M13-982)

  • The main study group included 107 people with previously-treated 17 deletion CLL
  • Roughly 50 patients will be enrolled in the safety expansion group
  • The main goal or key measurement of the study is the overall response rate, as determined by an independent review committee.

Next Steps

Data from this study will be submitted for presentation at an upcoming medical meeting and to the FDA and international agencies for approval consideration.

AbbVie and Genentech are evaluating venetoclax as a single medicine or in combination with other medicines. There are ongoing studies for venetoclax in CLL, and studies are also ongoing in several other blood cancers, including indolent non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, acute myeloid leukemia and multiple myeloma.

Background and Sources on BCL-2 and CLL

Dreger P, Schetelig J, Andersen N, et al. Managing high-risk CLL during transition to a new treatment era: stem cell transplantation or novel agents? Blood. 2014;124(26):3841-3849.

Czabotar PE, Lessene G, Strasser A, et. al. Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy.  Nat Rev Mol Cell Biol. 2014; 15, 49–63.

Reed JC. Bcl-2–family proteins and hematologic malignancies: history and future prospects. Blood. 2008;111(7):3322-3330.

Hassan M, Watari H, AbuAlmaaty A, Ohba Y, Sakuragi N. Apoptosis and Molecular Targeting Therapy in Cancer. BioMed Research International. 2014;2014:150845.

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