Targeted Therapies in CLL– Targeting BCL2

Dr. Michael Choi of USCD Moores Cancer Center gave a brief talk at the Patient Empowerment and Education Meeting held April 23, 2015 about why BCL2 is a target in the treatment of CLL.

Normal cells are programmed to die when defects or damage to their DNA occur and that genetic error is detected through the protein called p53. This sets in motion a series of events that leads to the death of the cell in a programmed manner, the process of programmed cell death which is called apoptosis

The term “apoptosis” comes from the Greek, whose prefix “apo” means “separation” and the suffix, “ptosis” is translated to mean “falling off” has been generally known as the falling off of leaves from trees or as pieces of leaves falling from the tree in autumn.

The last series of events that leads to the death of a cell are triggered at the mitochondria or energy factory of the cell. Typically the mitochondria have proteins on them that are guarded or sequestered by a protein called BCL2. When the cell detects damage, there are proteins that come and bind to BCL2. Releasing those other proteins allows them to form panels on the mitochondria, which then leads to the release of chemicals that trigger the death of the cell. For various reasons, CLL cells have high levels of BCL2 and that’s perhaps one of the reasons they don’t die when they are supposed to.

For some time, companies have been looking to develop drugs to mimic those proteins that can come and bind to BCL2. Venetoclax or ABT-199 is one of those drugs. They took a previously developed drug calls navitoclax. They saw where it bound to BCL2 and modeled that using X-ray technology. They also saw that it was not binding optimally, which could lead to possible side effects, namely low platelet counts. They engineered a new drug that bound to BCL2 the way they wanted it to and that became ABT-199.

Venetoclax data that has been presented publicly has been from phase I trials. One phase I trial studied the effectiveness of Venetoclax as a single agent in patients with relapsed/refractory CLL. One dangerous side effect that occurred in some patients was tumor lysis syndrome (TLS).

TLS is what happens when cells die too quickly or too many die at one time. As they cells die or break open, they release their contents into the bloodstream. The table below describes the chemicals released from the cells and the consequences that can occur.

Chemical released from cell content	Consequences of high levels of this chemical
Potassium (K⁺)	Heart dysfunction Arrythmias (abnormal heart rhythm) Sudden cardiac death
Phosphate	Nerve dysfunction or nerve damage
Uric acid	Kidney failure

These side effects are not usually seen with treatment for chronic leukemias, but more often with acute lymphomas. As a result of these events, the trials for Venetoclax were paused and redesigned to avoid this risk, specifically:

Increase dosages slowly over several weeks
Provide close monitoring, often in the hospital
- Patients with large tumors, very high numbers of WBCs or with compromised kidney function would be hospitalized
- Monitoring the potassium levels and uric acid levels in the hospital would allow them to intervene right away

Another Phase I trials was begun for patients with relapsed/refractory CLL where Venetoclax was administered in combination with rituximab and the same adjustments to increasing the dosage was made. Since these changes were made, no other serious events of TLS occurred in that trial or any others.

Venetoclax or ABT-199 is still only available within a clinical trial setting. It is currently being studied in Phase 3 trials compared to current standard of care regimens:

Study arm:	Compared to:	CLL Patient Population	Study
Venetoclax + rituximab	Bendamustine + rituximab	Relapsed Refractory	NCT02005471
Venetoclax + obinutuzumab	Obinutuzumab + chlorambucil	Treatment-naïve	NCT02242942