BETA - What is a BCL-2 inhibitor and how is this drug class used to treat chronic lymphocytic leukemia?

What is a BCL2 inhibitor, and how is this drug class used to treat chronic lymphocytic leukemia? So, a BCL2 inhibitor is a type of medication that is used in the treatment of CLL, which blocks the BCL2. Now BCL2, one of the things that is aberrant in the CLL cells is the apoptotic pathway. Apoptotic pathway is also known as the programmed cell death, or what we say in layman's terms, cell suicide. This is a mechanism in our body, in various tissues, where we maintain the number of cells that we have in the body. Now with this pathway being aberrant in CLL cells, the balance is tipped towards survival. So these cells basically forget how to die. What the inhibitor, venetoclax, does it, it binds to BCL2, which is an anti-apoptotic molecule. It binds to it and tips the cell towards apoptosis, towards programmed cell death. So this way there's an accelerated cell death. This is how it's used. So venetoclax is used usually in combination with an anti-CD20 monoclonal antibody. It has been used in clinical trials both with abinutuzumab as well as with rituximab. With abinutuzumab we use it in the front line setting. And what happens with using it with an anti-CD20 monoclonal antibody is that the treatment becomes fixed duration. So with venetoclax plus abinutuzumab, it's a one year of treatment where abinutuzumab is taken for six months, venetoclax is billed for one year, and the patients are done with it. Compared to Btk inhibitors, which as single agents are used as indefinite treatment. Yes, BCL2 inhibitors, primarily venetoclax, again was a remarkable advance a few years ago for CLL patients. It again is a very targeted drug. It basically targets the energy generation for the cancer cells. So when you don't have energy being produced, the cells die. And now over time, the cancer cell figures out ways to bypass that system and become resistant. So we again are getting smarter about it. We are developing newer drugs which can potentially work even if the cancer cells become resistant to the first generation BCL2 inhibitors. The other issue we had initially with the BCL2 inhibitor was that it was so effective that it would turn off all of the cancer cells all at the same time. Now what we have to remember is when the cancer cells or any cells in the body break, we are all healing every day, we are all making new cells. So bodies going through the cycle of life every day, millions of cells, billions of cells are probably being born every day and die every day. All of the junk that is being produced is removed from the body on a daily basis, your sweat, your urine, your feces, and so on. So what happened with the BCL2 inhibitors was it was shutting off all the cancer cells all at once. So now you have a surge of toxins that get built up in the body and can damage the body's organs because the kidneys won't be able to handle it and the kidneys can't flush it fast enough because you can't beep that much. So that's why there were some side effects early on. So we figured out how to handle it. You slowly increase the dose and then people were fine. So it was all a learning process for all of us, just like with any new drug. We figured out how to dose it properly, how to make sure patients take it safely, drink plenty of water and so on, and develop different strategies to make sure that the junk that is being produced by the cancer cells dying pretty quickly is managed appropriately. And we have patients who are older with marginal kidneys. The kidneys are not healthy or not perfect and they do fine too. So it's all a matter of learning how to manage the complications. So the next generation of drugs are potentially even more effective, safer, with less side effects and also work when you have a resistance to the first generation of drug. And that's how the field keeps advancing. The other beauty of the BCL2 inhibitor is that it is able to put the cancer in a very nice deep remission, which means that very few of the cancer cells are left behind. What that allowed us to do is to stop treatment. And when you stop treatment after, let's say, 12 months or 24 months, then you can live a normal life potentially without having to take any treatment for your disease and move on with life for a few years. Now, unfortunately, we haven't been able to eliminate the disease completely. So at some point in time, the cancer does slowly come back and then you have to treat again. But that five, six, seven years of remission is a nice time for patients to not have to worry about the disease, not have to be concerned about the problems that they might have with the disease coming back, and then live a life normally without having to take a pill.