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All about venetoclax and chronic lymphocytic leukemia.

What is venetoclax?

Venetoclax is a small molecule inhibitor of a protein called BCL-2, the protein is really important for the survival of tumor cells. It's also expressed in normal cells, but the tumor cells depend on it for a number of reasons. The levels of BCL-2 are high in many hematologic malignancies. So what venetoclax does is it specifically binds to BCL-2 proteins through a specific protein interaction, and it prevents essentially the collaboration between BCL-2 and prodeath proteins.

So what happens is that BCL-2 is being neutralized, and therefore the prodeath proteins that are naturally occurring in the cell are free to go ahead and kill the tumor cells because the leukemias are highly dependent on BCL-2. This approach is really effective in leukemia and does not kill as many normal cells as some of the other treatments. For example, chemotherapy does because it's not specific to the tumor cells like chemotherapy is to the normal cells. That's how it works. It's also called universal sensitization.

So by lowering the threshold of cell death, it essentially increases the sensitivity or responsiveness to many, many different types of therapy. This includes regular chemotherapy, targeted therapy, and immunotherapies.

So right now, venetoclax is used in multiple combinations. If you look at the clinical trial websites, probably more than 15 clinical trials are ongoing with different combinations of venetoclax in different hematologic diseases. So I think that's added value. By itself, venetoclax may not be as effective because the tumor cells are very smart and they get around a single agent. But if you combine it with some other therapies, then it becomes a killer and gets rid of leukemia.

How is venetoclax administered?

Venetoclax is an oral therapy. It's a pill. There are different strengths of pills, and the approved dose is 400 milligrams. The pills are large, and the full dose a patient would take is 400 milligrams, or four pills a day.

What are the side effects of venetoclax?

Who's eligible for treatment with venetoclax?

It doesn't cause a lot of nausea or diarrhea. It's a well-tolerated pill even when used at the 400-milligram dose. So very few patients have any particular gastrointestinal side effects. But there are some patients who may have issues with their GI tract, with stomach sensitivities or diarrhea. For those patients, having oral therapy might not be ideal.

So what are the common side effects of venetoclax? One is something called tumor lysis syndrome. Venetoclax has been approved for CLL for a while. AML and CLL cells are highly dependent on BCL-2. So when you hit them with a little bit of venetoclax, they're going to die. What happened in these patients, because they have a large tumor mass, usually with lymph nodes and a high white count, that's the typical presentation. When they took venetoclax in the initial studies, there was tumor lysis, so much tumor killing happening in a very short time. The drug works very quickly. So within hours, there was this complication called tumor lysis syndrome.

What happens is that when the cells burst open, they release a lot of substances, one of which is potassium. When potassium levels are high, that can impair cardiac function and cause arrhythmias. This can be lethal. This became a black-box warning for venetoclax. In the initial studies, CLL trials were held for some time until we figured out how to give it safely.

One of the biggest concerns, given that the drug is so effective, is that there is a problem in CLL called tumor lysis syndrome. When there's just a meltdown of the disease, because it's so responsive to the agent, it overwhelms and shuts down the kidneys. To use venetoclax, we have to be very careful and cognizant of that. We assess the risk based on the burden of the disease, white cell count, and the size of the lymph nodes. Based on this risk, we may need to be more careful in how we administer it. Some patients even have to be admitted to safely start venetoclax.

But one of the most interesting points is that one might think an older patient with not ideal kidney function wouldn't be eligible for treatment. In reality, the study that evaluated venetoclax-obinutuzumab was done in a group of patients who had comorbidities, had other medical problems, and didn’t have perfect kidney function, and it was absolutely doable.

The reality is that most patients should be considered for venetoclax, including older patients and those with less-than-ideal kidney function because it can be safely used in these settings. So there's almost no patient who cannot take pills, except for those who are unable to be admitted to safely start venetoclax. Even in these cases, there are ways to work around it. The comfort level of the prescribing doctor, understanding how to deal with these initial problems, and access to the clinic are important factors.

How can side effects be managed?

The two main side effects are tumor lysis syndrome. If potassium is high, we have special medications to bring it down. We have to repeat labs a few hours later. It's not just potassium; sometimes uric acid levels are elevated. This is something we see in general with leukemia, and we use prophylactic agents to reduce uric acid regardless of therapy.

Patients usually have to drink a lot of fluids to help wash out the debris. This is part of our management of tumor lysis. Phosphorous levels are another concern that is managed. For suppression, we may need to interrupt the duration of venetoclax treatment. But these are the main side effects.

We do not see any side effects related to kidney, liver, or cardiac function. Essentially, the only clinical significance of a side effect is the risk of infection due to low counts that develop with prolonged therapy. 

And then we also use growth factors sometimes.

So when their counts are low and they do not recover in time, we do use generally the growth factors to help the recovery if patients are in remission.

So that's another approach to manage the mild suppression.

There is a growth factor called granulocyte-colony stimulating factor. It's called G-CSF and has many different names depending on the company, but it is essentially an injection under the skin and you can give one or two or three injections like every day. And that facilitates the white cell count recovery. It's used routinely, for example, in patients who are undergoing stem cell transplantation to facilitate engraftment of the stem cells. So it's approved for the chemotherapy-induced low counts of white cells.

If you relapse after a BTK inhibitor, can you take venetoclax or vice versa?

So the question was, if I started with a BTK inhibitor, can I take venetoclax after or if I start over venetoclax, can I take a BTK inhibitor? And your answer is yes. And this is usually what is done today. We have data. It's not phenomenal data, because what happens in the studies that we used today were studies that were done in the time that patients that were starting BTK inhibitors in those studies had not seen venetoclax before or the other way around, patients that were treated with or venetoclax on the studies had barely seen BTK inhibitors. So we don't have a lot of solid, large data, but we have reports, some retrospective data. So looking back on patients that were treated with venetoclax who had been treated with BTK inhibitors before or the other way around. So we know that it works.

When we're starting with BTK inhibitors and we know that it won't be taking them for a long time. There are two ways that they can fail, that we can have problems. One is that you are on a BTK inhibitor and all of a sudden you start having toxicities that make you stop. So we know that in those circumstances now we have more than one BTK inhibitor and we can, in the majority of times try the other one and have the same disease control potentially with less toxicity, mainly if you're comparing a first-generation BTK inhibitor ibrutinib versus the second-generation BTK inhibitors, like acalabrutinib and zanubrutinib.

Now, if you progress in one of these agents and they are all the same class, they're called covalent BTK inhibitors, if one stops working, it's unlikely the other one would work. So then in this case, the next step generally is venetoclax. And venetoclax shows clear activity in these patients that are progressing on BTK inhibitors.

The opposite is true. Patients that are started on venetoclax and get the 12 months have great disease control, they will stop treatment because that's what we do, and now we're starting to see because the responses are so good and so long, start to see patients that have the disease show up again, have indication for therapy, and we have data that re-exposure to venetoclax works again. So we have that option of kind of the stop and go idea: you’re given venetoclax, okay, let’s stop. Disease is controlled. You're off therapy for a while, eventually have indication for therapy. You start again.

So on the study that evaluated venetoclax would have been obinutuzumab. We saw that those deep responses on average around 18 months later was SA to see detectable disease from that. MRD Negative status from the minimal residual disease that they could not even detect to the point of that can be detected. But then another 18 months to a point where it probably didn’t need therapy. So it’s quite a while, and re-exposure to venetoclax shows activity.

But if for whatever reason you want to switch to a BTK inhibitor, yes, there’s also data of BTK inhibitors working after venetoclax. Things are getting a lot more complicated, but it’s better now that we have a different class of BTK inhibitors that are arising called non-covalent BTK inhibitors.

So those that class of agents work even when the other class, the covalent BTK inhibitors, don’t work. So we have now the option of pretty much three classes. They can probably be alternated. In the first line, we have the BTK inhibitors: ibrutinib, acalabrutinib, zanubrutinib or venetoclax-based therapies. And then in the relapsed setting, you can flip around with those two or very soon start having the option of the non-covalent BTK inhibitor compared to ibrutinib.

A good amount of patients have absolutely no detectable disease, minimal residual disease. So when you evaluate that group of patients to the point that it had absolutely no detectable disease to some detection, on average, was around 18 months. But it doesn’t mean that in therapy, then it means that it was detectable. It goes back to when it was when you were initially diagnosed. You may have had detectable disease, but you just watch, you kind of reset the clock. Exactly the same idea. You go from an undetectable state, to the point that you eventually detectable but does not mean you need therapy at that point yet. You again go to the beginning where you need to have indication for treatment before you get treated.

When is venetoclax reintroduced? Is it given for another 12 months?

We don’t have that much clear data on what we do. Then we can reintroduce venetoclax by itself because then you’re talking about the relapsed setting. We have data on the relapse setting. Venetoclax was combined with rituximab in a study called Murano. And now we know that obinutuzumab is better than rituximab. So potentially you could do the same thing again. Obinutuzumab venetoclax one more time.

The role of this repetition is not really that clear, but probably depending on the time it took, how long it was, how well these were tolerated, we can certainly revisit the idea of re-exposing the patient to the same combination if it was very well-tolerated, gave a very long disease control. We can just try to be exposed again.