How effective is venetoclax?

When during the course of treatment is venetoclax used? When is venetoclax used during the course of treatment? It's a great question. So as I said previously, venetoclax is being used in combination with other agents. And venetoclax is what we call targeted therapy. So it's not a chemotherapy. It doesn't have many side effects, which is great. Despite the fact that B-C-O2 is expressed in all normal cells, the normal cells somehow they do not depend on B-C-O2. So nothing happens to the kidneys, liver, heart, or any of these other vital organs if you use venetoclax. So they're safe. There is no killing of these normal tissues, which actually allows doing it in combinations. So the idea of using venetoclax is really to elicit maximal synergy with whatever drug X that you're using. So we use it for the most part in combination from day one when we combine it with chemotherapy or hypermethylating agents or, as I mentioned, some of the new approaches with targeted therapy, chemotherapy. So we're really trying to get a lower threshold for the survival of the cells while there's another agent on board. So that's kind of the idea that we are exploiting. So essentially, venetoclax always overlays some other treatment that we are using. With that said, one side effect that I'll perhaps discuss later is there is some toxicity against normal myeloid cells. So normal myeloid cells are cells that are called, for example, neutrophils, and they're important for protection of infection. And it's because they're also cells of the bone marrow, so they're very closely related to leukemia, and they have B-cell-2 and they are dependent on B-cell-2. So that's one of the more challenging side effects that we encounter, which means that patients who are taking venetoclax, they will develop low white count for quite longer time than if they were treated with chemotherapy only, let's say. So there is a tight balance there. And obviously, if they have low white count, they're susceptible to infections. And unfortunately, the infections is the main cause of death in our patients. So because of that, we have to titrate the duration of venetoclax to the shorter period of time, and again, kind of aiming at this synergy with another drug and then allowing bone marrow to recover. Now you may want to ask me if venetoclax is approved for continuous use, which is true. So like all other small molecule inhibitors, the initial trials that led to venetoclax approval were using venetoclax on a continuous basis. With that said, over the time, we learned that we are unable to do so because patients will just not recover their counts. They will get infections and side effects, and that's really not the goal of it. So right now, while we use venetoclax for, let's say, one month of treatment in the induction, which is the first cycle of treatment that the patients will be getting, after that, we are trying to limit venetoclax use to three weeks or two weeks, depending on sometimes there's different patients who can tolerate a different duration. So to allow the recovery of the normal bone marrow. But to answer the initial question, when you use venetoclax, it's always kind of from the beginning. So you always use it in combination with something else, and actually a little bit longer after the agent access completed. How is venetoclax administered? So venetoclax is an oral therapy. It's a pill. There are different strengths of pills. The approved dose is 400 milligrams. So the pills, the larger size of the pill is 100 milligrams. So the full dose, the patient would take 400 milligrams or four pills a day. So now with that said, venetoclax is a drug that is being metabolized in a way that is affected by other medications that the patients take. And our patients in particular, they take a lot of antibiotics and antifungal medications that can affect the levels of venetoclax. So there are very clear dose reductions of venetoclax if patients are taking some of these medications. So what I'm getting at is, for example, if the patient is getting antifungal medication, usually he or she will take lower dose of venetoclax and get to the same effect, which is in some ways would be good. So first of all, it saves costs of the medication. Second is fewer pill burden for the patient. Generally, because it doesn't cause a lot of nausea or diarrhea, it's a well-tolerated pill even when it's used at like 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 the stomach sensitivities or diarrhea. And of course, for those patients, having oral therapy perhaps is not ideal. But these I would have to say minority. So for those having the intravenous medication might be more effective and more controlled in some sense. But of course, oral medication allows you to take it as an outpatient. So you don't have to be in the hospital for that. And in fact, we do not use that strategy. But I know that in other centers of America, even the first chemotherapy for leukemia when they're using venetoclax can be done as an outpatient. Again, we feel that this is perhaps too courageous, and we still admit the patients for the first cycle of treatment just because they are old and they have side effects related to their leukemia and infections. But on the subsequent cycles, all the therapy is outpatient. And so, for example, if they get isocytidine or dicytidine, they have to come for that IV portion of it. So every month for five to seven days a month, they have to come every day to get IV portion. But venetoclax is a pill they take at home. So right now, we have a lot of clinical trials where we're using oral chemotherapy agents as well. And these are not yet approved in combination with venetoclax. But eventually, once we show that they work similarly, for example, this oral dicytidine that we're testing oral isocytidine, if we show a similar efficacy, then it will be like totally oral therapy, which is amazing thing for the patient with acute leukemia. Because in the past, all we had is high dose chemotherapy with high side effect profile, lots of transfusions, a lot of complications. The patients had to be in the hospital. So that really changes. It's in a way what they call paradigm shift for all the patients because of the quality of life. And they don't have to be in the hospital that much. And that eventually becomes really important for many of those people to be able to take chemotherapy at home. And for example, in my clinic, I have a lot of patients who are in remission and they continue on this regimen. So they don't even come to me. So we have now, fortunately, the telemedicine option. So I'm calling them once a month. We're checking their counts. Obviously, they have local oncologists. And depending on how they tolerate, how they do, we tell them, oh, you're good to go. So you start on Monday, next cycle. So I have, for example, one patient I call here this week. And she didn't have to do any blood counts for the whole month. So she does blood work once a month. Usually, it's good. She starts her little chemotherapy for five days, right? And then she's done for the rest of the month. So of course, it's not always like that easy, right? But there are quite a few patients that are able to just get the therapy for a few days and then kind of be free of that. So I think it's really important. And in that sense, of course, having an oral agent is really beneficial. Now one population where it's a little bit more challenging are pediatric patients. Now Venetoclax is not yet approved for children. But they do have a liquid formulation for the kids. And that's something that is being tested because we really want this agent to be available for the children with leukemia as well. So what are the combinations that are being used with Venetoclax? Some of them I already mentioned. The ones that are FDA approved are combinations with hypermethylene agents and with low-dose siteribine. So these are the only ones that are approved. But there are many other combinations that are ongoing. With high-dose chemotherapy in younger patients, the studies are actively ongoing. And we hope it will get approved. But there are a lot of different things that are being still in the stage of clinical trial or early clinical trials. For example, one of them that is being pretty far advanced is a combination with the targeted therapy. There's a subset leukemia of AML that have a particular mutation called FLT3 mutation. It's pretty common. It's about 30% of patients have that, especially in younger patients, in fact. And this is what we call poor-risk mutation. So these patients usually respond to chemotherapy. And then they have to go for transplant. But even then, they relapse. So what we found is that if you use venetoclux in combination with the inhibitors of this particular mutation, there are now two approved, FDA approved. One is called Midostorin. Another one is called Giltritinib. They are FDA approved for a combination with chemotherapy. But if you add venetoclux to that, that can lead to the responses in patients who, for example, relapse after a standard of chemotherapy. Even if they had this drug before, if you add venetoclux, you can get them into remission. So this is pretty amazing. And now we have many clinical trials looking at these patients who are relapsing with the standard of care. But also, we moved it into the frontline therapy. So because we found that addition of venetoclux will increase the depth of response in combinations with, again, with this flix-3 inhibitors and also perhaps increase the cure rate. But again, we don't have that data. That's kind of what we're aiming at to increase the cure rate. So this is one example of combination that is pretty kind of far advanced. But there are other ones that I mentioned with immune therapy, for example, that are currently ongoing that look very promising as well. How effective is venetoclux? Does it tend to work best in a certain subset of patients? Yes. So I already mentioned that venetoclux is working best in certain subset of patients. For example, patients which have MP1 or IDH mutations. And it does not work well in some other subset of patients. So it does not work well for patients who have p53 mutations. And these are usually patients who have what we call therapy-related leukemias after they had some other malignancy. And this is the most difficult subset of patients that we cannot cure. What research is being done with venetoclux to make this therapy more effective? So there are many, many different ways that are being looked at. So one of them is using the inhibitors of other B-sute 2 family members. For example, mCil-1 is another one that is highly expressed in encephalitis leukemia. So if you take in the lab B-sute 2 inhibitor and mCil-1 inhibitor, they are highly synergistic in almost all types of EMR, including p53 mutated EMR, which is we cannot cure with venetoclux. So the clinical trials are ongoing with mCil-1 inhibitors. Unfortunately, they ran out into some side effect issues. So they have been taking longer time than we expected. So that's one highly promising but challenging to deliver therapy. The second one that I like a lot is combination with immune therapy. So for example, immune therapy is not yet approved in acute malo- leukemia. So it's somewhat experimental. We have developed, for example, a couple approaches like that. One is core targeting of something on the cell surface called CD123. So it's a protein that is highly expressed on the AML cells. It's very specific. Well, it's expressed to some extent in normal cells, too. But there's an antibody that can affect that, that binds to the cell surface, gets internalized, and kills the cells. So we show that the combination with venetoclux is highly effective when you do this combination. And the other antibody also is against a protein called CD47. So that's a very interesting story. So that was discovered by Stanford researchers. So CD47 is called don't eat me signal. So essentially, when tumor cells, not just leukemia, but tumor cells express the CD47 cell surface, they prevent macrophages from eating them up. So even if they're being hit with something, the macrophages are unable to engulf them. And that kind of makes the cells survive better. So they developed the antibody called N-D-C-D-47 antibody. It has a commercial name, which was taken by the company. And it did not work as a single agent, again, but in combination with Azacitidin, it works very well. So what we show that if we take venetoclux, then cells actually, in addition to blocking this 47, they express more like eat me signal. So they have like some eat me signal, and then you block don't eat me signal. So now the macrophages can come in and eat up these leukemic cells. And this is very cool because in some sense, the macrophages digest all the debris of leukemia cells, so you expect lower side effects. And both of these approaches are very safe. So that's something that is in clinical trials right now, and we are kind of highly excited about that. And then the last one that I already mentioned is combination with other targeted therapies, for example, the Flixri inhibitors that we discussed before, but also other, for example, in CML combinations with the tyrosine kinase inhibitors. But again, they are more used for the patients who have accelerated disease, more like AML type of disease. So these are the major combinations I can think of that are being currently exploited, but there are many, many, many more that are highly perhaps promising that I don't have time to do.