CLL Clinical Care: Impact of Science

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Transcript:

Dr. Varsha Gandhi: Thanks a lot for giving me this opportunity. It’s really absolutely fantastic to be here. We have, my lab has benefitted from CLL Global for many years, and this is really the first time that I can express the gratitude. And I will show you the example of, just one small example, but we have done many studies like that so that we can work in partnership with the clinical colleagues to move novel therapeutics or combinations to the clinic, and that’s the one example I will talk about today.

And that example is developing a combination strategy, and in this case, with the ibrutinib (Imbruvica), what you heard from Dr. Jain. And actually, to some extent, from Dr. Sampath’s talks. What is ibrutinib? As Dr. Jain mentioned that this was the first targeted therapeutic for patients with CLL. Prior to that, everything was chemotherapy, chemo-immunotherapy, or toxic regimens. But now, first time, we had a drug that just targeted CLL cells. And the reason it targeted just CLL cells is because it was targeting one enzyme which is present in CLL cells or other B cells.  And that enzyme is Bruton’s tyrosine kinase, or BTK. And you heard BTK inhibitor, BTK inhibitor. That’s where the term comes from. This is first time again oral agent, and it was very effective drug as a monotherapy.

It is also a drug that had very limited side effects, although there were side effects, but limited compared to prior toxic regimens. Our patient had to take this drug forever. It was almost like having insulin that you can control your diabetes, but you have to take it forever. It was like that. That’s when we started to think about that, what can we do? There were complete remissions, a desired outcome with the therapy. But it was very limited, and if patient took just ibrutinib, then there were no achievements of undetectable, measurable, residual disease. Or UMRD, which is another desired outcome for patients as well as physicians.

So, we thought, let’s do combination strategies. The best way we can do the combination strategy is when the single drug is given, take those patient cells and then incubate with the other drugs, which is the slide is going to show you. So, ibritinib, patient is taking three tablets or three capsules per day forever. We take blood samples, and I want to at this point pause and say thank you to all the patients who agree for giving the blood so that we can do this type of studies. We take blood sample from patient. We isolate flood blood mononuclear cells on anything in the blood. Now, majority of the cells are CLL cells; some patients even have 200,000 cells per microliter of blood. It’s really a high number. So, majority of the cells are CLL cells. We put them in the incubator in a flask, and then we treat these cells with different and new drugs.

Our question here is, which drug is going to be the best when we combine? And that data is shown in here on the excesses or abcessi, you can see there are many names written. These are all drugs that were at that time being used for CLL patients in the clinic, or they were approved agents. Navitoclax (ABT-263), more ibrutinib, bendamustine (Treanda), and duvelisib (Copiktra), those are the drugs. What we are measuring that when we after ibrutinib, patient got the ibrutinib, we are getting those cells after ibrutinib. If we add these drugs, which one is going to kill more cells? And that is where we learn that the two pink bars, those are two different concentrations of venetoclax (Venclexta), that of all the drugs we tested, those were the ones that eradicated most of the CLL cells in the flask, which were previously treated in the clinic with ibrutinib alone. So, this gave us a rationale that let’s combine ibrutinib with venetoclax, and you saw some of the clinical results that Dr. Jain presented during his presentation.

So, what is venetoclax? I introduce you to ibrutinib, now, venetoclax, which is one clax drug you may have heard. This is another oral, and it is FDA-approved, but its target is different. The previous one was BTK; this is BCL-2 that Dr. Sampath also mentioned. BCL-2 is a type of protein that allows CLL cells in the body to remain literally forever unless we target that BCL-2; the cells will remain there. So, it is not a disease which is highly proliferative in the body. You have the CLL cells remaining there because there are these survival proteins that maintain those CLL cells circulating in the body.

It is, as I mentioned, is also oral, very effective drug. Again, been used as a single agent, there are limited complete remissions and very limited undetectable, measurable residual disease. So, with those two, we decided to start combining and start with the investigative initiated trial. This is the schema of the trial, first three months, patient gets just ibrutinib, and there is a rationale for that. Ibrutinib hits the cells in the lymph nodes where the CLL is. So, cells from lymph nodes, egress out in the peripheral blood, that’s when we combine the two agents, venetoclax, and ibrutinib. And we are giving them for 24 months or 24 cycle. Each cycle is about a month, 28 days. So, instead of patient taking forever ibrutinib, now, they will have only 27 months or 27 cycles of therapy.

So, this is the fixed duration rather than forever duration of treatment. What happens in this? What we wanted to know that if we are combining these two drugs, do we have better complete remissions? And if you focus on the blue bar, so we start very first bar, which is the lighter blue bar, that is just ibrutinib for three months. And then, every three months, we are taking and measuring what is the complete remission rate. As soon as we combine the drug, you can start seeing complete remissions, and by the time patient reach this 18 cycles, here, the very last bar, you can see that 96 percent of the cells, or 96 percent of the patients, had complete remission.

Not only that, but as Dr. Jain mentioned, these patient, two-third of patient had undetectable, measurable, residual disease. If we can maintain UMRD for five years, to some extent, you can say CLL was cured for that patient. So that’s how important UMRD is. What happens when we look at the three-year survival rate for these patients? Progression-free survival? Ninety-three percent. That means they didn’t have CLL coming back again, no progression. Overall, survival 96 percent. In a simple term, if I want to explain everything that I just said, this is the slide.

In CLL, I mentioned there are two targets. One is BTK other is BCL-2, that are responsible for majority of the CLL cells in the body to proliferate in the body to progress from lymph node to peripheral blood to bone marrow and so on. And also, these cells survive because of BCL-2. If we use Ibrutinib, we are targeting only one target, which is BTK. Complete remission rate? Two percent. If we use venetoclax, we are targeting BCL-2; the complete remission rate is 20 percent. And this is the wow moment. When we target both BTK, BCL-2 with Ibrutinib, venetoclax in the sequence in the way we wanted, complete remission rate that I showed you in the previous slide, 96 percent. This is the best type of synergistic drug combination you can ever see.

Now, you can ask me, why when we combine both these drugs that why there isn’t 2 percent and 20 percent that is 22 percent complete remission, which would be expected, right? That you add two drugs and you should get that combination of those two drugs. But we got 96 percent and that’s because there is the CLL biology, which is shown in this slide. CLL resides in three compartments: lymph node, peripheral blood, and bone marrow. When we give ibrutinib, cells from the lymph nodes, they come out, egress into blood, now they are more vulnerable to venetoclax. Venetoclax targets both blood and bone marrow, so those cells are going to be killed by venetoclax. Also, venetoclax hits another survival protein that I didn’t talk about, which is MCL-1, and those levels go down.

So, it is a combination of CLL biology, CLL physiology, survival proteins targeting BTK and BCL-2 that resulted into what we saw in the clinic with 96 percent remission, complete remission rate. So, that is the type of research we like to do; we want to do so that we can move it to the clinic and help the patients with these types of combinations. Here is the final slide, and once again, I want to thank patients who are always willing to provide the samples which is very, very critical for us and then CLL Global, especially as Steve mentioned in his introduction, that under the current circumstances when we are really struggling to get any other type of grant, this is really our bread and butter to do our research. Thank you very much.