Breaking News: Expert Perspective on Venclexta (venetoclax) Approval

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The U.S. Food and Drug Administration (FDA) has approved a new drug Venclexta (venetoclax) for use in CLL patients with the 17p deletion. Andrew Schorr interviewed CLL expert Dr. Thomas Kipps to get his perspective on what this new approval means for patients.  

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Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That’s how you’ll get care that’s most appropriate for you.

Andrew Schorr:

Hello and welcome to Patient Power.  I'm Andrew Schorr.  With us is one of our regular guests, a leading CLL expert, Dr. Thomas Kipps from UC San Diego Moores Cancer Center.  Dr. Kipps, thank you for joining us.  We've just had yet another drug approved for CLL.  Tell us what it means for patients.  

Dr. Kipps:

Well, thank you, Andrew.  It's a pleasure to see you again and to join your program.  I think it's a great program. 

We're very excited.  Yes, venetoclax (Venclexta) was just approved for treatment of patients with chronic lymphocytic leukemia that have the 17p deletion.  This is approved for patients who have had prior therapy and have relapsed after therapy.  So it's a somewhat narrower indication, but we think it's actually a first step towards perhaps a larger indication for use of this drug. 

We've been fortunate to be involved in work on this drug since the very beginning, and we're involved in the first clinical trials with venetoclax here in this country, actually an international effort with Australia involved.  And the drug at first impressed me as being a very potent one.  It attacks a very fundamental mechanism that contributes to the leukemia's survival. And this is why we're very excited about it, because it's somewhat of a designer drug that goes specifically after a protein, which protects the leukemia cell from dying and protects the leukemia cell from dying even with chemotherapy. 

What the drug does is it circumvents this protein and makes the cell susceptible to just undergoing cell death spontaneously, and this can sometimes result in very dramatic reductions in the leukemia cell counts as well as reductions in the leukemia tumors that we see in the lymph nodes. 

Now, very early on when we were using this drug, we were impressed by the fact that even though it's a pill that patients can take it had a lot of very potent activities, and some of the first few patients that we had in our early Phase I clinical trial were patients treated in Australia who had very large tumor burdens. And the investigators there were concerned, because they had indication that the tumor responded so quickly to treatment that you saw increases in electrolytes that indicated what we were having was a tumor lysis syndrome.  Namely, it's great when we say tumor lysis to get rid of the tumor, but sometimes too much of a good thing can be a bad thing. 

And when the tumor cells are destroying themselves so quickly, they release the internal contents of the leukemia cell into the bloodstream. And that results in electrolyte imbalances, some of which can have some very deleterious consequences.  The most notable, of course, is that when you have an increase in, say, an electrolyte called potassium, that can interfere with conductivity of the heart, and we know that that's very important.  We want our heart to continue beating. 

And so we actually scaled back the dosage that we started out with.  We started out with a dose that we thought was going to be the right one, and we had to come way down and start with lower doses and only gradually escalate to higher doses.  And we were actually very impressed with the activity of this drug.  It was a drug that was developed after another drug that we had also been testing in the clinic called navitoclax, and unlike navitoclax this drug seemed to be specific for the leukemia. 

The earlier drugs seemed to also affect the platelet count in a way that was difficult to handle, because the platelet counts would go down, so we had a problem with going up with the dosage of the drug.  Now, with venetoclax we did not have that problem, but we still were concerned about this problem of tumor lysis.  It was unfortunate, this trial opened up in more sites across the United States and abroad.  There were two patients almost within one week of one another, happened during the ASH meeting, unfortunately, one patient on the East Coast, one patient in the Northwest that were treated with this drug, and these patients had very large tumors.  One patient had a tumor the size of large grapefruits and maybe a small basketball, if you will. 

And the tumor melted away so quickly, and it was not fully appreciated how dramatic this response was, and these patients succumbed to tumor lysis.  Namely, the potassium level got so high that the heart lost the ability to contract, and that's not something that's compatible with living.  This is something I tell patients, that the tumor lysis syndrome really has two symptoms until your heart stops. And that's a hard thing, so we have to be extremely careful with this drug. 

And we then adopted strategies to dose down, way down, and actually do something very extreme, namely, to take patients and bring them into the hospital and to watch over them like a hawk.  We watched over their electrolytes.  We watched over their cell counts and other factors. And if they had any indication of having this tumor lysism we jumped on it immediately, and we treated it medically.  I'm happy to say that we haven't lost any patients since on this drug, we've not lost any patients here at UC San Diego. And we've not had to even resort to such measures as what's called hemodialysis, which is the measure that you can use.  If the electrolytes go up and up and you can't keep it down with medicines, then you can have dialysis to lower the concentration of the electrolytes. 

I think it's been very well tolerated, and in fact most patients when they take the pill they don't experience any symptoms whatsoever, and they feel fine.  I have had some patients refuse to get out of their street clothes when they're in the hospital.  They say, well, I'm not sick, and that's the way it usually has been.  But still, the caution has been important. 

Now, we have been able to recognize, of course, that the more tumors you have the greater the risk of tumor lysis syndrome, and so what we've done is to stratify patients into risk categories.  Those patients that have high tumor burden are stratified into receiving the drug in a very close setting in the hospital, and those patients with low tumor burden who do not have the risk for tumor lysis can be then started to be treated as an outpatient. 

And as we learn more about when this tumor lysis occurs and how to avoid it and what measures to take when we start seeing the earliest indications of it, it's become easier to administer this drug as an outpatient.  And we're very excited that this drug is finally approved. 

You can imagine when we had patients on this protocol that I mentioned to you that died, no one wants to see this, but it was the dramatic effects that we had with this drug that really made the FDA say that, hey, wait a minute, there's some very important activity with this drug, and we should pursue further studies.  And I think if we can manage this drug safely, it is extremely powerful. 

It's powerful in patients who really are refractory to chemotherapy in the conventional sense, because what it does is it bypasses what the chemotherapy does.  The chemotherapy oftentimes works through a protein which we call p53.  This protein is lost in many patients who have the deletion 17p, and what this means is that the p53 is absent or dysfunctional, and it cannot induce the proteins inside the cell that act like this drug.  So this drug kind of bypasses the need for p53 and allows for the tumor to actually undergo this cell death process in a way that chemotherapy can only hope for and can't do when p53 is lacking. 

And for that reason, its indication now has been approved for patients who have the deletion in 17p.  Those patients I would not give conventional chemotherapy to because the cells, the leukemia cells, are resistant to the drug, and the chemotherapy can affect other cells in the body such as the bone marrow. 

I think this drug is important from the standpoint it has activity, but it's also been the only drug that I've seen that of all the new drugs that we've had come out to consistently give a fairly high yield, what we call complete responses, without any evidence of minimal residual disease.  And we can check for that in the bone marrow.  When we treat patients, we then see if they're responding.  If their counts normalize and their lymph nodes disappear, then we can look at the bone marrow and see if there are any residual cells there. 

And we have some very sensitive tools to do this with sensitive flow cytometry, which can detect one in 10,000 cells, and then we're now using genetic techniques that can detect one cell in a million.  And we've noticed that some of our patients actually became cleared of their leukemia cells so that we couldn't even detect the leukemia by these sensitive methods. 

Now, it's interesting that one patient I remember had no evidence of leukemia in the bone marrow but still had some lymph nodes on the CT scans that we could recognize. And we thought this patient had a complete response, so we actually biopsied these lymph nodes and found only scar tissue.  So this patient really has no evidence of detectable leukemia, and I think this is very encouraging because if we're going to cure this disease, it would seem that we have to eradicate the leukemia entirely. 

About a quarter of patients who take the drug may achieve this degree of clinical response.  We're seeing higher response rates in patients who are receiving this drug in combination with antibodies such as rituximab (Rituxan) or obinutuzumab (Gazyva).  I think that's very encouraging—still not a hundred percent, but still it's a step in the right direction. 

So I think that venetoclax, even though it's approved for this narrow indication might see a wider use for patients without 17p in the future, and clinical studies are undergoing right now to try and test that and to demonstrate the clinical utility of this drug for other types of patients as well. 

Andrew Schorr:

Thank you for stressing the safety.  I know that's so important.  Patients hear there's a new addition, and they say, is it for me?  So right now, under the approval, how do patients determine with their doctor whether this is the right drug for them? 

 

Dr. Kipps:

Okay.  The approval indication is pretty narrow.  Namely, patients must have received some form of prior therapy.  So if you've not received prior therapy for the leukemia, then it's really not an indication for you.  Now, if you've received prior therapy and have relapsed from therapy, then what you can do is to essentially have the FISH analysis, which you should have in any case.  With the FISH analysis, you can tell whether the leukemia cells have this deletion in the short arm of chromosome 17.  That's the deletion 17p.  So if you've relapsed after prior therapy and have the FISH analysis that shows you to have 17p deletion, then you are eligible to take this drug by the new FDA indication. 

Andrew Schorr:

Okay.  We want to thank you for your time, Dr. Kipps.  I know you need to get back to clinic, but this is news for patients, and we'll be following it carefully.  And, of course, what you said about monitoring with a very powerful new addition, this is critical, and having it be right for the patients with the 17p deletion who have had prior therapy. 

Dr. Tom Kipps from UC San Diego, thank you for being with us and telling us about a new addition to the CLL armamentarium. 

I'm Andrew Schorr.  Remember, knowledge can be the best medicine of all. 

Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That’s how you’ll get care that’s most appropriate for you.

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Page last updated on April 25, 2016