Living with CLL as a Chronic Disease



Kristie L. Kahl: Should patients be getting retested if or when their disease recurs?

Dr. Susan O’Brien: There are some tests that we should be repeating anytime we're considering a new treatment, that includes the FISH test which looks at chromosomal abnormalities inside the CLL cell as well as an important protein abnormality called the p53 mutation. A p53 mutation is a gene that can be mutated and the reason it's super important to know about these chromosomes and the p53 status is that those patients should never receive chemo or chemo-immunotherapy because they don't respond very well to it. But even with the small molecule therapies that we have nowadays, patients with those abnormalities can do better on one drug than another. So in other words, it's important to know that because it may affect the physician's choice of treatment.

Kristie L. Kahl: Outside of testing, are there other factors that should be considered when it comes to determining the next line of treatment?

Dr. Susan O’Brien: When you have treatment options, which we do nowadays, you want to look at the side effect profile. If you have a patient who has a history of atrial fibrillation or an irregular heart rate…maybe in that patient you want to go towards one of the other drugs. (Venclexta [venetoclax]) can cause tumor lysis so someone with a high-volume disease maybe you would be a little bit more cautious about using that. So you want to look at the side effect profile.

The other thing that's important is that for some of these small molecules, the length of time that the patient is on the drug is different. So what do I mean by that? With (Imbruvica [ibrutinib]) or (Calquence [acalabrutinib]), the drug is given indefinitely. So once the patient starts on it they just continue on it unless they have a side effect which makes them stop or unless x number of years later the disease starts to come back and is then resistant to the drug. With venetoclax-based therapy, the regimen that's approved for relapse is venetoclax with the antibody (Rituxan [rituximab]) and that's a time limited therapy. So the rituximab is given for the first six months only and then the venetoclax is given daily for two years. So that treatment actually stops at two years and that may or may not be important to the patient if they have a time-limited therapy and that may or may not be important to the patient in terms of whether continuous therapy is a problem or time limit is more attractive.

We all know that in the states with oral agents there are copays and so in some senses having a limited time duration might be attractive. On the other hand, there are some patients who say well wait a minute if I'm responding to the drug you're going to stop it anyway and they don't like that idea so they actually would prefer to have an indefinite therapy as long as they're tolerating it and it's working.

So, I think you have to look at the side effect profiles of the drugs, that they're different durations of time and then what the patient preferences might be or what's most important to them.

Kristie L. Kahl: Is there any current standard of care?

Dr. Susan O’Brien: All of the drugs approved for frontline therapy are also approved in the relapsed setting. That could also be how you factor in what you're going to use in relapse. So obviously if I gave a ibrutinib a patient up front and maybe five years later the disease is starting to come back, well clearly it's resistant to ibrutinib so I'm going to move on to something else. All of the drugs that we have in the frontline we have in relapse now.

We do have some drugs in relapse that are not approved for frontline and those are PI3K inhibitors and there's two of those drugs. (Zydelig [idelalisib) is one which is given in combination with the antibody rituximab and then (Copiktra [duvelisib]) is the other which is given as a single agent. Both of those can be options for relapsed disease but are not options for frontline therapy.

Kristie L. Kahl: What are some exciting trials going on in the relapsed/refractory setting?

Dr. Susan O’Brien: There are a lot of trials looking at new agents in the relapsed/refractory setting because the presumption is that the patients going on those kind of trials may be going on them because they've exhausted some of their more standard options, which are the drugs we're talking about. So sometimes these drugs have new mechanisms of action.

Bi-specific antibodies, for example, where the antibody binds to the CLL cell but it also binds to the patient's Tcells and re-engineers the T cells to attack the CLL cells, those are very interesting. We don't yet have any in CLL, but there are those agents in clinical trials.

We have antibody drug conjugates where an antibody is attached to a poison. The patient receives the antibody, but if they got the poison they would be very sick. The poison is only directed into the cell to which the antibody binds so it goes right into the CLL cell. There are also combination regimens in both the frontline and relapsedsettings. So combining, for example, ibrutinib and venetoclax or combining duvelisib and venetoclax, looking at whether the combinations are even better than the single agents.

And there are new drugs in these categories. I mentioned that there's two BTK inhibitors, ibrutinib and acalabrutinib. There’s actually a third one (Brukinsa [Zanubrutinib]) which is in clinical trials that could lead to an approval in relapsed CLL.

In the PI3K drugs I mentioned, idelalisib and duvelisib, umbralisib is also in trials actually in both the frontline and in the relapsed population. That one probably I would say of all the drugs we're talking about is the closest to having approval in CLL, which we could see probably next year.

Kristie L. Kahl: Is CLL considered a chronic disease?

Dr. Susan O’Brien: Very much so. There's no doubt that the novel agents or the small molecules have increased the lifespan of your average patient with CLL. It was on the order of years even when we only had chemotherapy or chemo immunotherapy. But it's clearly much longer now because we can go from potentially sequencing one drug and then if that stops working move to another drug. So there's absolutely no question that survival for CLL patients is much better than it was 10 years ago.

Kristie L. Kahl: So with that, what do patients with relapsed/refractory CLL have to look forward to moving forward?

Dr. Susan O’Brien: Even longer life spanbecause I'm mentioning all these noveldrugs that are in clinical trialsincluding CAR-T cell therapy, which most patients have heard of. We have a novelclass of agentsand the mechanisms of resistance to the drugs that exist hopefully will be very different with a totally different mechanism of action, which leads us to assume that some of these drugs that have a whole new mechanism of action. They are still likely to be effective

a different mechanism of action in the cell has managed to figure out how to become resistant to that.

Transcription edited for clarity.

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