EHA 2021 | Sequencing targeted therapies in CLL after intolerance versus progression
Jacqueline Barrientos, MD, MS, Feinstein Institute for Medical Research, Manhasset, NY, shares her views on the sequencing of targeted therapies for the treatment of chronic lymphocytic leukemia (CLL). Dr Barrientos discusses the importance of considering why patients cease to take their initial therapy and comments on the use of pirtobrutinib or venetoclax after progression with frontline treatment with a BTK inhibitor. Dr Barrientos also highlights the potential to use alternative BTK inhibitors in patients who cease initial BTK inhibitor therapy due to tolerability issues, talking on the difference between intolerability and progression. For patients who receive initial therapy with a BCL2 inhibitor, such as venetoclax, Dr Barrientos discusses the potential benefits of retreatment with venetoclax for patients who progress after they complete therapy, compared to treatment with a drug of a different class for patients who progress whilst still receiving BCL2 inhibitor therapy. This interview took place at the virtual European Hematology Association (EHA) Congress 2021.
Transcript (edited for clarity)
It depends a lot on what was the initial therapy, right? So, sequencing at this moment will depend on what you select for first-line therapy. So, let’s say you start with a BTK inhibitor. Why did these patients stop taking the BTK inhibitor? Was it because the patient progressed on the drug? If you have a patient that had been treated with ibrutinib and the patient progressed that patient could not be salvaged with acalabrutinib or zanubrutinib because usually the patients that progressed on ibrutinib have the BTK mutation or the PLC gamma mutation, and there’s no salvage therapy because they will bind to the same area, so it wouldn’t respond...
It depends a lot on what was the initial therapy, right? So, sequencing at this moment will depend on what you select for first-line therapy. So, let’s say you start with a BTK inhibitor. Why did these patients stop taking the BTK inhibitor? Was it because the patient progressed on the drug? If you have a patient that had been treated with ibrutinib and the patient progressed that patient could not be salvaged with acalabrutinib or zanubrutinib because usually the patients that progressed on ibrutinib have the BTK mutation or the PLC gamma mutation, and there’s no salvage therapy because they will bind to the same area, so it wouldn’t respond.
Now, that type of patient could be salvaged with drugs such as pirtobrutinib which right now is only in clinical trials. But it has been shown to have efficacy in patients with a BTK mutation. So, that’s the drug that used to be called LOXO-305. If the patient has developed a progression on ibrutinib or acalabrutinib, you have data that shows that venetoclax can be used for salvage. So, that patient would be able to be salvaged with a drug such as venetoclax. We have prospective data. We have real-world evidence that that is a salvageable agent.
If you stop the drug ibrutinib because you have tolerability issues, then you can use acalabrutinib or now, with the data presented at EHA, zanubrutinib could be an option if zanubrutinib were to be approved in CLL. It’s not yet approved for CLL. It’s only been approved for another form of indolent lymphoma. Acalabrutinib is available in the United States for the use of, in CLL patients. So, it could be an easy drug to get accepted for use if you are intolerant to ibrutinib.
You can also switch class. But in our experience in our clinical practice, what we do is we try to stick with that same pathway. For example, if the patient is no longer able to tolerate ibrutinib, I salvage the patient with acalabrutinib so that I can continue with the BTK inhibition and not deem this patient refractory to BTK inhibitors because they are not. They’re just intolerant. And I can tell you, I’ve had a couple of my patients that in clinical practice developed severe, severe rashes with ibrutinib or severe arthralgia and then I was able to give them acalabrutinib. But they’re doing fine without any issues.
Same with hypertension. Now, hypertension has been shown to be an issue that occurs over time, and so it might be difficult to control it with a drug such as ibrutinib because you might need several anti-hypertensives to control it and then you can salvage it with acalabrutinib and then you still have the hypertension, it’s just, I would say to a lesser degree and better controlled.
For patients that have progression or tolerability issues, now, if the patient was on a clinical trial with like ibrutinib and venetoclax and they stop and they are, like you saw on the data from CAPTIVATE that was just presented by Paolo Ghia at ASCO 2021, there are some emerging data that those patients that were in the treatment-free time period and then they relapsed when they were re-challenged with ibrutinib, they actually responded really well. So, in the future a combination treatment strategy where you have treatment-free periods, you could re-challenge in theory with the same agent and get the patient to respond again.
Now, that was if you start with a BTK inhibitor. Now, let’s say you start with a BCL-2 inhibitor like venetoclax. The drug is given or a period of time, right? If it’s treatment-naïve it’s usually one year. If it’s relapse/refractory, usually two years.
So, it depends on why you stopped. Did you stop because it was the treatment duration and it finished and then you relapsed? So, then you can actually re-challenge that patient with venetoclax again. And we have data now that shows that about three out of four patients will respond, and they will be seeing remission. So, that’s one way to treat the patients sequentially after venetoclax progression.
Now, if the patient progresses while taking venetoclax. And that means that the patient is not responding. So, you have to salvage them with a different agent, aid then I would select a BTK inhibitor for salvage. And there are data, too, that show that the ibrutinib or acalabrutinib can- ibrutinib be used to salvage patients that progressed after venetoclax.
If the patients are intolerant to venetoclax and they stopped taking the drug, you could re-challenge it. The most common toxicity that I have seen in my clinic is neutropenia. And that can be severe and cause infections. And so, what you could do is re-challenge it and start it at the lower dose and keep it at a lower dose and never go back to the full target, 400 milligram daily dose.
The sequencing will all depend right now on what was the reason for discontinuation? So, one way to select the next-line therapy will be always looking at what happened with the patient. Was it tolerability issues? If that is the case, try to use an alternate drug or try re-challenging at a lower dose. If it’s progression, then you can switch to a different drug that has activity on the drug. And if it’s because there was a treatment-free period, you could actually re-challenge or to introduce the drug and the patient should in the majority of cases respond again.
So, that’s what we know so far. We’re hoping to get more data. All these new drugs just started to be in our hands over the last couple of years. So, we’re all learning. And with more time, we will be better able to answer this question. But it’s a tough question at this moment because we don’t have, we haven’t had much data to go on from to answer this particular question.
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