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Which CLL Medicine When? An Expert's Perspective

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Published on January 8, 2020

Key Takeaways

  • How patients should navigate the multitude of CLL treatments now available
  • What discussions you should have with your doctor before making treatment decisions as a newly diagnosed patient or relapsed patient, and how they differ
  • How targeted agents can be best utilized for CLL patients

Chronic lymphocytic leukemia (CLL) specialist Dr. Alexey Danilov, from Oregon Health & Science University, joined Patient Power at the 2019 American Society of Hematology (ASH) Annual Meeting & Exposition to share the latest research on treatment safety, tolerability and efficacy, and how it translates to clinical practice. Dr. Danilov discusses CLL treatment developments, data on patient response and research on sequencing novel agents. Dr. Danilov also mentions clinical trials that are open to enrollment for CLL patients. Watch now to find out more.

This program is sponsored by Pharmacyclics and Janssen Biotech. This organization has no editorial control. It is produced by Patient Power, and Patient Power is solely responsible for program content.

Featuring

Because of this meeting, I created new networks by meeting new CLL patients, and we decided to keep in touch by emailing each other for support.

— CLL Patient, Town Meeting

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Transcript | Which CLL Medicine When? An Expert's Perspective

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.

Michele Nadeem‑Baker:

Michele Nadeem‑Baker here at ASH 2019.  I'm here with CLL specialist Dr. Alexey Danilov.  Welcome.  

Dr. Danilov:

Thank you. 

Michele Nadeem‑Baker:

So I want to know what you've been hearing, how you feel the hottest news is in the CLL area here at ASH. 

Dr. Danilov:

Well, there's certainly a lot of development in the field of chronic lymphocytic leukemia.  I believe that probably one of the most impactful studies that we learned about here, yesterday is ELEVATE TN.  This is the study of acalabrutinib (Calquence), a selective BTK inhibitor similar to ibrutinib (Imbruvica), which was compared to standard chemoimmunotherapy regimen, chlorambucil-obinutuzumab (Leukeran-Gazyva), and the results of the study with improvement in progression‑free survival actually led to approval of acalabrutinib in patients with CLL who have not received prior therapies.  So this is one additional therapy that we now have approval for in treatment‑naive CLL. 

Michele Nadeem‑Baker:

And how about for the progressions, these progressions after a certain amount of time?  How long did they study that?  

Dr. Danilov:

So this study—the study follow‑up—the study obviously is still ongoing.  The study follow‑up is now close to three years, and the data so far are very encouraging.  90 percent of patients are still progression‑free.  There is a little bit of an advantage it seems to a combination of acalabrutinib and obinutuzumab, the CD20 antibody similar to rituximab (Rituxan) over acalabrutinib single agent.  However, the study is not actually addressing that question.  Really it's comparing acalabrutinib alone or in combination with chemotherapy‑based regimen.  But so far the overall response rate is very, very high.  It's 94 percent.  Everybody benefits.  

What's also important is that the toxicities are very favorable.  Only about 3 percent of patients so far have developed cardiac arrhythmias, particularly atrial fibrillation, and this is what we always watch out for with novel agents such as BTK inhibitors with ibrutinib, and also importantly very few patients discontinued because of adverse events.  So this seems to be a very tolerable, very safe option for patients with CLL who have not been previously treated.  

Michele Nadeem‑Baker:

That does sound great.  Now, you were pointing out some of the adverse events with ibrutinib such as a‑fib.  Are patients being switched from ibrutinib—if they're not on a trial, are they being switched from ibrutinib to acalabrutinib because—if they're displaying that? 

Dr. Danilov:

Well, so this is a very good question, and really we don't necessarily know what is the right thing to do in this situation.  We do have options.  You know, there was a study presented several times in the past where patients would develop side effects on ibrutinib were switched to acalabrutinib and many of those side effects actually did not recur.  So that's very positive. 

There were few cases of atrial fibrillation there though.  The trouble of course with atrial fibrillation is that many of those patients then require blood thinners, and that in itself also presents a problem where inhibitors of BTK such as acalabrutinib and ibrutinib do inhibit the blood clotting by themselves, so that combination we really have to watch out for bleeding more carefully.  So if patients develop atrial fibrillation on ibrutinib, yes, one option would be introducing a different agent such as venetoclax.  Another option will be actually continuing on ibrutinib if they're doing well otherwise, and there will be an option of switching to acalabrutinib now.  

Michele Nadeem‑Baker:

Tell me a little more about the combinations.  We've been hearing even more this year of BTK and Bcl‑2 inhibitors, and now it sounds like we're adding in a third, so. 

Dr. Danilov:

Absolutely.  So this is certainly becoming a very interesting and controversial area.  There are combinations which have been presented of ibrutinib and venetoclax (Venclexta) and then acalabrutinib and venetoclax with or without a CD20 targeting agent, an antibody, so I think this is early days still.  Those are clearly active combinations.  Some of them do add a little bit toxicity when the drugs are combined.  Overall, they're still not as unsafe as some of the earlier days chemotherapy regimens that we use less and less now. 

But I think the question still remains whether those combinations early on are better than sequential therapies, better than using those drugs in sequence, and I do believe that many patients with CLL, particularly those who are older, will have very good response to one of those agents and will not need all three or two.  This is certainly an important area of research, and we will have to answer those questions in the future.  

Michele Nadeem‑Baker:

And what are you researching right now in your lab?  You've been presenting quite a few things here this year.  

Dr. Danilov:

Right.  So we have several projects in the lab, but one of the maybe more relevant to clinical practice, we have been exploring some alternative targets in the B‑cell receptor signaling pathway.  So B cell is the lymphocyte which is the origin of CLL cell, and B‑cell receptor is something which ibrutinib actually targets and specifically within the B‑cell receptor pathway targets BTK, Bruton's tyrosine kinase. 

However, this is not the only kinase which is responsible for cell survival.  Spleen tyrosine kinase is another kinase which sits in that pathway, and it has been also developed as a target.  So here we presented data from an investigating trial of spleen tyrosine kinase targeting agent, SYK targeting agent called entospletinib.  And so this entospletinib, it's a pill which was combined in the study with antibody, with obinutuzumab, which I mentioned before. 

And, interestingly, this combination was very, very well tolerated in patients with relapsed or refractory CLL, some of which actually came off ibrutinib for toxicity.  Only one patient discontinued on study for toxicity, and the majority of patients still remain on study and are still having a response. 

Michele Nadeem‑Baker:

That's great.  Now, is that trial closed? 

Dr. Danilov:

It's closed to enrollment, but it's still open as we have patients who are being treated on the study now. 

Michele Nadeem‑Baker:

Do you have any trials right now that are open to patients who are watching this?  

Dr. Danilov:

Yes, absolutely.  So currently at Oregon Health & Science University we have several trials which, for example, a trial which we developed pre‑clinically in the laboratory with a novel agent called pevonedistat which actually targets a completely different pathway.  It targets protein turnover.  In every cell proteins, as they are aging they are then destroyed before they start posing problems, and pevonedistat is a drug which interferes with this pathway, and actually we have shown in our early experiments that it's very good at killing CLL cells particularly in the modeled microenvironment like in the lymph node‑like microenvironment.  So we have a study of pevonedistat, a novel investigational agent in combination with ibrutinib.  That's one. 

We have studies with novel Bruton's tyrosine kinase inhibitors in the same class as acalabrutinib and ibrutinib for example.  Zanubrutinib (Brukinsa) you might have heard about, and we have studies specific to patients with Richter's transformation with immunotherapy.  Richter's transformation, as you may know, is one of the feared complications of CLL which is very difficult to manage, so we have an immunotherapy study for those patients.  

Michele Nadeem‑Baker:

Sounds fascinating, all the things that you're doing in your lab.  

Dr. Danilov:

Thank you. 

Michele Nadeem‑Baker:

We look forward to hearing more about those.  If you were a patient hearing all this news, I mean it sounds good, but do you consider it good and hopeful for patients?  What's the prognosis overall?  

Dr. Danilov:

Absolutely.  I think in the past five years there has been so much positive change in the field of CLL that the outlook has become so bright for patients with CLL.  You know, even when I was in fellowship which was, you know, I'd say a long time ago know, chemoimmunotherapy was really the only option, and that was actually also an amazing option, which was only introduced really in the late ‘90s.  And now, fast forward 15 years later, we have all these drugs which are non-chemotherapy novel agents with fewer side effects, are not known to cause other cancers and are known to work for a very long time.  

So this is a very exciting time where we are prolonging lives of patients with CLL and making those lives normal, completely healthy.  And furthermore there is also significant advances in the field of cellular therapy like CAR‑T cells, so this still requires a little bit more work but very promising as well.  

Michele Nadeem‑Baker:

Well, we know we need to watch out for CAR‑T.  We've seen all sides of that, and we look forward to hearing more from that as well.  

But I thank you for joining us today on Patient Power, and we look forward to hearing all about what you're up to in City of Hope in the future and on your clinical trials that are going on. 

Dr. Danilov:

Thank you. 

Michele Nadeem‑Baker:

Thank you very much. 

Dr. Danilov:

Thank you very much.  

Michele Nadeem‑Baker:

Thank you for joining us.  This is Michele Nadeem‑Baker from Patient Power. 

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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