Published on November 29, 2018
During this Ask the Expert replay, Patient Power founder Andrew Schorr is joined by renowned chronic lymphocytic leukemia (CLL) expert Dr. Richard Furman, from Weill Cornell Medicine in New York City, to answer questions from the Patient Power community. Tune in to hear Dr. Furman explain answers to your important questions; from diagnosis and prognosis, to treatment, emerging research and more.
This is a Patient Empowerment Network program produced by Patient Power. We thank AbbVie, Inc. and Pharmacyclics for their support.
Transcript | Ask The CLL Expert Replay
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And hello. Greetings. I'm Andrew Schorr in Southern California, San Diego area, and I've been living with CLL for 22 years, so I'm vitally interested in today's Ask the Expert session, this Patient Empowerment Network program. We want to thank PEN, as we call it, and also the financial supporters of this program, AbbVie Incorporated and Pharmacyclics, although reminding you that they have no editorial control. You'll be hearing from our leading expert in CLL in just a minute.
If you have a question, send it in to firstname.lastname@example.org. Again, that's email@example.com.
Over the next 30 minutes or so, we'll get to as many questions as we can. Remember not to make it too personal. Let it help everybody in the community. And also discuss what you learn with your own CLL provider so you get the treatment that's right for you. Okay.
Let's meet our expert joining us from New York City and Weill Cornell Medicine, and that's Dr. Richard Furman, who is the Director of the CLL Research Center in New York City at Weill Cornell. Dr. Furman, welcome back. Thanks for being with us.
Thank you. It's my pleasure. Thank you for having me.
Okay. We have lots of questions. One of them that somebody wants to know about is, first of all, if they've been—maybe this is an easy one. If they've been diagnosed with SLL, small lymphocytic lymphoma, is that the same as CLL and what we're talking about with CLL applies to them?
So that's a very important question, and this is one that I actually think is very indicative of how little we used to know. So in 1993 we actually had a diagnosis of CLL, chronic lymphocytic leukemia, and a diagnosis of small lymphocytic lymphoma. And we had patients that were diagnosed with SLL if they had a lymph node sent to the pathologist, or they were diagnosed with CLL if they had a bone marrow biopsy sent to the pathologist.
Clearly, we knew that patients could only have one diagnosis and not two, so in 1994 with the new lymphoma classification system the term was actually changed to be CLL/SLL. So they really are exactly the same entity. We don't actually refer to differences anymore, and the whole, the whole individual—the whole disease should be called CLL/SLL.
Now, an important thing is sometimes people require having a lymphocytosis to meet the definition of CLL, but the truth is both conditions are exactly the same. Both should be treated exactly the same, and there should be no difference based upon having a lymphocytosis.
Why this is most important, let me just add, is that there are sometimes people will be diagnosed with stage IV SLL and it's very important to recognize that these stage IV SLL patients unless they have thrombocytopenia below 100,000 like the Rai stage would indicate really are not stage IV. So the lymphoma staging system would automatically make them stage IV, and that's certainly not correct.
Okay. Good point. All right. Here's a question we got in from Julia and Betty and Shelly and Mark. They all asked a similar question. They've been on Imbruvica for five years now with success.
Is it working for most people, and what are some reasons why it doesn't work for everyone? And then what treatment options do you recommend if they relapse on ibrutinib (Imbruvica)?
So right now I think the most important, there are a lot of prognostic markers available for CLL. At last count, we're probably up to 115. What's most important is in 2018 what are those prognostic markers that really are relevant to the patient, and really as long as you stay as CLL you're going to be able to have your disease very nicely controlled with our current agents and our novel agents.
So there are certain things that do indicate patients are likely to progress on ibrutinib, not likely progress must but who may progress, and people who might need something more, and that's where a lot of our current clinical are research is focused. So patients who have a risk of developing a Richter's transformation or patients who have a likelihood of developing a BTK mutation that might generate resistance to ibrutinib are the two groups of people that we worry about most.
17p deletion is probably the most important predictor for predicting those patient outcomes. There are other things that are predictive as well like having a NOTCH mutation. Those are all readily obtainable prognostic markers that allow us to determine who's at risk and who's not at risk for progressing on ibrutinib. If you don't have 17p deletion or NOTCH1 mutation, you have almost a 99 percent chance of being free from progression at five years on ibrutinib. And it looks like most of the people who are going to progress will progress within five years. So I think making it to that five-year mark is really very—is the most important thing.
Okay. So if you do progress, what then?
So, fortunately, we have a lot of great agents.
Venetoclax (Venclexta) works very effectively in patients who progress on ibrutinib, generates some very, very deep responses and very long-lasting responses. So that's certainly one option. Another option is to be treated with a PI3-kinase inhibitor. So we have idelalisib (Zydelig) and duvelisib (Copiktra) now approved. We will shortly have umbralisib approved as well as a novel agent. We also have a whole array of other agents coming down the pipeline looking specifically at means for progression on venetoclax. So we have an MCL1 inhibitor, which targets the protein that's likely responsible for resistance to venetoclax. So all these things are actually currently in clinical trials and certainly will hold a great deal of promise.
Okay. Here's a question we got in from Jeff. He says, “For young and fit patients with relapsed disease, what are the best combos and trials now and coming?” And I suspect maybe Jeff had received FCR, so if he relapses after FCR, what about that?
So my belief is that these novel agents should always be used up front, or if you've gotten chemotherapy up front, they should be used immediately at relapse. A lot of patients and physicians have the idea that there's a benefit to holding back until you really need something, but I believe putting our best foot forward first is always the best approach. So I always recommend going forward first with BTK inhibitor therapy, followed by venetoclax or venetoclax followed by BTK inhibitor therapy. And I think so in a patient who has relapsed after FCR it will be ibrutinib or acalabrutinib (Calquence). In a patient who has relapsed after acalabrutinib and ibrutinib would then move on to venetoclax.
Now, what I'm really very excited about is the possibility of the combination of either BTK inhibitor therapy plus venetoclax or PI3 kinase inhibitor therapy with venetoclax.
You know, both of these combinations really take advantage of the synergy that happens when you take a BCR antagonist like ibrutinib, acalabrutinib or idelalisib and duvelisib and combine it with a Bcl-2 inhibitor. And it really sort of enables us to get very, very deep remissions with actually as short as just 12 months of treatment. And so those are what we're currently testing in patients right now and what I hope will be the frontline treatment for patients in the not-too-distant future.
Now, one of the things people wonder about is if you take these big guns and put them together could you, like you've been able to do with FCR, stop treatment or take a break from treatment at some time.
So I'm a big believer in that if something's working and you're tolerating it well, that we shouldn't mess with it, but we are currently studying two different processes with relationship to the ibrutinib plus venetoclax combination. So we're taking patients who become MRD-negative on the combination after 12 months and randomizing them to either just get ibrutinib or to get placebo. And so that's going to give us information as to whether or not it's safe to stop patients on the combination and treat them with nothing long term. We'll see, one, how many patients relapse, and hopefully none, and, two, if they do relapse whether or not we can then restart ibrutinib and control their disease. So this will provide us that important question as to whether or not we're giving up something by discontinuing the therapy.