Published on October 2, 2020
When Should CLL Patients Look Into More Aggressive Treatments?
Do chronic lymphocytic leukemia (CLL) patients with NOTCH mutations need more aggressive treatments? Can you back on BTK inhibitors if you go off of them for a period of time? Would receiving more aggressive treatments reduce the chances of Richter's Transformation? Host and CLL patient Andrew Schorr asked these questions to Dr. Paul Barr of the University of Rochester Wilmot Cancer Center. Tune in to hear the answers.
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Transcript | Aggressive Treatment Options: When Are They Right for CLL Patients?
“Do we have cellular therapy options? Should we use PI3K inhibitors?”
We want to continue to improve our standard therapies. We aren't satisfied with just getting BTK inhibitors especially for our high-risk patients who we know will progress through these at some point and then sequencing with venetoclax (Venclexta). There are a number of studies looking at novel combinations, combining BTK inhibitors and venetoclax. But for our patients that have relapsed after lines of therapy, we're looking at more novel combinations. One example of a clinical trial we're doing here is combining a novel, pretty well tolerated PI3K inhibitors with venetoclax-based therapy. The intent here is to drive deeper remissions, to help prevent resistance while ideally hopefully providing a limited duration of therapy, not requiring our patients to take unending pills until disease progression.
So that's one example of a combination that the specific drugs we're using in this clinical trial is umbralisib; PI3K inhibitor; ublituximab, an anti-CD20 agent; plus venetoclax. And there are many other similar trials going on with that same intent to drive deeper remissions to provide better outcomes.
Can CLL patients get back on venetoclax (Venclexta)?
Well, that's good news. Now, if somebody were on venetoclax and then they got to a minimal residual disease (MRD) negative status, and they went off but at some point, their CLL rears its head again, can they go back on it? So do you pay a penalty for going off or can you go back on it and get some benefit?
So we think that patients can. Typically, the resistance mutations won't develop in most patients after a year or two of therapy. We're actually looking at some of that data now to identify how well patients are doing after being treated with a year or two of venetoclax, time goes on, progression occurs and we have to restart the drug. The very early data suggest that some patients certainly can continue to respond. And the hope is that by not keeping patients on the constant, on the drug, on the constant pressure on the disease, hopefully, we can eliminate or a delay or prevent some of those resistance mutations. So time will tell but I think the preliminary results do suggest that patients can respond to subsequent courses of venetoclax-based therapy.
What's a NOTCH mutation? And what about more aggressive treatment?
So NOTCH mutations occur in the minority of CLL patients and the fancier the testing gets the more sequencing efforts patients go through, the more of these novel mutations we identify. It does look like... primarily look based on large datasets of patients treated with chemoimmunotherapy that NOTCH mutations may confer inferior outcomes. With BTK inhibitors or venetoclax-based therapy, this may not be the case. Those patients seem to respond well to those classes of agents. So we would say generally speaking when we do find a NOTCH mutation it does concern us. It does suggest to us like most patients these days, patients receive the novel therapies. But it doesn't mean that inevitably their remissions will be short the patients will progress quickly. On the other hand, in some of the earlier ibrutinib (Imbruvica) studies, the outcomes looked pretty similar for the small number of patients with a NOTCH mutation.
So still a lot of work to do here. But I do think it is something we watch closely, and we do at least think about some of the more aggressive therapies having those in our back pocket.
So those of us who've been around CLL world for a while know that there's a small percentage of people who develop what's called Richter's transformation, and we know that's not a good thing. So maybe you could describe what Richter's is. And the question that came in is, which of the more aggressive options reduce the chances of Richter's transformation?
So, as I mentioned before that the disease’s cycling can change over time, can acquire additional molecular changes, molecular aberrations. At times in a small number of patients the number of mutations can build up and the disease can become much more aggressive similar to a fast-growing lymphoma like large B-cell lymphoma. When this occurs, we call it Richter's transformation. It's not necessarily a new disease. It's the CLL becoming often just a more aggressive after acquiring a lot of these changes. So that happens thankfully in the minority of patients, we estimate the rate to be about 3% per year up to like 10 or 15 years. So, most patients won't suffer Richter's transformation, but the risk does go up as the years go by. We don't have a good understanding of which treatments help to prevent this.
That has been looked at in a number of datasets and there doesn't seem to be dramatic outcomes using one treatment or another. It seems to be largely based on the biology of the disease. So there certainly is much more work to be done here. Those patients can be very difficult to treat but at this time we're not really recommending one maneuver or another to prevent Richter's with a lot of certainty.