An Expert's Perspective: Why New CLL Treatments Supersede FCR

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Topics include: Treatment

Jeff Sharman, CLL expert, discusses what's hot in CLL. As a subject often broached in his popular CLL & Lymphoma blog, he explains how we are leaving a generation of chemotherapy and transferring into a new area of targeted therapies. While FCR continues to be a treatment option, Dr. Sharman believes its day is passing as targeted therapies continue to progress. The key question remains how to decide what targeted therapy to use when. While the long term side effects of the targeted therapies are unknown, the hope is a decrease in toxicty with an increase of efficacy. 

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Andrew Schorr:

Hello and welcome to Patient Power.  I’m Andrew Schorr. 

In our continuing devotion to bringing you the latest information in chronic lymphocytic leukemia, CLL, we’ve come to Atlanta to the annual meeting of the American Society of Hematology where the doctors gather to present their data on the latest studies, and there is a lot in CLL, particularly about new agents that are in clinical trials that may be better than what we’ve had before. 

To help us understand it is a leader researcher, Dr. Jeff Sharman.  He joins us here.  He’s from Eugene, Oregon.  Dr. Sharman, thank you for being with us.  Take us through what’s hot here and what it could mean for patients. 

Dr. Sharman:

We’re in really a phenomenally exciting time for chronic lymphocytic leukemia.  I think we’re quickly transitioning from an era of chemotherapy to an era of targeted therapy.  The adage in the past with most cancers has been that a mutation presents itself as a target for a drug, and so diseases like chronic myelogenous leukemia, there is an obvious drug for that, Gleevec (imatinib), works phenomenally well. 

The problem in chronic lymphocytic leukemia is that those mutations by and large don’t exist.  If you look at the genome complexity of chronic lymphocytic leukemia, look at the full range of mutations, there’s actually comparatively few mutations in CLL.  One might presume therefore that there are fewer drugs that would be appropriate for CLL, but where CLL is different is that we’ve known for a long time that certain biologic pathways become very important. 

We’ve suspected Bcl-2 has been important for a long time.  That’s a protein that’s sort of a seat-belt, if you will, on the cell death mechanism.  It helps keep cells alive.  We’ve been working with antibodies over the last 10 years, and we’ve gotten to be a lot better and more sophisticated in how we make those antibodies. 

And then for a long time the B-cell receptor, which is sort of the fundamental aspect of a B-cell, making antibodies, was thought to be unimportant in CLL.  We were looking at low levels of B-cell receptor and the fact that we couldn’t get it to signal and thinking that that meant it was largely irrelevant, but in fact what we found recently is it’s the key pathway.  We were looking at the evidence in exactly the wrong way. 

And as a couple drugs have moved forward targeting the B-cell receptor signaling pathway, key enzymes have become very appropriate targets for therapeutic intervention.  We’ve been using a drug called ibrutinib (PCI-32765), which inhibits an enzyme called BTK.  Another drug called CAL-101, which has gone through a number of name changes, CAL-101, subsequently GS-1101 and now most recently idelilisib. That inhibits an enzyme called PI-3 kinase. 

And these are all enzymes downstream of the B-cell receptor signaling pathway, and we have found them to be very effective drugs.  They make chemotherapy work better.  They work well on their own.  And even many of the patients who have traditional high-risk markers are having phenomenally good outcomes on these drugs.  They’re pills, sometimes taken once or twice daily, they’re very well tolerated, and most every patient responds, and many patients are experiencing durable responses. 

Andrew Schorr:

Are these new agents for a broad range of patients, even those that have had the poorest prognostic factors? 

Dr. Sharman:

I think that can be highlighted perhaps by a patient I’ve seen in my own practice. A young gentleman came in with bad high-risk disease, what we call 17p deletion, stage IV disease, very low platelets, very low hemoglobin, had to be transfused for both.  He was given FCR.  He didn’t respond.  We admitted him to the hospital, gave him chemotherapy called ESHAP, which was a very aggressive treatment, didn’t do anything.  Gave him Campath (alemtuzumab), got some mileage out of it.  Ofatumumab (Arzerra), bendamustine (Treanda), Revlimid (Lenalidomide), all these drugs did very little.  And for the last two years he’s been on CAL-101 (idelilisib) with normal hemoglobin, normal platelets, enjoying life, looking quite good. 

I don’t know how long this will last for him, but in many of my CLL patients, if I can get them a year or two on this drug or a year or two on this drug, the emerging therapies are so remarkably effective that I think even these worst case scenarios are seeing tremendous benefit. 

Andrew Schorr:

Dr. Sharman, thousands of patients, including myself, have received FCR, and today at many places, that’s what people would receive for CLL.  But in your opinion is FCR as a therapy passé?  Is it dead? 

Dr. Sharman:

I think that for patients’ now needing treatment for CLL it’s perhaps the most important time to participate in clinical research.  We have more drugs than we can realistically get to patients that combine this incredibly good efficacy and very minimal toxicity. 

FCR was a wonderful regimen for its day.  I think that day is passing.  FCR achieved durable remissions.  Some patients with low-risk disease are 10 years out without any evidence of recurrent disease.  Some have even started to wonder if those patients are cured.  But it comes with a cost, and that cost is it’s a difficult regimen on many patients.  In all but the most fit, younger patients, it’s intolerable.  Patients get secondary cancers.  Patients have profound impacts on their bone marrow, infections are common, and I think that most practicing oncologists have some trepidation about FCR.  It’s a regimen that’s to be treated with respect. 

For a patient needing treatment now, there are options that don’t involve damage to DNA, that don’t involve further harming the genome, that don’t involve the same infection risk and the same secondary malignancy risk.  Now, these are early days for these drugs, and so I think it’s important to take them with a seed of caution.  We’re going to find side effects with long-term use of these drugs that we don’t totally understand just yet, but with the data that we have now it seems like we’ve struck the right balance between improved efficacy and reduced toxicity that, I think, is really what patients want. 

Andrew Schorr:

You’ve got these new drugs in trials.  If someone comes to you, how do you decide what to use when? 

Dr. Sharman:

I’ve seen internet chatter about declaring a winner and which drug might be best.  I think that far too premature.  We’re lucky in CLL that targeting a pathway is more important than targeting a protein.  In CML we have one drug target for the most part, and that’s the Bcr-abl protein.  We have multiple drugs for that one target and we can improve upon how we drug that target, but what’s transformative in CLL is that we have multiple targets, and we will have multiple drugs for multiple targets. 

For patients right now who need therapy I think that any of these drugs represent very good options to participate in research studies.  Ibrutinib (PCI-32765) is an once-a-day drug.  I’ve treated a number of patients with it.  I find it to be incredibly easy on the patients to take, very minimal side effects, very effective.  CAL-101, which is now GS-1101, which is now idelilisib, targets downstream of BTK, farther downstream, and that may be important.  In fact, I have had a patient who had an insufficient response to ibrutinib, had a wonderful response to CAL-101.  I’m sorry for going back and forth on the names.  It’s confusing for all of us. 

I think that any of these drugs are good.  Some of them work slowly.  Ibrutinib and idelalisib, GS-1101, CAL-101, I consider them slow in one regard.  Patients oftentimes feel quite a bit better within 24 hours of taking their first dose.  If they have a number of symptoms that are arising from their CLL—I have one young gentleman on the drug who decided to go out running for the first time in months after taking his first pill, and he really does feel a whole lot better—but they’re slow.  You can see that the disease takes a long time to go away. 

Two other drugs, the Bcl-2 inhibitor and a drug we haven’t really spoken of, GA-101 (obinutuzumab), which is a third-generation, if you will, anti-CD20 antibody, work very quickly.  You see responses as soon as eight hours after the first treatment. 

And so I think that that’s where the research for the next three to six years is going to be is how do we rationally combine these agents.  It’s phenomenal that we have so many coming across the finish line, hopefully at roughly the same time.  The next era of research will be about how do we strategically combine these ways to help patients the most. 

Andrew Schorr:

Dr. Jeff Sharman from US Oncology in Eugene Oregon, thank you so much for joining us and your devotion to researching all these new agents and helping patients get better responses in beating back or even curing, we hope, their CLL. 

On location in Atlanta, I’m Andrew Schorr.  Be sure you’re signed up for alerts on our website so we can keep you informed as we post new, important interviews.  Remember, knowledge can be the best medicine of all. 

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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Page last updated on December 13, 2013