Treatment Issues in CLL

Guest:

Andrew Schorr
Susan M. O'Brien, MD
Thomas J. Kipps, MD, PhD
John C. Byrd, MD
Michael J. Keating, MB, BS

Andrew Schorr

More than 20,000 people have come from around the world to bask in the sunshine of Atlanta for the 49th Annual Meeting of the American Society of Hematology. And when it comes to CLL, now, maybe more than ever, there's a lot to talk about.

We're delighted that several of the world CLL experts are here, advisors to CLLPerspectives.com, and eager to tell us more about what the latest news is.

Thomas J. Kipps, MD, PhD

There's really a strong interest in trying to develop improved treatments for patients who have CLL, and not just the patients that we've typically treated in academic centers, namely patients in their mid-50s for the most part; but also, to address the CLL that we find in elderly patients. And these are patients in their 70s and 80s. Obviously, some of the treatment regimens that have been defined for younger folks might not be, actually, as well-tolerated by older individuals.

If you have a patient who is elderly and has comorbid conditions, the use of an agent such as chlorambucil may be actually quite acceptable. It may be easy to take, easy to monitor its toxicity, and if the leukemia is slowly growing and able to be palliated in this fashion, you may dramatically improve the quality of life with the drug Leukeran^®.

I think that FCR is an aggressive approach and I know we teach our medical students that the cellularity of your bone marrow, which is to say the population number of cells you have in the bone marrow compared to empty space, is 100 minus your age. So that means that, as we get to be 100-years-old, we have very little marrow left. But I think that the problem we run into as we get older, our bone marrow becomes less resilient to the agents of fludarabine and cyclophosphamide.

John C. Byrd, MD

There is also very promising data with lenalidomide at this meeting, which is an immunomodulatory agent. To the physician that's in practice right now, that's off – off-study. That's not an agent that I would give, because we're still learning how to use it. You see tumor flare. The company alluded to this in a paper that they just recently submitted or they just recently published in the JCL. But it is producing responses in high-risk CLL patients.

I think the other exciting thing that — was presented here, there is a new drug that beat out chlorambucil hand in hand, bendamustine, that the response was higher, the progression-free survival in the randomized Phase III was — improved. And you know, this is an important trial because it points to another drug that's different than fludarabine — that's effective in CLL. And one of the things that's not realized about bendamustine is this is an agent, this is an agent that, when you look at it in the laboratory with a very sophisticated screening process that the NCI set up, that it's, even though it has properties of chlorambucil, properties of fludarabine, and often people confuse it as just a single drug combining features of both of those, it's actually molecularly very distinct. So I think it's a drug that's been around a long time and it's going to be exciting to see it move forward and where it fits in the landscape of new therapies for CLL.

Michael J. Keating, MB, BS

The comparative trial of bendamustine versus chlorambucil shows a much better response rate, progression-free survival without any survival advantage — the traditional outcome of comparative trials against chlorambucil. Now again, I think we have to start looking at the breakdown by age, because this is the weak link that we continue to find in our clinical trials, but obviously it's an active drug.

It's still predominantly perceived as a somewhat different alkylating agent and they'll probably be to some degree similar mechanisms of resistance. So I think that the studies will fairly quickly move from being single agent into comparisons with bendamustine replacing cyclophosphamide in combination programs to see if they've become better.

I personally of course think that FCR is better than FR and better than PCR just based on what I know and what we've published. So I think whatever chemoimmunotherapy people are using in patients up to the age of 70 is a good strategy. If you have seven ANP, I'd recommend that they go on clinical trials because these patients are a) very difficult to treat, in practice anyway, and there are too few of them so that the more information we get, the better.

The lenalidomide data is intriguing. After Chanan-Khan and our group Dr. Farioli and colleagues, presented the data and she's presented the consensus of the two trials, it's obviously an active drug. It's a lot less predictable as a drug in CLL then in the other diseases, and there's minimal data on this and eventually we'll be thinking of combining it with alemtuzumab and other agents. But the other thing is that we'll probably start to use this as a consolidation for minimal residual disease.

There's the advantage of being an immune stimulant, if anything, and being available by mouth, so that I think that this time next year we may be reporting on three different clinical trials and a different phase of the disease, including lenalidomide in that equation.

Kanti R. Rai, MD

Coming to lenalidomide or revlimid — revlimid is going to be another important drug. But right now, excepting for its proven value as you just said in multiple myeloma, its proven value in myelodysplastic syndrome or MDS — for both of these conditions, the U.S. FDA already has given its approval.

The two main wrinkles are flare reaction. After initial exposure with this drug, the lymph nodes, which are somewhat large to begin with, suddenly get larger, painful, reddened, et cetera. And it is a very bothersome, frightening experience. It abates with continued treatment, but when it occurs, it sends frightening shockwaves to the patient and the family.

Second is tumor lysis syndrome, which is good and bad. Good that is shows that the drug is effective against CLL cells. Bad in that we have to find ways of controlling, find the right dose. Some people at M.D. Anderson use 10 milligrams by mouth daily. Others in Buffalo use 25 milligrams. Well, the effort is currently in place to start low and find a method of gradually building and finding out what is the necessary optimum dose, for we have not figured that out yet.

Susan M. O'Brien, MD

The original trial which is being updated here was the randomized trial of fludarabine and cyclophosphamide, plus or minus genasense in a relapsed CLL population. And that trial did meet its primary endpoint, which was the complete remission/nodular partial remission rate, which was 17% in the genasense arm and 7% in the chemotherapy-alone arm and this was statistically significant. What we saw at that time, however, is that, if you looked at the survival curves for the two arms, there was no difference; the median survival was the same.

Now, why would that be? Well, the reason is that that's a relatively low CR rate in both arms. But that's because it's uncommon to be able to achieve complete remission in the relapsed setting. So the problem is what's driving the survival curve in this trial, are the patients who don't get a CR or nPR 'cause that's the bulk of the patients.

So when you're looking at overall survival, it's the patients who are only nPR, who don't respond at all, who die much sooner, that have the biggest effect on the median. So — what we're showing now here is that, if the patients achieve this response, the CR/nPR, that these are very durable, and they are associated with prolonged survival. So, for example, we have follow-up now up to four and a half years, and, in the genasense arm of the people who are able to achieve that response, 60% of them are still alive.

Bendamustine is actually a drug that's been around for a long time. It was developed in East Germany, and the Germans have probably well over 20 years experience with it. But now they're looking to get approval in the United States. And, as you said, there was a randomized trial which was a poster here of upfront chlorambucil versus bendamustine. And what the data showed is that bendamustine produced higher response rates up front than chlorambucil, did have slightly more myelosuppression, but not serious infections, and the median progression-free survival was significantly longer with bendamustine than with chlorambucil. If you look at the bendamustine data, and then you think back to the original trials with fludarabine, they actually look very comparable. Response rates are very similar and progression-free survival are very similar. So it would appear, as a single agent, to have comparable efficacy. Now, it is a different type of agent, and there's actually some argument as to what exactly type of agent it is.

Andrew Schorr

So what does all this mean? Well, I think for all of us it means that there is so much more to talk about in CLL that can be significant and, certainly, in the next year, the next two years, prognostic factors, a whole range of treatments — they're bound to make a difference for people as we increasingly get into the era of personalized medicine.

For people who need initial treatment, no matter what their age is, I think there's a lot more to offer them and much more coming. So it's a very encouraging story. Stay tuned. For CLL Perspectives at the American Society of Hematology meeting in Atlanta, I'm Andrew Schorr.