Prognostic Factors 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.

Susan M. O'Brien, MD

We're all aware that now we have a number of fairly sophisticated prognostic factors that can help us know whether the patient is going to have a very indolent course or a more aggressive course. But then a question that gets asked very often is, "Well, how exactly do I use these? Can I use these to choose a treatment? Can I use these to decide when to start treatment?" And the really simple answer to that would be, "Not yet."

I think that, to some extent, that's coming, but it's not quite there. Where we can really use them right now — and this is already being done in randomized trials — is that we can ask the question, "If somebody has high–risk features, should we really take a watch–and–wait approach, or should we treat those people earlier because we know that they're going to go on to progress?" But, without clinical trial data, to say that they do better if you treat them earlier, it's just a supposition.

So the Germans have a large randomized trial where they're taking patients with high–risk disease, but who are not very symptomatic — so normally we would watch them — and they're randomizing them to watch and wait, which is what we would do now, or immediate treatment with FCR. But it's going to take a while to get some of the answers from those trials. So, without the data, I would say that right now we cannot use the high–risk factors to say we should immediately start treatment.

Now that doesn't mean they're not useful to know, because where I find it very useful is in counseling the patient. So, for example, I can have two people who come in with very early-stage disease, asymptomatic. But one of them has a high beta 2-microglobulin, is unmutated, is ZAP-70 positive, has maybe an 11q deletion on FISH — so lots of bad prognostic features. And the other, let's say for the sake of argument, doesn't have any of those. Well, what I would tell those patients is very, very different in terms of what's going to happen to them.

Thomas J. Kipps, MD, PhD

I think the prognostic markers are unquestionably a help right now in terms of trying to identify differences between patients; that we can now recognize who is going to be in trouble, who is going to have a greater probability of not requiring treatment for a longer period of time.

I think this is very important because I'm looking for improvement so we can change the way we treat this disease in a fairly radical fashion, which might avoid then some of the longer problems that we have with some of the older therapies.

Then we could start focusing our attention on developing regimens for those individuals. We have to be very careful here so that we don't impinge on their quality of life or use regimens that may actually shorten their life. That's very critical.

We do have evidence, for example, that patients who have certain cytogenetic lesions will have a more difficult time achieving a satisfactory response with our current chemotherapy, even chemoimmunotherapy, and the most important lesion is the loss of material on the short arm of chromosome 17, the so-called 17p abnormality that involves the locus of p53. Many of these patients have loss of p53 function; not invariably so, but many do. And patients who have this typically have a poorer response to chemotherapy. They may respond initially, but then the disease seems to be refractory and doesn't get cleared from the bone marrow. Consequently, you have a bone marrow that's still pretty well subdued from the treatment, but the leukemia there is resistant to the drugs and you can't give more drugs because you risk further myelosuppression. So this is not a good situation to be in. I think that the 17p minus — we need to be mindful of it — is worthwhile to try and recognize this early on and, after the diagnosis, to see whether there are noted cytogenetic lesions, such 17p minus and, to a lesser extent, the 11q minus, which is involving the long arm of chromosome 11.

John C. Byrd, MD

There's a lot of interesting new data on prognostic factors, where some of the traditional prognostic factors, such as interface cytogenetics, are holding very, very strong. But we're picking out groups of CLL patients that, perhaps, who have the bad, the less–favorable genetic markers— the 17p, the 11q— that how many of the cells they have really matters. And Michael Keating's group had a very interesting paper showing that, in a subset of 11q– and 17p-positive CLL patients, that the abnormality over time is lost.

Michael J. Keating, MB, BS

The good news is that 17p is very uncommon initially; the bad news is that it becomes a lot more common as time goes by and the treatment of relapsing patients is very difficult. There's evidence that alemtuzumab is active, quite active, for a short period of time in patients with 17p. There's emerging data on the use of allogeneic transplant in 17p, so that I think that we're going to be doing the acute leukemia–type thing and carving out and making decisions on the whole strategy of these patients, not just in lumping them in a clinical trial, but perhaps separating them out de novo.

I think from the prognostic factor point of view, the things that I hold onto are three. One is the beta 2–microglobulin, which is probably the best consensus prognostic factor that we have, and it's dirt cheap. And it's a number. Secondly, the mutation status which is complicated and expensive, but it remains constant through the disease and it's giving a lot of information on longer–term outcome. The FISH analysis going on to clinical trials or on to first therapy is very important from the point of view of the 17p. The 11q I think is becoming a lot less of an issue because the addition of cyclophosphamide to regiment really is transforming that disease. It's a very good outcome and there are abstracts to support that at this meeting.

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.