Therapeutic Management of CLL - Episode 4

Treatment for Cytogenetic-related Outcomes in CLL


Thomas J. Kipps, MD, PhD: I think it’s very important, these risk factors that I have talked about. I mentioned the study done in the year 2000 by Döhner’s group, and that was using FISH to define subgroups of patients. As I mentioned, the patients who had deletion 17p had the least favorable outcome with a poorer survival, and the intermediate category was patients who had deletions in chromosome 11. We recently completed a study with the CLL Research Consortium, and what we found actually was very interesting. The same hierarchy applied: Patients with deletions in chromosome 17 still were faring as the poorest subgroup. But their survival has improved, and this, we think, is through the advent of chemoimmunotherapy or immunotherapy regimens, and getting the word out that you should not treat these patients so that they’re almost near exhaustion with chemotherapy. It’s not going to work.

And so, survival has improved in patients with deletions of 17p but prognosis is still worse than with the rest of the patients. The patients who had deletions in the long-arm of chromosome 11 still were not showing much improvement over what was published about 17 years ago. They still did not fare as well as patients who did not have any detectable abnormalities, or patients who had deletions in chromosome 13 or chromosome 6 or trisomy 12.

When we looked at the data for patients treated in the early trials with ibrutinib, it was interesting, because it was noted that patients who had prior treatments—many, sometimes up to 5 or 6 prior treatments—were treated with ibrutinib in the earlier treatment trials. You could see that patients were, over time, developing resistance to the treatment with ibrutinib. And so, you can define the progression-free survival when patients, even though they were taking the drug, would show that they had to stop the drug because they were developing resistance. And in that analysis from the early trials, it was the same hierarchy going on again. So, I was saying, “Here we go again,” that there’s something about this hierarchy. But I’ve always maintained to patients that, really, we shouldn’t put the onus on the patient. I like to not say to the patient, “You have bad disease,” but rather, “We just have bad medicine for your disease.” If we had better medicines or better treatment strategies, we should be able to turn a bad prognostic marker into one that’s not so bad, or maybe even favorable.

I think what we’ve been able to show while we were conducting studies with ibrutinib—I helped chair a study that compared patients over age 65 who were randomized to receive treatment with a chemotherapy like chlorambucil versus treatment with ibrutinib, the RESONATE-2 trial. This was frontline therapy for patients over age 65. And in that study, we found that patients who took ibrutinib and continued to take ibrutinib enjoyed a longer progression-free survival and overall survival than patients who were taking chlorambucil. And so, this trial led to ibrutinib being registered for treatment in the frontline, namely as initial therapy.

We began to look at the data, and it appeared that the patients who had deletions in chromosome 11 were actually doing quite well, and this seemed to go against what the former studies had indicated. So, with help, the members who conducted all these trials—with Pharmacyclics—were able to go through the data of patients not only treated on the RESONATE-2 study, but patients treated on the RESONATE-1 study, who were patients who had some prior treatment and were randomized to receive ibrutinib versus ofatumumab. And also, data from the HELIOS trial—namely, these patients were randomized to receive ibrutinib versus a placebo, and that was done in the setting of bendamustine and rituximab.

What we were able to do by combining these 3 studies was gather a large group of patients together who had known cytogenetic features. We excluded those patients that had deletion 17p, because they were not included in the RESONATE-2 study, because we did not think it was appropriate to give patients with deletion 17p chemotherapy. So, those patients were excluded from the RESONATE-2 study.

We focused our attention on the patients who had deletion 11q versus other cytogenetic changes, and it seemed to bear itself out. But the patients with 11q were doing not only as well, but also seemed to be doing better than patients who did not have 11q, or deletions in chromosome 11. So, clearly there’s something going on here that would indicate maybe it’s not so incorrect to tell a patient that they don’t have bad disease, just bad therapy.

As we change our therapies, we may change how we view these so-called prognostic markers. As I mentioned earlier, there’s a difference between a prognostic marker and a predictive marker. The predictive marker is a marker that helps to predict how well you’re going to do with this given therapy. A prognostic marker is one that tells you how well you’re going to do overall. That should be independent of therapy. And so, I think what we’re seeing is a divergent between predictive markers and prognostic markers. That’s improving the prognosis, but we also have to say that the predictive markers we had before, with say chemotherapy, are perhaps no longer applying to newer types of therapy. That’s quite exciting, because we shouldn’t say that it’s a done deal—that if you have a bad marker, it just goes back to saying, “We just need improved treatment options and improved drugs and improved combinations of therapies.”

I think that patients should have cytogenetic testing. The FISH testing is very useful, it’s available everywhere, and it should be applied. It’s an easy test. It can be run on leukemic cells in the blood if they are present, or we like to look at the leukemic cells in the marrow, because we find a higher proportion of them there. And this gives you invaluable information.

We also do another test, which is to look at the chromosomes, and for that we stimulate the cells and try to induce some proliferation. What we can do then is now take the cells and look at the chromosomes themselves, and that could spot genetic changes that are unusual or rarer than the ones that are detected by FISH. Several years ago, we got the cytogeneticists together at a lot of the institutions across the country under the auspices of the CLL Research Consortium, and we got them all together in the Mayo Clinic, and we came down with a unified way of stimulating the cells to do what we call a karyotypic analysis.

The cells are stimulated with a cocktail that includes what’s called an oligonucleotide, which stimulates the cells to grow. And then we look at these cells and what we find is that you can sometimes detect translocations, which are one chromosome latching on to another chromosome, or deletions, and you could not detect those by standard FISH analysis. And that’s what we have been able to define as a complex karyotype—when we find 3 or more different genetic changes within the cells that we’re analyzing. That’s seemingly very important as well, and I would encourage that we test that. Obviously, I tell patients that the simpler your genetics are, the better off you are. If you have genetics that seem like the chromosomes have mixed themselves up like they were put into a Waring Blender, that could be difficult. It could indicate that the leukemia has an ability to maybe resist some forms of treatment. We’re trying to look at the significance of that right now.

I think that getting these tests is very important. Looking at other genes, such as p53, we think is important too. Because, as I mentioned before, if p53 is not present, the ability to respond to chemotherapy is very much reduced. So, knowing ahead of time—it’s like you’re mapping out a journey. If you don’t check the weather report and you’re going down the highway and you find the highway’s closed because of a snowstorm, that would indicate you haven’t done your job of checking the path before you go there as to avoid trouble down the road.

Transcript Edited for Clarity