ASCO 2011: New Developments in Chronic Lymphocytic Leukemia

Susan O'Brien, MD

ONCOLOGY talks with Dr. Susan O’Brien, professor in the department of leukemia at the MD Anderson Cancer Center. Dr. O’Brien will be one of the presenters at the upcoming ASCO session on therapies for chronic lymphocytic leukemia, and she gives us a preview of what some of the highlights of the session are likely to be, as well as some insights into her own work.

-Interviewed by Susan Beck

ONCOLOGY: We’re talking today with Dr. Susan O’Brien, professor in the department of leukemia at the MD Anderson Cancer Center. Dr. O’Brien will be one of the presenters at the upcoming ASCO session on therapies for chronic lymphocytic leukemia, and we’re hoping she can give us a preview of what some of the highlights of the session are likely to be, as well as some insights into her own work.

Dr. O’Brien, let me start by asking what, in your opinion, are the areas of CLL therapy in which there are the most exciting new developments?

DR. O’BRIEN: Well, there are a couple of new molecules that are very exciting, and in keeping with the theme in oncology in general of targeted therapy, these are molecules that target enzymes that are present in the B-cell receptor pathway. The relevance of this of course is that CLL is a B-cell lymphocytic disease, and activation of B-cells in general and activation of B-CLL cells provides a very strong survival stimulus to those cells. So if you could block downstream one you get activation of the B-cell receptor so that the messages that normally would be carried to the nucleus are blocked, then potentially you could interfere with these pro-survival signals and get death of the cell. And there are two drugs targeting completely different proteins but having remarkably similar mechanisms of action and efficacy that are going to be talked about at ASCO.

So the first one is a drug – and this shows you how new they are because they don’t have names yet – the first one is CAL-101, and this is an isoform selective inhibitor of a protein called PI3K kinase. And again, this PI3K kinase is downstream in the series of enzymes that are activated after ligation of the B-cell receptor. Now this drug is very specific, as I mentioned, for one isotype, which is the delta isotype. And the relevance of this is that the delta isotype is the one usually more highly expressed in B-cells.

So the phase I study with this drug is going to be updated at ASCO. This is interesting because it’s an oral agent, generally given twice a day, and not surprisingly, the patients going into these phase I trials tend to be very refractory. This is a trial that actually was opened for lymphoma, based on the same rationale, and CLL, but the data that you’re going to see updated at ASCO is specific for the patients that were treated in that trial.

What’s interesting about a this drug – and the second one I’m going to tell you about – is that when you start treating the patients with these B-cell receptor inhibitors, the first thing you notice is that you get this very dramatic shrinkage in the lymph nodes, but at the same time, the white count goes up. And it’s important to recognize this because you don’t want to just be looking at the white count and thinking “oh, the patient is progressing on treatment.” What happens over time is that, although initially it looks more like a compartment shift – in other words, cells going from the lymph nodes into the blood – over time in many cases the cells in the blood also start to die off, and the hypothesis is that because you are – and there is some nice preclinical data to support this – that because you’re interrupting the stromal environment and CLL cell interaction, this drives the cells into the blood. OK, well what causes them to die inevitably? What causes them to die inevitably is that they will die off over time as any cell would because they are not in contact with the stroma and constantly receiving pro-survival signals. But the mechanism of action is interesting and important from a clinical point of view so as not to mistake this initial rise in the white count as progressive disease and take the patient off study.

ONCOLOGY: I was going to ask if there are any side effects that are noteworthy, or is this one of those novel agents that has a much better side effect profile that the . . .

DR. O’BRIEN: You anticipated exactly what I was going to say. So, the main toxicity of this drug appears to be asymptomatic increases in transaminases, or liver functions, and this was generally seen at the higher doses, although interestingly it was seen much more commonly in the lymphoma patients than in the CLL patients, for reasons that are not really very clear. The good news, however, is that from a patient point of view, this isn’t a toxicity that they experience in a symptomatic way, and in many cases – no, in all cases in which there was a significant rise in the transaminases, the drug was held, and this was a reversible rise, and there actually were patient that could go back on the trial at a reduced dose and continue without any problem to receive therapy.

Now, one of the other very exciting things about this agent is that it’s not myelosuppressive. And why this is so exciting is because, remember in CLL, being a leukemia, particularly in heavily pretreated patients, the patients have very compromised immune systems, and they often even have cytopenias, based on the extent of marrow disease as well as prior therapy. So look at most of the treatments that we have for CLL: almost all of them are significantly myelosuppressive, and that’s why, in general, the most common complication of treatment of CLL is myelosuppression and infection. So to have an active agent that doesn’t cause myelosuppression is a very attractive concept in CLL.

There are several ongoing studies, but one that we’re participating in, along with a few other centers, is a combination regimen which is CAL-101 and rituximab. Remember that rituximab is the monoclonal antibody targeting CD20, a cell surface protein on most B-cells or B-cell malignancies such as lymphoma or CLL. This is a trial that’s open for frontline treatment of patients over the age of 65. And the rationale here is that, although in healthy younger patients a regimen such as FCR (fludarabine, cyclophosphamide, rituximab combination) would be considered standard of care, just as I was alluding to a few minutes ago, that’s a regimen that produces a significant amount of myelosuppression and infections. And there’s very clear data, and it’s been published, that in people over the age of 65 or 70, not surprisingly, not just because of age but because of concomitant comorbidities, these therapies are a lot more toxic, they run into a lot more problems tolerating them, and in many cases you can’t finish it. So the rationale here is, combining CAL-101 with an antibody, we have a presumably extremely nontoxic and almost completely non-myelosuppressive regimen for an older population. So I think that’s a very exciting ongoing study.

ONCOLOGY: Now, are you talking about a frontline therapy in the older patients?

DR. O’BRIEN: Yes.

ONCOLOGY: Wow, OK. Because my understanding was that most of these novel agents were being used in refractory disease.

DR. O’BRIEN: Now both of the drugs – and I haven’t mentioned the second one yet – are going into combination regimens. Obviously the phase I’s, because they’re phase I’s, were done in primarily refractory populations. But now there are some combination regimens, both with chemo in the relapse setting and this particular one, which happens to be in the frontline setting but only for patients over the age of 65.

ONCOLOGY: Is there anything else that you wanted to say about CAL-101, or did you want to move on to the second agent?

DR. O’BRIEN: No, I can talk about the second. So, the second one also doesn’t have a name yet. This is called PCI-32765, and this again is targeting a protein in the B-cell receptor pathway, but a different one that CAL-101. This is targeting a protein called Bruton’s tyrosine kinase, or BTK for short. And like the CAL-101, this is an oral agent; this one is given daily continuously, and like the CAL-101, it has that same initial profile in terms of response, where you see the lymph nodes shrinking dramatically and the white count going up at the same time, and then over time the white count goes down and you have your true partial remissions by standard criteria. It’s also very nontoxic. It does not have the hepatic transaminase elevation that CAL-101 has, so that has not been seen with this drug. It’s also essentially non-myelosuppressive, and in fact with both drugs, another interesting point is that many of the CLL patients that started with cytopenias, such as anemia or thrombocytopenia, have had significant improvement in their cytopenias on both of these drugs.

This drug is also in combination trials with chemotherapy as well as with antibodies, but the data that you’re going to hear at ASCO are updates on the phase I trials.

ONCOLOGY: Did you want to talk a bit about the treatment implications regarding some of the new markers?

DR. O’BRIEN: Yeah, it’s interesting. So for example, some of the things that predict for either suboptimal response to chemo or, if not a suboptimal response, a shorter remission duration, are, to give one example, something called the mutations status. Some patients that are unmutated – and these are often the patients that express ZAP-70, which is another poor prognostic feature – have shorter remission durations after standard frontline regimens such as FCR, so if the patients’ CLL cells are unmutated, their remissions don’t last as long. Now what’s interesting in particular with respect to the two drugs we just talked about is that when we’re talking about the patients who are unmutated, we’re talking about the B-cell receptor. And the reason that patients who are unmutated appear to have a poorer prognosis is that they have much stronger downstream signaling after ligation of the B-cell receptor. So in other words, if they’re unmutated, and the B-cell receptor is activated, there is much stronger signaling than in the patient who’s mutated. So it’s an interesting hypothesis, and this is something we’ll see later, but it’s a little too early to suggest that the B-cell receptor inhibitors, the ones I just talked about, might if anything be more effective in the unmutated or the bad risk subgroup because those are the ones where it’s very clear that the downstream signaling from the B-cell receptor is so important in keeping the cell alive. So you could hypothesize that that particular poor risk feature – mutation status – might actually be correlated with a better response or at least as good a response, whereas the effect of the mutation status shows a poorer long-term effect after chemo. Sos that’s very exciting, that some of these new agents might be able to override some of the known poor prognostic features associated with response or remission duration with chemo. The reason I say it’s too early is that that data is being collected, and remember in the phase I, we’re talking about 40 or 50 patients, so there’s a lot of heterogeneity in terms of prognostic factors, but this is a very exciting idea, and it’s being looked at in all of the ongoing trials, including the combination trials. Are the prognostic factors that are associated with somewhat worse outcome with chemo going to be less relevant with some of these new targeted therapies?

ONCOLOGY: Well, this has been tremendously informative, Dr. O’Brien, and I thank you very much for your time.

DR. O’BRIEN: OK. You’re welcome.