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(Drug information on 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(Drug information on 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.