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.
Susan O'Brien, MD
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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.
