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CLL Perspectives with Susan O'Brien
Guest:
Susan O'Brien, M.D.
Andrew Schorr:
Hello. This is Andrew Schorr again with another one of our CLL Perspective interviews with a leader in the field of treatment and research in chronic lymphocytic leukemia. With us is Dr. Susan O'Brien, Professor of Medicine in the Department of Leukemia at the University of Texas M.D. Anderson Cancer Center in Houston and well known for authoring and coauthoring numerous publications related to CLL. She specializes in that along with CML. Dr. O'Brien, thanks for being with us.
Susan O'Brien:
A pleasure to be here Andrew.
Andrew Schorr:
Dr. O'Brien, so are things changing the way we can now approach the treatment of CLL, the way it's been for so many years with what you have to offer patients, targeted therapies, and what you're seeing in research? Could physicians begin to look at treating it differently in the community?
Susan O'Brien:
I think that they can, and I do think that there may be an age difference in the sense that with the current therapies that we have, particularly combined chemoimmunotherapy, we can get high complete remission rates and we can get very durable complete remissions, and that should still be the standard approach for younger patients, but I think you could easily state that there really is no standard approach for older patients.
Now, what is older is a little bit in the eye of the beholder I suppose, but there is no question that if you look at clinical trial data, our data from M.D. Anderson and it's true if you look at CALGB data, etc., the median age of most patients treated on those trials is around the late 50s to 60s, and yet the median age at diagnosis of the patient's with CLL in general is probably closer to 70. Now, the reality is that patients that are 80 years old don't get referred for clinical trials, and that's reasonable in the sense that you might want to take a much more palliative approach in that patient rather than going say for a PCR-negative CR, which might be what you'd like to get in a young patient with CLL.
So, it is reasonable to have a different approach, but the reality is that most of the very effective regimens that have been described have been described to be effective in a younger population, and if you do look at the small percentage of patients treated on those trials that are over the age of 70, this true for example for FCR, that they are usually not able to complete the planned six cycles. They definitely have more problems with myelosuppression and infection, and so I think that although those therapies can work in older patients, the ratio in terms of the morbidity associated with the response is very different.
So particularly with older patients I think in the academic community there is a strong wish to try alternative treatments in those patients that may be effective and may have less toxicity, and this is where as you said Andrew, the phrase "target therapies" which is probably a little bit of an exaggeration, but what do we mean by that? Well, we mean that the research into CLL has identified various biologic pathways that may be upregulated in CLL, and so it potentially targets in terms of interfering with those pathways or proteins that are constitutively phosphorylated and upregulated in patients with CLL where we might want to target that protein to try and interfere with the disease, and so some of these agents that we have now that look to target specific proteins or specific pathways in the preliminary trials appear to have very little toxicity, and so these types of agents may wind up being nice therapies for older patients if we can show in the trials that the efficacy is reasonable with such agents.
Andrew Schorr:
Now, people who are referred to M.D. Anderson who you see often have had many other therapies before. What would you say as far as a relationship between the community oncologist and you related to maybe seeing some of those patients earlier where some of these newer experimental therapies you are working on might have a better chance?
Susan O'Brien:
I think that's a very good point. I mean, the reality is, I mentioned, that we have very good frontline regimens for patients that are younger, and that those remissions are durable, but the reality is, and this would include even younger patients, that once a patients relapses, there is not really a standard of care. If they have had a durable first remission, then you can treat them with what you gave them the first time around or a similar regimen and get a reasonable response rate, but for example complete remission rates drop off dramatically.
So let me give you an example. With FCR up front, the complete remission rate is about 70%. If patients receive FCR as a salvage regimen and they've only ever failed one prior therapy, which in some cases is FR or single-agent fludarabine, that's the best group because now they've only failed one treatment rather than multiple, and the CR rate drops down to about 35% or 40%, so almost half. So again, it doesn't mean you can't get some type of response in patients, but CRs in the relapsed setting are very uncommon and once you go beyond first relapse you almost never see them. So, the point being that although patients can be retreated and get some type of response, the responses are generally not as good quality, and they tend to be much shorter. So, I think that really even starting with first relapse is a time where we should be thinking about alternative treatments, again particularly in elderly patients where retreating with chemotherapy another time may be even more problematic not just for older patients but even for younger patients where we don't really have a standard of care.
We tend to keep using the same drugs we have because they provide some kind of a response and because the truth is there aren't many drugs that are effective, and now that we've gone to chemoimmunotherapy, we're using two or three drugs at the same time and so exhausting, if you will, what the options are for relapse other than using the same drugs again. So, I really think that as early as the first time the patient relapses is when people can start thinking about, are there some potentially good alternative therapies out there?
Andrew Schorr:
Okay, let's get to the nitty gritty. What are the ones you think of whether in trials or what's available?
Susan O'Brien:
Well, there's quite a number of agents that are available in trials, and of course trials aren't for everybody and we already touched on the fact that elderly patients may not get referred because it's much harder for them to travel, etc., and the reality is there is a lot of variability in these trials in terms of how much the patient needs to come to the center where the trial drug is, so you might have a study that's a first-in-man, and we're participating in one of those now, where because it's the first time that drug's ever been given to humans, and they happen to have CLL, the patients have to be seen every week, and that may not be feasible for a patient who really doesn't live within easy driving distance of a center that's participating in the trial. However, we have other trials of investigational agents that have been given to other patients. For example, we have a trial with an investigational drug where it's been given to several hundred patients with lymphoma. So, there's a very good safety profile on that drug. The investigational part is giving it to patients with CLL but because we know much more about that drug, the patients after their first visit at 1 month only have to come back every 3 months, which is pretty doable for many patients even if they don't live in that immediate area. So, there is heterogeneity in what the trial requires to some extent partly based on how much we know about that drug and whether we have some perspective on how easy or hard it is to use based on the fact that it may have been given in other patient populations but certainly there are enough clinical trials out there that I think almost any patient, even if they don't live close to a center, could probably fit on one of them.
Andrew Schorr:
So, give us some examples though Susan on in a relapsed setting then what you begin to think about beyond repeating the same treatment? So, for instance, what you're doing there, understanding some have to be done right at the research center and only at the research center, and some can be done in cooperation with the community or they can come back with some frequency but not all the time. Help us understand what some of those agents are that you're using now.
Susan O'Brien:
Well, you know, as I said, if a patient has had FCR up front, let's talk about what other drugs are actually out there that are commercially available. One is chlorambucil, and that’s a weak, relatively ineffective alkylating agent, so I don't think anybody would move from FCR to chlorambucil. Alemtuzumab is an excellent drug, but it is limited by the fact that it's particularly good at clearing blood in marrow disease. It's very good in patients who have baseline cytopenias. It's not very good in the patient's with bulky adenopathy. So clearly that's a drug that's commercially available and can be prescribed in a relapsed setting and can be quite effective, but there's going to be a whole subset of patients, i.e., those with very bulky lymph nodes where you know going in that you would get a suboptimal response and wouldn't be that crazy about using that drug in that setting.
So, what else do you have then that you haven't already used? Really nothing. I mean, you're talking about going perhaps to lymphoma-type regimens, platinum-based, etc., and obviously those have their own toxicities and myelosuppression and in general you're going to get more myelosuppression on the second go around or the third go around of relapses because probably you've had more of a battered bone marrow, if you will, from prior treatment. So, there really isn't a lot out there, which again speaks to the point that in many cases using the same drugs again are what's done, and again that's not unreasonable except that you have to expect that you're not going to get a CR, and you're not going to have anywhere near as durable a remission as you got the first time.
I can speak to a number of agents that are in clinical trials now, obviously I'm particularly familiar with the ones we're participating in, but there are a number of categories. There are new monoclonal antibodies. So, there is the HuMax, which is anti-CD20. This binds to a different epitope than rituximab and appears to be particularly effective at low CD20 antigen density, and we know that in patients with CLL the number of molecules of CD20 is much lower than in patients with lymphoma.
There is another new monoclonal antibody, which is lumiliximab, that's an antibody to CD23. Currently there's a trial in the relapsed setting where the patient's get FCR and are randomized to receive lumiliximab with it or not. There's another antibody that's in phase 1, and that's an anti-CD40 antibody, and so that one has a little bit more stringent followup, but that's just antibodies.
There are trials now with Revlimid, which clearly is proving to be active in CLL. It's an oral agent that makes it attractive, but it is myelosuppressive, so although we don't think of it as chemotherapy per se, in terms of the myelosuppression profile, it's very similar to chemotherapy but attractive to patients because it's oral and they don't have to come in and get IV infusions.
There's another drug in clinical trials that's oral called enzastaurin, which is a PKC inhibitor, and PKC is constitutively upregulated in CLL, and that was actually the agent that I was thinking of when I said there's a pretty vast experience in lymphoma and so the patients after the first month only have to come back to the centers every three months because we know that this is a very safe drug that hardly has any side effects, and there are a number of other trials.
We have trials with a drug that inhibits Hsp90. Now, what's the attractiveness of that? Well, we know that the patient's with ZAP70 positivity have a worse prognosis, so ZAP70 would be something that potentially you would like to target, but the downside of targeting ZAP70 is remember that that's a normal protein in T-cells, so if you just target it you may wind up with a very immunosuppressive drug that even if it's eradicating the B-CLL cells will be also dramatically depleting T-cells, but Hsp90 is a chaperone protein to ZAP70 in CLL cells but not in normal T-cells. So here the drug, which is an oral agent. It doesn't have a name yet, it's just got a number, and is targeting Hsp90 to hopefully downregulate ZAP70 in the patients who are ZAP70 positive but not affect the T-cells, and again, that's in phase 1, and that's an oral agent, but that's also a first-in-man, so that requires a little bit more followup.
There is another drug that was developed at Ohio State called flavopiridol, which in a very refractory group of patients there produced about a 50% response rate, and that's now going into clinical trials in many centers across the United States, and I'm just giving you a snapshot. I could even name more drugs that are in clinical trials including new alkylating agents. There's new nucleoside analogs. Forodesine is one that's an oral agent; clofarabine, which has been approved for pediatric; ALL is being investigated in CLL, and really there are a number of others. So, I think that there actually are a huge number of trials out there, but of course if you're not involved in them, how do you find out about them? I think that's where we can make it easier for physicians to know about this trial it might make it easier for them to refer patients also.
Andrew Schorr:
Dr. O'Brien, you're sort of our crystal ball into what we hope could be a better future for CLL patients. So for the community physician, when someone is diagnosed with CLL and now we have proven regimens that do well up front, then they have a discussion about well hopefully you're going to live a long time with this disease and they say okay, what's coming down the pike? If they say well I just heard a talk by Susan O'Brien, and the future looks good, would that be the right characterization, or how would you counsel them on what they could tell their patient on other lines of therapy developing if and when the CLL then comes out of remission?
Susan O'Brien:
Well I think one thing that could be very helpful is to make the patient aware that there really are not very good choices out there for them other than an investigational trial, and it's a little bit of a psychological issue because patients with CLL have had their disease for a long time. Now the irony is, and this is referring to patients who have required treatment, there are certainly indolent patients who might go 20 years without requiring treatment, but now we're talking about people who at some point in time had gotten to the point where they require treatment.
The reality is that those patients, although they may now have lived a long time, are probably going to die of their disease at some point in time when they become refractory, and yet the longer they go with their disease, the least likely they are to think that. It's sort of a conundrum because you've had it for so long, the patient just keeps feeling like well this I will just keep going on, and I'll get a little bit more fludarabine, and I'll respond the next time, etc.
So I think one of the issues we face in the academic center when we're conducting these trials is that a patient is referred, but maybe the doctor has not really sat down with the patient and said I do not have anything to offer you. You will not respond to the standard treatment. You're at a point in time where this is a very serious issue because your disease has now failed all of the standard treatments, and you really need to think hard about what we're going to do next. I don't always think that conversation occurs like that.
Let's be realistic. Who wants to have those kinds of unpleasant conversations? It's more like, well let me just refer you. So the patient comes and I don't think they're necessarily always even wanting to be there. Sometimes they think well I'm here because my doctor sent me, and then you talk to them about the investigational agent, and they have to come back let's say every two months, and they look at you and think that's kind of too hard and besides this drug doesn't have a big track record, obviously because it's investigational, so I don't think I want to do this.
It's very difficult when you're the physician seeing them for the first time to address this because you don't have a relationship with the patient that their own physician has. You don't have the rapport with them, and if you then try and sit down and convince them not necessarily to go on a study but that their survival at this point is going to be short and alternatives are needed. Sometimes you just come across as a black cloud that they don't even know who is giving them all this bad information, and it actually gets them to want to get out of there even more.
So I think what would be very helpful is if patients are referred that they really kind of know. You know it's a difficult conversation, and again that's why it's a better conversation for a patient to have with a physician with whom they have a good relationship because you don't want to say to the patient your time is up, but you don't want them to think that they're going to go another 10 years just getting a dose of fludarabine here or there because it's simply not going to happen, and if they think it's going to happen, then why are they going to bother to go on an investigational trial?
So, I know this because I also treat acute leukemia, and there it's very different, and that's frankly because the patient who has acute leukemia who fails chemotherapy has a very short survival, and they all know it. So, they're gung ho for going on investigational treatments, and they have a whole different perspective because they have a whole different disease that they haven't lived with for years and sort of gotten the feeling that this is going to go on forever. So it's really very different when you talk to acute leukemia patients about investigational trials as opposed to talking to CLL patients about them. So again I think this is something where if the patient came more psychologically prepared it would really be very helpful in terms of getting these patients on trials.
Andrew Schorr:
Okay. And the hope is getting on trials with what you outlined, all those agents that you're investigating, that we'll do better, but it sounds like there has to be that serious discussion. This is a serious disease. You're relapsing. The therapy we had won't do as well the second time around. We need to look at what's investigational that could make a huge difference for you, and I think that's an important discussion. Did I get it right?
Susan O'Brien:
Yes, you got it right. And it would be fair to say that we don't know that all these investigational approaches are going to work, and so you have to come up with a happy medium. I mean, that's why we don't test them out on patients who've never received treatment because even though we know we're not curing CLL if we know we can give somebody FCR and get a six-year remission, well of course there's no rationale for giving them an investigational drug.
On the other hand, once a patient has failed six therapies, their likelihood of first of all being eligible goes down because they probably have severe cytopenias and other problems related to the extensive prior therapy and then even if they are eligible, their likelihood of responding, let's be realistic, is slim because they have such refractory disease. So I think there has to be a window. I mean I don't think we're suggesting treating previously untreated patients, although I would say that in an elderly patient and patients say above 70, you could even make a case for some of these investigational approaches up front because of the toxicity and the morbidity that we know we're going to see if we give these people triple drug regimens, but that aside, you know, in younger patients nobody is talking about using an investigational agent up front and maybe not even at first relapse if they had a very long first remission and they're likely to re-respond to the same agents. But the problem is that the reality is that when we see these patients usually it's not first or second relapse, it's sort of, you know, they've had fludarabine six different ways and maybe they've had alemtuzumab and they've had just so much prior therapy that then it becomes problematic both in terms of eligibility and in terms of the likelihood of benefiting them.
Andrew Schorr:
Well, as always Dr. O'Brien, you have a very frank perspective, and you call it as you see it, and really I think elucidate some very important issues here. I want to thank you, Dr. Susan O'Brien, Professor of Medicine in the Department of Leukemia at M.D. Anderson in Houston for being with us and sharing your unique CLL perspectives. Thank you Susan.
Susan O'Brien:
A pleasure Andrew.
Andrew Schorr:
I'm Andrew Schorr. Be with us again next time for CLL Perspectives with other experts in CLL. Thank you for joining us.
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