New Prognostic Markers in CLL: Relevance to Current Clinical Practice
Guest:
John Byrd, M.D. Director of Hematologic Malignancies at Ohio State University and at the Arthur James Comprehensive Cancer Center and Hospital
Andrew Schorr:
Hello, this is Andrew Schorr with a podcast on CLL Perspectives. Thank you so much for being with us. Our goal here is to connect you with leaders in the field of CLL research and treatment and help you gain their perspective on important and topical issues in CLL. Joining us today is Dr. John Byrd. Dr. Byrd is the director of the Hematologic Malignancies Program at Ohio State University in the Arthur James Comprehensive Cancer Center and Hospital in Columbus, Ohio. His research interests focus on experimental therapeutics in hematologic cancers. Dr. Byrd currently heads several novel studies of promising new agents in the treatment of CLL, and he has earned numerous awards, including the 2000 Col. William Crosby Superiority in Research award, and that was from the Army American College of Physicians. Did I get that right, Dr. Byrd?
John Byrd:
That's correct.
Andrew Schorr:
There you go. Thank you so much for being with us, sir.
John Byrd:
Thank you so much for asking me to talk with you a little bit today, and I look forward to discussing some of the important issues that you alluded to.
Andrew Schorr:
Right. Dr. Byrd, so there you are at Ohio State, and you're well known in CLL, and so patients come to you from around the country and obviously they have community oncologists who have been helping them with CLL either in the diagnosis or also in the treatment. Do you have some comment on what you see at your end and any concerns or opportunities here we have today for discussion?
John Byrd:
Yes. Well, first of all, it's always very impressive with, in general, the care that community oncologists give to patients with CLL, particularly early on, and despite taking care of an array of patients with different diagnoses, and it always amazes me with the skill that many oncologists have. I would say, are there areas for improvement, and one can highlight a few areas of common things that we often hear at a secondary referral center where people come for second opinions often after being diagnosed. A very common thing, and we've been guilty of it ourselves and remind ourselves, is that when we're seeing a patient with very early stage CLL who comes with a white count of 12,000 who is not anemic or thrombocytopenic, and we've done the workup and have confirmed that it is CLL in its very early stage that there's a tendency when one has 26 other sick people who are much more ill than that patient to not spend the time initially during that first visit after the diagnosis has been established to really explain every aspect of CLL and what it means; but instead say, well this is a type of leukemia which we don't treat, there is not a curative therapy, but its something that won't cause problems for a long time, and not really go through and explain every component in detail and then having a short visit, and the patient leaves.
To the patient, that is often found as very confusing, and often they are very scared. They don't hear a lot of the assurance. If one spends more time and goes through and really explains things well and even brings the patient back a second time. That's how we do our visits, we do two visits for second opinions where we talk about the prognostic factors a second time to really explain things early on because there is a whole group of patients where things in our perspective as a secondary referral center where patients don't really understand the disease, particularly those who are early stage, and then they become very scared, and there's a much, much longer time then of adjustment to having CLL, having a disease that you're not receiving treatment for but that's there. Explaining things early on just from our perspective and explaining things well and spending lots of time can really, really make a difference in helping people get on with their lives with CLL.
Andrew Schorr:
Okay, so there you are in the way you approach a patient like that. Now, what happens though is at the community level there are often therapies that are introduced early, sometimes not optimized for CLL, if you will, as I have heard. Are you concerned about some of the treatment approaches that are taken and whether they were the right course at the right time?
John Byrd:
Yes. You know, it's always a challenging thing. After that initial visit is then you follow somebody longitudinally, and here again it becomes the education issue that if a lot of time is spent early on then; even if the count is going up a little bit or the nodes are increasing a little bit on the 3-month interval visits, but the patient is not having symptoms, and one provides continued assurances that in the absence of symptoms we don't treat; what can happen and what we see often is that the white blood cell count is going up, and it's 75 or 100, but it's going up, or the nodes are a little bit big, and there are subtle symptoms but not really deferrable symptoms that are causing the patient discomfort where therapy is sometimes started sooner than it should, and what one has to appreciate; and again, this is something that all of us see a lot of CLL have an appreciation for; is that the disease can wax and wane, and patients' counts can progressively rise to 100 and then plateau and remain at that level for some period of time. So, a big thing that I see often is starting therapy perhaps a little bit earlier than it should be started.
The other thing that I think is important, Andrew, is that when treatment is started, starting a treatment that is really individualized to the patient and say, what do we take into consideration for that? Certainly age is important, so somebody who is in their late 70s or 80s, we're going to treat very differently than somebody who is in their 50s. The genetic features, so if you have a deletion 17p, we're going to treat that patient differently than patients who have other genetic abnormalities and how we approach them, particularly if they're younger. So, I said 17p, but the 11q subset of patients would also fall into that group.
So, when you look at those groups, rather than putting those patients in the same basket, for instance for the older patient, the patient over 75, that's going to be somebody that you don't give fludarabine to or you tend to give fludarabine to much more sparingly because of the issues of neurotoxicity and increased myelosuppression seen with the nucleoside analogue. Whereas with the 50-year-old there is no reason, say if that patient otherwise does not have comorbidities, to use a combination chemoimmunotherapy; fludarabine/rituximab or fludarabine/cyclophosphamide/rituximab; because there you're shooting for a long remission and the risk of toxicities are much less.
Certainly for the high risk genomic patients, the patient that has 17p or maybe 11q; the 11q is more of a wild card; that's going to be a patient that if they're under the age of 75 you're going to treat aggressively with combination therapy, and if they have a sibling donor it's somebody that if they don't get a complete remission, so they still have disease at the end of their treatment, you're going to consider either consolidation therapy as part of an investigational trial or maybe a transplant. Again, I think that's a common thing that we see when patients come to us for a second opinion, when we render slightly different thoughts than the person who referred the patient, is sort of the individualization to the patient's age, the risk factors, and other comorbid factors that are co-contributing with their disease.
Andrew Schorr:
Let's go back to diagnostics for just a second. So, there are all sorts of things that have been discussed among researchers, like ZAP-70, but related to the genetics you were talking about, what do you think should be done initially at the community level to get a clear picture of this patient's situation?
John Byrd:
I think the genetic testing that is done at the beginning can really be helpful to putting the patient at ease about their disease. Again, of the prognostic factors that are available at Ohio state and what we do; and I think it's representative of what's available in most community hospitals; is everybody gets flow cytometry, we do interface cytogenetics that include the 11p and the 17p probes, which are the two adverse probes, we do immunoglobulin gene mutational analysis. This is available at many of the CLL Centers of Excellence in the U.S., but it's also available commercially through Genzyme, and they have a validated assay, that is actually the assay that's been validated by research labs that is being used in the early intervention CLL study that the Intergroup is about to undertake. We generally don't do ZAP-70 right now. I believe that it's important. I don't believe, however, that the testing that's being done commercially is validated and reliable. So, that's a test that we don't do, and it actually represents sort of the bane of our existence sometimes at Ohio State in the sense that we will have patients come with two reports, one that's negative and one that's positive, and then ask what does this mean? We don't know what it means, and that test is really not validated enough to be used in clinical practice to tell patients how their disease is going to behave or try to predict how the disease is going to behave over time.
Andrew Schorr:
Okay, so, you have these genetic prognostic factors though that would with some people mean earlier intervention and others that it would not.
John Byrd:
I think what these prognostic factors tell us is that we're still not going to treat the disease sooner off clinical trial. So, if you have 17p or 11q or your immunoglobulin gene mutational status is unmutated, that tells us that your disease is likely to progress quicker, and your treatment may be different when it gets time for treatment, but outside of a clinical trial, these still are not being used to treat the disease before it becomes symptomatic. Now, there are clinical trials, as I said the U.S. Intergroup trial of early intervention in CLL, will be testing patients soon after diagnosis for immunoglobulin gene mutational analysis status and then randomizing patients to early treatment with fludarabine and rituximab versus observation until the CLL progresses, and that's a big study. There is a similar study going on in Germany right now. So, there are clinical trials that are asking the question for patients that we know have a high likelihood of developing symptomatic disease, does early treatment benefit that group of patients? Off study, we would not treat just based upon a high risk genetic marker in an early stage CLL patient who was asymptomatic from their disease.
Andrew Schorr:
Okay, while we're talking about treatments of course, going back, an old line treatment has been chlorambucil or Leukeran, and we also have another approved agent, Campath or alemtuzumab. Where do these come in now in your array of treatments and for whom?
John Byrd:
It's always interesting that the therapies that are approved sometimes for frontline treatment of diseases are not representative of what is used in practice, and I would certainly say that's the case for CLL, Andrew as you alluded to, chlorambucil or Cytoxan and now most recently alemtuzumab are all approved for first line treatment of CLL, and unfortunately while they're approved for marketing for that indication, that doesn't really translate to are these appropriate therapies or the best therapies for newly diagnosed CLL patients, and if we look at the clinical trials, and as you alluded to chlorambucil is an older therapy, there have now been three randomized trials that have shown that combination therapy with fludarabine and Cytoxan are superior to chlorambucil or alkylator-based regimens, and probably fludarabine/cyclophosphamide is better than fludarabine as well. So, if we use evidence-based medicine and what our clinical trials have taught us, particularly for patients under the age of 65, fludarabine and cyclophosphamide is probably the best therapy for CLL.
Now, you're going to ask me next, well what about rituximab?
Andrew Schorr:
Right, either used in combination or repeated as sort of a maintenance therapy too.
John Byrd:
Right. So, there are studies that have added both the study at Houston that combines rituximab with fludarabine and cyclophosphamide and a study that we performed at CLGB with fludarabine and rituximab, and both showed much higher responses and remission durations than these fludarabine/cyclophosphamide studies. So many physicians, and I think not incorrectly, have decided that they're going to use that approach for the treatment of CLL because the remission rate is high, and the remissions appear to be longer, but these studies are phase II, they're not phase III studies. There is a big phase III study in Germany that just closed combining fludarabine, cyclophosphamide, and rituximab comparing it to fludarabine and cyclophosphamide, and hopefully we'll have the results of that study. We all anticipate that it will be positive and then say the rituximab will be validated as an appropriate therapy for CLL.
Relative to rituximab and something that we sometimes see in our practice that is probably an inappropriate recommendation on behalf of a treating physician is the use of rituximab maintenance in CLL. There really are no data thus far of using rituximab maintenance after initial treatment of CLL. In follicular lymphoma when rituximab maintenance was looked at versus just giving rituximab when you needed to give it, when patients became symptomatic, there was not a difference in the total time that one had until resistance to rituximab developed, so there really wasn't a difference in those two patient groups. So, using rituximab as maintenance versus in combination, which is good, maintenance is probably not something right now that is supported by the information that we have.
If it's okay, I'd just like to comment on Campath a little bit and its use in the up front setting. That is based upon a study comparing Campath or alemtuzumab to chlorambucil that is going to be coming out in the Journal of Clinical Oncology real soon, and unfortunately that phase III study showed that Campath or alemtuzumab was better than chlorambucil, but the schedule of chlorambucil that was used was not really the best schedule for chlorambucil, and the side effects with alemtuzumab were quite substantial in the sense that a fair proportion of people reactivated CMV, which is a virus that can cause fevers and in a small number of patients can cause life-threatening infections, and more importantly the remissions with either therapy were relatively short; 20 and 14 months, I believe, somewhere in that area; and so both of the average remissions in each of the arms of the study were shorter than what is seen with the combination therapies that I was mentioning before. So really where I use alemtuzumab, in terms of up front, it's a very, very small population. It's our very elderly patients who have deletion 17p abnormalities because alemtuzumab does work in that subset of CLL who don't have big lymph nodes, because alemtuzumab doesn't work in patients with big lymph nodes. So, again, some of the details that I'm telling you and we're talking about are details that sort of emphasize the importance of individualizing therapy based upon patient's clinical, laboratory, and genetic features.
Andrew Schorr:
Okay. Dr. Byrd, you're very involved in the investigation of novel agents. Are there any you want to comment on as far as putting it on the radar for our community healthcare providers?
John Byrd:
I think there are a couple of agents that are coming along nicely. In the antibody area, there is a new antibody, the HuMax CD20 antibody, which has generated a lot of excitement. There are studies ongoing right now in relapsed CLL patients whose disease has not responded to other therapies. The story is still out, but that antibody is fairly far along.
There has been a lot of excitement about Revlimid. We are very excited about Revlimid at Ohio State. It's a drug; it's a pill; it's approved in myodysplasia and multiple myeloma, and in those diseases it is active and in CLL. Both Dr. Chanan-Khan at Roswell Park Cancer Institute and Dr. Ferrajoli at M.D. Anderson have shown that it's active in CLL. I think the challenge with this is we really don't know the right dose to give. There actually have been fatalities in patients receiving it because of the tumor flare. So when you start taking it, it can cause the lymph nodes and the count to go up and cause what's called a tumor flare, and that can be life-threatening, and so while there's the temptation; this is a commercially-available drug; to give this, it probably at this point should not be given outside of a clinical trial, but it's a very exciting drug for CLL.
I think other things that look promising that are in late-stage clinical trials with lumiliximab or the CD23 antibody and say flavopiridol. There has been a lot of work in Europe with bendamustine which has chemical features of an alkylator agent as well as a nucleoside analogue like fludarabine, but when one looks at it in on the COMPARE Program, which is something the National Cancer Institute uses to distinguish drugs that have different mechanisms, it looks different mechanistically than the nucleoside analogues or alkylator therapy, and there have been nice responses in relapsed CLL patients with that in several studies, and there is just not a lot of experience unfortunately with bendamustine in the U.S., but it's much more commonly used in Germany and in eastern Europe.
Andrew Schorr:
There's one last area I wanted to ask you about, and this is sort of looking ahead to ASH. One of the presentations at the educational session is going to be from Dr. Lynn Golden from the NCI, and she is going to be giving information about familial CLL. So if you think about it from the perspective of the community doc, someone is diagnosed with CLL and says okay, do I have to worry about my kids? So, how are you counselling people at Ohio State?
John Byrd:
I think CLL is one of the most common diseases that has a strong familial association. About 8% of CLL patients who are diagnosed will have a mother, father, brother, or sister who also has CLL. So, despite the high frequency of familial CLL relative to other types of cancers, there has only been one gene, and we just reported that in the journal, Cell in June called DAP kinase, and it has in one family this gene when it's broken segregates with people who are at risk for developing CLL. Now, say for most patients, there is not going to be a gene like DAP kinase that we can identify. When we identify a family that has a strong family history of CLL, we generally will have them see our genetic counsellors because what we were talking about earlier about making patients as comfortable as possible with their disease by helping them understand; seeing a genetic counsellor can help to talk about those issues and then encouraging them to participate in the CLL Research Consortium, say the National Cancer Institute led consortium of investigators studying familial CLL because it's a lot of work to identify additional genes, and the way we're going to identify those genes and then be able to tell patients well yes you have the gene that predisposes or not is by getting more patients in the banks so we can do linkage to identify genes that are associated with CLL.
Andrew Schorr:
Dr. Byrd, one last question. As we look forward to ASH and all the discussions that come out of there, and we'll have another one with you there, are you encouraged? So, if people are living with CLL and making it truly chronic; it can't be cured at this time; are you encouraged that it can be managed for a long, long time and people can live a full life?
John Byrd:
I think at this point, the progress that's been made in CLL over the past decade has just been phenomenal. We really are getting to the point where we understand many of the things that are broken that actually cause the disease, and when you know the cause or you're merging in on the causes because CLL is not probably going to be one disease but it's several diseases that looks like one, one can then develop targeted therapies. A lot of the investment that was made over the past decades is really coming to fruition now where we have several new novel therapies that target these different aspects of CLL that are broken; the immune system, making the immune system better so it recognizes the CLL cells and destroying them; the targeted therapies. And I do believe that we're seeing the benefit in terms of the therapies that we're giving now, but the future looks all the more positive, and I think one could see in the next decade us even getting away from using some of the therapies that are the backbone of therapy right now, like fludarabine for instance, and maybe not becoming completely chemotherapy-free in terms of the treatment of CLL when it's necessary to treat but getting away from some of the more toxic therapies that are given for CLL by combining them with newer biologic therapies. So, in sum, I think things are very exciting relative to the future for CLL both in terms of therapies, supportive care, and understanding the disease and predisposing factors to the disease.
Andrew Schorr:
Dr. John Byrd, Director of Hematologic Malignancies at Ohio State University and at the Arthur James Comprehensive Cancer Center and Hospital, thanks for being part of CLL Perspectives and bringing your perspective to physicians and healthcare providers across the country and around the world today. We appreciate your time.
John Byrd:
Well, thank you so much again for asking me to be on this today.
Andrew Schorr:
Thank you. This is Andrew Schorr. Stayed tuned for other interviews we'll be doing with other leaders in the field of CLL to help you enrich your knowledge of CLL and do the best for your patients. I'm Andrew Schorr signing off.
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