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CLL Perspectives with Thomas Kipps, M.D.
Guest:
Thomas Kipps, M.D.
Andrew Schorr:
Hello. This is Andrew Schorr, and welcome to another edition of CLL Perspectives where we connect you, the practicing healthcare professional, with leading experts in CLL, the folks who devote themselves to chronic lymphocytic leukemia.
Our guest today is Dr. Tom Kipps. Dr. Kipps is Professor of Medicine and Deputy Director of Research at the Moores Cancer Center at UCSD, University of California San Diego. He is also Director of the Chronic Lymphocytic Leukemia Consortium. Dr. Kipps, thanks for being with us.
Tom Kipps:
Thank you very much, Andrew. It's a pleasure to be here.
INTEGRATING NEW INFORMATION INTO CLINICAL PRACTICE
Andrew Schorr:
Dr. Kipps, so when we talk about what maybe is well understood and what isn't related to CLL in the community, are there some areas where you think there may be confusion? Maybe we could use this time to clear that up.
Tom Kipps:
Yes, I think that that is a very important point. Obviously CLL has been a topic of intense research over the past decade, and there has been a lot learned about the genetics and biology of this disease, and the attempt to integrate some of that knowledge into the clinical practice obviously has to be done with the intent to validate any assumptions that you make so that we don't make an erroneous assumption and apply that to the clinical situation.
So, there's been a tremendous wealth of new information about markers on CLL cells that could influence the tendency for the disease to progress early versus late. There are also markers that are associated with a tendency to respond better to this treatment regimen or that treatment regimen, and some of these markers are going to be certainly very useful, particularly in defining maybe prognosis as well as treatment regimens in the future. But I think that when they are being integrated into standard clinical practice, there may be some confusion as to how best to integrate them into the practice.
GUIDELINES FOR TREATING CLL AND CONSIDERATIONS FOR USING NEW TREATMENTS
Andrew Schorr:
Let me ask you this question. I understand that you have new guidelines related to the treatment of CLL that are coming out in the journal Blood very soon. Give us sort of a look at that and what you think the bottom line is really.
Tom Kipps:
Yes, as you know, the previous guidelines were published over 10 years ago in 1996, and they were very helpful in being able to define what sort of features to look for in patients who do require treatment and how to assess the response to treatment, and in the attempt to integrate some of the new knowledge that has been gained in recent years, we have attempted to try and revise the guidelines.
I think it's very apparent, though, after many meetings with experts around the country and also around the globe; this is really an international effort; there is a consensus that we still are at the stage where the treatment and community practice of a patient with CLL should still be governed by the principles that were somewhat summarized in the 1996 guidelines.
Namely, it's clear that when the bone marrow is having compromised function because of leukemia cell involvement of the bone marrow that something needs to be done. So, patients with late-stage disease or more classically the Rai stage III or stage IV or Binet stage C, those patients are clearly in need of some therapy because oftentimes they may have further deterioration of marrow function, and that may preclude them from taking some of the agents that typically are used in treatment of this disease.
The other factor, too, to consider is whether the patient has symptoms that can be directly related to the leukemia, and those symptoms whether they are progressing as the disease progresses, obviously trying to improve the quality of life is important, and I think that physicians really have to address that issue.
A third aspect, too, is do we have clear signs that the disease is progressing rapidly? So, conventional measurements of lymph node size over time and lymphocyte doubling times are very important in trying to assign which patients are clearly progressing. I think that we have new markers certainly that can help maybe segregate patients who are more likely to have the tendency for progression earlier. I think some of these markers actually are quite useful. They are now being used to test the possibility that if you have markers that indicate that you will have progressive disease whether it's wise to engage in therapy sooner than these conventional criteria, but that needs to be tested critically, and the major question is whether it's going to really improve the outcome, and the next question, of course, is what type of therapy do you wish to have recognizing that some therapies do cause some problems, and one thing that you might get into is that for patients who don't have symptomatic disease, you're giving them potentially something to worry about or have problems from in initiating therapy too soon.
Andrew Schorr:
Okay, so it sounds like while there's a lot more to talk about, the practice-changing elements of it are not that great yet.
Tom Kipps:
That's correct. I think that there have been actually very few studies to show that treatment of patients before the standard indications effects an improvement of outcome. Obviously those studies are ongoing, and until we have that data it is difficult to make the assumption that earlier treatment is necessarily going to effect an improvement.
Coupled with that, there are so many advances now that are being ushered into the treatment of CLL; namely new monoclonal antibodies, new therapeutic agents, new small molecules, new targeted therapies, including gene therapy and vaccine therapies, as well as the aspect of stem cell transplantation. With all this ferment going on, I truly believe that the treatment of CLL is going to improve over time, and so the question is, do we want to buy into today's treatment now versus maybe have tomorrow's treatment when we get to a fuller understanding of how to best use it?
CAMPATH: DISCUSSION ON SUBCUTANEOUS VERSUS INTRAVENOUS ADMINISTRATION
Andrew Schorr:
Now, you mentioned about the new tools we have now; new approved drugs or drugs that have proven to be useful in CLL and I'm thinking of like the monoclonal antibodies Campath approved for CLL and rituximab, of course, that has been used widely in these illnesses. So, do you have any comment on at least what you're doing at UCSD or from your perspective with the CLL Research Consortium about clearing up any confusion there or your thoughts on the use of these drugs?
Tom Kipps:
I think the antibodies unquestionably have provided an advance, and they've improved the activity of standard chemotherapy, so when used in combination with chemotherapy or with newer agents it may improve their activity. I thing that there's recently also been a study which has shown that Campath or alemtuzumab used by itself may have a superior outcome in the treatment of patients than the drugs such as chlorambucil.
I think the confusion sometimes is, is when best to integrate the treatment with these newer agents into the current treatment and how best to use them. The Campath or alemtuzumab has more and more been used in a different route of administration than is approved by the FDA. It is actually approved for use as an intravenous drug; however, more frequently we see it being used as a subcutaneous drug, and I think recent studies done by a number of groups are showing that the drug levels that you might achieve with IV administration versus subcutaneous administration clearly are different, and it may require then a much more protracted treatment course of subcutaneous administration compared to intravenous administration.
This is something of a confusion because they recently completed a study that shows that Campath may be used as an agent even in frontline therapy has really used the intravenous route of administration where patients were given 12 weeks of therapy, and I think it's a mistake to equate that then with 12 weeks of subcutaneous therapy because this is clearly not the same in terms of the drug levels that you achieve and perhaps the clinical activity as well.
I think that we need to be able to determine how best to use Campath. Obviously giving it subcutaneously may give you fewer infusion complications; however, I think that the IV use can also still be safely rendered if given in the appropriate setting. I think that this needs to be, I think, done with some degree of caution and not to over interpret data from studies where the drug was used intravenously and then equate that with subcutaneous use.
THE ROLE OF RITUXIMAB IN TREATING CLL
Andrew Schorr:
Let me ask you about rituximab. So, in indolent lymphoma, of course, it's used widely, and there has been the maintenance approach of Rituxan after earlier use, and in combination now increasingly with chemotherapy agents, but it's also used in CLL by some that way. What's your comment about that?
Tom Kipps:
I think that rituximab is a very useful drug. Although not approved for the use of CLL patients, it's accepted as an important aspect of therapy. The use of rituximab has shown itself to be most effective when used in combination with other agents. The single use of rituximab as a single agent, either in maintenance or as therapy, has difficulty in achieving complete responses, and even the proportion of partial responses may be lower than one would consider acceptable.
The use of rituximab in a setting where the patient does not have clear indications for therapy, sort of, to speak, getting a tune-up, is not really given much in terms of data to support that activity. One can give rituximab. The relative toxicity is lower than compared to say combination chemotherapy, but one still has effects on the B-cells that make antibody. There may be problems with the infusion, so I think that the treatment itself is not necessarily free of any risks, and the important question is, is this truly making a difference? So when one gets maintenance therapy, I think it needs to be established that that maintenance therapy is really going to extend the duration of the response or improve survival, and those two aspects have not been demonstrated in any studies to date.
ARE CT SCANS USEFUL IN TRACKING PROGRESSION OF DISEASE IN CLL PATIENTS?
Andrew Schorr:
One other area of confusion or variance, if you will, is the use of CT scans, I imagine in looking at what is the patient's situation before treatment and then what are changes over time. What are your thoughts about that?
Tom Kipps:
Yes, it's a very controversial issue right now, and the Journal of Clinical Oncology recently asked me to write a brief editorial to comment on that, and in looking over the entire world's literature, there are very few articles that comment on the utility of CT scans in CLL. There is a study that was published by the group in Spain that actually looked at patients who have early stage disease, stage A or stage 0, and they did CT scans on these patients, and they were surprised to find that some of the patients, even though they were by physical exam felt not to have enlarged lymph nodes or enlarged spleens, that a small fraction did indeed have an enlarged spleen and some enlarged lymph nodes. Suffice it to say, those types of patients that had some enlargement did tend to have earlier progression of their disease than patients who did not, and so the question was whether the CT scans could benefit in the early diagnosis stage when you're not sure.
I think the other outcome of that study was that there are other markers or parameters that were associated with that group of patients, and it's unclear whether markers such as the expression of ZAP-70 or the expression of unmutated antibody genes or just basic issues of how long does it take for the lymphocytes to double in any one patient, whether those actually could be used in lieu of the CT scan to make that distinction. That's not really completely resolved.
There's another study that just came out from the Journal of Clinical Oncology (JCO) that commented on the ability to do CT scans after therapy and to try and use that information to see if it helped in determining how long the duration of the remission would be, and it seemed to be that there was no real improvement, no added value, from getting the CT scan that could help to make that assessment.
I think that there are other considerations to be made, and namely I mentioned Campath earlier, and many of the studies that have used Campath have found that patients who have bulky lymph nodes, that is lymph nodes in excess of 5 cm, typically do not enjoy complete responses when you use Campath. That's been born out in multiple studies, and I think that the use of Campath in that particular setting is challenged because one would not expect to have a favorable outcome with regard to the ability to achieve a complete response.
So, I think that the aspect here is somewhat needing more investigation. Suffice it to say that I think that the use of CT scans is sometimes equated to the use of CT scans in patients with other types of lymphoma, and I think CLL is different than most other types of lymphoma in that typically it's not just one lymph node or so that's enlarged or one small area of lymph nodes. It's more tending to be in multiple lymph nodes that are amenable for physical exam, so it's very surprising to see discordance between the physical exam and the CT scan. I think that it's more the exception to find a surprise from trying to compare the results of the two different studies.
I think that as far as CT scans and the consensus with the new guidelines that are coming down, it is felt that perhaps we should look at a CT scan before treatment and after treatment in clinical studies where we truly wish to assess before and after and try to really critically look at that information to determine whether it's truly adding added value to our clinical practice. I think I would really strongly discourage the use of the CT scan at intervals say of three to four months, which I have seen in some practices. I think that that is exposing the patients to significant radiation, and it's not really clear that that's going to provide a benefit over a good detailed physical exam and laboratory testing.
LOOKING TO FUTURE THERAPIES FOR TREATING CLL
Andrew Schorr:
Dr. Kipps, I want to take just the last couple of minutes of our interview to just look in your crystal ball, because after all you're on the leading edge of research. So, you mentioned all these new things, many that are not ready for prime time, but what are you particularly excited about as you look to where the treatment for CLL will be maybe just in the next two, three, or four years?
Tom Kipps:
I am very excited about the ability to use our own immune system to recognize and destroy the leukemia cells. I've been excited about that prospect for some time, but in more recent times I think that there may be some developments that may make it more practical and more feasible for more patients, and I think that we have to look at the issue of transplantation where patients have achieved curative treatment when they've received a transplant because the graft can sometimes recognize and destroy the leukemia cells. That can also be achieved by not having a transplant by just activating our own immune system, and I'm very excited about this because even the most resistant leukemia cell that's resistant to all different drugs is still very sensitive to being killed by cytolytic T-cells in the immune system.
More recently, the use of such aspects of gene therapy to activate the immune response is, I think, something that we will be seeing further developments of and then more recently we've also been able to find unique proteins that are expressed by the leukemia cell that seems to be present on the leukemia cells but not on normal lymphocytes or normal adult cells. It seems to be proteins that might be expressed only as we develop in embryo in the fetus, and these are so-called oncofetal proteins, and they may give us a handle at which to direct vaccine therapy so that we can now truly think about developing a CLL vaccine that could be potentially used early on, perhaps at diagnosis, to try and induce that immune response to hold the disease in check so as to obviate other types of treatments that we know have some toxicity.
Andrew Schorr:
It sounds like you're excited.
Tom Kipps:
I'm very excited.
Andrew Schorr:
Well, coming from you, the Director of the CLL Research Consortium, that means a lot, and of course your life's work at UCSD, Professor of Medicine and then Deputy Director of Research at the Moores Cancer Center. Dr. Tom Kipps, thank you so much for being with us on CLL Perspectives. We look forward to talking to you more and getting your take on the research that's presented at ASH.
Tom Kipps:
Thank you very much, Andrew. It's a real pleasure, and I hope to see you soon.
Andrew Schorr:
Thank you. This is Andrew Schorr. Thank you for joining us.
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