Date: February 10, 2005
by Chaya Venkat
There is little doubt that smarter therapy choices can be made in CLL, if you know what type of CLL you have been blessed with. In their important paper Prognosis at Diagnosis, Dr. Neil Kay, et. al., make a strong case for prognostic testing of CLL patients at the time of diagnosis, so that a rational game plan can be designed. Gone are the days of one shoe fits all - welcome to the age of risk stratification and therapy choices based on individual prognostic profiles of patients. This is the single most important development that has taken place in the past few years. You are missing a lot if you don't get benefit from it.
We have discussed in detail the list of modern prognostic indicators in our article What Type of CLL Do You Have? You may ask, what is the point of knowing this information? How does it help to find out, for example, that you are one of the unlucky few that has the p53 defect (defective TP53 gene)? Besides worrying about it, what is the point of knowing this information, how does it help you live longer or with better quality of life? This specific what-if scenario makes it easy to figure out why ignorance is not bliss.
Most busy or otherwise occupied community healthcare providers still consider fludarabine as the "gold standard" frontline therapy, especially if they have not been doing their home work and staying up to date on the latest research. If you have aggressive disease (and you are very likely to have aggressive disease with a p53 defect in your CLL cells, as in this example), you will come up against the need to make therapy choices pretty soon after diagnosis. Not for you the luxury of waiting around for years while you contemplate your choices. Chances are that your CLL will percolate right along, and when the time comes you will go along with the recommended fludarabine therapy, in the absence of any information to the contrary. If you are lucky, your oncologist would have read What You and Your Oncologist Need to Know about CLL, and you will get the fludarabine with appropriate protection against reactivation of Herpes virus and you might be spared a strong and painful dose of shingles. We have read in recent reports of other nasty viruses that can seize the opportunity, come back roaring in an immune suppressed patient. Viruses such as TB, Epstein-Barr, hepatitis, etc. If your oncologist is a good sort, he might take the trouble to warn you about the risks of skin cancer during periods of immune suppression, and you might be as good as gold in taking appropriate precautions. Maybe your post-therapy neutropenia will not be so pronounced, and you sail through the fludarabine therapy with not too many infections or side effects.
But even with this optimistic scenario, there is no question that fludarabine as well as other purine analogs and alkylating agents such as chlorambucil (Leukeran), cyclophosphamide (Cytoxan) cause significant immune suppression and carry significant mutagenic risks. It has been clearly established by now that p53-defective CLL cells do not respond to fludarabine therapy (Fludarabine Monotherapy No Longer the Gold Standard; Fludarabine, FISH, Prognostic Indicators), and patients with this defect will get very short and unsatisfactory remissions with this drug. There is even the chance that your CLL will pick up other mutations, as a consequence of the therapy. What a crying shame. All that toxicity, pain and suffering, not to mention new mutation risk factors caused by the therapy itself, the potential for secondary cancers such as skin cancer - all that and nothing more than a short remission to show for it. Would it not have been a better scenario if you had bothered to get your FISH analysis done right up front, as soon as you were diagnosed, so that you had this critical piece of information about your p53-defective state?
Don't get me wrong, getting the prognostic tests done do not change the nature of your CLL. But they can surely change your therapy choices. With a p53 deletion you would not consider fludarabine a slam dunk choice for single agent frontline therapy. If your oncologist absolutely insisted on this particular choice, you might even steel yourself, fire the guy and get yourself a new oncologist. And one other point to clarify: fludarabine is an important drug. It is a potent and dangerous drug, and none of us would take it for recreational purposes. But given that we are cancer patients, it is all about making pragmatic choices, making sure we get maximum bang for the buck. Some times none of the choices are particularly good and we have to make the best of it, just like we do every four years when we vote.
Prognostic information would also be useful in giving you guidance on what you should do, not just what to avoid. If you are a young man with family to raise and mortgage to pay for many years, high risk prognostic factors such as a p53 deletion and unmutated IgVH gene status may make you take a harder look at bone marrow transplants (Primer on Bone Marrow SCTs). You would make sure you were extra nice to your siblings from then on - one of them may well turn out to be a perfectly matched stem cell donor for you. "Mini" allo transplants are still the only procedures out there that have the potential for an outright cure, and these procedures are a lot better tolerated by younger patients and those that have not been through every chemotherapy regimen known to man and mouse. Several CLL experts I spoke with at the ASH2004 had this to say about patients with p53 deletions: that they are well advised to get a solid response with some sort of a Campath based therapy, and then hot-foot their way to the transplant center.
The other side of the coin - if I were a patient with a nice 13q deletion, mutated IgVH and all the other indicators of a comfy Bucket A situation, I would kick back, relax, and not let my angst trick me into signing up for some heavy duty combination therapy. I would rest easy knowing that the chances are good my CLL would take a long time to come to a simmer, and by that time there may well be a whole lot of better therapy choices. I might do my bit to get a little healthier, lose that extra weight, improve my nutrition and exercise habits and lead a virtuous life, hopefully improving my chances of winning the battle when and if I have to engage.
OK, I hope we are all now on the same page, it is important to know the prognostic bucket you fall into, so that you can make smarter therapy choices. But I agree, getting these tests is done is a logistical nightmare right now, far easier said than done.
There is now general consensus on what tests to do. The FISH panel for CLL and IgVH gene mutation status are the most important and robust of the modern prognostic indicators. ZAP-70 is important, but there are still many quirks to be worked out in the testing methodology. B2M and CD38 levels provide insight into the status of your CLL, but since these two indicators change over time, depending on the phase of your CLL, they are not that useful as long term prognostic indicators. (If all of these acronyms sound like gibberish to you, I suggest you read our article What Type of CLL Do You Have? in which each of these prognostic indicators is discussed in detail).
Sure, each of the expert CLL centers such as the Mayo Clinic and M. D. Anderson do a full battery of prognostic tests, but they are hardly "inexpensive". In any case many patients do not have the luxury of going to one of these centers. Last I heard, if you wish to avail yourself of M. D. Anderson's comprehensive CLL screening package without the benefit of adequate insurance coverage, you had to bring with you a cashier's check for thousands of dollars (I heard the number $12,000, but I cannot confirm it). None of the other expert centers are much cheaper either, I would bet.
Some of the commercial testing labs say that they do each of the necessary tests. One of our volunteers checked into this claim. It is a matter of garbage in, garbage out. It is easy enough to produce a piece of paper with numbers on it, impressive sounding jargon and even multicolor graphics. We came to the conclusion that with few exceptions, the test results reported were undependable and the methodology unproven. Without technically credible lab results to back them, our patients will find it hard to "sell" their local oncologists on all these new fangled tests. Furthermore, without a prescription from the guy in the white coat, in many states you cannot even get the tests done and insurance companies are likely to tell you to go pound sand.
I am happy to report help is on the way. After conversations with several organizations, we have gone far enough in our negotiations with Quest Diagnostics (the nation's leading provider of diagnostic testing; NYSE DGX; www.questdiagnostics.com) that I feel a progress report to our readers is in order. Quest is the country's biggest commercial testing company. Unlike some new start-ups they have the muscle and the market savvy to deal with various insurance carriers, Medicare, Medicaid, etc. One of the small labs that I spoke with earlier did not accept any insurance carrier - they just could not handle the credit risk or hassle - and it was entirely up to the patient to negotiate coverage. Like you do not have enough things to worry about already. Quest, on the other hand, accepts just about all the major carriers and that is a big plus. Unlike more research oriented-facilities or ivory towers, Quest's commercial agenda makes it easier to push for rapid development of a good product at a decent price, a win-win situation for the customer (that's us) and the company. Time is money for the company; and time is life, from our perspective. That common ground makes it a lot easier to get this show on the road.
But for my money, the biggest plus with this company is that the hematological pathology department at Quest is now headed by Dr. Maher Albitar. I met this gentleman during one of my several visits to M. D. Anderson. He is probably one of a handful of truly expert pathologists specializing in hematological cancers in the world, and you will see his name on just about all the major CLL papers that came out of Anderson for the past many years. Much of the highly regarded research out of Anderson rested on solid lab work conducted under the guidance of Dr. Albitar. He still works closely with many of the researchers in the CLL Research Consortium. Very recently he has moved from M. D. Anderson to Quest, and thereby opened a window of opportunity for us.
Where do we stand in our negotiations? I think we will be able to get the ducks lined up and announce the prognostic package deal from Quest within the next couple of months. The role of CLL Topics in this negotiation is strictly as pro-bono representative of patients to articulate their needs. There are no payments or kickbacks in either direction. No money, no perks, nothing. We are trying to make sure we get a good price on an initial prognostic package, as well as potentially an annual monitoring package. We expect that the price should be at least as good as the price negotiated by Medicare. As we know, Medicare is the 900 pound gorilla in payment negotiations. It is simple common sense: we are less likely to have hassles with insurance coverage for the tests if they don't cost an arm and a leg. In addition, we are trying to see what can be done for those patients who do not have insurance coverage, or where the insurance carrier refuses to cover the expense out of sheer cussedness.
The letter below from me to Dr. Albitar is pretty self-explanatory. Your thoughts and suggestions are welcome. The whole idea is how to short circuit some of the frustration and hassle in this process. We will also be setting up a whole section on the CLL Topics website on the subject of how to read these lab reports. We will try our best to help Quest make their prognostic package reports patient friendly but where jargon is absolutely essential from their perspective, possibly from regulatory compliance and liability concerns, we will backfill with down-to-earth explanations that could be more useful to patients. All in all, if we reduce the barrier between patients and modern prognostic testing, I think we would have done a good days work. Agreed?
Maher Albitar, MD
Quest Diagnostics, Nichols Institute
February 8, 2005.
Dear Dr. Albitar,
I thoroughly enjoyed the telephone conference call this morning with you and Ms. Babineau from your marketing department. I would like to update our membership on the progress we have made thus far in our negotiations, and I have jotted the highlights of our discussion, for your review.
It is rapidly becoming clear to me that the majority of CLL patients are not benefiting from the breakthroughs in prognostic testing that has happened in the last couple of years. All the CLL experts (including members of the CLL Research Consortium) now recommend therapy choices made on the basis of solid prognostic information, but this expert guidance is not percolating down to the local oncologist level fast enough. Our membership is large, pro-active, and willing to short circuit the delay in implementing these modern guidelines and thereby improve their own healthcare. But we need your help to get this show on the road. Every month of delay in getting this prognostic information available to patients means that many more patients who pay with their very lives as a result of inappropriate therapy. As an example, several recent studies have identified that fludarabine therapy as a single agent is not likely to be effective in the case of patients with 17p defects. Most community level oncologists still consider frontline therapy with fludarabine as the "gold standard". How can patients make the decision to go or not go with this recommendation, unless they are able to have definitive information on their FISH cytogenetics status?
At present, there are several roadblocks in the way of even the well informed and pro-active patient in getting comprehensive prognostic testing done, outside of going to one of the CLL expert centers. Not every one has the luxury of going to one of these centers, and we would like to remedy this situation. Your personal reputation, experience and research credentials as one of the top rated CLL pathologists, combined with Quest Diagnostic's ability to deliver high quality, commercially viable service and support makes for an attractive combination. I am delighted to hear that in the next couple of months you will be able to meet most if not all of the needs we have identified. We are looking forward to working with you.
Once we get the go-ahead from Quest Diagnostics, we plan to give wide publicity to this prognostic package on CLL Topics' website www.clltopics.org. You should be prepared to handle the volume, we think there is a large unmet need here. While this prognostic package is limited to CLL, and that is the extent of our interest, we think your experience in working with this patient group can be translated to a number of other situations. Working together on this package is a win-win situating for your company and our patient community. We will do our best to help you make this patient friendly prognostic package the one to emulate in the industry.
CLL Prognostic package: Patients' wish list:
I have listed below the specific tests that should be in the comprehensive CLL prognostic package. I fully concur with your concerns regarding the dependability of ZAP-70 testing. As it is presently done, this test can only provide ancillary information. Prognostic information obtained by IgVH gene mutation status and chromosomal abnormalities identified by FISH panel are much more robust indicators. Obviously, as we learn more about CLL and find better ways of doing the testing, some of the testing protocols may change, some tests may to prove to be less than useful and therefore dropped, while new ones may get added. That is exactly as it should be.
A major source of frustration for patients is how lab results are currently reported. No attempt is made to make the information patient friendly. As you suggested, we would be happy to give you feedback on how the report format can be customized so that patients are better able to understand the information. Some of the aspects of the reporting that we think can be improved are listed below.
It is very important that we establish streamlined procedures for ordering the comprehensive prognostic package, as well as the smaller monitoring package. We hear from many patients who are frustrated because there is no single easily accessible site that gives all the information necessary for patients to get these tests done. Local healthcare providers are often too busy to dig out unfamiliar tests, especially if they require multiple codes and sample handling instructions. Here are some suggestions that would make the logistics a lot simpler, make these prognostic and monitoring packages much more accessible both to patients and their healthcare providers.
Dr. Chaya Venkat
CLL Topics, Inc.
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Topic: Prognostic Indicators