Our last workshop was entirely devoted to the subject of prognostic indicators. After four hours of pretty intense discussion, most of us felt we could have gone on for quite a bit longer. The subject does not lack for complexity or interest.
In this article I will not be describing the tests themselves, or explaining what they are all about. For that, I refer you to our publication of the workshop slides as well as detailed comments. You may also find our much earlier (but recently updated) article “What type of CLL do you have?” worth reading.
Are Prognostic Factors in CLL Overrated?
- Is there any benefit in assessing prognostic factors in CLL patients at presentation?
- Which prognostic factors need to be determined at the time treatment is required?
- Do these prognostic features alter our approach to therapy?
- What is the benefit in assessing prognostic features at presentation?
Here are a couple of direct quotes from Dr. Gribben’s editorial:
“There is increased value in assessing prognostic markers at the time treatment is required. Genetic abnormalities detected by FISH are not stable and change over time. Therefore, even if a full FISH panel was performed at the time of diagnosis, this would have to be repeated. Other factors, such as immunoglobulin mutation status, are stable, but this assay is complex and not readily available in routine laboratories. Assessment of ZAP-70 expression is fraught with the difficulties of both the relative non-reproducibility of the assay and the need to determine an appropriate cut-off that has prognostic significance. While I perform a full prognostic marker work-up, this is for academic reasons; in practice, assessment of stage, performance status, beta-2-microglobulin level, and CD38 level, along with cytogenetic analysis by FISH, may well be sufficient.”
“Taken together, the impact that the advances in our understanding of the pathophysiology of CLL has made on the management of the disease remains rather modest. The challenge going forward is to align our scientific advances with our clinical practice.”
I share Dr. Gribben’s lack of faith in ZAP70 testing. After much discussion among experts, we still do not have consensus on how this marker should be measured so that it is reproducible and consistent. But when it comes IgVH gene mutation status testing, I respectfully disagree. You do not have to take just my word for it either. To get a different perspective on this issue, I refer you to a recent post on Dr. Terry Hamblin’s blog. Terry is no stranger to IgVH gene mutation status as a prognostic indicator – he credited for having discovered its pivotal importance in the first place. Does that make his opinion biased? I don’t think so, but you be the judge.
Must-have, non-negotiable testing
OK, let us cut to the chase. What testing must you have, if at all possible, at the time of your diagnosis?
Since it is impossible to make any decisions without having a rock solid diagnosis in the first place, testing done to confirm CLL and ruling out several of its kissing cousins that may masquerade as CLL - that defines must-have testing. Basically, in addition to the possibly routine blood test that flagged too high a white blood count and started this whole ball rolling in the first place, you need to have flow cytometry done to identify the CD markers on the B-cells. CLL cells have a particular set of markers, a kind of fingerprint of the disease. Other blood cancers have different sets of markers. Here is a comparison of CLL’s fingerprint, compared to other common B-cell blood cancers.
If what you have is indeed CLL, your cancerous cells should exhibit CD5, CD19, and CD23. CD20 and surface immunoglobulin (“Sig”) should be detected, but at low intensity – also called “dim” expression. And they should not exhibit FMC-7, Cyclin D1. That is the short version of the cheat sheet. ”Atypical” CLL may sometimes confuse matters. And since atypical CLL may also carry the penalty of aggressive disease, if your flow cytometry results do not match the straightforward pattern of CLL, you should be seeing an expert and getting a second opinion in any case.
If I were in your shoes, I would also get the standard “metabolic panel” blood test that determines stuff like liver function, kidney function, sugar levels, electrolyte levels etc. CLL does have the habit of infiltrating the liver, for example (“hepatomegaly”). And many of the drugs you may need to take down the road are not friendly to the liver and kidneys. Getting a baseline established on how these two important organs are functioning is important. If you are the type that is going to indulge in every over-the-counter potion and pill out there, it is even more important to know how your liver is doing, so that you do not create toxic conditions. Liver failure can kill you a lot sooner than CLL!
I would also get vitamin D3 level checked. This too is a simple blood test and I noted with interest that my GP now routinely orders it for me at my annual consult, as part of well-patient routine monitoring. The role of vitamin D3 insufficiency in CLL is still being debated. But prudence is the better part of valor, in my opinion. Vitamin D3 supplementation under medical supervision is easy to do, something to consider especially if you are going to be smart about avoiding excessive UV (sun) exposure – CLL folks are more likely candidates for skin cancer, and that is something you can take to the bank, no debate on that front! Here is a link to just one of many articles we have on the subject of skin cancer. Use “BCC’ or “SCC” as key phrases in the search box at the top right hand corner of our home page to find other articles.
What don’t you need to get done? What is a waste of time, money, and downright wrong-headed and painful to do? You do not need painful and expensive lymph node biopsy. Everything that needs to be learned to make CLL diagnosis can be done by simple blood tests. Flow cytometry to determine the CLL “fingerprint” of classic CD markers (discussed above) is a blood test, no more painful to do than the routine blood tests people get all the time. And it is all that is needed to do the job right. When my husband was diagnosed back in the summer of 2001, we were bamboozled into a painful and quite expensive lymph node biopsy by our local guy. It provided no additional information, achieved nothing more than padding the bill. Don’t you fall for it!
Do people need CT scans right away, at the time of diagnosis? No. Unless there are complicating considerations, I do not think so. Sure, down the road such scans may be necessary to judge the status of lymph nodes etc. But at the time of diagnosis, it is quite enough to have detailed physical examination by a trained oncologist. Swollen spleens can be felt quite nicely by prodding. Palpation can feel many of the swollen nodes under the jaw, armpits, groin etc. True, some of the nodes buried deep in the abdomen cannot be evaluated by physical examination. But there is time enough to worry about that later on. It is not an pressing issue at the time of diagnosis. Who needs the extra exposure to radiation, not to mention steep charges on your healthcare bill, if it is not really necessary at the time of diagnosis?
Do you need a bone marrow biopsy at the time of diagnosis? No. Expert opinion has been shifting on this one. Back in 2001, M. D. Anderson felt it was, and in fact they did a bone marrow biopsy at each of three visits we had there in the first year of my husband’s CLL career. Type of bone marrow infiltration ( diffuse or nodular) was considered of prognostic value. More recently, this perspective has changed. Bone marrow and bone marrow aspirate testing is being done in the context of clinical trials, where the ability of a drug to clear the bone marrow needs to be evaluated. In other words, percentage infiltration before and after therapy is still crucial in new drug evaluation. But BMB is no longer a standard of care procedure necessary at the time of diagnosis. That is good news, since it is by no means a painless or cheap test.
Down the road, perhaps after series of therapy interventions, it may be necessary to do bone marrow biopsy to judge level of infiltration. This is particularly the case if the patient is suffering from decreased red blood cell or platelet counts. We have discussed in prior articles the difference between anemia or thrombocytopenia caused by autoimmune disease (AIHA, ITP) or more dangerous late stage infiltrative CLL. If the bone marrow is so choked up with CLL cells that it is no longer able to carry out its job of creating new red blood cells or platelets, that is important information you must have – and the only way of confirming bone marrow health is through a bone marrow biopsy. Since BMB results are only as accurate – and therefore useful – as the experience level of the pathologist examining the slides, I strongly urge you to go to an expert center when and if you need a BMB.
Looking into the crystal ball
OK, you have done your due diligence, gotten a rock-solid CLL diagnosis. Now you come to the more complicated part. What kind of CLL is it? Does your particular flavor of “good” cancer put you into the lucky indolent group of patients that may not need therapy intervention for a nice long time? Or are you holding the short end of the stick, with very aggressive disease that is going to be a driving the bus of your life right from the start? No way of telling, not without doing some of the modern prognostic tests.
Let us get the cheap ones out of the way right up front. B2M (beta-2-microglobulin) is easy to do. It is a cheap and routine blood test. B2M levels change over time, so its best value is giving you a sense of where things stand at any given point of time. My husband’s oncologist ordered it every three months, regular as clockwork. No big deal.
CD38 testing is pretty standard by now. It does not suffer from the lack of reproducibility problems that ZAP70 suffers from. Again, it is an easy to do blood test and not all that expensive. There was a time when experts hoped CD38 levels are a surrogate for the more expensive IgVH gene mutations status – but that did not turn out to be the case. CD38 levels change over time. So, like B2M results, it too is of value as a marker that you follow over time to get a fix on how things stand.
The standard FISH panel looks for deletions in the 13q, 11q, 17p locations, as well as trisomy 12. Please be aware that FISH results that report “normal” as the status just means you have none of the above defects. It does not mean you have entirely normal and pristine chromosomes. The more accurate description of “normal” FISH results is “none of the above” or “something other than the ones we tested for”. You get it?
FISH tests are limited not just by the probes used (the present day standard CLL panel uses the four probes mentioned above), but by the limited information they provide. For example, FISH test cannot tell if the crucial bit of 17p is present but somehow messed up and not doing its job as it should – possibly due to subtle mutation of the gene located there, or because it is silenced by crud covering it up (Epigenetic silencing).
Limited though it is, the information provided by FISH is quite crucial to our patients, especially when it comes to making smart therapy choices. Patients with “only” 13q deletion may be at liberty to consider less aggressive therapies, reducing their exposure to more toxic choices. 11q deleted patients may consider FCR as opposed to FR. While this is still a topic open to debate, several recent clinical trials have suggested 11q deleted patients do better with FCR than FR. As for folks with 17p defects, it is important to pay attention to this prognostic indicator. As we discussed in several articles, these patients are not well served by fludarabine containing regimens (such as FCR, FR, FC etc). Alternative choices such as Revlimid, Campath based regimens and still experimental flavopiridol may be better choices. R+HDMP may also work well – if you are inclined to go that way.
But here is the clincher. A recent and very important consensus paper from Europe recommends that patients with 17p defects are candidates of mini-allo stem cell transplants, sooner rather than later. In fact, the conventional wisdom is now trending to transplanting suitable candidates with 17p defects in their very first remission. Waiting longer and letting the patient go through several layers of ineffective chemotherapy options just means the patient is less likely to get successful outcome from a mini-allo transplant.
Since clonal evolution of CLL cells is a fact of life (whether or not you believe in Darwinian evolution of species!), things can always change in your FISH test status. Clonal evolution is more likely after therapy, and especially in people with unmutated IgVH gene. Since FISH status influences therapy decisions, it is probably a good idea to have the test repeated just before you sign up for the next course of therapy. I mean, would you want to put your poor body through the six months of FCR therapy, if you knew ahead of time that your newly minted 17p deleted status suggest this therapy is not going to give you much of a response?
That brings us to the grand-daddy of them all, the most crucial bit of the puzzle, IgVH gene mutation status. We discussed it in detail in our workshop, please go there for the juicy details. It is unfortunate that this test is still quite expensive, even though more commercial labs are doing it now and the prices are coming down. If you want my opinion, I think you should get this test done at the time of diagnosis. The good news is that the result does not change over time and you do not need to get the test done again.
Why would anyone not want to get prognostic testing done?
Now let us look at the other end of the argument, why prognostic testing may be either unnecessary or unwanted.
Consider an elderly patient, elderly even by CLL patient standards, who has had CLL for a decade or so – and doing just fine. Nothing predicts the prognosis of such a patient better than his track record thus far. If he has had CLL for a while, with nothing much to show for it, chances are excellent that he would continue to trundle along and live out his natural life span. Or, at the very least, pay only a small cost in reduced life expectancy. Detailed prognostic testing may not be necessary to gild the lily.
Patient’s personality plays a big role in determining how much prognostic information is necessary. While the aggressive patient advocate in me balks at the concept, I must nevertheless admit that many patients really do not want to know the details. They are quite comfortable in “outsourcing” their CLL worries to their doctors. If you are in this group, more power to you. In your shoes, I would just want to make sure I have a good oncologist that I trust to keep an eye on things and make the right calls on my behalf when therapy become necessary.
Recently I got to know a few patients who came to this country from far less developed parts of the world for CLL diagnosis confirmation and prognostic testing. They then went back to their home countries where the only therapy choices available are chlorambucil – or at a pinch, fludarabine. What is the point in getting detailed prognostic information if your situation does not allow you to act upon the guidance such information provides? This would only make quality of life worse for such patients.
Fear is a strong motivator. In some people it motivates to increase desire to learn, try for better control over the situation in an effort to influence a better outcome. But in some folks it motivates an entirely different response, a strong desire to run away and try to put it out of their minds. Both are human responses and I am not here to make a value judgement. I can only speak from my own perspective as a card carrying type A personality. It would drive me crazy not to know, I would want to be in charge of my own healthcare – at least to the tune of being an informed participant in the decision making process. Only you can decide how fear motivates you.
Since I am not a religious person, I am not qualified to comment on how patients’ faith and strong belief in their religion and prayer play a role in the value they place on prognostic information. Perhaps one does not influence the other. Only you can decide what seems right to you on this front.
The good news is that the availability of quality information online has made it easier for people to come up the learning curve and be better advocates for themselves. That is the single most important objective of this website – give you a choice. I cannot do the heavy lifting of actually reading and learning. You have to do that for yourself. But I hope the long hours I spend reading and writing, translating medical jargon into something approaching straight English gives you a choice. I have no claims on wisdom. But I do try to keep things pretty much on a level keel. This website tries hard to keep snake oil and miracle-of-the-month reporting to a bare minimum.
Dr. Gribben’s editorial addresses some important questions, from the perspective of a highly regarded CLL expert. The answers to each of the questions he highlights are driven by both scientific and pragmatic issues. With galloping health care costs, how much prognostic testing can we afford? How much of the costs will be covered by reluctant insurance companies? These are real issues, and they must be considered in any serious discussion of the subject.
Dr. Gribben suggests some of the more expensive tests should only be done in the context of clinical trials. He does not see the need for doing all out “Prognosis at Diagnosis” for the general CLL patient. I have a problem with that approach. If some of the more detailed prognostic testing is only done in the context of clinical trials, how can we as run-of-the-mill patients apply the knowledge gleamed in such clinical trials to our own cases, if we do not know our own prognostic test results? How can our community based healthcare providers guide us in therapy decisions, without knowing our own prognostic test results?
Let me clarify this issue by one simple example: just about every clinical trial in the recent past has confirmed that patients with 17p defects (either frank deletions or mutations) do not respond to fludarabine based therapy. Even when we add Rituxan to the mix, making the standard chemotherapy drug regimen into the more sexy chemoimmunotherapy version (such as FR, FCR etc), the response statistics and overall survival statistics truly suck for 17p defective patients treated with fludarabine containing regimens. Time spent chasing after FCR in these patients is better spent using other approaches that may work better in their case. This is important information that we have learned from clinical trials that did the prognostic testing to find out which patients had 17p defects. How can we use this hard won and precious information, if our physicians refuse to test patients for this important prognostic indicator? And, since 17p status can change over time, especially in patients who have already been through a couple of layers of therapy, how can we convince our healthcare providers to repeat the test before the next round of therapy? Fortunately, Dr. Gribben does support the use of the standard CLL FISH test – which determines 17p deletion status.
Let us take another prognostic indicator, one that is a bit more expensive to run, but one that colors every aspect of your CLL history from the word go. I am talking about IgVH gene mutation status. Many researchers have tried to find cheaper and more readily obtainable surrogates for this fundamental prognostic indicator. Patients with mutated IgVH gene (and those that do not use the sterotype genes, the bad kind of IgVH genes we discussed in our workshop) live a lot longer, respond better to therapies of all sorts and in general are far luckier in the CLL lottery. Unmutated IgVH confers shorter overall survival, poorer responses, more chance of clonal evolution and more aggressive disease. If doing IgVH gene mutations status testing only in the context of clinical trials becomes standard policy, it will become a lot harder for patients to get this test done and paid for by insurance companies.
I can think of a bunch of “life” decisions patients may need to make, depending on their long term CLL prognosis. Do you change jobs, possibly risking healthcare coverage or the quality of the coverage? Do you take on additional debt and move to a more expensive house, based on the assumption that your healthy paycheck is going to be around for a long time to protect your family? Would you slow down, take the time to smell the roses and spend more quality time with your family, if you knew you were in the more aggressive unmutated IgVH risk bucket? Would you make different therapy choices, perhaps line up your ducks for an eventual stem cell transplant – sooner rather than later? Would you continue to indulge in behavior such as smoking and excessive sun exposure, if you knew high risk CLL also means higher risk of secondary cancers? If on the other hand you found out you have the best of best prognostics, would that help you relax and procrastinate getting your will and last testament in good shape, and resist a bit more if your local guy tries to sell you on the most aggressive therapy option available? I can think dozens more such questions. But here is the problem: would healthcare providers consider such one-of-a-kind personal issues, if the slam dunk expert opinion is that detailed prognostic testing is only to be done in the context of clinical trials?
CLL is a complicated disease. With the exception of a percentage of patients who luck out and have very indolent disease, majority of patients will find their CLL diagnosis comes with the guarantee that it will dominate big chunks of their lives. You will need room to maneuver, take care of personal and family issues that are not part of any standard healthcare providers’ do and don’t lists. The choice should be yours, the decisions should be made based on what you want and need.
Pragmatic guidelines restricting prognostic testing based on costs and logistics I can understand, even though I would strongly wish things were otherwise. But if any of these decisions are being made on the basis of old fashioned paternalistic attitudes – patients won’t understand all this new fangled stuff, no need for the poor dears to worry their pretty little heads about stuff that only experts can understand – if that is driving the debate to any extent, I respectfully disagree. We can learn, we can be plenty smart, when our lives are riding on the issues. I am willing to bet serious members of CLL Topics patient community will fare much better on any CLL quiz than garden variety local oncologists who see just a couple of CLL patients in their practice each year. It is not that we are smarter than they are. It is just that we have a whole lot more skin in the game.
What say you?