Prognostic Indicators
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?
That is the title of a provocative and recent editorial by Dr. John Gribben of Barts Cancer Institute. Click on the link to read his full editorial. Dr. Gribben addresses the following four issues:
- 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.
Editorial
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?
48 comments on "Prognostic Indicators: Who, When, What and Why"
Nice article about the hazards and benefits of the various CLL prognostic markers. It is not a trivial issue since clinical trials for CLL should take up to 25 yrs to determine the true benefit for those “lucky enough to have the smoldering”. As a shortcut in many papers, we see people claiming their analysis coincided with prognostic markers of outcome as a surrogate, usually using IgH, CD38 or ZAP70. The problem is that each has about 20% outliers and 20% p=0.05 is the standard for significance. Caution in required. Having a good marker is no guarantee of 25 years and having a bad one is not a 7 yr sentence. They are averages with many outliers.
It is really only a few years that FISH has been able to be reliably performed. Most CLL people are very refractory to new ideas so maybe Dr. Gribbens was just being overly dramatic to make his point. I am sure he does not really expect clinicians to stop ordering IgVH.
I would respectfully disagree that Dr Hamblin gets credit for inventing IgVH. In a classic prognosis at diagnosis paper by Tait D Shanafelt, Susan M Geyer and Neil E Kay 2003, they give dual credit as both papers were in the same issue of blood. I have never heard which one hit the editors desk 1st, but as a possible tiebreak indicator, the Damle paper comes before Terry’s.
7. Damle RN, Wasil T, Fais F, et al. Ig V gene mutation status and CD38 expression as
novel prognostic indicators in chronic lymphocytic leukemia. Blood. 1999;94:1840-1847.
8. Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK. Unmutated Ig V(H)
genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood.
1999;94:1848-1854.
Sorry, a typo with too many 20%, p=0.05 is a 5% standard of error, which is a pretty big % of 20% outliers.
Thank you, thank you as always for a very informative article. it is always so much appreciated the work that you do.
Anne
For those of us with the SLL variant of CLL (about 15-20%) I believe that a lymph node biopsy is the only way to diagnose the disease and do the prognostics. The blood is normal and shows no evidence of the disease. Also, I believe that a CT scan is the only way to stage the disease (Ann Arbor not Rai staging).
Thank you for updating us on the latest info regarding prognostic indicators. I attended your workshop which enabled me to follow along with this article as an actually “educated” person. I owe that to you. Thank you.
In that currently I am one of the “lucky” CLL patients whose prognostic indicators seem to point to a “long life,” I still appreciate reading your latest findings because one thing I have learned in my 8 years since having been diagnosed is CLL is unpredictable and definitely has a mind of it’s own in every human body that has been labeled with it!
So, keeping up with the latest info, doing my own reading, and always quizzing my doctor when I see him is now the way I handle the diagnoses. No more standing around waiting until “they” say I need treatment!
Again, thank you for keeping us all informed and for your faithful dedication to such a cause.
Perfect Chaya,
“””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.”””
this says it all, thank you. There are patients for whom ‘more’ testing may not be necessary, or they may not want to know, but without the tests you suggest, as a standard, universal protocol, we are losing history of this disease, hampering our ability to know what is truly needed in new treatments. For those who wish to remain in the dark, or totally trust their physicians, I say, fine, opt out of the reports. With what we now know this protocol seems very reasonable, and if it were applied universally, we would have so much more information going forward. That would benefit research, patients, and anyone involved in the disease going forward. Sadly the decisions to do or not to do tests is often taken from patients by insurance companies and governments.
Thanks for the reasonable approach. Beth Fillman
‘Bravo Zulu'(BZ)
Thank you Chaya for your ongoing teachings.
Kind Regards from ‘down-under’.
Sydneydutch.
Thank you, Chaya.
Monique
grifj:
You are right, for patients with “SLL” variant of this disease, CT scans earlier in their clinical history may be preferable. Thanks for pointing that out.
Good article. Thank you!
I hope patients will not have to fight for the diagnostics that are so important at diagnosis. Even if one is not inclined to learn all the facts, I would hope oncologists will continue to obtain the test results you listed as the most valuable at diagnosis and periodically as indicated.
Terry learned in his second year of CLL that his status was mutated. He had a mixed bucket with very high CD38. He was treated 8 yrs after diagnosis with FCR Lite. He is now in remission. I hate that people could be treated with an agent that is contraindicated because a vital test was not performed before treatment. We made sure FISH was repeated before treatment. His local oncologist had already ordered it.
One month into remission he had marrow failure, which recovered quickly. It recovered before we totally understood the danger. He stayed away from people, monitored his temps and returned 2-3 times/week until he was out of danger. We knew hospitalization was a sure possibility, but after five years with his oncologist, he trusted us to notify him if Terry’s temp rose or anything else happened. He is mostly recovered now.
Thanks for the latest, Chaya.
Linda
WillB
Chaya,
You came through again. Thorough and up-to-date stuff. Right on the money with the various tests, treatment types etc.
Many thanks..as usual.
William Bates
Chaya,
Thank you again for a very informative article.
I remember so well a few years ago when you explained my FISH test to me and it was 11 and 13 deletion.
Many Blessings,
Rita
I cannot improve on the excellence of your thoughts on this topic. In my own life I have always tried to tackle problems by understanding all the components of any given situation. Being an artisan/contractor It was way over my head when confronted by CLL DX. I can remember telling the oncologist that my nodes did not feel to me like indolent disease even if the tests I requested came back with “Good” markers. The one exception was the ZAP-70 58% +. This led my determination to gain as much info as I could to better assess what I would be dealing with.
Living in a very rural area and not having ready access to a CLL expert made my quest for knowledge of CLL a positive way for me to mentally deal with the disease. In a practical sense I believe I avoided some treatment traps from knowledge obtained through diagnostics and the interpretation of such through CLLTopics. The ZAP-70 test (right or wrong) led me to try and understand the importance of dysfunctional signaling which in turn led me to recently enter a Phase I Clinical Trial using PCI-32765 monotherapy with some degree of confidence after two convention therapies nearly killed me.
For the above reason, diagnostic testing in general was a tool through which I gained understanding of CLL/SLL. Diagnostic test results gave me a way to talk about my cancer with my Oncologists. I had a unique perspective regarding the ignorance of CLL by general oncologists as my local clinic went through 6 oncologists in as many months before I left for more stable oncology pastures.
I believe the course of my treatment and outcome could have been much worse in light of my unique kidney complications and drug treatment reactions if I had not studied CLL with the help of diagnostic tests. That said, I think people who prefer not to know will in the main be in good hands with good outcomes if they are managed at a CLL/SLL expert’s clinic. Patients need luck when remaining ignorant and being managed by a generalist. I have met patients who have been treated with Fludarabine who were never tested to see if they had a del. 17p and associated p53 pathway dysfunction. Nobody should suffer the poisoning of Fludara without testing knowledge of its probable efficacy.
I would argue that even more detailed scanning diagnostics be required and made available to patients in light of more targeted treatment choices. Leukemia Lymphoma Society has announced partnering with a company to begin individualized treatment protocols for Mixed Lineage leukemia (MLL) patients. Can CLL be far behind? Let’s hope not.
WWW
Thanks again Chaya.
I so agree with you as to how complicated CLL is and to understand. Having someone like you to sort out a great deal has been soooooo helpful. One thing I still have a difficult time understanding in my dx, I was dx in 2009 with 13q14. My local onc. told me it would probably be a few yrs before tx. (I already had some swelling nodes). 6months later I had a ct scan and there were growing lymph nodes. I had another scan 6 mo later and they had grown more (near organs, and starting splemeglia. He felt tx was very near. I went to a CLL specialist in Tampa, went through, BMB, and putting all the test together, I learned I an IGvH unmutated and also cd38 positive 46% of cells. After alot of Q&A, RB for 6mo was the tx I received. I am now in remission. My confusion is still with the 13q/unmutated with cd38 + Does this mean I am still on the slower end of CLL with a little more agressiveness. I read very little about this type of DX. The minute I read unmutated, the discussions go into 11q or 17p. I feel a little thick in my understanding. Like you, I go nuts if I can’t find the answers. I know I feel less tense when I have some straight answer. The specialist is good about answering my questions. He told this group is about in the 30% average. What am I not getting.
Thanks again
Midge82
As usual Chaya, great presentation. You were right on when you mentioned the need for knowing prognostics when making limportant life choices. Unfortunately for some reason my husbands pcp and cardiologist failed to tell us that his lab work for four years prior to his CLL/SLL diagnosis indicated he had CLL. We added a costly addition to our home a year before my husband was finally sent to a hematologist oncologist for evaluation. We were both quite angry for a long time because had we been told that he had leukemia four years before, we would not have taken on this large loan. Both doctors had no answer for us why they didn’t inform us of increasingly elevated WBC’s and lymphs. My husband just had his 6 month BMB along with flow, fish, along with blood work, done locally but slides and copies of all reports go to DFCI, Boston (11q, unmutated, zap70 neg, 2 years post 4 rounds of FCR, persistant low platelets, in CR)
Stargazerlily17
midge82:
Prognostic risk buckets in CLL are hardly clear-cut with no overlapping boundaries. Buckets are sloppy. The contents slosh around, sometimes they overflow from bucket to the next. In fact, that is why I used the “bucket” imagery in defining risk categories in the pivotal and very first article we published on our flagship website: http://clltopics.org/PI/Type.htm
In your case, I would venture to guess the 13q deletion is nice to have, but it is surely trumped by unmutated IgVH. That and the high positive CD38 means the CLL cells proliferate more rapidly than normal. They may still be easier to kill because of the 13q deletion (as opposed to, say, 11q or the even more therapy resistant 17p deletions). So, if you want to split the difference, you probably have a chemo sensitive disease that will respond well to therapy – but the other side of the coin is that it will grow fast. You will get good responses, but the remissions may not last long.
We discussed the question of patients with more than one FISH abnormality. If the patient has 13q deletion as well as 11q deletion (as my husband PC did), the “good’ prognosis of 13q deletion is trumped by the bad prognosis of 11q.
Some experts believe unmutated IgVH also carries with it the possibility of more unstable genome that is more likely to undergo clonal evolution, more likely to accrue other FISH defects over time – especially after patient undergoes chemotherapy.
None of this is cast in concrete. The best that can be said for prognostic indicators are that they give a murky view in the chipped and cloudy crystal ball. Is that any better than going in blind? Only you can make that call.
Thank you, Chaya!
May I email you directly with a few questions pertaining to my particular situation? I’d be most grateful.
Really appreciate all the great information you share, and your caring support!
Regards,
Tina
Bost01907:
Yes, please feel free to send me a personal email. You can get my email address by clicking on the feedback/contact us button on the right hand side of the page (scroll up!)
I try to answer most emails I get within a day or two – but I must also confess purely “social” emails sometimes end up at the bottom of the pile. You must also be careful to remember I am not qualified to give medical advice. Just my two cents, but cheap at the price since I do not charge you even the two cents :)
hi !!! my first posting … i was 54 when a routine blood test and sudsequent testing confirmed cll with what i was told was good prognosis…i will be 60 next monday and still being told that my cll is indolent … i exercise most day feel no different and more importantly try to forget about it and get on with life … cll sucks but as of today i’m doing ok … this site has been a great help and comfort so thank you chaya … oops!!! i’m an aussie
Chaya, again to the rescue. Thank you. I think I got it this time. The complexity of CLL is something else…. The old saying, Just when I think I know the answer, They change the questions…….Again thank you. The answer you gave was a big help. For awhile I think my brain can quiet down. I’m sure there will be new things in the future that will pop up. It is such a learning experience about this disease and my self. Your work is so appreciated.
midge82
Chaya,
I try to place myself in the shoes of my hematologist oncologist, who deals with patients daily whose diseases are no doubt much more progressive than my own. I know this, because I can hear in the examining rooms on either side of me thier conversations. Which may be why he reads my chart, pokes me under my arms, liver, spleen, groin, pats me on the back and after the requisite 10 minutes tells me to come back in three months. He does ask me if I have any questions and takes his time trying to answer them. Except when it comes to prognostic indicators. His standard reply, which I now realize is a fairly common school of thought is basically, I will suggest treatment once your CLL reaches a still undefined point and knowing the prognostic indicators will not change that.
However I want/need to know: “I can think of a bunch of “life” decisions patients may need to make, depending on their long term CLL prognosis”. I know some of my pronosticators, Zap 70 +, high CD 38, lymphocytes doubling less than a year. Looking forward to finding out IgVH mutation status end of this month. I love the sound of Patient Advocacy. Thanks for fighting the “good” fight.
Chaya
Once again I thank you for all of the information you have provided to so many of us. I know you have given me your opinion of my Fish results. I have so appreciated all the information you have provided over the years. I am one of those people that want to know all the details rather than just leaving it in the hands of my Dr. I do better when I understand what they are looking for. The time and effort you put into this site is so great. I am lucky because my Dr trained with the great physicians at Bethseda and when she goes to seminars on CLL she actually gives me her notes and the papers she obtains. Yes I can understand them because of the training you haved given me from this website. I am truly grateful for this information.
JimBob, remember you are the consumer and deserve the respect to know any and all test results, regardless or not if knowing the markers change the outcome of your disease. My husbands cardiologist treated us in the same manner and we dumped him and moved on to a doc who respected my husbands right to have his questions answered as thoroughly as he and his family needed and wanted. It still angers me to hear that some docs out there would rather not discuss results with us mere patients.
Chaya thanks again for your great work. Your info always helps me become better educated when dealing with my CLL my thoughts are knowledge is powerful.
Chaya,
Thanks for all the good information. I can’t say enough how glad I am that you do what you do for all of us.
Dottie
midge82:
I agree with everything Chaya said, but if you are interested in how fast the cells are growing, lymphocyte doubling time (LDT) may be the one you want to ask for. That measures the speed instead of relying on surrogates. CD38’s functional role is a big mystery. It has been associated with a higher LDT, correlation with some cell cycle markers and of course worse outcome if over 30% but there is no decent explanation for why almost all normal B cell samples have 90-100% CD38 but when it disappears it is a good thing in CLL, but when they reappear at 30% or more (rarely returning to the level of normal B cells) this is a bad thing. Obviously there are other factors at play that are not understood. I am not trying to give any medical advice, just pointing to a way to answer any question about speed.
Chaya, thank you for an excellent review of an most important topic. You are a great blessing to the CLL community!
As a type A personality I wanted to know my prognostic profile. I had all the prognostic tests done when I was Dx in 2009 (standard FISH, flow cytometry, IgVH, Zap70, B2M, CD38). I also had testing for Cyclin D1 & FMC7 to rule out MCL & SLVL.
Knowing my prognostic profile enabled me to get a sense of where I was with my CLL. I studied & learned about CLL from this excellent CLL Topics website among others.
However I am confused about the IgVH mutations that act clinically as if they were unmutated (stereotypes)such as the VH3-21. In addition to VH3-21 mutation some other mutations have been identified. Dr. Terry Hamblin wrote about this on his website 1/13/11.
My IgVH is 4.5% mutated (per VH3-7). What I want to clarify is can you have multiple IgVH mutations? For example can someone like me with
VH3-7 mutated also have additional unfavorable mutations such as the VH3-21? I have not yet found anything that answers this question.
Thank you again Chaya for another great article.
Patti
Patti:
One given CLL clone can have only one specific type of IgVH gene mutation; or no mutation at all. It cannot have a couple of different mutations.
As for the difference between “good” mutated and “bad” (stereotype) mutated (using VH3-21 type gene, for example), may I refer you to our recent workshop on prognostic indicators. There I try to give a cartoon version of the difference between mutated, unmutated and stereotype mutated varieties of IgVH.
Don’t know if I’m even doing this posting thing right yet. Mostly it is a question and some assistance. My dad at 87 just passed away in Feb of a heart attack, quite quickly. So last month I started accompanying mom to some mysterious doctors appt. she’d been going to for 4 years. She is now 85. Over the past 3 years she’s noticabely lost quite a bit of weight, but just answered our questions with saying she was not hungy as much. As it turns out the doctor was a hemotologist/oncologist. All he told me “after mom signed the Hippa form” was that mom had B-cll and initially her numbers were 50,000 in 2009, 100,000 in 2010, and now in 2011 200,000. She has quite large lymphnodes that are getting larger on her neck and something about her spleen. We are in what is being called a watch and wait mode. However mom is completely exhausted lately and does not want to eat or go out much. I do not know if it is due to dad’s recent death or these awful blood numbers. I read some of your site and understand that her age does not bode well and I just do not know what to do. Any insights?? Thanks so much.
Chaya,
Thank you for your response to my question about multiple IgVH mutations.
I want to clarify – if a person has a specific IgVH mutation
(say VH3-7) then they will not have any other VH type mutations (now or in the future). Is that a correct understanding?
My IgVH was tested at UCSD and their test is on the VH3-7 so I suppose this is the standard to test for at the CRC centers.
Thank you again Chaya for all your help!
Patti
bbell:
Your mom has CLL, that seems to be clear. Given her climbing white blood counts and more especially her “B-symptoms” (fatigue, swollen spleen – possibly the cause of her not wanting to eat – and significantly enlarged lymph nodes, lymphocyte doubling time that seems to be about a year or less, based on the numbers you quoted), I am surprised her hematologist still considers her to be in Watch & Wait.
This is a patient education and advocacy site. We are not qualified to give your mom medical advice. You are certainly welcome to go to our “Newly diagnosed” section (even though your mom is hardly newly diagnosed, it seems appropriate since you are just getting started learning about this disease) to educate yourself. A more practical suggestion may be that you get your mom to one of the CLL expert centers. In my layperson opinion therapy to control her CLL may be needed sooner rather than later. It is a pity she handled her cancer diagnosis completely on her own, without involving family members in the process.
Patti: You are right, if UCSD said you have VH3-7 gene usage IgVH gene mutation, that is the only type of CLL IgVH mutation you will have, now and forever more.
Thank you Chaya for your responses to my IgVH questions.
Patti
Thank you so much. I’ve been pouring over the internet the past few weeks for information. You site has provided more than I have found anywhere else. I realize that this is not a medical advice site, however the experience and care that I see being shared on this site is most helpful.
One more question. What type of questions should I be asking when I accompany my mom to he hematoligist based on my previous description of her symptoms. If we are approaching the end of the Watch and Wait phase, what is next? And my big question is at 85 years old and a bit fragile how will treatment adversely affect her? Will the treatment be worse than the current Cll symptoms. I don’t know what the prognosis is for her. What am I looking at? Is she stage 1, 2, 3,??? And at 85 years old what is the best for her? I want to help her make good informed decisions while at the same time give her the best quality of life for whatever (??) time she has left. I cannot believe that after loosing dad 5 months ago now we are thinking she may not be with us much longer. I feel like I need to get some kind of handle on this situation. I hate not knowing what the right thing to do is and what exactly we are facing. Thanks again.
bbell:
Send me a personal email (you can get my email address by clicking on “feedback / contact us” button at the right hand side of the page (scroll up!). I also just sent you my phone number – I am willing to chat on the phone with you and explore therapy options open to your mom.
PLEASE PLEASE PLEASE Address the issue of CLL & RADIOGENICITY as a trigger…….David B. Richardson and SteveWing and Jane Schroeder from the Department of EpidemiologySchool of Public Health University of North Carolina at Chapel Hill, and Inge Schmitz-Feuerhake of the University of Bremen, Germany and Wolfgang Hoffman of the Institute for Community Medicine, Division of Health Care Epidemiology and Community Health Ernst-Moritz-Arndt-University Greifswald Greifswald, Germany and many others believe that CLL is a radiogenic form of cancer!!!!!!
Wladyslaw Warnenczyk:
Already did. Please look up our earlier article “Does radiation cause or make CLL worse?” Here is the link:
http://updates.clltopics.org/357-does-radiation-cause-or-make-cll-worse
This issue needs to be readdressed since October 2009 there have been many papers written on the subject….particularly since Cedar Sinai Hospital in LA California is fighting a class action suit from 209 patients, and the FDA & other US Govt agencies are running checks on other x-ray machines manufactured by General Electric. I will provide the reference cites and URLs if you like?
Hello, Chaya and all–
I had a brain hemorrhage about 14 months ago, and it was discovered that my WBC was elevated. During my 12 days in hospital, it ranged from 14-20. I was asked to follow up with a doctor after I was released, the assumption being that I had a UTI due to catheterization. I was diagnosed with CLL about 2 months later. My doctor ordered several prognostic tests including IgVH, CD-38 and ZAP-70, all with good results. My WBC count, however, doubled in about 7 months and she ordered a FISH test which showed 11q deletion and 12 trisomy. My apologies as I am relatively new to this and found your wonderful sites only recently and have been trying to educate myself, but does my mutated status trump my poor FISH results? Do I have an aggressive CLL? I am stage 0, asymptomatic and WBC at 37.5. I am 58.
Thank you for any insight, and I will continue to educate myself!
P.S. I have had an excellent recovery from the brain hemorrhage.
Scot58:
I answered your question in a personal email.
Thank you, Chaya.
Chaya, I’ve been looking at this website and it is wonderful, but I have no idea how I fit into the overall scheme of things. I was diagnosed with CLL/SLL May 2011. It was caught through bloodwork on my immune system. The pathologist also did a bone marrow biopsy. My blood work showed that 97 percent of the CD5 pos b cells expressed CD 38 and 23 percent expressed ZAP 70. My white blood count is low and the bone marrow biopsy showed 25 percent of the cells have lymphoma cells. A CT scan showed malignancy in the lymph nodes in my abdomen. I also have some intermittent swelling in the lymph node under my arm. My oncologist is not at all concerned and I am on a watch and wait protocol. I see the doctor every 4 months. He says that I will probably never need treatment and I don’t need my IgVH status checked. I am ca 57 year old female. Does all of this sound plausible to you or should I get a second opinion? I understand if you are hesitant to address this, but I am completely lost. Thank you so much for any advise that you may offer, Nancy
nweibel:
I am not a medical doctor and I cannot give you medical advice. The best I can do is tell you what I would do if I were in your shoes.
Based on the information you provided above, you have highly CD38 positive as well as marginally ZAP-70 positive CLL cells. While ZAP-70 can be “temperamental” if not done at one of the expert centers, as things stand both prognostic indicators are pointing to more aggressive disease.
In your shoes I would ask for the FISH test and IgVH gene mutation status test. At the very least, the FISH test. At 57 years of age you have a lot of life left to live and I do NOT buy your doctors’ rather glib statement that you will probably not need treatment. What is he basing this prognosis on? I strongly urge you to get a second opinion. ALL newly diagnosed patients should get a second opinion from one of the CLL experts, if at all possible. This disease is complicated, comes in many forms and it is only too easy to dismiss it as the “good” cancer. You did not give us the results of your bone marrow biopsy (which is only as reliable as the expertise of the pathologist examining the slides), but you do mention lymphadenopathy (swollen nodes). That, combined with unfavorable CD38 and possibly ZAP-70, is enough for me to suggest a second consult with an expert.
Just my two cents, because you asked. In the final analysis, the decision is yours to make, after careful consultations.
Thank you so much. I’ve been living my life and trying to dismiss this disease, but as I read the postings I’m not so certain that I want to live or die by what this doctor says. Does anyone know where to find a CLL expert? I live in Oklahoma but I can always travel to MD Anderson in Houston. I’m not in a big rush because the disease seems stable and I have some other health issues to deal with first. Thank you again. I really appreciate this website. Nancy
I forgot to mention that my oncologist did say that I was stage 4 since I have cancer in my bone marrow, but once again he was not overly concerned. I like his prognosis, but it doesn’t agree with what I’ve been reading. Thanks again, Nancy
nweibel:
If your doctor says you are at Stage – IV, then I am really at a loss to understand his statement that you will never need therapy. Stage 4 CLL (the last stage in CLL) almost always requires therapy sooner rather than later.
M.D. Anderson is surely one of our leading CLL expert centers. They do a very good job of doing all the necessary prognostic testing. You will get a good second opinion there, based on solid information. I urge you to get that done.
As long as your insurance coverage sufficient for the purpose (MDA is not cheap, by any stretch of the imagination), I believe you can self refer for a consultation. That is, you can do this even if your present doctor will not give you a referral. (That along with the somewhat inexplicable prognosis he has given thus far would be sufficient reasons for me to find myself another local physician – if I were in your shoes).
Thank you. I’m not afraid to get a 2nd opinion. Have a happy new year and keep translating all of this info to us. You are literally a life saver.
Nweibel~
My diagnosis at a major cancer center was SLL stage4 but NIH says current diagnosis is MBL so a second opinion can really change your perspective and prognosis. Good luck!
Leave a Comment