Two prognostic indicators have become the focus of much discussion in recent months, ZAP-70 and IgVH mutation status. These two indicators, in combination with FISH analysis to pinpoint the chromosomal aberration that is at the root of the CLL, go a long way toward defining the risk category of the patient in question. We have discussed both ZAP-70 and IgVH in prior articles (What Type of CLL Do You Have?, Prognosis at Diagnosis, Prognostic Indicators).
But to tell the truth, they are not the easiest concepts to understand. If you are like me, even if you actually understand the complicated jargon when you read the article, stuff like this has a way of evaporating out of your mind in a week or two, and then it is back to scratching your head the next time you see the acronyms. Several new articles have just been published that makes it worth our while to revisit this topic. For the first time, I see glimmers of hope that our understanding is reaching a point where therapy breakthroughs are within the time-frame of today’s patients.
ZAP-70 and IgVH Gene Mutation Status: Which One Is More Reliable as a Prognostic Indicator?
The abstract below is from a very recent issue of the New England Journal of Medicine, authored by all of the experts from the CLL Research Consortium. I will summarize the highlights for you, but if you want to read the full text of the article for yourself, or make a present of a hard copy of this important article to your local oncologist, write to us and we will help you locate it.
If you have been following prior discussions on these two prognostic indicators, you know that low levels of ZAP-70 and mutated IgVH genes spell good prognosis, whereas high ZAP-70 expression and unmutated IgVH genes spell trouble. The paper describes 307 CLL patients who were tested for ZAP-70 levels as well as the mutation status of their IgVH gene. This is a statistically large sample of patients, and the results make it clear that it is strong (but by no means perfect) correlation between ZAP-70 IgVH gene mutation status. The table below gives the details. As you can see, not all IgVH mutated cases are ZAP-70 negative and not all unmutated cases are ZAP-70 positive. For a significant percent of the patients studied the two prognostic indicators do not agree, 71 out of the 307 patients have conflicting indications. That is not a small number!
Correlation between Prognostic Indicators
Based on 45 patients
Patients Without Treatment
N Engl J Med. 2004 Aug 26;351(9):893-901
The graph above makes a crucial point. The authors point out that in the ZAP-70 positive patients, the median time from diagnosis to when therapy was needed was roughly the same, independent of whether they were IgVH mutated or not. It looks like when there is a difference of opinion between the two indicators, ZAP-70 trumps IgVH gene mutation status.
The bottom line conclusion by this panel of CLL experts is quite clear: “Although the presence of an unmutated IgV(H) gene is correlated with the definition of ZAP-70, ZAP-70 is a substantial predictor of the requirement for treatment in B-cell CLL”. Moral of the story, if you have managed to find your IgVH gene mutation status, you might want to finish the job and get your ZAP-70 test done as well, just in case you are one of those patients who have discordant results on these two prognostic indicators.
As we learn more about the molecular basis of CLL, it is rapidly becoming clear that CLL prognosis depends to a great deal on the ability of the cancer cell to interact with its surroundings. Cancer cells are blind, and they cannot really “see” or “think”, they live, proliferate or die depending on their ability to receive and transmit signals to the surrounding cells. The B-cell receptor (BCR) is one of the most important “data ports”, a mechanism through which the cell receives signals to survive and reproduce.
As the second abstract below points out, ZAP-70 is part of the BCR mechanism, a high level of ZAP-70 indicate a CLL cell that is only too happy to receive signals through this port. In general, IgVH unmutated cells are more likely to hear the message whereas cells with mutated IgVH genes have unresponsive BCR ports. That is why, in general, IgVH unmutated CLL is more aggressive and proliferates faster. However, there are special circumstances where even cells with mutated IgVH are responsive to antigen activation, and in these cases, the ZAP-70 is positively reflecting the BCR responsiveness of the CLL cell in question. (To get a slightly more risqué analogy explaining these concepts, you might want to read the next article on the continuing saga of Harvey, our hypothetical Bucket C and Round-Headed Kid).
The good news is that ZAP-70 protein levels are likely to be much easier to measure, compared to determining IgVH gene mutation status. But there is work to be done before ZAP-70 becomes a prognostic test that delivers its value to CLL patients. Right now, there are no standardized procedures, no consensus across the board on appropriate cut-off points to define ZAP-70 positive and negative levels, and outside of top rated research institutions, the validity of the results or their interpretation is suspect. We badly need some reputable organization such as the NCI, CLL Research Consortium, or highly regarded cancer centers such as the Mayo Clinic, Dana Farber, M. D. Anderson and the like to take the lead in defining the parameters of this test.
Here is a pop quiz, just to find out how many of you have actually read this long-winded article up to this point: how many of you think CLL Topics as a patient group should become pro-active in getting standardized and readily available ZAP-70 testing for all CLL patients, something that is quality controlled to yield meaningful results, that is within our reach in terms of logistics, and a test whose cost is covered by the major insurance companies? Write and let your opinion count. We have a lot more leverage working as a group than we do on individual patients.
Common Features in CLL Cells from Different Patients
Until very recently, the conventional wisdom was that each of us was uniquely different, even in the exact type of our CLL. Let us get this point straight, while the word “clone” implies that each of the CLL cells in a given patient is all the same. It was thought that no two CLL patients would have the exact same shaped immunoglobulin (Ig) tips. In fact, the analogy was made to fingerprints: it is statistically next to impossible for two individuals to have the same fingerprints, and no two CLL patients could have the exact same Ig. This is one of the reasons why idiotype peptide vaccines are considered such an expensive proposition as each patient would need a custom-made vaccine to work with the specific Ig that his or her CLL cells have, and no other patient would match this exact shape of Ig.
Well, this is one concept that has been proven wrong in recent months. Below are four abstracts that make the same point, but the first one below by Ghiotto, Rai, Chiorazzi et al., really caught my attention. It is a beautiful piece of detective work. I am really impressed by the quality of research coming out of North Shore Hospital in recent months (part of Long Island Jewish Hospital system, I believe). In case you are interested in reading the full text of this terrific article, please write to us. What I would give to be able to get these researchers to answer a few questions for us and explain some of the more difficult concepts: connect the logic dots as it were.
Here are the nuts-and-bolts of the article. The authors examined the CLL cells from 25 different patients, all of whom expressed a subset of immunoglobulin called IgG (don’t worry about exactly how IgM and IgG differ, for now. The differences are important, but the subject of another article). The chances that any two of these 25 CLL cases would just happen to have, by sheer coincidence, the exact same shaped pincers on the tips of the immunoglobulins expressed by the CLL cells is roughly one in 3.5 million. Imagine the surprise of the researchers when not two but five out of this set of 25 had absolutely identical shaped Ig pincers!! It is as if the detective in the murder story had five of the suspects matching exactly the fingerprints on the murder weapon. This is a major finding. Since CLL cells that have come in contact with an antigen express the pincer tips at the ends of their Ig to match that particular antigen, the unavoidable conclusion is that each of these five patients has CLL that reflects interaction with a common antigen!! Think what this means: for these five patients, there is a common thread, a common focal point at the heart of their CLL.
What could this common antigen be? It could be a self-antigen, something that is common to all five people, a piece of protein that exists as a natural part of their bodies. “Normal” people can handle this self-antigen just fine, but in the case of people with some predisposition to cancer, the same self-antigen could spell CLL. Or it could be an environmental toxin that each of the five patients came into contact with, at some defining moment in their lives. Or it could be a protein fragment from a common virus or bacteria, something that is ubiquitous in the general population. The detective story unfolds: these distinct groups of CLL patients with this common theme to their CLL are not from one geographic location and probably not linked by trade or type of work. It is looking more and more as if the common antigen may be a viral or bacterial pathogen.
Something that is probably common and present in most of humanity. We already know that once we are infected, viruses such as the Herpes Simplex virus, EBV, and hepatitis virus etc., lie dormant in us for the rest of our lifetimes. Many cancers have been shown to be caused by viral or bacterial pathogens, including some types of non-Hodgkin’s lymphoma. Mononucleosis, which is characterized by uncontrolled proliferation of B-cells, is caused by Epstein-Barr virus (EBV), transmitted from person to person through saliva. The common name for it is the “kissing disease” for obvious reasons, and there is a reasonable level of research pointing to links between mononucleosis and the development of some kinds of B-cell lymphoma. The vast majority of humankind has learned how to deal with these antigens, except the unfortunate few that were susceptible, and in these folks, this common antigen precipitated their CLL.
Why is this important? Think about it, while we cannot completely eradicate some viruses such as EBV and Herpes Simplex, in recent years we have learned how to control them, drive them into dormancy by anti-viral medications such as famciclovir (Famvir). I am sure you have all seen recent advertisements for controlling genital or oral herpes outbreaks. I am using the Herpes Simplex and EBV viruses as an example only, the common antigen we are talking about in these 5 patients is entirely likely to be something different.
But once we know what it is, we can attack the CLL from that perspective. Lock up the antigen, block it, drive it out, eradicate it, whatever. As long as it is not around to be a constant goad to the CLL cells, activating them and making them go into a state of proliferation, it will help in controlling the disease. CLL is caused by a small mismatch in the rate at which new cancer cells are created versus the rate at which they are killed. If we can slow down or stop the proliferation aspect of the equation, we will gain control over the situation, not just for these five patients but for all other patients who happen to fall into this specific group. The exciting news is that there may be many other such “clumps” of CLL patients, each clump corresponding to a particular pathogen. The same logic would work for all these people – it would be a matter of identifying the specific pathogen responsible for each clump of CLL patients.
Here is the question I would like to have answered by the expert researchers. In the absence of knowing the specific nature of the antigen that is implicated in these clumps of CLL patients, can we devise therapy strategies that use a broad spectrum approach, some way of neutralizing the antigen by a carpet bombing approach?
Since the new research is suggesting the antigens in question are common and ubiquitous in the general population, it stands to reason that the general healthy public has found ways of dealing with them. Otherwise, we would have whole populations coming down with CLL. Can we then use the antigenic wisdom of the healthy population to protect the few of us who don’t quite know how to do it for ourselves?
Immunoglobulins within our blood are a reflection of the lessons learned by our bodies as they faced down different antigens. Immunoglobulins collected from the blood of thousands of donors reflects the combined wisdom of all those donors. Between the lot of them, chances are good that they have battled most of the common antigens and won. Intravenous immunoglobulin (IVIg) infusions have been around for a long time, and have been used as broad-spectrum protection against infections in immune-compromised patients. In fact, CLL is one of the conditions listed for which IVIG is an approved therapy.
Now we are asking the question if IVIG infusions have a second, and even more vital role to play in a subset of patients by neutralizing the specific and universal antigen that might be the driver for the CLL proliferation. IVIg is commercially available, and the recent introduction of better purification processes in collecting the immunoglobulins from pooled blood has made the products better, with less chance of adverse effects and allergic reactions. Surely this concept deserves evaluation? Some of you have sent me your medical records, and I thank you for the trust you show in doing so. I will never breach your confidentiality. The point is this: having access to many different scenarios of how the CLL plays out gives me a better perspective. Here then, is what I have observed: in at least a few anecdotal cases, a series of regular IVIg infusions (generally once a month) have led to a gradual and steady decrease in tumor load, a remission that has not needed any chemotherapy or other drugs, and therefore free of any side effects or toxicity. You can understand my level of interest in this concept!