What Type of CLL Do You Have?

Much has changed in our understanding of CLL in the past two decades. If you are a newly diagnosed CLL patient and you are anxious to understand exactly what this diagnosis means for you and your family, read on. This is not an easy article to read, you will have to work at getting all the details. I have tried hard to keep it "Just the facts, Ma'am" , and provided references where you can learn more later on. Print it out, highlight it, mark it up to customize it for you. But do try to read it, and you might also find much of this information useful in working with your specialists.

The good news is that with better understanding we are able to classify patients into distinct risk profiles, that need different management strategies. That word, "management", is an important one. I doubt any of us expect overnight miracles, a magic pill that will cure all of us, once and for all. That is not how science works. In our life times, "management" of this disease is very much achievable for a large majority, and this is nothing to sneeze at. If you do not like the idea of "management", and would like an outright cure, think of all the patients with high blood pressure, diabetes, and other chronic diseases. With proper diagnosis, medical care and "management" of their diseases, their quality and quantity of lives are dramatically improved from just a decade ago. They do not get the pitying glances that most of us have learned to hate, one of the side effects of a cancer diagnosis.

I see the CLL landscape as a continuum. For a small percentage of "lucky" CLL patients, lucky to have the right phenotype, good prognostics, the right diagnosis, access to good medical care and the right therapy choice, CLL may soon become a dim memory, a nightmare that they can put behind them. For the majority of us, again with proper diagnosis and risk classification and pragmatic therapy choices, CLL may be "managed" to the point where its impact on our lives is minimized, and we can look forward to good quality of life for many years ahead. For the small percentage of patients on the other side of the curve, the ones with the aggressive disease and poor phenotype, accurate diagnosis and risk classification is even more important, they don't have a lot of time to waste. For this unfortunate subset of CLL patients, making the right first therapy choices are crucial. Under-treating an aggressive form of CLL, waiting too long or wasting time with ineffective and tentative therapies spells trouble. The article "ZAP-70 Why Should You Care?" might prove instructive.

Choose Your Bucket

We have made the first step, we have decided to sub-divide CLL patients into three groups. The next step is to define the nature of each group, and for each of you to compare your own medical information against these yard-sticks and decide which "bucket" you belong to. Bear in mind, the buckets do slosh and splash, and some one in one bucket may "graduate" and move up the scale to the next bucket. All the same, this is an interesting and important exercise, getting a reality check of your own prognosis. Much of this material is covered in other articles on this website in greater detail, this essay is for the purpose of putting it all together.

Just so you can see the point of doing any of this, here is a graph that shows overall survival of CLL patients, depending on when they were first diagnosed. 50% of patients diagnosed between 1980 and 1984 did not make it past 7.5 years. But patients diagnosed ten years later, between 1990 and 1994, 50% of them were still around at 12 years. That is a solid gain, and my guess is that the improvement would be even better when we look at patients diagnosed another decade later, between 2024 and 2024, just look at the rate at which our understanding of this disease is growing! It would be a shame if you were diagnosed recently, but got stuck with 1980 survival odds, because of lack of information.

Graph from Keating article on Medscape showing that the overall
survival of CLL patients depends upon when they were first diagnosed
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Source: Management Strategies for Chronic Lymphocytic Leukemia by Michael J. Keating. CME clinical update on Medscape®.

Important Link: http://www.medscape.com/viewarticle/456068. (full text article; you have to login to medscape.com first - membership is free - then copy and paste this url into your web browser.)

This is a Medscape® reference and in order to view it, you have to register first. Registration is free and highly recommended, since we shall be using Medscape references with some frequency. Once you register, all you have to do is supply the user ID and password when asked. The initials CME refer to Continuing Medical Education, an accredited program for physicians and other health professionals intended to bring them up to date on essential areas. Please keep a record of your login data for Medscape and certain other sources of critical information that we will be using.

Make sure you are indeed a CLL patient

First things first: you need to be sure that you are a bona fide CLL patient, not a patient of one of the "kissing cousins" such as the much more aggressive Mantle Cell Lymphoma (MCL) or Splenic Lymphoma with Villous lymphocytes (SLVL), or Follicular lymphoma. At the very least, your local oncologist should have requested a flow cytometry of your blood, to determine your immunophenotype. That report would have information of various CD markers, such as CD5, CD19 and CD23. These three markers happen to be the classic pattern for CLL. Each CD marker is also labeled as weak (+), medium (++) or strong (+++). The table below differentiates between CLL and the other look-alikes, in terms of the CD markers.

Antigen	B-CLL	Mantle Cell Lymphoma	SLVL	Follicular Lymphoma

sIg	Weak	++	++	++
CD5	++	++	–	–
CD19	++	++	++	++
CD20	+	++	++	++
CD22	Weak or –	++	++	++
CD23	++	–	–	–
CD79b	Weak or –	++	++	++
FMC7	–	++	++	++
CD10	–	–	–	++
Abbreviations: sIg - surface immunoglobulin; SLVL - splenic lymphoma with villous lymphocytes.

Immunophenotype of B-cell chronic lymphocytic leukemia (B-CLL) and lymphomas
that resemble it

The content of this table is from an article titled, "The Nature and Natural History
of Early-Stage B-CLL" by Terry J. Hamblin from the ASH Education Book of 2024.
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Now that we have that sorted out and we are all CLL patients here, and the SLVL or MCL folks have logged off, let us get on with the job of defining the three buckets. Bucket "A" are the lucky ones, who will probably "smolder", it may be a long while before they will need therapy, if ever. Bucket "B" is the intermediate group, for whom therapy decisions will be harder to make, just because things are not black-and-white, a lot of grey areas. Bucket "C" is the aggressive group, the best advice I can give you is to make sure you get the best possible expert medical help you can afford, listen and learn to talk to your doctors, do not neglect your CLL. Watchful (or head-in-sand) Waiting is not for you, not without some serious soul searching and rational game plan to put into motion when you need it.

Cytogenetics, FISH (fluorescence in-situ hybridization)

Every cancer starts with a single cell, and in the case of CLL, five distinct commonly recurring genetic defects have been identified. FISH analysis has demonstrated that a very large number (more than 92%) of patients can be grouped into five groups, based on their particular chromosomal aberration. The table below lists them, in the order of decreasing virulence, 17p deletion is considered the most dangerous, since it is often accompanied by deletion of the tumor suppressor gene p53. On the other hand, people with 13q deletion as their sole genetic abnormality are likely to live out their full life spans, and not have to deal too much with CLL. But do remember, one patient can have more than one type of aberration, I guess I would then look at the "worse" aberration as the one in charge of driving the CLL bus. If you are bothered by these labels, and would like to know what they mean, go to the article titled "Genetic Abnormalities in Blood Cancers" where you can learn more.

Source: The content of the following table and the two graphs that follow are from an article titled "Genomic Aberrations and Survival in Chronic Lymphocytic Leukemia" by Hartmut Dohner, Stephan Stilgenbauer, Axel Benner, Elke Leupolt, Alexander Kröber, Lars Bullinger, Konstanze Döhner, Martin Bentz and Peter Lichter that appeared in the New England Journal of Medicine issue of December 28, 2024.

Hierarchical Model of Chromosomal Abnormalities in Chronic Lymphocytic Leukemia
Karyotype*	No. of Patients (%)
17p deletion	23 (7)
11q deletion	56 (17)
12q trisomy	47 (14)
Normal Karyotype	57 (18)
13q deletion as sole abnormality	117 (36)
Various abnormalities	25 (8)
* The five major categories are defined a follows: patients with a 17p deletion; patients with a 11q deletion but not a 17p deletion; patients with a 12q trisomy but not a 17p or a 11q deletion; patients with a normal karyotype; and patients with a 13q deletion as the sole aberration. Twenty five of the 325 patients with various chromosomal abnormalities could not be assigned to one of these five major categories.

Probability of Survival from the Date of Diagnosis among the Patients
in the Five Genetic Categories
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The median survival times for the groups with 17p deletion, 11q deletion, 12q trisomy, normal karyotype, and 13q deletion as the sole abnormality were 32, 79, 114, 111, and 133 months, respectively. Twenty-five patients with various other chromosomal abnormalities are not included in the analysis.

Probability of Disease Progression, as Indicated by the Treatment-free
Interval in the Patients in the Five Genetic Categories
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The median treatment-free intervals for the groups with 17p deletion, 11q deletion, 12q trisomy, normal karyotype, and 13q deletion as the sole abnormality were 9, 13, 33, 49, and 92 months, respectively. The differences between the curves were significant. Twenty-five patients with various other chromosomal abnormalities are not included in the analysis.

The following highlights the effect of a p53 deletion upon the prognosis for a CLL patient.

This graph is from another Dohner article that appeared in Blood.
The difference between the two curves is highly significant both
statistically and in lay terms.
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Source: p53 gene deletion predicts for poor survival and non-response to therapy with purine analogs in chronic B-cell leukemias. H Dohner, K Fischer, M Bentz, K Hansen, A Benner, G Cabot, D Diehl, R Schlenk, J Coy and S Stilgenbauer. Blood Online March 15, 1995. The title says it all.

The survival and disease progression graphs above make it very clear why we should be interested in the exact nature of the genetic abnormality that is driving our particular brand of CLL. Based on this excellent and pivotal analysis, I would define Bucket A as people with 13q deletion only, Bucket B as people with 12q trisomy or normal karyotype, and Bucket C as people with 11q deletion of 17p deletion. In particular, people with 17p deletion may also have deletion of the important tumor suppressor p53 gene. There is a whole article in this website on just the p53 gene and what it does. If you find out early in your CLL career that you have deletion of this important gene that has a great deal to do with keeping cancers at bay, you are probably a good candidate for early and effective chemotherapy and perhaps you should also consider a bone marrow transplant down the road. Not for you the luxury of indefinite dithering, you need to get real with lining up good medical care. Remember, even if fate has dealt you a poor hand, the idea is to play it to best effect. Even patients with so-called poor prognosis can do very well, provided they take charge of the situation and avoid the trap of the head-in-sand syndrome.

As you read this and other sections in this long article, bear in mind this very important fact: all the survival data presented in this essay are based on historical data, and as we discussed right at the top of this essay, the CLL landscape is changing for the better, and patients diagnosed more recently can hope to do better than the historical norms. Information, accurate diagnosis of the patient, therapy decisions based on his/her particular risk profile are at the heart of the improvements in cancer survival. FISH analysis of genetic aberrations is an incredibly important and powerful tool, it is a shame that it is not used more routinely. If you go to one of the expert cancer centers, this is one test to request, if it is not routinely done.

It would be nice if you can go home reassured, or at least reasonably well aware of your particular genetic mutation, and that is that for the rest of your life. Unfortunately, things do change in CLL. The PubMed abstract below by Finn et al describes a common feature of CLL, called clonal evolution. As time goes one, for a subset of patients, their CLL clone acquires more genetic aberrations. Over a period of about 4 years, the authors detected additional mutations acquired by 22 out of 51 patients. "Disease progression, as measured by advance in Rai stage or death from the disease, was observed more often in the clonal evolution group than in the karyotypically stable group. The authors conclude that clonal karyotypic evolution is common in B-CLL, and that clonal evolution correlates with clinical disease progression". Bottom line, it makes sense to check periodically that you are still in the bucket you thought you were in, that your game plan is still valid for your situation. This well documented clonal evolution may make you re-think the strategy of watch and wait till the last bitter moment.

Beta-2 microglobulin, or B2M

This has been an important prognostic indicator, and fortunately for CLL patients, it is one that can be measured routinely by commercial testing labs, using just a blood sample. You may not want to get it done as frequently as your CBC, but it is certainly worth getting every so often and especially if you and your oncologist feel something unusual is happening re your CLL.

Graph from Keating article on Medscape showing the relationship of
B2M to survival in CLL
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Link: http://www.medscape.com/viewarticle/456068. (full text article; you have to login to medscape.com first - membership is free - then copy and paste this url into your web browser.)

With data from more than 1,200 people, M. D. Anderson has developed survival statistics based on B2M levels.

As you can see from the graph here, we can reasonably divide patients into our three buckets: patients with B2M less than 2.0 are in Bucket A; patients with B2M between 2.0 and 4.0 are in Bucket B; patients with B2M greater than 4 are in Bucket C. The cut-off points are obviously arbitrary, and B2M levels also change over time, especially if you are going through therapy. In fact, I get the feeling that B2M tells you where you are now, not where you will be; sort of like the weather guys going out side, looking around and saying "yup, bright and sunny today"; not exactly helpful in predicting the weather next week, let alone a few years down the road!

IgVH gene mutation status

This prognostic indicator has done more than any other in increasing our ability to define patients into low risk and high risk categories. You can learn a lot more of the details of what this is all about in other articles on this website: IgVH gene mutation status and CD38 expression as prognostic indicators in CLL and CD38 and IgVH Gene Mutation Status. Unfortunately, determining your status in terms of this prognostic indicator is not easy, at this point in time only the most sophisticated research hospitals are able to do this. But hey, if you have the connections and the money, and can get this test done, you will have a pretty good idea where you stand with regard to your CLL. For the rest of us, there are other, more easily available tests that mimic the IgVH gene mutation status, and we will be discussing them as well.

Unmutated IgVH Genes Are Associated With a More Aggressive
Form of Chronic Lymphocytic Leukemia

The two curves compare Stage A CLL patients with mutated and unmutated V_H genes.
Median survival for unmutated IgVH CLL: 95 months.
Median survival for mutated IgVH CLL: 293 months.
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Source: The graph is from an article in Blood, by Terry J. Hamblin, Zadie Davis, Anne Gardiner, David G. Oscier, and Freda K. Stevenson. Again, the title says it all: Unmutated IgVH Genes Are Associated With a More Aggressive Form of Chronic Lymphocytic Leukemia.

Let me see if I can take some of the mystery out of IgVH gene mutation status. Remember, we said all cancers start with the first malignant cell, in our case the first malignant B-cell that is the great-grand-daddy of all the other CLL cells that came from it. Well, IgVH mutation status pinpoints the exact time in the life of this crucial first CLL cell, when it became a malignant cell. In some patients, this patriarch of the CLL clonal family became a malignant cell before it finished its "education" in the germinal center. This "ignorance" of the first CLL cell is reflected in the immunoglobin (Ig) of the cell being unchanged, it is just as it was when it was created in the bone marrow. Since this first cell eventually gave rise to all the other cells in the CLL clonal family, all of the CLL cells in these patients have unchanged or "unmutated" Ig. The mutation of interest is in the heavy chain of the Ig, in the variable region. Put all that together, and we come up with unmutated IgVH (unmutated immunoglobin, variable region, heavy chain). In other patients, their very first CLL cell became a cancer cell after its trip to the germinal center. In these patients, since the first cell had graduated from the germinal center, the IgVH of this first CLL cell is mutated, and this trait is carried forward by all the off-springs of this first cell. These patients have mutated IgVH,

In this extremely important study, Hamblin et al studied 35 women and 49 men with classic CLL. The mean age at diagnosis was 63.3 years. 62 of the patients were stage Binet A, 9 stage B, and 13 stage C. 34 of the patients had progressive disease while 50 had stable disease. For each patient, the IgVH mutation status was determined. There are clear differences between the two groups of patients: those with unmutated V_H genes had a more malignant type of CLL than those with mutated V_H genes. Lack of mutations was clearly associated with progressive disease and had a huge impact on survival statistics.

For example, comparing only stage A patients (see graph above), Median survival was 95 months for the patients without mutations and 293 months for those with mutations. Just so you don't have to take out your calculator, 293 months is just under 25 years. Let's see now, the median age of the patients was around 63 years, add 25 to that, and we get 88 years. Half of the patients with CLL but with mutated IgVH gene lived to 88 years "only", the other half of that lucky group managed to live even beyond that. For my money, I read these statistics to say that for this group of patients with mutated IgVH genes, CLL did not have any real impact on their survival, they probably lived just as long as their neighbors and friends that had never even heard of CLL.

Moral of the story, don't you wish every patient had CLL where the first nasty cancerous B-cell did not drop out of germinal school, bothered to finish its education and get its merit badge of IgVH gene mutation, before it decided to go bad and become a cancerous CLL cell? You might want to use this story next time one of your kids or grandkids wants to drop out of school. May be not, perhaps there are easier ways of explaining the value of getting a good education.

Unfortunately for our three bucket division of patients, IgVH gene mutation status allows only a two bucket split. You either have the IgVH gene mutation (good news!!) or you don't (too bad, but it is not the end of the world).

CD38 level on CLL cells:

There was a lot of excitement a couple of years back, when it was thought that the expression of CD38 marker on CLL cells closely paralleled IgVH gene mutation status. Unlike IgVH status, which cannot be done routinely by labs other than cutting edge research facilities, CD38 levels on CLL cells can be measured by straight forward flow cytometry. Remember, this is CD38 levels on CLL cells, not just all cells. The measurement therefore requires that we first be sure we are talking of CLL cells only, and then look for CD38 on these cells. Going back to the first section of this paper, we learned that co-expression of CD5 and CD19 is a classic pattern of CLL cells. In other words, if we focus on cells carrying both the CD5 and the CD19 markers, and then look to see how many of them are carrying the CD38 marker as well, we have done the job right. In their pivotal paper Damle et al defined the cut-off point as 30%, if less than 30% of the CD5/CD19 positive cells expressed CD38, that was good news. Patients whose CLL cells had more than 30% CD38 positive cells were like patients with unmutated IgVH gene, and had poorer prognosis.

Below is the comparison of prognostic capabilities of CD38 and IgVH gene mutation status that created all the excitement.

Survival based on V gene mutation status and CD38 expression among B-CLL patients
in Rai Stages II and III.

(A) Plot comparing V gene mutation status with survival among the cases within the Rai intermediate risk
category (unmutated: 16 cases; mutated: 9). Median survival of the mutated group: 17 years; median
survival of the unmutated group: 9 years.

(B) Plot comparing numbers of CD38⁺ B-CLL cells with survival among the cases within the Rai
intermediate risk category (≥30%: 11 cases; <30%: 9). Median survival of the 30% CD38⁺ group:
10 years; median survival of the <30% CD38⁺ group: not reached. None of the patients in the <30%
CD38⁺ group died during the follow-up period.
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Rajendra N. Damle, Tarun Wasil, Franco Fais, Fabio Ghiotto, Angelo Valetto, Steven L. Allen, Aby Buchbinder, Daniel Budman, Klaus Dittmar, Jonathan Kolitz, Stuart M. Lichtman, Philip Schulman, Vincent P. Vinciguerra, Kanti R. Rai, Manlio Ferrarini, and Nicholas Chiorazzi

Closer examination of the data, and additional work done by other labs and other researchers suggested that the correlation between IgVH gene mutation status and CD38 expression was not as good as one could have hoped. True, low CD38 expression was still an indicator of good prognosis, and patients with high CD38 expression typically had more aggressive disease and poorer survival odds. But the two indicators did not track each other exactly, and that was a disappointment. Also, the 30% cut-off level was questioned, several researchers felt a cut off of 20% or even 10% was a better choice. All in all, we are not too far from reality if we use percentage of CD38 positive CLL cells as a semi-independent indicator, and use both the 20% and the 30% cut-offs: patients with less than 20% CD38 positive CLL cells are in Bucket A, between 20% and 30% they are in Bucket B, and patients with more than 30% CD38 expression on CLL cells are in the ugly Bucket C.

ZAP-70

This is the latest sexy new prognostic indicator to hit the wires. So far, it looks set to become the indicator to measure, since it has a number of advantages:

1. Unlike IgVH gene mutation status, it is relatively easy to measure, and once the experts have decided on all the details and standardized the procedure, it should be possible to get it done routinely by commercial blood testing labs.

2. Unlike CD38 expression, it seems to track IgVH gene mutation status pretty well, as you can see from the graph below.

3. Perhaps because it is still early days after the discovery of this prognostic indicator, no real challenges have emerged to the cut-off point of 20% (less than 20% ZAP-70 expression is good, higher than that is bad). We have several interesting articles and case histories of hypothetical patients as they pertain to ZAP-70. You can read more about this important indicator by going to: ZAP-70: A Valuable Prognostic Indicator and ZAP-70: A Breakthrough Prognostic Indicator?

4. The only fly in the ointment is that it is early days, and most of the CLL expert centers are not yet doing this test on a routine basis, except for "special" patients and special circumstances, I suppose.

Rate of disease progression as assessed by the treatment-free time interval measured in months
from diagnosis
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Source: Blood First Edition Paper, pre-published online February 20, 2024; DOI 10.1182/blood-2002-10-3306

Adrian Wiestner1,2, Andreas Rosenwald1, Todd S. Barry3, George Wright4, R. Eric Davis1, Sarah E. Henrickson1, Hong Zhao1, Rachel E. Ibbotson5, Jenny A. Orchard5, Zadie Davis5, Maryalice Stetler-Stevenson3, Mark Raffeld3, Diane C. Arthur3, Gerald. E. Marti6, Wyndham H. Wilson7, Terry J. Hamblin5, David G. Oscier5 and Louis M. Staudt1

Putting it all together

Below is a table that summarizes all the details we have discussed above, and divides patients into the three Buckets. I have also included the classic prognostic indicator, Rai stage, as well. You can get more detail of the Rai (and Binet) staging systems by going to: Survival Statistics Based on Rai/Binet Staging May Need To Be Modified. Nothing in life is simple, for many of you not all of the prognostic indicators will line up exactly, making it crystal clear which bucket you belong to. You will have to use your judgment in how you deal with a split decision. But if you get all these prognostic indicators down (well, perhaps not the IgVH gene mutation status), I am willing to bet you have a much better idea of how your CLL is likely to progress.

I have said this before, but I want to repeat it so that there is no chance of you missing the point: Bucket C is not an automatic kiss of death. It just means you do not have the luxury of dithering, indulging in wishful thinking, or trying to cure an aggressive form of CLL with home remedies. Time you waste in exploring half measures and ill thought out strategies will be precious time that would have been better spent coming to pragmatic grips with the issues involved. Similarly, panicking at the mention of the 'Big C" when you are in Bucket A, over-treating an indolent disease that will probably do you little harm over your natural life span, that is tantamount to spoiling your good fortune. If you are fortunate enough to have a smoldering variety of CLL, last thing you want is to screw up the lucky phenotype with aggressive chemotherapy. If you are a type A personality and just hate the concept of sitting on your hands waiting, you might wish to explore some of the natural chemo preventives like curcumin, green tea, resveratrol etc., or you may decide you want to learn more about immunotherapy options such as monoclonal antibodies and patient specific vaccines. These have a better chance of working in patients with low tumor burden and a good phenotype to begin with.

Last but not least, please do not write out your last will and testament based on the survival statistics presented here. For starters, these are historical statistics, and we have every reason to believe things are improving for CLL patients with newer therapies and better understanding. Also, statistics are great for giving you the odds, but you may still be the one person that falls way outside the norms, you may do a lot better (or a lot worse, if you are unlucky) than the statistics. No, it is not a crapshoot. You would not bet on a horse race without knowing the odds, would you? And you would not expect the odds to guarantee a win either. Same story here. Knowing the odds makes it easier for you to play the hand you have been dealt to best advantage. None of us can hope to do better than that.

Abstract:

Secondary abnormalities of chromosome 6q in B-cell chronic lymphocytic leukemia: a sequential study of karyotypic instability in 51 patients.

Department of Pathology, Northwestern University Medical School, Chicago, Illinois, USA.

Although karyotypic abnormalities are well documented in B-cell chronic lymphocytic leukemia (B-CLL), few sequential cytogenetic studies have been done. In this study, peripheral blood lymphocytes from fifty-one patients with B-CLL were sequentially karyotyped over a mean interval of 13.8 months (range, one to 51 months). Cytogenetic clones were detected in 33/51 patients (66%) on initial study, including 17 patients with structural abnormalities of chromosome 13q14, and three patients with trisomy 12. Karyotypic evolution was documented in 22/51 patients (43%). The most common secondarily acquired chromosome aberrations were structural abnormalities of the long arm of chromosome 6 involving the region of 6q21-q24 (six patients). Four patients each had acquired structural abnormalities of 1q, 3p, 12q, and 13q. Disease progression, as measured by advance in Rai stage or death from the disease, was observed more often in the clonal evolution group than in the karyotypically stable group (11/22 vs. 5/29; P = 0.017). Patients with secondary abnormalities of 6q had a significantly decreased progression-free survival interval compared with other patients in the study (P = .023). The authors conclude that clonal karyotypic evolution is common in B-CLL, and that clonal evolution correlates with clinical disease progression. Furthermore, the poor outcomes previously attributed to CLL with 6q abnormalities may be related to the clonal acquisition of these abnormalities over time. Future studies should focus on the relevant genetic events underlying the clinical progression observed with karyotypic evolution of B-CLL.

PMID: 9798660
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Prognostic Indicators