Disease Characteristics el pt

Staging — The Dawn of a New Era

Date: February 24, 2024

by Chaya Venkat

At Last! The New Think on CLL Is Finally Here

The February 24, 2024 issue of the prestigious New England Journal of Medicine has an article in it that is of pivotal importance to all of us battling CLL. More than half dozen of our members bought and sent me full text copy of this article. Just goes to show we are a wide awake patient community. Since this article does not come with an abstract, I have given below the journal citation and an extract from the first paragraph.

Abstract:

Full-text Article from the New England Journal of Medicine (PDF)

NEJM, Volume 352:804-815, Number 8, February 24, 2024

Chronic Lymphocytic Leukemia

Review Article, Mechanisms of disease

Nicholas Chiorazzi, M.D., Kanti R. Rai, M.B., B.S., and Manlio Ferrarini, M.D.

When chronic lymphocytic leukemia (CLL) was last reviewed in the Journal, it was considered a homogeneous disease of immature, immune-incompetent, minimally self-renewing B cells, which accumulate relentlessly because of a faulty apoptotic mechanism. In the past decade, these views have been transformed by a wealth of new information about the leukemic cells. CLL is now viewed as two related entities, both originating from antigen-stimulated mature B lymphocytes, which either avoid death through the intercession of external signals or die by apoptosis, only to be replenished by proliferating precursor cells.

My review will describe some of the highlights of this article for your reading pleasure. A link to the full-text article, should you wish to read it, is provided above. Mind you, the article is not written with layperson patients in mind, and the jargon is a little intimidating. However, if you want to impress your local oncologist with your up-to-date awareness of what is happening on the cutting edges of CLL, by all means take him / her a copy of the full length article. Sometimes busy oncologists are not always caught up with their reading and there is no harm in patients helping the process of "information trickle down" from the expert researchers to the community level healthcare provider. A better informed oncologist will be a better doctor for you, and a better doctor for the next guy who walks in the door.

What Is the Excitement All About?

After informing you that you have CLL, one of the first things your oncologist would have (could have, should have) told you is your Rai staging. For the longest time, the Rai Staging ("Binet" Staging in Europe) has been the cornerstone of defining the different stages of CLL (Survival Statistics Based on Rai and Binet Staging May Need to Be Modified; What You and Your Oncologist Need to Know; Prognosis at Diagnosis). If like most newly diagnosed patients you were early Rai stage, say Stage 0 or Stage 1, and you had no symptoms, the absolute slam dunk conventional wisdom was to assign you to "Watch and Wait" (W&W). Oh yes, if your oncologist was the chatty type, he might also have told you this is the good cancer to have, and since you are early Rai stage, most likely you will not need therapy for a long time. The Rai staging gets its name from Dr. Kanti Rai, one of our best known experts in CLL. At the time of their development, the Rai and Binet staging systems were as good as it got.

The problem was that not everyone with early Rai stage disease had a similar experience during W&W. Some patients "smoldered" for a good long time with nothing much happening and indeed these folks had little need for therapy of any kind for many years. However, some patients were not as fortunate — they very quickly progressed from an early Rai stage through all the intermediate stages and galloped on to late stage disease before anyone figured out what to do. Very often in such cases, not only did the disease progress much faster, it did not respond very well to any of the conventional chemotherapy drugs used for treating CLL. In other words, while the Rai and Binet staging were useful in a rough segregation of patients into groups based on the level of tumor load, neither of these staging systems did very well in providing prognostic data. It was still pretty much a crapshoot as to who progressed rapidly and who did not.

Now, notice that one of the authors of this seminal article is none other than Dr. Rai himself. Here is one quotation from the article, in which Dr. Rai is commenting on the staging system that bears his name:

"In the past, physicians told patients with CLL that a “watchful waiting” mode had to be adopted until the disease progressed, whereupon therapy would be initiated. In my opinion, this approach is especially disturbing, given that the novel prognostic markers indicate that some 50 percent of the patients assigned to watchful waiting have one or more features portending a poor outcome."

In the last couple of years several experts have been sounding the call for a new approach, where therapy decisions are made on the basis of modern prognostic indicators, not an automatic W&W for all early Rai stage patients. With this article, the age of prognostics-based therapy is officially here. Modern prognostics-based therapy decisions are the way to go and one-size-fits-all W&W is now obsolete. Dr. Rai has fulfilled one of the cardinal requirements of a true expert and leader, by acknowledging that with the passing of time and a better understanding of the disease, the staging system that bears his name should be replaced by better methods. This article pulls together many of the breakthroughs in our understanding of what makes CLL tick. Truly, this is a must-read article for all CLL professionals.

I'd be kidding you if I said this article is light reading — even the very nice diagrams do not make it easy. I have given the highlights below, simplified as best as I could. The first part of the article recapitulates our new prognostic understanding of CLL. Much of this has been discussed by other researchers as well in the last couple of years. The second part of the article then goes on to bring into clear focus the implications of all this new stuff. Reading some of the reviews we have published of these new developments may help in setting the stage for you.

Staging Does Not Predict Survival;
Prognosis at Diagnosis;
What Type of CLL Do You Have?;
Mayo Best Practices;
ZAP-70 and IgVH Gene Mutation;
FISH-ing for Answers;
Shopping for Therapies;
Cytogenetics of ATM and TP53.

Article Highlights

• CLL is derived from mature, activated B-cells that differ in their level of IgVH gene mutation. IgVH gene mutation status is the single biggest factor that identifies different varieties of CLL clones.
• The primary role of the Rai and Binet staging systems was to help clinicians decide when patients should be started on therapy. However, since these approaches define the tumor load at the time of diagnosis, but do not predict the clinical course of a patient with precision, they are not very useful as long-term prognostic indicators.
• Patients with a clone having little or no IgVH gene mutations, or with many CD38 positive, or ZAP70 positive CLL cells are likely to have an aggressive disease, whereas patients with mutated IgVH genes or few CD38+ or ZAP70+ CLL cells are the lucky ones, they will have an indolent form of CLL.
• IgVH gene mutation status and the CD38 indicator do not always correlate. (For my money, CD38 is looking less and less a dependable prognostic indicator).
• Typically, unmutated CLL cells express more ZAP70 than do mutated CLL cells.
• The most common chromosomal abnormality detected by FISH is at 13q14, this chromosomal deletion occurs in more than 50 percent of CLL cases over time.
• The most ominous alterations are deletions at 11q22-23, 17p13, and 6q21. 17p deletions lead to defects in p53 function and 11q deletions cause defects in ATM function. These deletions are more frequent in unmutated CLL cases with a poor outcome.

For those of you who have kept up with your reading, all this should sound pretty familiar. The article then goes on to describe more recent work, and its implications:

• New evidence suggests that CLL cells avoid death and continue to proliferate when they are subjected to the goading influence of specific antigens.
• CLL cells with unmutated IgVH seem to be able to react to a variety of antigens. This "promiscuous" response to many antigens is perhaps why IgVH unmutated CLL cells are prone to rapid proliferation, and therefore poor prognosis. These CLL cells are not 'choosey', many different antigens seem to be able to turn them on, get these 'floozies' into a proliferative frenzy.
• IgVH mutated CLL cells in a given clone tend to be more 'monogamous', they respond to one specific antigen, not just any antigen can get their proliferative juices flowing. This may explain why mutated IgVH genes mean a slow growing and indolent disease. (My analogy of unmutated IgVH clones as floozies and the mutated variety as virtuous monogamous cells is just a way of remembering the point, not meant to be judgmental).
• The most interesting finding that has come to light in recent months is that CLL cells from a surprisingly large percent of different patients have similar IgVH tips, suggesting that the CLL cells in all these patients respond to the same antigen. Several such "clumps" of patients have been identified, patients in each clump having identical IgVH tips. This was entirely unexpected. The mathematical odds of this being a mere coincidence are about as high as a bunch of people in a crowd having the exact same fingerprints.
• As many as 10 percent of all CLL cases fall into these several distinct 'clumps'.
• The obvious question to ask, if patients in any one of these clumps are all responding to a particular antigen, what is this culprit antigen? We are not sure, but it is possible that latent viruses or bacteria that are around all the time within our bodies may be among the culprits. One can imagine that repetitive activation of the CLL clones by an antigen that is around all the time, goading the cells over and over to proliferate - this would result in an aggressive disease. The authors suggest this mechanism is similar to gastric lymphomas that evolve in response to Helicobacter pylori.
• Some viral drivers of different cancers have already been identified, such as the human papilloma virus in cervical cancer, hepatitis virus in liver cancer, Epstein Barr virus in some types of lymphoma, H.Pylori in stomach cancer. Alternatively, environmental antigens (I wonder, can 'Agent Orange' be an example of a common antigen precipitating CLL in our service men and women who have been exposed to this antigen during the Vietnam war era?) or even home-grown self-antigens could provoke clonal expansion.
• This mechanism is plausible for a few cases of mutated CLL which turn out to be fast paced growers, if their one-and-only 'significant other' antigen just happened to be an antigen that is around all the time. Even with their exclusive response behavior, just the fact that the specific antigen is one that is present most of the time means higher than expected proliferation.
• Using radioactive "labeling" studies the authors have shown in a prior article (abstract below) that CLL cells are more dynamic than is usually appreciated. CLL cells have surprisingly brisk birth rates, ranging from about 0.1 to more than 1.0 percent of the clone per day. Total number of CLL cells in a typical patient with moderate tumor load is approximately a trillion cells. With a 0.1% to 1.0% birth rate per day, this adds up to 1-10 billion new CLL cells, each and every day. Wow!
• How can we use this information? If we are able to identify the mystery antigen that is provoking the CLL proliferating in a given patient, then blocking or removing this antigen may have beneficial effects on the rate of growth of the CLL. Makes sense.
• ZAP-70 is part of the signaling mechanism where by the antigen goads get their messages through to the nucleus of the CLL cell, telling it to proliferate. Preventing the ZAP-70 from activating, and therefore preventing the message from getting through may slow down the rate at which the cancer grows.

I have also attached several recent abstracts (links to full text articles when possible) that cover much of the same ground, for your reading pleasure.

Cheat Sheet

I can hear the grumbles and bewildered groans already. So what does all this mean for us patients, besides giving us defcon 2 headache as we try to sort out the jargon? Here is the cheat sheet, if you were going to take a pop quiz on the latest and greatest news on CLL. Come to think of it, you will be taking a pop quiz on this the next time you have to make therapy choices. Your life may depend on whether you pass or fail the quiz.

• Rai and Binet stagings were useful - note the emphasis on the word "were", past tense. Even the inventor of the Rai staging system is now on record that we are better off making therapy choices based on modern prognostic indicators, specifically IgVH gene mutation status, FISH cytogenetics, ZAP-70 and perhaps CD38. As we reported recently, CLL Topics is in the process of negotiating a cost-effective package deal with Quest Diagnostics for providing the full slate of prognostic tests to our members (Progress on Prognostics).
• Next time your local oncologist refuses to order these new fangled tests, because as a low Rai stage patient you do not need to worry your pretty little head about therapy decisions, make him a present of the full text of this article.
• Come to think of it, full text versions of this article as well as the earlier the Mayo "Prognosis at Diagnosis" , "Best Practices" , "CLL and skin cancer" articles are good to have around in your files, useful the next time you have to pick a fight with your insurance carrier for coverage. Write to us, we can help you locate the full text versions of each of these articles.
• If you are in one of the poor risk categories ("Bucket C"), you might want to initiate therapy sooner rather than later. Just look at the proliferation rates. For someone with a rapidly proliferating CLL clone, there are as many as 10 billion new CLL cells created each and every day. A poor prognosis phenotype also probably means these newly minted clonal cells are harder to kill, making for a real problem down the road.
• I am a firm believer in Murphy's law. CLL cells are wonky to begin with. They have an unstable genome, and each time one of them decides to multiply, there is a chance that the daughter may be even more screwed up than the mother cell that gave birth to it. The more often CLL cells divide, the bigger the chance that something else will go wrong, that a new and worse chromosomal defect would be added to the repertoire. "Clonal evolution" seems to be a fact of life in CLL. Letting the tumor load grow unchecked into ever larger hordes of CLL cells may be a poor strategy for patients with bad prognostic markers.
• On the other hand, if you are blessed with an indolent variety of CLL, one that is barely growing and easy to kill anytime you decide to pull the plug on it, you would be foolish to declare thermonuclear war on it, bring on the heavy chemo and end up with more problems than you had to begin with. How would you know what to do, unless you have a fair idea which type of CLL you have? Ignorance is not bliss for CLL patients, what you do not know can come back to bite you.
• There is reason for optimism. Someone said the most important thing in winning battles is better understanding of your enemy. We are getting a better handle on CLL, what makes it tick. Just for example, if down the road it can be shown that your particular version of CLL is proliferating due to the constant goading of the human papiloma virus, and that by taking care of those ugly warts on your knuckles you can slow down the rate at which the CLL grows, don't you think that is progress? They are even developing a vaccine for HPV, for crying out loud. Same logic works for other viral drivers: Herpes Simplex can be controlled by antiviral drugs such as Famvir and even the dreaded hepatitis virus can be controlled to some degree. Bacterial drivers are less of a problem since we have many good broad spectrum antibiotics.
• Rai and his co-authors sum it up nicely: "When the antigens that engage these (IgVH) receptors are precisely defined, it may become possible to develop another arsenal of specific therapies." Amen.

Abstracts:

Article From Journal of Clinical Investigations (Full-text PDF)

J Clin Invest. 2024 Feb 10; [Epub ahead of print]

In vivo measurements document the dynamic cellular kinetics of chronic lymphocytic leukemia B cells.

Messmer BT, Messmer D, Allen SL, Kolitz JE, Kudalkar P, Cesar D, Murphy EJ, Koduru P, Ferrarini M, Zupo S, Cutrona G, Damle RN, Wasil T, Rai KR, Hellerstein MK, Chiorazzi N.

Institute for Medical Research, North Shore-LIJ Research Institute, Manhasset, NY

Due to its relatively slow clinical progression, B cell chronic lymphocytic leukemia (B-CLL) is classically described as a disease of accumulation rather than proliferation. However, evidence for various forms of clonal evolution suggests that B-CLL clones may be more dynamic than previously assumed. We used a nonradioactive, stable isotopic labeling method to measure B-CLL cell kinetics in vivo. Nineteen patients drank an aliquot of deuterated water ((2)H(2)O) daily for 84 days, and (2)H incorporation into the deoxyribose moiety of DNA of newly divided B-CLL cells was measured by gas chromatography/mass spectrometry, during and after the labeling period. Birth rates were calculated from the kinetic profiles. Death rates were defined as the difference between calculated birth and growth rates. These analyses demonstrated that the leukemic cells of each patient had definable and often substantial birth rates, varying from 0.1% to greater than 1.0% of the entire clone per day. Those patients with birth rates greater than 0.35% per day were much more likely to exhibit active or to develop progressive disease than those with lower birth rates Thus, B-CLL is not a static disease that results simply from accumulation of long-lived lymphocytes. Rather, it is a dynamic process composed also of cells that proliferate and die, often at appreciable levels. The extent to which this turnover occurs has not been previously appreciated. A correlation between birth rates and disease activity and progression appears to exist, which may help identify patients at risk for worsening disease in advance of clinical deterioration.

PMID: 15711642
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Article from the Journal of Experimental Medicine (Full-text PDF)

J Exp Med. 2024 Aug 16;200(4):519-25.

Multiple distinct sets of stereotyped antigen receptors indicate a role for antigen in promoting chronic lymphocytic leukemia.

Messmer BT, Albesiano E, Efremov DG, Ghiotto F, Allen SL, Kolitz J, Foa R, Damle RN, Fais F, Messmer D, Rai KR, Ferrarini M, Chiorazzi N.

North Shore-LIJ Research Institute, 350 Community Dr., Manhasset, NY

Previous studies suggest that the diversity of the expressed variable (V) region repertoire of the immunoglobulin (Ig)H chain of B-CLL cells is restricted. Although limited examples of marked constraint in the primary structure of the H and L chain V regions exist, the possibility that this level of restriction is a general principle in this disease has not been accepted. This report describes five sets of patients, mostly with unmutated or minimally mutated IgV genes, with strikingly similar B cell antigen receptors (BCRs) arising from the use of common H and L chain V region gene segments that share CDR3 structural features such as length, amino acid composition, and unique amino acid residues at recombination junctions. Thus, a much more striking degree of structural restriction of the entire BCR and a much higher frequency of receptor sharing exists among patients than appreciated previously. The data imply that either a significant fraction of B-CLL cells was selected by a limited set of antigenic epitopes at some point in their development and/or that they derive from a distinct B cell subpopulation with limited Ig V region diversity. These shared, stereotyped Ig molecules may be valuable probes for antigen identification and important targets for cross-reactive idiotypic therapy.

PMID: 15314077
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J Clin Invest. 2024 Apr;113(7):1008-16.

Remarkably similar antigen receptors among a subset of patients with chronic lymphocytic leukemia.

Ghiotto F, Fais F, Valetto A, Albesiano E, Hashimoto S, Dono M, Ikematsu H, Allen SL, Kolitz J, Rai KR, Nardini M, Tramontano A, Ferrarini M, Chiorazzi N.

Department of Medicine, North Shore University Hospital and New York University School of Medicine, Manhasset, NY

Studies of B cell antigen receptors (BCRs) expressed by leukemic lymphocytes from patients with B cell chronic lymphocytic leukemia (B-CLL) suggest that B lymphocytes with some level of BCR structural restriction become transformed. While analyzing rearranged V(H)DJ(H) and V(L)J(L) genes of 25 non-IgM-producing B-CLL cases, we found five IgG(+) cases that display strikingly similar BCRs (use of the same H- and L-chain V gene segments with unique, shared heavy chain third complementarity-determining region [HCDR3] and light chain third complementarity-determining region [LCDR3] motifs). These H- and L-chain characteristics were not identified in other B-CLL cases or in normal B lymphocytes whose sequences are available in the public databases. Three-dimensional modeling studies suggest that these BCRs could bind the same antigenic epitope. The structural features of the B-CLL BCRs resemble those of mAb's reactive with carbohydrate determinants of bacterial capsules or viral coats and with certain autoantigens. These findings suggest that the B lymphocytes that gave rise to these IgG(+) B-CLL cells were selected for this unique BCR structure. This selection could have occurred because the precursors of the B-CLL cells were chosen for their antigen-binding capabilities by antigen(s) of restricted nature and structure, or because the precursors derived from a B cell subpopulation with limited BCR heterogeneity, or both.

PMID: 15057307
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N Engl J Med. 2024 Aug 26;351(9):893-901.

ZAP-70 compared with immunoglobulin heavy-chain gene mutation status as a predictor of disease progression in chronic lymphocytic leukemia.

Rassenti LZ, Huynh L, Toy TL, Chen L, Keating MJ, Gribben JG, Neuberg DS, Flinn IW, Rai KR, Byrd JC, Kay NE, Greaves A, Weiss A, Kipps TJ.

Chronic Lymphocytic Leukemia Research Consortium, University of California, San Diego, La Jolla, CA

BACKGROUND: The course of chronic lymphocytic leukemia (CLL) is variable. In aggressive disease, the CLL cells usually express an unmutated immunoglobulin heavy-chain variable-region gene (IgV(H)) and the 70-kD zeta-associated protein (ZAP-70), whereas in indolent disease, the CLL cells usually express mutated IgV(H) but lack expression of ZAP-70.
METHODS: We evaluated the CLL B cells from 307 patients with CLL for ZAP-70 and mutations in the rearranged IgV(H) gene. We then investigated the association between the results and the time from diagnosis to initial therapy.
RESULTS: We found that ZAP-70 was expressed above a defined threshold level in 117 of the 164 patients with an unmutated IgV(H) gene (71 percent), but in only 24 of the 143 patients with a mutated IgV(H) gene (17 percent, P<0.001). Among the patients with ZAP-70-positive CLL cells, the median time from diagnosis to initial therapy in those who had an unmutated IgV(H) gene (2.8 years) was not significantly different from the median time in those who had a mutated IgV(H) gene (4.2 years, P=0.07). However, the median time from diagnosis to initial treatment in each of these groups was significantly shorter than the time in patients with ZAP-70-negative CLL cells who had either mutated or unmutated IgV(H) genes (P<0.001). The median time from diagnosis to initial therapy among patients who did not have ZAP-70 was 11.0 years in those with a mutated IgV(H) gene and 7.1 years in those with an unmutated IgV(H) gene (P<0.001).
CONCLUSIONS: Although the presence of an unmutated IgV(H) gene is strongly associated with the expression of ZAP-70, ZAP-70 is a stronger predictor of the need for treatment in B-cell CLL.

Copyright 2024 Massachusetts Medical Society

PMID: 15329427
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Blood. 2024 Mar 1;105(5):2036-41. Epub 2024 Oct 28.

ZAP-70 directly enhances IgM signaling in chronic lymphocytic leukemia.

Chen L, Apgar J, Huynh L, Dicker F, Giago-McGahan T, Rassenti L, Weiss A, Kipps TJ.

9500 Gilman Dr, UCSD School of Medicine, La Jolla, CA

Chronic lymphocytic leukemia (CLL) B cells that express unmutated immunoglobulin heavy-chain variable region genes (IgV(H)) generally express ZAP-70, in contrast to normal B cells or most CLL cases with mutated IgV(H). Following IgM ligation, ZAP-70(+) CLL cells had significantly higher levels of phosphorylated p72(Syk), BLNK, and phospholipase-Cgamma (PLCgamma) and had greater[Ca(2+)](i) flux than did ZAP-70-negative CLL cases, including unusual ZAP-70-negative cases with unmutated IgV(H). IgM ligation of ZAP-70-negative CLL B cells infected with an adenovirus vector encoding ZAP-70 induced significantly greater levels of phosphorylated p72(Syk), BLNK, and PLCgamma and had greater[Ca(2+)](i) flux than did similarly stimulated, noninfected CLL cells or CLL cells infected with a control adenovirus vector. We conclude that expression of ZAP-70 in CLL allows for more effective IgM signaling in CLL B cells, a feature that could contribute to the relatively aggressive clinical behavior generally associated with CLL cells that express unmutated IgV(H).

PMID: 15514014
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