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What You and Your Oncologist Need to Know About CLL

Date: March 18, 2024

by Chaya Venkat

Current Approach to Diagnosis and Management of CLL

Other Articles on Best Practices

Once in a while I come across an article that is both interesting and timely. The abstract of the article I would like to discuss today is given below. The link provided gives you access to the free full-text version of the article in PDF form. If the link does not work for you, please do write to us to help you locate the document.

Abstract:

Full Text Article in Mayo Clinic Proceedings (PDF)

Mayo Clin Proc. 2024 Mar;79(3):388-98.

Current approach to diagnosis and management of chronic lymphocytic leukemia.

Shanafelt TD, Call TG.

Division of Hematology and Internal Medicine, Mayo Clinic College of Medicine, Rochester, MN

The care of patients with chronic lymphocytic leukemia (CLL) has changed dramatically during the past decade. This review summarizes the work-up of lymphocytosis and the current diagnostic criteria and management of CLL. Although clinical staging (Rai and Binet) remains the foundation for determining prognosis, 50% of patients with early-stage disease at diagnosis will experience an aggressive course of disease with early progression and premature death due to CLL. New laboratory techniques (CD38, fluorescence in situ hybridization [FISH]) can identify some patients with early-stage CLL at high risk of rapid disease progression. The array of treatment options has expanded in recent years and now includes monoclonal antibodies used alone or in combination with purine nucleoside analogues and alkylating agents, which have culminated in dramatically improved response rates. Supportive care guidelines now include vaccination strategies, surveillance for secondary malignancies, and aggressive management of infectious complications. An early hematology consultation is recommended for all patients at diagnosis to identify and counsel high-risk patients with early-stage disease who may benefit from more frequent follow-up or early treatment as part of a clinical trial.

PMID: 15008611
____________

This article takes us from 1975, when Dr. Kanti Rai et al developed the staging system that bears his name, to the latest developments in 2024. Much has changed and much has been learned in these almost three decades. Unfortunately, the lessons learned have not always percolated down to the community practicing oncologists, something that should be of concern to all of us. As the authors put it, "the burden of diagnosis, supportive care, and appropriate referral is the responsibility of the primary care providers. We summarize the recent advances in diagnosis, prognostic tools, treatment, and supportive care measures relevant to the primary care provider of patients with CLL".

What Has Changed?

Around 15,000 new patients are diagnosed with CLL each year in this country. With the advent of automated and cheap instruments for measuring blood counts, CLL is often diagnosed as an unexpected and unexplained elevation in absolute lymphocyte count (ALC). The authors point out that mere elevated white blood counts are not enough to make a CLL diagnosis. Their detailed flowcharts spell out what is both necessary and sufficient for a reliable diagnosis. Just these clear and logical flowcharts are a must-have resource for all local oncologists that deal with a variety of cancers, and do not necessarily specialize in CLL. Diagnosis of CLL requires that each of these conditions must be satisfied:

• elevated ALC higher than 5.0 x 109, that is not explainable by a transient up-tick due to infection of some sort,
• there must also be proof of a clonal population of b-cells of one kind and only one kind. In healthy individuals, there are roughly as many "kappa" and "lambda" light chain type of b-cells. In CLL patients, an overwhelming majority of the b-cells are of either the "kappa" variety or the "lambda" variety. The ratio of kappa / lambda type of cells is terribly skewed in CLL patients.
• Besides proving a clonal and elevated b-cell population, it is very important to rule out other b-cell cancers such as Mantle cell lymphoma, Hairy cell leukemia, follicular lymphoma etc. This is done by careful study of the characteristic markers found on the clonal b-cells, and the test that does it is called 'flow cytometry'.

Once a solid diagnosis of CLL has been made, the next step is to "stage" the patient. The Rai staging system has five stages in it:

Staging Factors

Rai Stage	0	1	2	3	4
ALC greater than 5 x 10 e9	Yes	Yes	Yes	Yes	Yes
Enlarged lymph nodes	No	Yes	+/-	+/-	+/-
Enlarged spleen/liver	No	No	Yes	+/-	+/-
Hemoglobin less than 10.5	No	No	No	Yes	+/-
Platelets less than 100	No	No	No	No	Yes
Median Survival (months)	150	101	71	19	19

  " +/- " in the chart above means a " maybe"

As you can see, the median survival is very strongly dependent on the stage of the disease. The authors make an important point that although the Rai and very similar Binet staging systems are useful clinical tools for grouping patients into low, intermediate and high-risk categories, patients in the same risk category can have very different rate of progression of their disease. "Approximately 50% of patients with early-stage disease develop more advanced disease and die of CLL or its complications." This single fact highlights the limitations of a staging system based solely on markers which are all looking at the tumor load, the number of CLL cells in your body (as measured by swollen nodes, spleen, bone marrow etc) rather than the biology and nature of CLL cells in your body. While the Rai and Binet staging systems focus on the quantity of tumor cells, more modern prognostic indicators such as FISH, CD38, ZAP70 etc., are important to give us information on the type and aggressiveness of CLL cells in any given patient.

The "Watch & Wait" Approach

The National Cancer Institute has defined criteria for treatment of CLL patients. In other words, if your stage of the disease does not meet the criteria set forth, you are advised to stay in the "Watch & Wait" (or, as many patients see it, "Watch & Worry") phase. The NCI criteria are clearly based on the Rai and Binet staging systems, and therefore focused on the quantity of the cancer cells in you body rather than the quality of those cancer cells. It is a point of serious frustration for this reporter that this set of criteria have yet to be changed officially. No wonder they still represent the conventional wisdom for many local practitioners, the gold standard of care.

I do not think it is an over-statement to observe that patients are being short changed by knee-jerk acceptance of this one-size-fits-all philosophy even after it has been shown to be less than the most effective way of caring for a wide variety of CLL patients. As they say, if the mountain does not come to Mohammad, it is time for Mohammad to go to the mountain instead. The logical way for information flow is from the CLL experts and institutions like the NCI to the local practitioners, who then educate their patients. Since that pathway does not seem to work very well in all cases, how about patients learning about their disease from expert research, through the intermediation of advocacy groups such as CLL Topics, then carrying that hard-won information to their local healthcare providers? Just remember, each time you make a point of taking a hard copy of one of these immensely important expert articles to your harried and over-worked local guy, you are making it that much easier for him to pick up the new information and skill-set he needs and therefore that much more effective in treating the next CLL patient that walks in his door.

The New Risk-based Therapy Approach

The authors review all of the new prognostic indicators that have been discussed in the past few years (What Type of CLL Do You Have?). Several of these are commercially available tests, and therefore of pragmatic value to all of us. Some, like the IgVH gene mutation status, are immensely important but still not within our reach since they can only be done by high power research labs. Some others, like the much discussed ZAP-70 test, may become routine in a couple of years, but we are not there just yet. Independent of Rai stage, the authors identify short duration LDT (stands for Lymphocyte Doubling Time, or how long it takes for your ALC to double. Less than 12 months for it to double is an indication of rapid proliferation, therefore high risk category), CD38 positivity, unfavorable FISH cytogenetics, elevated Beta-2-microglobulin as criteria for defining high risk patients who are well served by a more pro-active management of their disease, not the old style Watch & Wait, until the cows come home.

We have discussed most of these prognostic indicators in previous articles on this website, including the latest article titled FISH-ing for Answers. Here are the blunt statistics that spell out the importance of FISH information: chromosomal aberrations were detected in more than 82% of all CLL patients, and a good 29% of patients had more than one chromosomal aberration. In some cases, the second or third chromosomal aberration has been a documented case of "clonal evolution". The present-day commercial FISH probes look for four distinct chromosomal defects:

Cytogenetics

Chromosomal Defect	% of patients with defect	Median Survival (years)
17p deletion	7	2.5
11q deletion	18	6.6
Trisomy 12	16	9.0
13q deletion	55	11.0

In this context, patients classified as "normal" or "no chromosomal aberration" do not necessarily represent folks with pristine chromosomes. It is probably more appropriate to call them "none of the above", since typically the lab looks for only these specific four aberrations, with probes geared to do that and only that. Down the road, as our understanding grows, we might have a more exhaustive list of aberrations to look for — and then the so-called "normal" group would be whittled down some more.

One rather picky but important point, FISH analysis only looks for the presence or absence or mutation of particular genes, such as the all-important TP53 tumor suppressor gene at a particular location on the 17th chromosome. Either TP53 is present and accounted for on the 17th chromosome, or it is not. Well, this is a little bit like looking at a security camera, and saying yes, it is there, or no, it is not. However, that is not the whole story. What if the security camera is there, but there is no film in it? Or there is a great big blob of chewing gum sticking to the lens of the camera? Yeah, the camera is there alright, but much help that is if the lens is blocked. Welcome to the wonderful world of epigenetics. This branch of science deals with the actual functioning of the genes, not their mere presence. It is known, for example, that in a percentage of cancer patients with an intact TP53 gene (as detected by one of the FISH probes) this important tumor suppressor gene may be present in the flesh, but not so that it does any good. It may be blind and unresponsive for a variety of reasons. (One reason could be a malfunction in the ATM gene (11q deletion), since the ATM gene is one of the most important mechanisms for waking up the TP53 gene (Cytogenetics of ATM and TP53), another reason could be "hypermethylation", or too many methyl groups sticking like a large wad of chewing gum to the TP53 gene). Bottom line, the table of percentages of FISH defects detected in CLL patients may underestimate the actual level of chromosomal mayhem going on in CLL patients. It is unfortunate that neither this paper nor many of the recent expert papers on CLL prognostics discuss epigenetic silencing of crucial tumor suppressor genes.

Modern "Best Practices" Standard of Care for CLL

The authors identify several important standards of care that are routinely followed at Mayo Clinic - as patients we can only hope that Mayo's venerable reputation will do something to get these best practices accepted at the community oncologist level in the near future. (I would not count on it, not if my idea of "near future" concerns my own healthcare.) I have summarized and reduced the Mayo approach to the following bullet points:

• Confirm CLL diagnosis, rule out close relatives like Hairy cell, Mantle cell etc by detailed flow cytometry, FISH (identifies mantle cell) and review of morphology by expert pathologist.
• Clinical work up, including staging, evaluation of symptoms.
• CBC, CLL FISH panel, CD38 by flow cytometry, B₂M.
• Repeat CBC at defined intervals, to get a fix on lymphocyte doubling time.
• Bone marrow biopsy is optional, but recommended prior to initiation of therapy.
• Risk-adapted therapy, particularly for high risk patients, as defined by modern prognostic markers.
  • Exclude an infectious cause of fevers, chills, night sweats, or rapid increase in ALC prior to initiating chemotherapy for these symptoms.
  • Exclude autoimmune cytopenias (hemolytic anemia, ITP, pure red cell aplasia) prior to initiating chemotherapy to treat cytopenias since autoimmune phenomena may respond less toxic treatment approaches.
• Since CLL patients have high risk of auto immune hemolytic anemia (AIHA), and this risk is increased by fludarabine therapy, it is important to do a Coombs test for autoimmune antibodies prior to fludarabine therapy, and to avoid it altogether in patients who are have positive Coombs test results.
• Pre-emptive treatment with medications to protect against opportunistic infections such as pneumonia, herpes, etc prior to fludarabine therapy. Neutropenia and general susceptibility to infection is quite common after fludarabine therapy. Painful attacks of shingles are quite common. 
• Referral of younger patients with high risk CLL to bone marrow transplant experts, to explore this option.
• Annual vaccination against the flu, and against pneumonia every five years, starting at the date of diagnosis.
• Consider CMV infection as a potential cause of fevers in all patients with CLL. Blood test are available to identify CMV infection and oral antiviral medications can effectively treat this infection.
• Treatment of hypogammaglobulinemia ( too low levels of gamma globulins) with immunoglobin intravenous infusions, at 0.3g/kg at regular intervals.
• Since CLL patients are much more likely to get aggressive skin cancers, patient counseling about sun protection and regular skin examination is important.
• Over and beyond skin cancers, CLL patients are three times as likely to get other secondary cancers. Regular screenings(mammograms, colonoscopy, prostate specific antigen testing) are very important.
• 5% - 8% of CLL patients have their disease transform to a more aggressive diffuse, large b-cell lymphoma (called "Richter transformation"). Richter transformation requires aggressive therapy, implemented quickly. The healthcare provider must be aware of the symptoms of Richter transformation (rapid LDT, massive lymph nodes, rapid onset of b-symptoms, increased lactate dehydrogensase, etc.) and keep an eye out for it.

That, my friends, is the short list. Now, tell me honestly, how many of your local practitioners follow this list of best practices? And if they are not following these guidelines, why ever not? As they say in the expensive hair color ads, you are worth it. Even if it takes your own efforts to bring your primary caregiver up the learning curve, I think it is time well spent, you have a lot more riding on it!

Editorial

It has been my pleasure to know both of the authors of this article, PC and I have spent quite a few pleasant hours of interesting conversation and good food with both of them. But back when I used to teach, I had the reputation for being a tough grader, and that has not changed over the years. So I hope the authors will forgive me if I grade them just short of an "A". The content is right on target, the analysis is impeccable, the motivation is beyond reproach. How I wish these two CLL experts from one of our best research institutions had gone just a little bit further in their recommendations! Mayo's reputation for excellence would have provided such an important bully pulpit. 

For example, the authors point out fludarabine therapy is not appropriate for patients with autoimmune problems, and it is also important to protect patients against opportunistic infections as a result of fludarabine therapy. They make the case for FISH testing to identify high risk patients with 11q and 17p deletions. This is the rationale of their own best practices in their institution. How is it that they do not have a more blunt warning against the inappropriateness of fludarabine (and other purine analogs) in patients with these high risk cytogenetic abnormalities? Recent papers by several CLL experts have raised the issue in no uncertain terms (FISH-ing for Answers, Campath — Looking Better and Better).

Without institutions such as Mayo taking the lead in changing the status quo, for too many local oncologists fludarabine is still the unquestioned and across-the-board frontline therapy for CLL. Why should any patient absorb the significant toxicity of purine analogs as frontline therapy, if his or her cytogenetics predict ahead of time that it is not likely to be effective? If monoclonal therapy with Rituxan or Campath are better options for this subset of high risk patients, how is it that these patients are not counseled against waiting too long, waiting until the point where they have bulky disease that does not respond well to monoclonal antibody therapy? How is it that even expert papers such as this publish the outdated NCI guidelines for initiation of therapy, guidelines that are still defined only by onset of b-symptoms and heavy tumor load and not prognostic cytogenetics, with no strong rebuttal of those guidelines?

It worries me that without strong and vocal leadership from our premier research institutions, the Watch & Wait paradigm may stay in place far longer than it should, as the standard of therapy for all CLL patients. Or, and this may be even worse, this paradigm may be replaced by yet another one-size-fits-all approach to CLL management, where all patients are routinely treated with aggressive chemo-immunotherapy combo regimes such as FRC or RPC. Do not pass go, do not collect $200, do not worry about risk-based therapy choices, go for highest severity and maximum tolerated dosage therapy around, never mind the fancy stuff about cytogenetics. Going through six months of FRC therapy is no picnic. If at the end of it you fall short of a PCR negative remission, or you relapse too soon after completion of therapy, would it then help you to find out you had 17p deletion cytogenetics all along, that you might never have been a good candidate for therapy regimes containing purine analogs? True, I freely admit we do not have the definitive answers regarding purine analogs in combo chemo-immunotherapy regimes such as the FRC, and how they perform in the case of high risk patients with ATM and/or TP53 defects. Where then is the clarion call for retrospective studies to identify these important answers?

I fully understand the need for academic prudence and caution, the need to protect professional and institutional reputations. I have been there myself, I know the reasons. But tell me if this does not sound ironic to you: the stated objective of this paper is to get the message out to practitioners at the local level, improve the quality of care received by CLL patients, get the word out on best practices that should be the norm not the exception. And yet, would you believe it, neither the local practitioners nor patients such as we can get hold of the full text of this published paper for several months, not until the editorial staff of the Mayo Proceedings have done all that their institutional red tape requires of them. Just doing their jobs, no blame to them.

Let's see, from the time when the researchers decided to write this paper because the message is important, to the point where it is freely available to the intended audience, it may be any where from 6 months to a year. Not all that long, a mere blink of the eye from the perspective of venerable institutions such as the Mayo, which have been around for more than a hundred years. But it is way too long from the perspective of one patient who wrote to me recently. A couple of years after diagnosis, his local oncologist treated him with fludarabine, the "gold standard" for frontline CLL therapy. No determination of risk category, no FISH testing, no preemptive medications or warnings against opportunistic infections. The patient did not get much of a remission, but did get a whopping case of shingles. Treatment with acyclovir was too little, too late, to prevent significant post herpetic neuralgia (fancy talk for lots of pretty intense pain that lasts for way too long), and permanently blurred vision since the patient had developed shingles in his eyes. Here are his exact words in his email to me:

"My question is why aren't CLL patients warned of these possible diseases striking? They seem to take advantage when the immune system is low, isn't there a preventative measure we can use? Have many other CLL patients suffered with any of these diseases as well. Any articles or studies been done on this subject?"

Would you agree, this patient has a somewhat different perspective on what is a reasonable time frame for things to change? Not to worry, that is what we do at CLL Topics, pushing the envelope where experts and institutions cautious of their reputations may be unwilling to go. As advocates of patients and their families, we have a different take on things. Are we upsetting the apple cart with our new found activism? I sure hope so! I will be counting on as many of you as possible printing out and hand-delivering to your local oncologists important and expert articles such as this one. Write to us if you need help locating the full text articles. The research is being done, the results coming in are important, but business-as-usual may be too slow for the word to percolate through the many layers of our healthcare system. Perhaps we as patients can do something about short-circuiting some of these delays. How about it, folks?

 

 

“Will you walk a little faster?” said a whiting to a snail,
“There’s a porpoise close behind us, and he’s treading on my tail.
See how eagerly the lobsters and the turtles all advance!
They are waiting on the shingle--will you come and join the dance?
Will you, won’t you, will you, won’t you, will you join the dance?
Will you, won’t you, will you, won’t you, won’t you join the dance?”

            — Lobster Quadrille from Alice in Wonderland by Lewis Carroll