Disease Characteristics

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CLL versus SLL                

4/21/02

by Chaya Venkat

There seems to be a lot of confusion in terminology, even between the experts. For example, I am told that Small Lymphocytic Lymphoma (SLL) and Chronic Lymphocytic Leukemia (CLL) are one and the same disease, in fact, there is no such thing as SLL, it is all CLL (this from an expert in the leukemia section at M. D. Anderson). I was told just as vigorously by another 'expert' that SLL is a better name for this set of symptoms, and in any case it is better to call it "lymphoma" as opposed to leukemia, since many of the experimental protocols and clinical trials will accept lymphoma patients but not leukemia patients. Also, several of the health insurance companies pay for Rituxan for lymphoma, but not leukemia! Long term disability is also defined differently for the two classifications, I am told. Go figure.

I am not sure, but I think the WHO Classification is a little out of date. The one that seems to be in vogue now is something called the REAL classification. According to that, lymphoma and leukemia are different beasts. A rose by any other name .....

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Spontaneous Remissions in CLL

9/8/02

by Chaya Venkat

Reference:

Here is a well documented case history of a CLL Patient that went into complete remission, basically he cured himself. No one seems to quite know why, the only clue is that there were a bunch of T-cells (here we go again, I am beginning to like these pesky CTLs) in the man's bone marrow. Read all about it by clicking on the URL below:

http://www.medscape.com/viewarticle/438233_2

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CLL Parallels

9/19/02

by Chaya Venkat

My husband was diagnosed with CLL just about the time of the terrorist attack on the World Trade Center and the Pentagon, little over a year ago. The two events are linked forever in my mind. Don't take this analogy too seriously, it is meant to be tongue-in-cheek.

Once upon a time there was a land called Afghanistan (your body). As fate would have it, a malignant idea called jihad (chromosomal aberration or what ever) came into being in the land and infected the minds of a few people (a malignant CLL clone was born). The first of the Taliban were created.

There was no one to stop the proliferation of this malignant concept. The authorities (your immune system) was sleeping on the job. A few people opposed the Taliban, and indeed some of them were killed (CLL cell apoptosis), but not at the same rate as new fanatics were being created in the religious schools (bone marrow, lymph nodes). The balance was definitely in favor of increasing numbers of the militants (Lymphocyte counts grew unchecked). The Taliban were clever, not all of them wore black turbans, and many of them looked just like good innocent citizens (CLL cells look a lot like good b-cells, not very antigenic). As they grew in numbers, they oppressed the women and children (red blood cells, platelets) and gave them no room to breathe free in their own land (bone marrow was getting stuffed with malignant b-cells, no room for other necessary cells). Some of the women were killed by their own people (auto hemolytic anemia, red blood cells destroyed by the body).

Pretty soon, the crimes of the Taliban could no longer be endured, they attacked very visible targets at WTC and Pentagon (spleen and liver), and caused a great deal of anguish and anxiety (night sweats, fevers, swollen lymph nodes). Something had to be done (w&w was over).

One of the options was to nuke (chemotherapy) the whole country of Afghanistan, in the hope of killing off all of the Taliban (CLL cells). But in the process a lot of innocent people (the healthy B-cells and other cells of the body) in Afghanistan would also have been killed. Also killed would be many of the Northern Alliance (killer T-cells), the only local opposition to the Taliban. If even a few Taliban were left alive after the nuke attack (only partial remission following chemo), the peace and quiet (remission period) would be sadly all too short. With even fewer good people (good T and B cells) to oppose them, the Taliban numbers would grow even faster than before (lymphocyte doubling time is quicker than before treatment). Who knew, in the absence of any one to control them even a little (immune system even more damaged after chemo), the original malignant idea may transform to something even more aggressive (Richter's transformation) and dangerous for the world (reduced life expectancy).

The world chose a more prudent course of action: carefully calibrated strikes (MOABs, vaccine therapy) to improve the effectiveness of the Northern Alliance (help and boost body's own immune defenses). Slowly but surely, the Taliban were destroyed (lymphocyte counts began to drop) and people all over the world relaxed a bit (night sweats and fevers were a thing of the past) and went shopping. The religious schools where new terrorists were trained in the past (CLL colonies in the lymph node and in the bone-marrow) were cleaned out. Afghan women could breathe free again, children played (Hemoglobin counts went up, platelets danced in the blood). This time around, the world was smart. It did not abandon Afghanistan as soon as the immediate problems were solved (partial remission), Rumsfeld, Bush, Powell et al (Keating, Kipps, Byrd et al) kept up their efforts till there was not one single Taliban to be detected in all of the population (complete remission, PCR negative). The balance of nature is restored to the country of Afghanistan (YOU ARE CURED!!)

P S: One of the perks of power, I get to goof off one day of the year. Between this and the Fatal Attraction article, I am done for the year. Its all serious stuff from now on...sigh!!

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Nodes

9/23/02

by Chaya Venkat

A member raised the topic of the significance of the growth, size and distribution of lymph nodes in CLL.

First of all, I would not stick with a doctor or specialist that is too fastidious to do a **physical** exam. Cripes, the very name implies touching the patient physically! How will he/she know what your nodes feel like, what size they are, and even more important, how your spleen and liver feel, are they enlarged etc, without the sense of touch?

Nodes are important. If they get too big, they can pose problems with therapy down the road. It is easier to clear CLL cells from the blood than it is to clear it from the bone marrow or the lymph nodes. The larger the nodes, the harder it is to get the drugs to them, since the vascularization is not always sufficient to get good blood flow through out the large nodes, and the drugs can only travel with blood flow. Campath, for example, is not recommended for anyone who has large nodes, since it has a hard time clearing CLL from lymph nodes.

Nodes can cause pain, if they are distended, or if they begin pressing on other organs or nerves and blood vessels. The anecdotal information (and I do not have any higher authority than that to vouch for it) is that hot compresses and gentle massage will help the lymphatic circulation, and that will help ease the pain. Unlike the blood circulation, which is carried out by an active pump, the heart, the parallel lymphatic system's flow is sustained only by large muscle activity. Physical activity (walking, jogging, swimming) are good ways to get the lymph system going, and not be a stagnant pool.

I think it was Dr. Keating who mentioned in one of his interviews, the percentage of the b-cells in the lymph nodes, spleen and liver add up to about 90-95% of the total. The peripheral blood has only about 5-10%. Like toothpaste, which moves from one side of the tube to the other when you squeeze it, I understand that lymph nodes wax and wane, as more b-cells enter or leave them, and from/into the blood. That is why there is some scatter in the CBC numbers, depending upon if you have just gone through a vigorous bout of exercise just prior to the blood draw. As you can imagine, the lymph nodes with 90-95% of the hoard of b-cells have to shrink just a little and put out b-cells into the blood, to have that register as a huge increase in the blood counts. One more reason not to panic with every little up-tick in the CBC numbers, you need to keep in mind the bigger picture.

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What is CLL?

9/30/02

by Chaya Venkat

A member asked for my help in composing a short description of the disease for a presentation he had to give. I thought it (my response) might help our new members.

There are approximately 10,000 new cases of B-cell chronic Lymphocytic leukemia (CLL) diagnosed each year, making it the most common form of leukemia in the Western hemisphere. At this stage, CLL is considered to be an incurable disease. The good news is that the median survival of about 7 years for CLL patients is longer than that for more acute forms of leukemia. However, till very recently, majority of the patients did not attain complete remission after undergoing "standard" chemotherapy regimes, and all patients seemed to relapse sooner or later. Some patients become resistant to the drugs, severely limiting therapy options. Many of the chemotherapy drugs used to treat CLL have substantial toxicity associated with their use. It is often a tragic choice between the patient succumbing to the disease, or being unable to tolerate the toxicity of the drugs that may help hold the disease at bay.

Birth of new cells, and death of old cells that have outlived their  usefulness, is one of the most fundamental and strictly controlled mechanisms of all living things. Old and unwanted cells obediently commit suicide ("apoptosis") when commanded to do so by chemical signals from the body, or if they become defective in some way, they are attacked and killed by the cells of the immune system. New cells are created as needed and the balance is preserved.

When this fine-tuned balance goes awry, and there is an unwanted accumulation of cells, the result is cancer of one sort or another. In the case of CLL, the problem is not because of accelerated formation of new B-cells, but rather the refusal of the old ones to die on command. The malignant cells are able to accumulate in vast numbers because they have developed an ability to circumvent the death signals from the body. They are also very good at hiding from the surveillance of the immune system, since they are, in fact, an important part of the immune system themselves. This survival advantage allows the CLL cells to accumulate gradually over time.

This gradual but relentless accumulation of defective immune system cells leads to many complications. Mild infections that are readily shaken by healthy individuals may become life threatening, since the ability of the immune system to protect the body against invading bacteria or viruses is compromised. Sometimes the damaged immune system inappropriately attacks other cells in the blood, such as red blood cells and platelets, creating severe anemia and clotting problems. Major organs such as the liver and spleen may get badly damaged, as the disease progresses. One of the major consequences of advanced CLL is that the bone marrow gets progressively packed with these dysfunctional CLL cells, and becomes unable to produce all the other cell lines required for proper functioning of the body. Majority of deaths caused by CLL are due to these reasons.

After many decades of status quo, things are finally beginning to change for CLL patients. Recent advances in "smart drugs" such as monoclonal antibodies and radio labeled antibodies has led to more effective therapies with fewer toxic side-effects. Our understanding of how the immune system works is increasing by leaps and bounds. Designer drugs that target the cancer cells without harming healthy cells of the body, and immunotherapy approaches that use the body's own defense systems to fight the remaining traces of cancer are making it possible to dream of a day in the near future when CLL is no longer an incurable disease.

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Weight Loss, B Symptoms

10/11/02

by Chaya Venkat


We are told to watch out for unexplained weight loss, since it is one of the "b-symptoms" that indicates the CLL may be progressing more rapidly, and treatment of some sort may be indicated in the near future. Not all cancers are alike, in fact patients with hematologic malignancies have significantly smaller problem with weight loss, compared to patients with other solid tumors. Count your blessings.

There are many reasons for cancer related weight loss (the technical term is "cachexia", pronounced ka-hex-ia). Side effects of chemotherapy or radiation such as nausea, vomiting, food not tasting good, constipation and diarrhea can all contribute to weight loss. So also depression, anxiety, and changes in normal social interactions, all of which are associated with cancer. The Eastern Cooperative Oncology Group (ECOG), which analyzed 12 different clinical trials and found that weight loss predicted a shorter survival than patients who did not experience weight loss. Not only did the weight loss predict an overall poorer prognosis, but it also indicated a trend toward lower chemotherapy response rates. When looking at the prognostic effect of various cancer symptoms, it was also found that loss of appetite predicted a poor outcome for cancer patients. The best way to treat cancer cachexia is to cure the cancer. But this may not always be possible, and a number of attempts have been made to address the more immediate problem of halting unwanted weight loss. Till recently, the efforts centered on nutritional counseling, and drugs to improve appetite. While steroids undoubtedly make some patients feel better, they do not appear to affect the process of cachexia. Serotonin has been tried, since is thought to have a role in appetite control. Melatonin has also been suggested to influence TNF-alpha production, one of the cytokines implicated in cachexia.

If you have read my previous articles on changes in metabolism as a result of cancer, you will remember that while normal cells get their energy by the very efficient Krebs cycle, cancer cells are wasteful and use a very much less efficient mechanism for converting glucose to energy. Hydrazine inhibits phosphoenolpyruvate carboxykinase, an enzyme responsible for gluconeogenesis from lactate (the Cori cycle), the mechanism used by cancer cells. It was hoped that interrupting this process would normalize some aspects of glucose metabolism in cachexic cancer patients and so improve nutritional status. However, recent studies have not demonstrated any real benefit of this compound.

A combination of a relatively non-toxic drug and a food supplement have shown the most promise. Ibuprofen (and several other non-steroidal anti-inflammatory drugs, or NSAIDs), in combination with fish oil seems to work best. Promising results have been seen in weight gain, improved quality of life and physical performance status in well documented studies, where nutritional counseling, appetite stimulants, NSAIDs and fish oil have been combined.

This country is obsessed with weight loss, but surely we know that unintentional weight loss in a cancer setting can be quite dangerous. If you find yourself losing weight, becoming less energetic and generally "wasting away", you may wish to click on the URL below. 

http://www.medscape.com/viewprogram/2008

It is an excellent article in Medscape that should be more widely read. You may have to register to be able to read this article, but the Medscape registration is free of charge. Please keep a record of your registration information since we will use Medscape references often. The information is provided in a patient-friendly manner, and even if you do not have the energy to read it, make sure your care-giver reads it. Families can do a lot to help in this regard.

People, there are some areas where you can influence the outcome of your condition. Better nutrition, better information, more exercise, more water, and a generally optimistic view of life will all help greatly. They will improve the quality of your life, as well as improve your chances with any therapies that you may undertake down the road. Our motto should be "stay healthy today, live to fight another day".

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Probability of Cure for CLL

10/14/02

by Chaya Venkat

Some patients are under the impression that CLL cells do not die. CLL cells do die, they are not immortal. The problem is that they live longer than they should, and just as in human populations, when life spans increase, even without any change in the birth rate, there is an overall population explosion. Billions upon billions of new cells are created daily. If the CLL cells are truly immortal and did not die at all, they would accumulate so fast we would all be giant lymph nodes and nothing else, in a matter of days and months.

Now, since the net accumulation of CLL cells is due to the cancer cells dying at a slower rate than they are being produced, the progression of the disease can be stopped, and reversed, if we introduce a new mechanism that increases the death rate. All it takes is for the cancer cells to die faster than they are being made.

This is what sets apart indolent disease versus rapidly growing disease, it all depends on the difference between the rate of death versus rate of birth of  cancer cells.

Another point to remember: majority of people have a few cancer cells in their body, caused by some random mutation or the other, and they never even know about it. The reason is that these cancer cells are rapidly killed by the immune system, before they have a chance to gain a foothold.

In a full blown case of cancer, the cancer cells have obviously won the first battle(s), gained that all-important foothold. They can now start their subversive campaign to make the immune system cells inactive and inefficient. The snowball effect will get out of hand, unless we intervene to change the rules of the game. If we give the immune system a hand, through some form of therapy, kill off the major bulk of the cancer cells, and thereby remove the chemical signals put out by the cancer cells that ties the hands of the immune system, it is possible to get back to a situation where the immune system can start doing its job again, hold the cancer at bay, eventually eradicate it.

Think of the cancer cells as the Mob. If they are allowed to flourish and get out of hand, they begin to subvert and bribe into inaction the very system (judges, police, FBI) that are supposed to control them. Get in some law enforcement from the outside, put away the majority of the mobsters for life, the remaining dregs are no longer able to bribe the local police force into inaction, and gradually they too will get cleaned out.

Bottom-line, we have to get away from the totally wrong notion that cancer cells do not die. They do. Just not fast enough. Anything we can do to increase the rate of death and slow down the rate of birth will control the cancer's progression. A cure is not only logically possible, in the case of CLL, everything I have read says it is likely to happen, in our lifetimes. I am no starry eyed optimist, but it is my considered opinion that we will start seeing indefinite "remissions", at least in some patients, sooner than many of us think. That is the basis of my motto, "stay healthy today, live to fight another day".

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Possible Connection between Hepatitis C and Splenic Lymphoma

10/19/02

by Chaya Venkat

Here is an interesting connection between Hepatitis C (HCV) and Splenic Lymphoma, a very close kissing cousin of CLL. For at least one of our members  there is some question whether her husband has CLL or splenic lymphoma.

A recent article in the New England Journal of Medicine reported a study that had 15 patients with Splenic Lymphoma. 9 of the patients also tested positive for the Hepatitis C virus, 6 did not. All 15 patients were treated with interferon alpha, the standard therapy today for viral infections such as Hepatitis. Out of the 9 patients who were positive for Hepatitis C virus to start with, 8 had complete tumor remission, the 9th one had a partial remission. There was no tumor response to the interferon therapy among the 6 patients who were not Hepatitis C positive to begin with. Sounds crazy, but according to this study, you were luckier if in addition to splenic lymphoma, you also had Hepatitis C!

This backs into the several articles I wrote on Epstein-Barr virus (EBV) and cytomegalovirus (CMV) and possible connection to lymphoproliferative disease in immune compromised individuals. These are all viruses that seem to like residing in B-cells. Hit the virus hard, where it lives, with effective antiviral drugs such as interferon, and in the process of destroying the virus, you destroy its home as well, the infected B-cell.

Also below is an URL link that has a lot more on Hepatitis C, and a brief extract from their website. If I were a CLL patient, and my otherwise indolent disease suddenly decided to take off, with WBC increasing rapidly, I think it might be prudent to see if I have recently picked up on of these viral infections, or if I were positive all along, just that the virus was dormant up to now and decided to wake up for some reason. Anti-viral therapy is heck of a lot easier to consider than chemotherapy. Many of these viruses, especially the EBV are present in large percentages of the population, and I think it is not all that expensive to test for them. May be worth considering.

http://cpmcnet.columbia.edu/dept/gi/ribavirin.html

Abstract:

All current treatment protocols for hepatitis C are based on the use of various preparations of interferon alpha, which are administered by intramuscular or subcutaneous injection. Interferon alpha is a naturally occurring glycoprotein that is secreted by cells in response to viral infections. It exerts its effects by binding to a membrane receptor. Receptor binding initiates a series of intracellular signaling events that ultimately leads to enhanced expression of certain genes. This leads to the enhancement and induction of certain cellular activities including augmentation of target cell killing by lymphocytes and inhibition of virus replication in infected cells.

HCV treatment improves outcome in splenic lymphoma

A small clinical trial has found that interferon alfa therapy can bring about tumour regression in patients with splenic lymphoma and hepatitis C virus (HCV) infection. The study, published this week in the New England Journal of Medicine, suggests that HCV may have a role in lymphomagenesis - with significant implications for the treatment of this common cancer.

Olivier Hermine (Hôpital Necker, Paris) and collaborators enrolled 15 patients into the study. Nine had HCV and a type of non-Hodgkin's lymphoma characterized by slow progression of splenomegaly and a gradual increase in tumoural B cells in the peripheral circulation. The other six subjects also had splenic lymphoma with villous lymphocytes but tested negative for HCV infection. All patients received interferon alfa-2b three times a week for 6 months, and ribivarin was added in HCV-positive patients who failed to respond to interferon.

At six-month follow-up, all patients tested negative for HCV RNA. Furthermore, interferon therapy was associated with complete tumour remission in seven of the nine initially HCV-positive patients. The other two patients had partial and complete remission, respectively, following the addition of ribivarin, and one patient relapsed when his HCV RNA load again became detectable.

In contrast, none of the HCV-negative patients responded to interferon therapy.

`We obtained therapeutic evidence that HCV may have a critical role in splenic lymphoma with villous lymphocytes,' write Hermine et al. `The relation between the course of [disease] and the HCV RNA load was also illustrated by the observation that a complete haematologic response occurred in patients who had a partial response or a relapse after the addition of ribivarin and the loss of detectable HCV RNA.'

Likening their finding to the discovery that Helicobacter pylori has a pathogenic role in the development of gastric lymphoma, they add: `Systematic screening for HCV infection should be performed in patients who have a diagnosis of splenic lymphoma with villous lymphocytes.

`In HCV-positive patients, antiviral therapy may be an alternative to splenectomy, chemotherapy, or both.'

New England Journal of Medicine 2024; 347:89-94
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Inherited Predisposition to CLL

10/23/02

by Chaya Venkat

As the mother of a talented and much beloved daughter, it is with reluctance and dread that I read this latest article in "Blood". Healthy, first degree relatives of CLL patients are likely to have an inherited predisposition to CLL, at a rate that is statistically four times higher than the normal population. Sounds scary.

Then some level of logic came to my rescue: I am personally convinced that we are a lot better off in therapy options today than we were even just a few years ago. And the rate at which new information is becoming available is increasing rapidly. Down the road, many years from now, if your son or daughter develops CLL, they will probably fix it with a quick vaccine inoculation, in the doctor's office, and that will be that.

Meanwhile, prior warned is prior armed, get your kids to stay healthy, develop life long habits of healthy living, exercise and nutrition, and not miss those routine annual check-ups. Kids think they are immortal, nothing will ever go wrong with them, until it does.

Abstract:

Blood, 1 October 2024, Vol. 100, No. 7, pp. 2289-2290

Inherited predisposition to CLL is detectable as subclinical monoclonal B-lymphocyte expansion

Andy C. Rawstron, Martin R. Yuille, Julie Fuller, Matthew Cullen, Ben Kennedy, Stephen J. Richards, Andrew S. Jack, Estella Matutes, Daniel Catovsky, Peter Hillmen, and Richard S. Houlston

From the Academic Unit of Haematology and Oncology, University of Leeds, HMDS, West Yorkshire; Academic Department of Haematology and Cytogenetics, Institute of Cancer Research, Surrey; Section of Cancer Genetics, Institute of Cancer Research, Surrey, United Kingdom.

Monoclonal chronic lymphocytic leukemia (CLL)-phenotype cells are detectable in 3.5% of otherwise healthy persons using flow cytometric analysis of CD5/CD20/CD79b expression on CD19-gated B cells. To determine whether detection of such CLL-phenotype cells is indicative of an inherited predisposition, we examined 59 healthy, first-degree relatives of patients from 21 families with CLL. CLL-phenotype cells were detected in 8 of 59 (13.5%) relatives, representing a highly significant increase in risk (P = .00002). CLL-phenotype cell levels were stable with time and had the characteristics of indolent CLL. Indolent and aggressive clinical forms were found in family members, suggesting that initiation and proliferation involves distinct factors. The detection of CLL-phenotype cells provides a surrogate marker of carrier status, potentially facilitating gene identification through mapping in families and direct analysis of isolated CLL-phenotype cells.
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For those of us with children (or siblings), the abstract below is like a kick in the stomach. 

These researchers examined first degree relatives of CLL patients, people who are in apparent good health. Flow cytometry done on 33 relatives showed that 6 out of the 33, a whopping 18% of the relatives examined, showed the tell-tale CD5/CD19/CD20/CD23 positivity, the classic pattern for monoclonal B-cell phenotype. This 18% is to be compared with 0.7% or so one would expect in a normal population. 

Just to be clear, this does not mean the 6 relatives above have CLL. Some or even all of them may be ultimate smolderers that continue indefinitely below the threshold defined for CLL diagnosis, never even aware that they had a sub-detection level of B-CLL monoclonal phenotype. If a tree falls in the forest, and there is no one to see it, does it matter? 

All the same, I am happy that there is continuous and encouraging spate of new drugs and new therapy protocols being investigated. For those of you who chose to participate in clinical trials, thank you, there is a new generation out there whose lives may some day be saved because of your generosity. 

Abstract:

Cytometry 2003 Mar;52B(1):1-12

B-cell monoclonal lymphocytosis and B-cell abnormalities in the setting of familial B-cell chronic lymphocytic leukemia. 

Marti GE, Carter P, Abbasi F, Washington GC, Jain N, Zenger VE, Ishibe N, Goldin L, Fontaine L, Weissman N, Sgambati M, Fauget G, Bertin P, Vogt RF Jr, Slade B, Noguchi PD, Stetler-Stevenson MA, Caporaso N. 

Flow and Image Cytometry Section, Laboratory Stem Cell Biology, Division of Cell and Gene Therapies, Center for Biologics Research and Evaluation, Food and Drug Administration, Bethesda, Maryland. 

BACKGROUND: Among all hematologic malignancies, B-cell chronic lymphocytic leukemia (BCLL) has the highest familial clustering (three- to sevenfold increase), strongly suggesting a genetic component to its etiology. Familial BCLL can be used as a model to study the early pathogenesis of this disease.

METHODS: We examined nine kindreds from the National Cancer Institute's Familial BCLL Registry, consisting of 19 affected members with BCLL and 33 clinically unaffected first-degree relatives. Flow cytometric immunophenotyping to detect a B-cell monoclonal lymphocytosis (BCML) was performed. Monoclonality was confirmed by polymerase chain reaction analysis of whole blood DNA. Cell cycle analysis for aneuploidy was conducted. 

RESULTS: In all affected individuals, we observed the classic BCLL CD5/CD19/CD20/CD23 immunophenotypic patterns. Six of the 33 unaffected individuals (18%) had evidence of BCML. Additional individuals (13/33, 39%) showed some other abnormality, whereas 14 individuals (42%) were normal. Based on an estimated prevalence of 0.7% for BCML in the general population, the finding of six subjects (18%) with clonal abnormalities in this relatively modest sample was significantly greater than expected (i.e., 18% vs. 0.7%, P < 5.7 x 10(-9)). 

CONCLUSIONS: Individual  components of BCML and other B-cell abnormalities were observed in almost half of the apparently unaffected individuals. Our findings suggested that BCML may be an early detectable abnormality in BCLL. The spectrum of some of these observed abnormalities suggested the involvement of different B-cell subpopulations or different pathways in clonal evolution. Population-based, longitudinal studies will be required to determine the incidence of BCML and other B-cell abnormalities and their relation to disease progression in BCLL and other closely related B-cell lymphoproliferative disorders. Cytometry Part B (Clin. Cytometry) 52B:1-12, 2024. Published 2024 Wiley-Liss, Inc.  

PMID: 12599176
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Blood Counts are a Dim Reflection of Disease Progression

12/28/02

by Chaya Venkat

Here are some fundamentals of what this disease is all about:

The source of the disease is the bone marrow and in the lymphatic system. That is where all the action is. That is where the new generations of blood cells are created. Not in the peripheral blood. Think of the former as the factory, the later as the highways leading to and from the factory. Clearing up the traffic on the highways does not solve the problem if the factory is not functioning right, not making the right widgets. 

Since we cannot easily measure the populations of the various cell types in the bone marrow or lymph nodes (imagine having a lymph node biopsy or a bone marrow biopsy done as frequently as a simple blood test), doctors and patients depend upon the ever popular CBC (Complete Blood Counts). Normally, when the bone marrow, lymph nodes and peripheral blood are in equilibrium, the counts in the peripheral blood reflect, very roughly, what is happening in the bone marrow and lymph nodes. The CBC therefore has some limited diagnostic value. Some patients have very advanced disease, as measured by swollen nodes, spleen, infiltrated marrow and other complications, but relatively low WBC, and vice versa. 

CLL patients do not die because there are too many white blood cells (WBC) in their peripheral blood, CLL cells or otherwise. Yes, the blood's viscosity increases slightly, and the pumping action of the heart becomes more difficult, when the WBC reach very, very high numbers. I am talking about ranges in excess of 200K. This is very  rare phenomenon. Several of the consortium experts don't believe this is ever a real problem, other more immediate problems (see below) will get you first. 

One of the things that kills CLL patients is the bone marrow getting so packed with cancer cells that it stops producing the good infection fighting cells of the immune system, and simple infections that are easily shaken off by normal people become life threatening  in the case of CLL patients. Viral, bacterial and fungal infections are what kill majority of CLL patients. 

Also, the gradual decay of immune surveillance means that secondary cancers can take hold. MALT, the topic of discussion in recent articles, is one of them. It may be triggered by H. Pylori, a bug that lives in the stomach and gut. It becomes active and takes advantage of the situation to proliferate, when there is no immune system able to fight it. 

Also at issue is the effect of diseased spleen and liver, which not only stop doing their normal functions but may start chewing up perfectly good red blood cells and platelets as they get progressively more diseased. This is the onset of autoimmune hemolytic anemia (AIHA) and thrombocytopenia, both of which are alarmingly common in CLL patients. The former causes anemia, progressive fatigue and inability for the body to carry out its vital oxygen transport, the later can result in strokes, uncontrolled bleeding etc. 

So. Immediately after therapy, especially if the drug used differentially takes care of CLL cells in the peripheral blood but not in the bone marrow or lymph nodes or swollen spleen, nothing much has been accomplished. This is a very small part of the total population of cancer cells, it will soon be replenished from the vast stores in the lymph nodes etc. Does it diminish the other risks of the disease? Not in my opinion. The bone marrow is still infiltrated and producing the wrong type of cells. The patient is still at risk of developing conditions that lead to sudden and serious infections, anemia, thrombocytopenia etc. 

Think of the peripheral blood CBC as a dim reflection of what is actually happening in the other more important sites of the infection. At best, it gives us some idea of what is going on, and it is used because it is done easily, and it is cheap. At worst, it totally fails to reflect the reality of swollen lymph nodes, swollen spleen, potentially infiltrated bone marrow. 

There is no such thing as a free lunch. Here are some of the "costs" of an ineffective (repeat, ineffective) bout of Rituxan: 

1. All b-cells can carry CD20 marker, as well as several other important cell lines, it is not specific to CLL b-cells only. Rituxan therefore kills all b-cells, good and bad. B-cells are the source of a big chunk the antibody defenses of the body against infections. Rituxan therapy leaves us without these defenses for a good period of time. When the remission is over, brief or otherwise, the b-cells grow back, a few good ones, and mostly those darned CLL type b-cells. Same as before. Nothing has changed, since the source of the problem, the bone marrow and lymphatic system had not been cleaned out. 

 2. There is a huge dollar cost to this therapy. Not every one has health insurance that covers these sorts of costs. Besides, even with health insurance, guess who finally pays for these drugs. That's right, we the consumers pay for every thing, either up front or later on as higher insurance premiums, or cancelled insurance coverage's when insurance companies go broke. This group talks to the wide variety of patients, not just the fortunate ones. Ironic, to think of any CLL patients as fortunate.. but guess how much worse this disease feels, if you are broke, laid off, without insurance, and a family to support. You get precious little respect from big name doctors, if you do not have money to back you up. 

3. The other thing an ineffective bout of Rituxan uses up is the window of opportunity. As we have seen in several Patient Profiles, Rituxan takes a significant amount of time to show its full function. It is not possible to make a good call on whether or not it worked, right off the bat. If it did not work, and we are looking at a person with one of the high risk profiles, the individual may be significantly worse off for not having initiated a more aggressive and hopefully more effective therapy right away; worse off in the sense of more infiltrated bone marrow, more swollen and intractable lymph nodes and more diseased spleen/liver. 

Don't get me wrong, I am a big fan of Rituxan and the other monoclonals, you can judge by the number of articles I have produced on the subject. Rituxan, Campath, IDEC152 and their combinations with immunomodulatory drugs like Interleukin-2, low dose Prednisone, GM- CSF, Interferon alpha etc are the wave of the future. I am rooting for these interesting studies to become the new standards, in our lifetimes. 

But it bothers me to see the phrase "at worst, Rituxan does no harm". A small percentage of people are quite allergic to it, can have very severe responses. As "Granny" Barb can attest. A risk worth taking, since the percentage is small, if and I repeat, if one is a good candidate for this particular drug. It comes back to the good old idea, there is no such thing as a free lunch. And I for one would rather know whether or not I have the variety of CLL that is likely to respond well to Rituxan only therapy, **before** I put myself through it. Why not know what your odds are, ahead of time? I know there are no guarantees, our understanding of how these drugs work is far from perfect. But why not line up the odds a little better with prior information?  As for the other questions of a more philosophical and emotional nature, I am certainly not competent to comment. Also, I am not about to tell any one what their therapy choices ought to be, it is an individuals right and responsibility to do that for himself or herself. In life, we all live with the choices we make, the roads we choose to walk. 

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CLL and Estrogen

3/7/03

by Chaya Venkat

A member wrote to ask whether women are less likely to acquire CLL and those who do generally have a more benign CLL because of some 'protective' function of estrogen and further whether this should be something to be considered in opting for HRT.

This is a very logical question about the role HRT may play in protecting against immune function cancers like CLL. But I have not come across any solid data shedding light on this subject. 

This I read some where: Women have more "trigger happy" immune systems, compared to men. When having to decide whether a given cell is self or non-self, women's effector cells are more prone to define a questionable cell as "non-self" more frequently than men. This may have something to do with the need to get rid of fetal cells that are left behind in the woman's body and circulate within the blood stream  for several years after childbirth. This more active immune system is also the reason why women are less prone to diseases like CLL which are caused by an inactive immune system, but more prone to auto- immune diseases  like MS, Lupus and rheumatoid arthritis which are caused by an over-active immune system. 

It is also observed that this potentially overactive immune system in women is dampened down during pregnancy, in order to prevent aborting the growing fetus. Women who suffer from rheumatoid arthritis have a "pregnancy holiday" from the disease, and the disease returns back  in full force soon after the baby is born.

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Chronic Infections

3/20/03

by Chaya Venkat

I have been interested in the connection between chronic inflammation and cancer for some time. Attached below is an URL of a paper that discusses this relationship in some detail. 

Most researchers seem to agree that this relationship exists, and manipulating it provides a route for the potential control or even prevention of cancer. We have published several articles on CLL Topics on the role of drugs such as Celebrex in the inhibition of Cox-2, and the inflammatory pathways associated with it. Also "nutraceuticals" such as curcumin (from the spice turmeric), catechins (from green tea) etc which are known to be anti-inflammatory and also considered to be of great interest in cancer prevention / control strategies.

Much more specifically, there has been a lot of discussion on this site on the Nf-KB pathway, which is triggered when the body goes into an inflammatory mode. It is known that when this important pathway  is triggered, the cells on which this switch is "turned on" go into a proliferative mode, as well as become protected from apoptosis (cell death). Normally, the Nf-KB pathway is not routinely turned on, but it now known that this pathway is stuck in the "on" position for large majority of cancer cells, including CLL cells, making it possible that this contributes to greater proliferation rates for the cancer cells, as well as making them harder to kill. A number of drugs, including simple ones like aspirin, are known to be blockers of the Nf-KB pathway. One of them which is similar to aspirin, a simple molecule called methyl salicylate is actually in clinical trials for B-cell cancer. 

I also hear rumors that a new small molecule drug of unspecified nature is likely to be in clinical trials soon at M. D. Anderson, and this molecule is supposed to be an extremely effective blocker of the Nf-KB pathway. If successful, this orally administered drug is expected to provide a non-toxic and simple method for maintaining patients in long term remission. I understand it is a derivative or variant of an already well known anti-inflammatory drug. 

IDEC-152 is another very interesting monoclonal antibody. As we have discussed before, this monoclonal targets CD23 marker on CLL cells. CD23 is the activation marker for cells, high levels of this marker means the Nf-KB pathway is activated on these cells and they are in a proliferative mode. It is an elegant concept, killing specifically the very cancer cells that are multiplying rapidly and trying to protect themselves from death. Even more interesting is the combination of this monoclonal antibody with Rituxan. Combination of the two monoclonals gets the cancer cells in the cross-hairs, as it were, and has the potential for much higher levels of efficacy, without increasing the toxicity. This kind of a combination would be of particular interest to those of us who do not exhibit either marker (CD20 or CD23) to very high levels, and the combination of the two may get us to the critical levels required for efficient CLL cell kill. In fact, I have written about murine (mouse) studies where the survival of animals with lymphoma was much higher when both monoclonals were co-administered, a classic case of synergy where 2 plus 2 is more than four. I am aware there is an ongoing clinical trial (phase-1) using IDEC-152 by itself for CLL patients. I would very much like to see this trial get beyond the phase-1 stage, and especially see combinations of the two monoclonals used together in CLL. 

The following is a link to a technical paper that discusses this topic in some detail.

http://www.cancernetwork.com/journals/oncology/o0202d.htm

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Swollen Lymph Nodes

3/25/03

by Chaya Venkat

There is really not much mystery about swollen lymph nodes in CLL. Enough CLL patients have had lymph node biopsies so we know what makes them large: they get stuffed with lots and lots of clonal CLL cells, and the structure of the lymph node grows in order to make space for all these new residents. 

Why do some patients have large lymph nodes and relatively low WBC numbers? Think of it this way: there are three buckets. one is the bone marrow, the second is lymph nodes, and the third is peripheral blood. The CLL cells distribute themselves between these three buckets. Those with most of the CLL cells in the bone marrow and a puny 5-10% left over in the blood are at the "leukemic" end of the spectrum. Those with most of the CLL cells residing in the swollen lymph nodes are more the "lymphoma" type. In fact, there is no real distinction between CLL, a leukemia, versus SLL, a lymphoma, except in the sense that the cancer cells seem to prefer one location more than the other in the two types. 

Get this point folks: bulky lymph nodes represent a reservoir of a large number of CLL cells, that can multiply quite happily in the lymph nodes, providing more copies of themselves. Very often, with most therapies, the cancer cells in the blood are the most accessible, and therefore the easiest to kill. From everything I have read, CLL cells in peripheral blood pose little danger, over and beyond providing a pool of cancer cells for future proliferation. It is the accumulation of these cancer cells in the bone marrow that is the real danger, at sufficiently high levels it shuts down the absolutely vital production of other cell lines like red blood cells, that can only be made in the bone marrow. Heavy infiltration of the lymph nodes, to the tune where they are bulky means that when the CLL decides to go into a higher proliferation mode, maybe kicked off by something as innocent as a slight viral infection, the numbers can go up very quickly indeed. 

This is why we have the definitions of PR, NPR, CR etc. All of these various definitions of response to therapy take into account the response of the lymph nodes. They are a serious aspect of the disease, more so if they threaten other vital functions, such as squeezing shut blood flow in adjoining arteries etc.

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Susceptibility to Infections

4/9/03

by Chaya Venkat

One member has asked the question whether there is any increased susceptibility to infections for individuals in Stage 0 CLL.

I do not know whether there is a difference in vulnerability to infections between "normal" population and those with early stage CLL. I expect there is some deficit, probably small, even at early stage CLL, because of lower levels of IgM, IgA and IgG.

But that is not really relevant in the case of SARS. This virus has such a high rate of infection, for a change we are all in the same boat, early stage CLL patients and normal people. (Obviously, immune compromised late stage patients and neutropenic patients need to be extra, extra careful).

Some simple precautions to take, since SARS seems to be spread by close contact with infected persons:

a. Avoid crowded places as much as possible.

b. Wash your hands frequently!

The Centers for Disease Control and other sources recommend the following procedures, especially after using a restroom and before eating:

c. Break the habit of touching your face, rubbing you eyes, nose, mouth.

d. Do not neglect or ignore early signs of infection, seek medical help immediately. If you are seeing emergency room staff or a doctor that does not know you, make sure they are aware of your CLL and any other complications. Also make them aware of any traveling you might have done recently, especially if you have been to the China, Hong Kong, etc., recently.

I have no doubt that SARS will be a tougher nut to crack for CLL patients, as it will be for patients with other diseases that also weakens the immune system. Since they do not yet have any curative therapy for SARS, and depend only on the body's own immune system to do the healing, it really makes sense to reduce your chances of getting the infection in the first place, as much as possible.

A member had this to offer in a recent post: "My point in this letter is to highlight three areas that all CLLers should treat with the utmost care and that is firstly as mention the skin, secondly the mouth and lastly the rectum. All these are areas where infection can get a grip and must be treated with care..."

I would like to thank him for highlighting a very important aspect of dealing with CLL. 

These are not glamorous areas to discuss, but of great practical importance. By now all of us know CLL means your immune system is less than adequate. So you need to be extra vigilant about making sure the borders of your body are well protected. Skin is the single largest barrier between your insides and the big bad world of nasty critters who would like nothing better than a soft warm place to live and multiply. Personal cleanliness, keeping your skin well moisturized so that it is supple and does not crack, taking stock of your body before the mirror each day, to look for "sun spots", or blemishes that were not there before, these are all essential aspects of managing CLL. Something as simple as making sure your hands are quite clean before you cut your nails, and then trying not to cut too close and nick the cuticles, this can make the difference between picking up a bad infection and staying healthy. Personally, I would stay away from commercial nail saloons, if you can handle the vanity issue. 

I am still surprised every time I hear about some one going for dental work of any kind without taking appropriate antibiotics ahead of time. This is gross to think about, but even with all the brushing and flossing your mouth is like a cesspool just teeming with bacteria of all sorts. It is impossible to do dental work without  nicks and cuts. This provides the hordes of bacteria in your mouth a direct pipeline to your bloodstream. If you are not on antibiotics, more often than not, you will be infected. Not smart. 

The third area Trevor mentioned, correctly, is the rectum. Even less glamorous than dental hygiene is taking good care of the other end. Some of us are lucky enough to be born with good functioning of the digestive system, never have to deal with Milk of Magnesia, so to speak. Why is this important? Same concept as in dental work: if you really have to strain to do your daily morning duty, often there are tiny, miniscule cuts and breaks in the skin in and around the rectum. Again, a combination of direct access to the blood stream, and a location where you would expect lots and lots of germs to be present spells trouble. The nicks and cuts are often not large enough for you to notice, not sufficient for you to see any blood in the stool. But enough for the bacteria to find their way into your blood stream. 

The answer to this issue is very simple, something your mother told you to do many times: Eat your vegetables! This is the best source of dietary fiber, and a healthy diet is the best way of keeping your digestive system working smoothly, no need to strain in the morning. The other major cause of irregularity is not drinking enough water. I said water, not fruit juice, not soda pop.  Some of this is so obvious, but it is often overlooked. If you cut yourself shaving, you take care of the cut, right? The skin on your face is probably a whole lot cleaner in terms of hosting bacteria, than is your mouth or rectum. Makes sense to protect this window of vulnerability. 

Some one wrote and said we are too technical in our posts, not enough practical advice on how to handle CLL in daily life. It does not get more practical than this! You get the logic, you can extend this to another couple of areas that we have not discussed. "Safe sex" takes on a whole new meaning and urgency in immune compromised patients like us. 

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Will Cancer Ever Be Cured?

7/26/03

by Chaya Venkat

I came across this beautifully written article in the Michigan News. I was impressed by Mr. Haney's report. It touches on many of the issues we have been discussing in the past few days, the deep chasm that divides our desire for that perfect magic bullet that will cure us, and the reality of where we stand today. I have quoted the introduction to his article and attached the URL for the full piece.

"Cancer 'R' us" is one of the sound-bites we should remember. The human body is a wonderfully complex, with a bewildering array of mechanisms for protecting us from harm over the course of our lives. Cancer is very much a part of us, IT IS US. Not so wonderful perhaps, but just as complex and with as bewildering an array of mechanisms to protect itself. Every useful trick and method our bodies have learned over the millennia to protect us from a hostile environment, eventually the cancer cells have access to the same tricks and methods, to protect them from the hostile environment of cancer therapy. In terms of the analogy I used in my piece a couple of days back on "Multiple Drug Resistance", the bad guys will also have access to the bullet-proof vests, eventually. 

I watched a program a few weeks back on TV, Maria Bartiromo interviewed six or so of the top experts in cancer. Yes, the experts agreed, we have made significant gains in prolonging life, and increasing cure rates for many of the more common cancers. We have increased the life span of cancer patients, and we have improved the quality of that life span. This is the part that was an eye-opener for me: almost all of the improvements depended on conventional chemotherapy. We have learned how to administer chemotherapy better, whom to treat, when to do it, which p particular combination, how to monitor the patient while we do it so that we can catch the inevitable side-effect problems sooner, and treat these complications with better and more effective drugs. The blunt evaluation of these guys who spent their entire lives on the frontlines of the fight against cancer was that "smart bullets" like the Gleevec are sexy, they gives hope to many, but it helps only a very precious few. They are most effective when used in combination with conventional therapy: chemotherapy, surgery and radiation. 

Just because it has not happened so far does not mean it will not happen in the future. May be we will get that perfect cure for CLL, one that works for all patients, 100% of the time, and cost us nothing. Nothing wrong with hope, keeping our fingers crossed. But when rubber meets the road, we have no choice but live in the real world. 

Article:

Will cancer ever be cured? Recent results leave many in doubt

By DANIEL Q. HANEY
The Associated Press
7/26/03 12:43 PM

Not long ago, the defeat of cancer seemed inevitable. Decades of research would soon pay off with a completely fresh approach, an arsenal of clever new drugs to attack the very forces that make tumors grow and spread and kill. 

No more chemotherapy, the thinking went. No more horrid side effects. Just brilliantly designed drugs that stop cancer while leaving everything else untouched. 

Those elegant drugs are now here. But so is cancer...

URL for the full article: 

Two different links to this syndicated article are provided below. These news items tend to get moved into archives with altered URLs. If both links are broken, you might want to search for the title and author on AP News, Google News or USA Today. 

http://www.kstp.com/article/view/109900/

http://www.usatoday.com/news/health/2003-07-27-cancer_x.htm

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Two Steps Forward, One-and-a-half Steps Back?

8/12/03

by Chaya Venkat

I cringe every time I hear a patient talk about the serious dangers of chemotherapy, how he/she would never put all those toxic materials in their bodies, especially now that the new immunotherapy drugs are available, the sexy new targeted therapies. The logic seems to go like this: "immunotherapy may not be able to cure you, it may only end up helping you just a little bit, or may be not even that, but at least it is not going to do you any harm!" How many people volunteer for immunotherapy clinical trials, based on this notion that immunotherapy approaches cannot hurt you? 

Have you seen wistful posts about Gleevec, patients wondering when it would be our turn, when CLL would have its own 'Gleevec'? With high visibility media coverage, some of the new targeted therapies like  Gleevec, Avastin, Iressa, Rituxan, and Herceptin are household words, even in families that have not had to face cancer in their midst. The specifics are rarely spelled out in these breathless reports of cancer breakthroughs, interviews with jubilant experts in white coats, doing their best to look both brilliant and modest at the same time. Even the few details that they do manage to get in parenthetically, we tend to forget them five minutes after the TV report. We just remember the sound bites, the sense of excitement, the warm glow of hope. 

I will be doing a series of posts on how immunotherapy works, its promise, its perils, and why we need to keep our eyes open, our minds unbiased, and keep asking questions. Below are a few excerpts from a Boston Globe article that appeared today. It sets the stage for the next few posts. Truly, what you don't know can surely kill you in this cancer game, a lot sooner if you make poor choices. 

Just don't shoot the messenger, OK? 

Excerpts from Press Article:

The help and harm in new cancer drugs

© Copyright 2024 Globe Newspaper Company.
By Judy Foreman, Globe Staff, 8/12/2003

Dean Gordanier is a tax lawyer, fitness buff, father of three and, at age 54, a veteran of the roller-coaster ride of hope and despair that is becoming a way of life for growing numbers of people with cancer, thanks to the promise, and the heartbreak, of a new generation of cancer drugs. The science behind many of these drugs, which oncologists call "targeted therapies," is breathtaking. With names like Gleevec, Avastin, Iressa, Rituxan, Herceptin, even the still- nameless drug known as SU11248...", they are the closest scientists have come yet to the holy grail of cancer treatment -- knocking out cancer cells with great specificity without wreaking too much havoc on the rest of the body. 

The article describes how Gordanier underwent surgery for GIST, a potentially deadly stomach cancer. He had radical surgery, which failed to contain the cancer and then joined a clinical trial of Gleevec for GIST. Initially successful, Gleevec had stopped working in 18 month (as it does in about 75 percent of people after two years, probably because tumors mutate to avoid its effects...) Since mid-January, Gordanier has been taking SU11248, which targets a different group of kinases from Gleevec. So far, it's working.

As Gordanier and others with life-threatening ill-nesses have learned the hard way, it's important to ask a lot of questions about any new drug, even an apparent wonder drug that sounds like the best, or only, option. "With any kind of experimental drug, you want to know two things: How likely is it to help, and what kind of harm can it cause?" Gordanier said. 

For instance, even when a new drug is successful by statistical standards, the clinical impact in real life may be minimal...

Patients also should ask doctors to explain carefully the figures they quote from studies...

Ask about side effects, too...

The bottom line for patients is that these new drugs, imperfect as they are, can buy time -- time in which even newer, and possibly better drugs, may be found. 

The full article may be purchased at the Boston Globe website for $2.95. http://www.boston.com/news/globe/

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