Updated: March 23, 2011
Tumor Reduction Is Harder than It Looks
by Chaya Venkat
Some members imagine that leukapheresis is a harmless way to reduce the leukemia tumor burden. The reality is more complicated. Think of it this way. Let's say you have 100 units of lymphocytes in your total body. Roughly 90 of these 100 lymphocytes are sequestered in your bone marrow, lymph nodes, spleen, liver, etc. No more than 10 units of the lymphocytes are circulating in your blood. If leukapheresis succeeds in removing 80% of the lymphocytes in your blood, this number goes down from 10 units to 2 units. The overall load of lymphocytes in your whole body has gone down from 100 units to 92 units. Not a big deal, in terms of reduction of the total tumor burden in your body. This is why leukapheresis is not used as a therapeutic agent in CLL. It is simply not worth the hassle. Incidentally, leukapheresis removes a percentage of all leukocytes in your blood, which means all white cells — B-cells, T-cells, neutrophils, NK-cells, etc. If you are struggling with low T-cells or neutrophils to begin with, leukapheresis is hardly a no cost "free lunch".
Leukapheresis does have a role to play in another context. Tumor Lysis Syndrome (TLS) is a very dangerous and potentially fatal complication if too many cancer cells are killed too quickly. When cancer cells are killed by chemotherapy, the contents and debris from the dead cells has to be disposed of carefully by the body. Too many dead cells to dispose of in too short a time means tremendous load on the liver and kidneys, and sometimes this can be serious enough to cause fatality. When chemotherapy or monoclonal antibodies are administered via IV, the access of the drugs to the cells in your blood is immediate and quick. It takes a lot more time for the drug to slowly penetrate to the lymph nodes and bone marrow, etc. If you have very high peripheral blood WBC, there may be reason to worry that this large number of cancer cells in circulation will be killed too quickly for the body to handle. In such situations, it might be prudent to use leukapheresis to reduce the peripheral blood WBC to a lower level temporarily, in order to reduce the risk of TLS.
Of B-cells and T-cells
by Chaya Venkat
This is a word of explanation about the term lymphocyte. The term covers both T-cells and B-cells. Both are part of the immune system and called immunocytes too. Both are born from the lymphoid pre-cursor stem cells. But what happens after that is different for the two groups of cells. T-cells migrate to the Thymus, where they receive their advanced training in killing pathogens, and as a result of their thymic education, they are called T-cells, T for Thymic. B-cells never visit the thymus.
The two groups of cells have very different make-up, in terms of their function, the CD markers they exhibit etc. B-cell CLL is the disease that interests the members of this group. There is also an entirely different disease called T-cell leukemia, which is sort of a CLL of the T-cell lineage. It is very, very unusual for one person to have both B-cell CLL as well as T-cell leukemia. SO you can stop worrying about T-cell clones, if you have CLL, all you have to worry about are B-cell clones.
Besides the relatively uncommon T-cell leukemia, another very well known disease of T-cells is AIDS. This is not a cancer, but driven by the HIV virus, which infects and takes over the T-cells in the body. Since both T-cells and B-cells are part of the immune system, AIDs patients, and CLL patients, share common problems associated with weakened immune systems. The majority of the deaths in CLL and AIDs is due to opportunistic infections, infections that are life threatening to these patient groups but are minor inconvenience to people with normal immune systems.
As I pointed out in my WBC refresher course, in a normal individual there are more neutrophils in the blood than there are lymphocytes (combination of B and T cells). This is obviously changed in a CLL patient. In advanced cases of CLL, the very vast majority of the white blood cells are B-cell clones, with a a few T-cells and neutrophils, eosinophils and basophils thrown in. The overwhelming hordes of clonal B-cells not only decrease the numbers of the other cell lines from getting made in the first place, they actively interfere with the proper functioning of these cell lines.
WBC Refresher Course
by Chaya Venkat
I see a lot of questions on the ACOR list on what is a white blood cell, does Rituxan kill all white blood cells, does it only kill the bad CLL cells, etc. For the benefit of our new member, here is a brief refresher course on white blood cells. The WBC counts in your monthly blood test refers to these cells.
White blood cells can be divided into two general groups: (1) the immunocytes, cells with immune function, namely B-cells and T-cells. (2) the phagocytes, cells that are capable of killing and eating other cells, namely monocytes, neutrophils, eosinophils and basophils. The last three, namely neutrophils, eosinophils and basophils are also classified as a group and called granulocytes, since they have granules within their cell walls. Monocytes go on to mature to produce macrophages, which are like huge garbage trucks to haul away the debris from dead cells. All of these cells, B-cells, T-cells, neutrophils, eosinophils, basophils and monocytes are called white blood cells, to set them apart from red blood cells and platelets.
Rituxan is an interesting therapy for us because it targets cells that carry the CD20 marker. All mature B-cells carry this marker, not just the CLL B-cells, to some degree. So you must accept the fact that therapy with Rituxan kills all B-cells, good B-cells, CLL B- cells, all B-cells. The good news is that T-cells, neutrophils, eosinophils, basophils, monocytes and macrophages do not carry CD20, and they will not be killed in droves. If you compare Rituxan versus Campath, that is the big difference. Campath targets the CD52 marker, which is present on all B-cells and T-cells, as well as the granulocytes etc, so all of these cell lines are targeted during Campath therapy. But do remember, anytime you have a major duty war going on in your system, such as precipitated by therapy, or a bad infection, there will be a certain amount of disarray in getting the right cytokine messages to the right parts of the bone marrow etc, and you will see transient dips in all cell counts, soon reversed if these cell lines are not directly targeted by the therapy of choice.
The other piece of good news regarding Rituxan is that the CD20 marker is not, repeat, not exhibited by precursors to B-cells (baby B-cells), or the all important stem cells. In a few months after therapy, the B-cell population will recover, hopefully more good B-cells and less CLL B-cells. In the meantime, the rest of your immune system, the T-cells and neutrophils etc, can carry on the job of protecting you from infections pretty well. This is the major reason why opportunistic infections are not a problem with Rituxan, but is very much an issue in the case of Campath.
Here is some background on what a healthy individual has by way of white blood cells:
(B-Cells & T-cells)
|1.5 to 3.5 K|
|Neutrophils||2.5 to 7.5 K|
|Eosinophils||0.04 to 0.4 K|
|Monocytes||0.2 to 0.8 K|
|Basophils||0.01 to 0.1 K|
|Total WBC||4.0 to 11.0 K|
As you can see, in a healthy individual, neutrophils are the largest group of cells in the family of white blood cells. Both B-cells and T-cells are lumped together in the routine CBC as lymphocytes and only special tests can tell them apart. T-cell counts vary depending on the individual and his/her state of health, they are typically around 1K. (K = kilo or thousand).
Metabolic Panel Analysis
by Chaya Venkat
A member asked for help in understanding certain terms and numbers from her blood work.
Creatinine is a waste product of protein digestion and a measure of kidney function. High levels are usually due to kidney problems. Doctors use the creatinine level as most direct sign of how well the kidneys are removing waste products from the body. Also, please remember that a very high protein diet, or inadequate hydration can result in spikes in creatinine numbers. Hint: drink plenty of water, it is good for you!!
Bilirubin (a yellow fluid produced when red blood cells break down). Note: certain antiviral drugs such as indinavir (Crixivan®) can increase bilirubin.
Finally, lactate dehydrogenase, also abbreviated to LDH. Please refer to some of my earlier articles on sugar metabolism, and how the body converts food to energy. There is a difference in how healthy cells do this, as compared to cancer cells. It is not my intention to go into the working of the Krebs cycle or how cellular respiration happens in this response, so the short answer is that some researchers/doctors feel that elevated LDH level is one of the prognostic indicators of poorer prognosis, an indication that some of the energy production of the body has been hijacked by cancer cells.
One question that comes up concerns normal values for the variables measured by routine blood lab work.
Here are two sites that have good information. The first is an AIDS help site (don't freak out, they have very good blood work information), and the second is the CLL FAQ maintained by David Thomas. Both are pretty extensive, please do take the time to browse through them, you will get your time's worth of solid information from both sites.
Bone Marrow Biopsy
Diagnostic Value and Cost
by Chaya Venkat
As our specialist explained it, the source of the problem for CLL patients is the bone marrow. You can look all you want at the peripheral blood details, you will not get a good idea of the true nature of the problem you are facing, until you have had a decent bone marrow biopsy.
Here are the few pointers I can think of:
Everyone seems to respond differently, but in my guy's case it was no big deal. This is one test that is worth the trouble, because it goes to the heart of the problem in CLL patients.
One member reports that his oncologist questions the value of a bone marrow biopsy since he feels a bone marrow biopsy would not change anything with regard to treatment.
I guess it would depend on the situation, the specific patient and the confidence level of the initial diagnosis. It is possible sometimes to misclassify CLL and several other NHLs that could be a lot more aggressive.
Another point, bone marrow pathology, whether it is diffuse or nodular, percentage infiltration, etc., are considered to be important prognostic indicators, along with CD38, CD23, lymphocyte doubling time, etc. More and more we are seeing fine tuning of therapies to the individual case, not just the timing of the therapy but which particular therapy to use. For example, both patient and oncologist may wish to know the level and type of bone marrow infiltration, in choosing between Rituxan versus Campath. The former is supposedly less effective in cleaning out bone marrow, compared to the latter. Similarly, younger patients with a likelihood of poorer prognosis disease may wish to explore transplant options.
Again, as I said, different strokes for different folks. I am not trying to sell any one on this particular test. However, the logic does seem reasonable to me, that given CLL originates in the bone marrow, it is good to have a base line reference point of how it looks at initial diagnosis time, for comparison with later stages of the disease. I think the results from it could influence therapy decisions for some patients.
Variability in CBC Numbers
Trends Over Time Tell the Real Story
by Chaya Venkat
Today I have had two friends who wrote to me with what they thought were significant changes in the absolute lymphocyte numbers, elated in one case and upset in the other.
I am a firm believer in developing a database with all your CBC numbers and graphing them if you can. Trends are much easier to spot in a graph, than they are in a jumble of numbers. The template provided under the Your Charts section may help you do just that.
But....please do not read a lot into every up and down in the CBC numbers. Recently, in an interview on HealthTalk, Dr. Keating said that about 95% of the lymphocytes reside in the bone marrow, spleen, lymph nodes etc. Only about 5% of the lymphocytes are in the peripheral blood.
Now, consider a situation where your lymph nodes swelled up a little in the last few days, just before your CBC blood draw. Let us say that instead of 95% of the lymphocytes, 96% of the lymphocytes are now sequestered in the lymph nodes, spleen, BM etc. That leaves only 4% in the blood, as opposed to 5% before. That is a 20% drop in the absolute lymphocyte count you would get in the CBC. But nothing has really changed, and there are the same number of CLL cells still in your body, overall.
Recently some members who happen to be jocks have reported that the absolute lymphocytes in the CBC go up if they have been exercising vigorously just before the CBC blood draw. Makes sense, the large muscle activity is what gets the lymphatic system pumping more vigorously (unlike the blood circulation, which is carried out by a pump, the heart, lymphatic system has no pump, and just depends on the action of various large muscles in the body to get the lymph fluid circulating). Exercise means there are no sluggish pools of lymph sitting around, some people find that the nodes seem to be more rubbery, less hard, after a vigorous work out (or even a hot bath!). Fewer lymphocytes get stuck in the lymphatic system means more are in the peripheral blood, even if the overall number has not changed one bit.
Another point to consider: say your absolute lymphocyte number last month was 15,000. and this month it went up to 16,500. A difference of 1,500. Now fast-forward to three years from now. Your absolute lymphocytes went from 80,000 to 88,000 in one month. Wow!! a change of 8,000 in just one month!! Hold on, look at it more closely. In the first example, change of 1,500 starting from a base of 15,000 is a 10% change, same as in the second case of 8,000 on a base of 80,000.
Actually, all the data I have seen from several people now suggests that the rate of growth of the CLL population is not a linear (straight line) relationship, it is more an exponential function. For the non-mathematicians, exponential function means the larger the number gets, the faster it will increase. That is why one of the criteria that is looked at is doubling time, not the actual number change. If the doubling time stays the same, your ALC number will climb from 10,000 to 20,000 in the same time that it takes to go from 30,000 to 60,000.
Trend lines and statistics are important, but you must take care to interpret them carefully.
Log Entry Title
by Chaya Venkat
DiSC Assay stands for Differential Staining Cytotoxicity Assay.
Basically, samples from a patient (blood or bone marrow) are processed to obtain the mono nuclear cells, which are then treated under controlled conditions with the different standard chemotherapy drugs. After a fixed period of time, the process allows counting of the percentage of cancer cells that have been killed by that particular chemotherapy drug.
The advantage is this, according to proponents of DiSC Assay: Let us say you are a CLL patient that is reaching the end of the w&w period, and it is time to make therapy decisions. If your DiSC results say that your particular clonal cells do not react all that well to fludarabine, you may wish to consider other treatment options, such as Rituxan, instead of wasting time and money checking out fludarabine, not to mention the toxicity your body will absorb, all for nothing.
The problem, if it is one, is that DiSC Assay is an experiment done ex-vivo (outside your body). Cancer cells are notorious for reacting differently depending upon their micro environment. (In this context, Dr. Kipps' nurse-like cells and their effect on behavior of CLL cells is important). If it were possible to say with confidence what will happen inside a live patient, based on what happens in a test tube with cultured cells from the patient, we would have no need for clinical trials. All research would be done in the lab, and the results translated into full blown available therapies. Unfortunately, neither mouse studies nor cultured cell studies give us the whole picture.
As far as I can tell, the jury is still out on the clinical value of DiSC Assay, you get different perspectives on it depending on the expert you talk to. My bet would be this: if your insurance covers it, and your oncologist recommends it, nothing to be lost in getting the test done, provided you take the results as only part of the whole picture, to be assessed and evaluated along with all the other prognostic information available, before reaching decisions on choice of therapy.
The following link is to a brochure for DiSC Assay that gives a patient's view of the process: Oncotech Document. Oncotech is a commercial outfit, so take their gospel with a pinch of salt. But they have a phone number you can call, where you may get more info.
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