Secret Handshakes

Questionmarkpic[1]I want to let you in on a little secret: the medical jargon that patients find so intimidating is just that – jargon. Plumbers have their jargon, accountants and engineers have their versions, doctors’ jargon is no different. It is a short hand way that the members of the club talk to each other, because they all know what the jargon means, it saves time and it makes for efficient communication. It also has the added benefit of shutting out riff-raff like you and me, cloaking often very simple concepts in awe inspiring mystery. In reality, it is often nothing more than the ’secret handshake’ you must know before you are a full fledged member of these exclusive clubs. After reading these series of articles I promise you will be able to understand every single last number on your latest CBC report. This first article of the series will focus on lymphocytes, one variety of white blood cells.

CBC

There it is – the very first acronym we will de-mystify. “CBC” stands for complete blood counts. Yes, it is a blood test, but I would hardly call it complete. But we will let that pass for now as unjustified self importance.

Before we discuss the results on your CBC, it is important to know a little bit more about blood – you know, that gory red stuff that oozes out when you cut yourself. Since CLL is a blood cancer, it sort of makes sense we understand a bit more about blood, you think?

Blood is made up of a clear liquid called plasma, with a bunch of cells floating in it. In general terms there are three types of cells: red blood cells, platelets and white blood cells. Red blood cells carry oxygen  and I will write a lot more about these very important cells in a later article; we have discussed platelets before, they help clot blood so you don’t bleed to death every time you nick yourself shaving; last but by no means least, white blood cells are the ninja police force that help keep your body free of germs and other pathogens.

Blood = plasma + white blood cells + platelets + red blood cells + a few other cells.

White blood cells are awfully important. Without these fearless warriors patrolling every nook and cranny of our bodies looking for foreign invaders, we would soon succumb to every viral, bacterial and fungal infection out there. Without them our bodies would be so much dead meat, spoiling in the heat unless refrigerated. I know, that is a gross image but it is also a very accurate image.

CBC blood compositionIf you were to take a few tablespoons of fresh blood, put it into a glass tube and spin it around really fast in a centrifuge, all the cells in the blood would settle to the bottom of the test tube and a clear liquid will be on top.  In between the two layers will be a thin boundary of off-white grubby looking stuff, called the “buffy coat layer”.  The liquid above is plasma (mostly water), and it makes up more than half of the blood by volume.  The thin buffy coat layer contains all the white blood cells and platelets. Red blood cells settle to the bottom and this layer is slightly less than half of the total blood volume.

The lab tech draws your blood, puts it a little tube that then goes into a machine about the size of an office Xerox machine, and in a few minutes the machine spits out a sheet of paper with the numbers of these three types of cells (white blood cells, red blood cells and platelets) and a few more details. That’s it, that is a CBC test in a succinct nutshell.

Just a decade ago it used to take a lot more time and effort, lab techs squinting into microscopes to actually count the cells manually. Nowadays this test is completely automated and dirt cheap; which is why insurance companies don’t complain about paying for it and so many more CBC tests are ordered by doctors. Some researchers think the number of people diagnosed with CLL each year is increasing simply because more people are getting an annual medical check up that includes a CBC

White Blood Cell counts

Or WBC, if you prefer acronyms. There are three main kinds of white blood cells. (I am ignoring eosinophils, basophils and monocytes for now. Their numbers are small and not all that relevant to us. I will discuss them briefly later in this article). There are B-cells and T-cells. Both of these are generally lumped together as lymphocytes since they like to hang out in lymph nodes. The third type of white blood cells are called neutrophils. Older labs may refer to them as “segs” or “bands” or “granulocytes”. Don’t let that spook you, same thing little difference.  So, here are the first shortcuts to understanding your report:

White blood cells = B-cells + T-cells + Neutrophils

Lumping together B-cells and T-cells, this becomes

White blood cells = Lymphocytes + Neutrophils

Absolute Lymphocyte Count

Now you are ready for the next three letter acronym, ALC (absolute lymphocyte count). It is nothing more than the name implies, the total number of lymphocytes (B-cells plus T-cells) in the sample of your blood. Since CLL is a cancer of B-cells  and the cancerous B-cells grow out of control as the disease progresses, it is understandable that patients get a little fixated on the WBC and ALC in their lab reports. Understandable but not really recommended. We will discuss that point later in this article. 

(CLL is a B-cell cancer most of the time.  There are a small percentage of patients with a type of CLL associated with T-cells.  Not my sand box, we do not really discuss T-cell variant of CLL on this website).

Sometimes labs report the ALC number directly. Sometimes the report just gives the WBC and the percentage of lymphocytes; you need middle school math to sort it out, to calculate the ALC. Here is an example.

WBC is reported at 27.8K and the percentage of these white blood cells that are lymphocytes (“%lymphs”)  is reported at 75%. How many lymphocytes are present in this case? What is the ALC?

ALC = WBC x % lymphocytes.

(Remember, 75% expressed as a fraction is 0.75)

ALC = 27.3K x 0.75

ALC = 20.5K

See, piece of cake. Same way, if your report gives the WBC and the ALC,  you can calculate the percent of lymphocytes by plugging into the same equation.

ALC = WBC x % lymphocytes

20.5 = 27.3 x % lymphocytes

% lymphocytes = 20.5 / 27.3 = 0.75 or 75%

Importance of ALC

As we said above, ALC is the sum of T-cell and B-cell counts. Since we are talking of B-cell CLL on this website, as your disease grows it makes sense that the cancerous CLL cells will increase in number and therefore your B-cell counts will increase, which in turn will increase the ALC. It is unlikely a big change in your ALC is due to huge increase in your T-cells or healthy B-cells (see exception below), therefore it is reasonable to attribute almost all of the increase in ALC to increase in cancerous CLL cells.  One of the functions of the periodic CBC is to monitor the rate at which ALC is increasing, since this is an indication of the rate at which the CLLL cells in your blood are increasing. Patients with indolent CLL are usually asked to get their CBC done once every 3 or 6 months.  Patients with a shorter fuse and more rapidly progressing disease may need to get it done each month or even more frequently.

Lymphocyte doubling time

One of the guidelines physicians use in monitoring progression of CLL is to look how fast the lymphocyte counts are increasing. The measure used is the time taken for ALC to double. Doubling time of one year or more is considered hallmark of a slow, indolent disease. If the ALC doubles in a matter of a few months, we are looking at a more aggressive disease. The shorter the time it takes to double the ALC, the more aggressive it is.

When considering doubling times it is important to use common sense. If your ALC was 4.1K (4,100)  in July and it went up to 8.3K  (8,300) in August, should you freak out? Is that a doubling of time of just one month? Should you write out your last will and testament? In one word, the answer is NO.

First, 3.1K and 6.2K are both within the normal range for ALC even in healthy individuals. Second, even the best maintained CBC machines run by the most talented and conscientious lab techs have a built in error. In my experience, the numbers reported can be off by as much +/- a couple of thousand. If the numbers in July and August were actually 6.1K and 6.3K instead, well within the known built in error of the test, there is not so much to get excited about, right?

Because of the built in errors (we discussed some of the trivial reasons why lab counts could be off in our article on “When platelet counts start dropping”), I strongly urge you not to get fixated on every little blip up or small drop in your lab counts. The sensible thing to do is plot your data on a chart, look for overall trends. You can do it with a simple piece of graph paper and a pen, or you can do it on the computer, downloading the free-of-charge  “Your Charts” spreadsheet program we supply on www.clltopics.org

So when should we sit up and take notice? If the ALC went from 50K in July and 100K in August, now that is worth talking to your doctor about; that is a significant jump, not explained by a simple built in fudge factor in the machine doing counting. It might be worth getting the CBC done more frequently in future to keep an eye on things. It could be that you had a mild infection of some sort, and your body correctly increased the number of white blood cells in your body to fight the infection, hence the sudden rise in ALC from 50K to 100K. If this is the case you will be relieved to see the ALC trend back down to its baseline once the infection has resolved. If on the other hand the march upwards in ALC is relentless, month after month, then it is safe to assume it is really due to increasing CLL cells in the blood.

I am always bemused when patients write to me bent out of shape because their ALC “jumped” by a few points. One patient held the unshakable opinion that his latest herbal treatment is curing him of his CLL, since his ALC count dropped from 27.3 to 25.1 in just one month! WOW! That is more than 10%!  At this rate, in a few more months, it will be down to normal levels and he will have been cured. Not so quick my friends.  This kind of a drop (or increase) is well within the normal variations in ALC counts and it is foolish to consider it a cause for celebration (or despair).

There is another reason why ALC can go up suddenly.  Some drugs, such as steroidal drugs (prednisone, dexamethasone etc) or immune modulating drugs such as Revlimid (lenalidomide) can cause dramatic increase in ALC.  In the case of steroids it is because the drugs cause cells in the lymph nodes to get flushed out, dumped into open blood circulation.  All those CLL cells hiding out in the swollen lymph nodes suddenly getting kicked out into the blood will make the ALC numbers shoot up.  But this is nothing to worry about.  In fact, it is one of the reasons why high dose steroids work in the case of patients with bulky lymph nodes.  Once the CLL cells are out in the open blood, they are fair game and much more easily killed.  This is one explanation of why combination therapies such as Rituxan + HDMP (high dose methyl prednisolone) and Campath + HDMP work well in bulky adenopathy cases.  The high dose steroids do a good job of flushing out the CLL cells into the open, then the monoclonal antibody drugs (Rituxan or Campath) get a chance to kill them before they can hide again.

“Treating the numbers” is not smart

There is another good reason why it does not make sense to get fixated on your ALC counts and that has to do with the nature of CLL. As we mentioned above, the word “lymphocytes” is used for B-cells and T-cells because they hang out in lymph nodes which includes “glands” under your chin and around your neck, armpits, groin, and many more lymph nodes you cannot feel deep in your abdomen; even your spleen and bone marrow are considered a part of your lymphatic system.

Did you know as much as 90% of the CLL cells are not to be seen in your blood because they hang out in the lymph nodes, swollen spleen or liver, or bone marrow? Measuring the ALC is like looking at the very tip of the iceberg and trying to estimate how big the sucker really is, how much of it is hidden from view under water. What makes it harder still is that different patients have different distribution patterns of the CLL cells in their bodies.

Let us take an example. Patient A has an enlarged spleen and swollen lymph nodes under his chin, enough to make him look like a pregnant chipmunk. His ALC is a around 30K, does not seem to increase all that much from month to month but his spleen is getting bigger and his doctor is suggesting a CT scan to look for even more enlarged lymph nodes hidden in his abdomen.

Patient B has no swollen lymph nodes in his swan-like neck, and even with digging deep his doctor cannot feel the tip of his spleen. Belly is flat (unless there is beer involved). But the poor guy does have a problem with his ALC. It is around 70K and rising by about 5K or so every month. ALC of 70K and rising, that is much worse than Patient A with his stable 30K, right?  Wrong!

Patient A probably has many more enlarged abdominal nodes that cannot be felt by mere physical exam, but given his bulky lymphadenopathy (big word that means swollen nodes or glands) and swollen spleen (“splenomegaly”), chances are good a CT scan will find a lot more enlarged lymph node clusters in his abdomen. The 30K ALC in his blood test is nothing. It is a mere tip of the iceberg, as much as 90% or more of his disease burden (total number of CLL cells in the body) are in those swollen lymph nodes, spleen, may be liver and bone marrow, beyond the reach of a mere blood test.

What makes it a more dangerous situation for Patient A  is also that CLL cells floating around in the blood are a lot easier to kill by just about any therapy. But CLL cells tucked away in lymph nodes are in a protected environment surrounded by “nurse-like cells” that make it easier for them to survive and avoid getting killed by chemotherapy. Potent drugs such as Campath cannot even touch them, not if the nodes are bulky. Besides, if the CLL cells are lurking around in the bone marrow they can do much more damage – as in prevent proper function of the bone marrow and prevent creation of needed red blood cells, platelets and neutrophils. Heavy liver infiltration (“hepatomegaly”) means poor liver function which leads to all kinds of other problems. Spleen that is heavily infiltrated with CLL cells can cause trapping of good red blood cells and platelets (pretty much the same effect as a clogged filter), causing anemia and bleeding problems. One (but not the only) option for dealing with a grossly swollen spleen is surgical removal – splenectomy.

Patient B, on the other hand, is probably in much better shape. True, his CLL is progressing (as seen by ALC increasing each month), but given his total lack of lymphadenopathy (no swollen nodes, normal sized spleen etc.), he probably has far smaller overall tumor load than Patient A. His lymphocyte doubling time is about a year, indicating a pretty laid back and indolent variety of CLL. He will also most likely respond better to any therapy when it is initiated. Just based on the pattern of his disease, I would bet Patient B has good prognostic indicators as well. Patients with the dangerous 11q and 17p deletions (FISH TEST, see our earlier article “Three important blood tests“) often have bulky lymph nodes. Not so patients with the much more indolent 13q deletion. Patients with Trisomy 12 are also likely to have bulky disease.

This comparison between Patient A and Patient B is one of the reasons why knowledgeable physicians do not make decision on when to initiate treatment based solely on ALC. Doubling time is important, but not if there is bulky adenopathy involved, not if there are extenuating circumstances. It is important to consider all the other criteria (B-symptoms, anemia, thrombocytopenia, frequent infections, autoimmune disease etc) before deciding to start treatment. In other words, treat the patient, not the numbers

This is the part that concerns me most about local oncologists with busy practices, who are short on time and not quite caught up on their latest CME (continuing medical education) programs. Deciding to treat the numbers does not take much time or smarts.  Looking at the whole picture and making decisions based on full understanding of prognostics, risks, rewards and coming up with a long term game plan takes time and expertise.  One reason why I recommend that if you (and your insurance company) can afford it, it is a good idea to get a second consultation with a CLL expert before you make that crucial first therapy decision. Shoot first and ask questions later is not a good protocol for CLL patients (or anyone else, for that matter).

T-cells

Let us talk a little bit about T-cells. As we said, the routine CBC does not break them out;  B-cells (healthy ones as well as cancerous CLL B-cells) and T-cells get lumped together as “lymphocytes” and therefore T-cell numbers get buried under the heading of ALC.

T-cells are the frontline troops when it comes to fighting viral infections. If these important cells are destroyed or not working the way they should, patients are much more vulnerable to viral infections. The infections can be due to new invaders coming into the body and proliferating unchecked, or they could be dormant traces in the body left over from a prior infection using the window of opportunity to stage a comeback – this later case is called “viral reactivation”.

Some of the best sites on the internet for people interested in learning more about the risks associated with poor T-cell function are the AIDS / HIV sites.  HIV is caused by a viral infection of the very T-cells that are supposed to defend against viruses! Patients with full blown AIDS have very low counts of fighting T-cells. They are therefore very vulnerable to viral infections, especially viral pneumonia.

A most painful example of viral activation is shingles. Shingles is caused by reactivation of long ago chicken pox infection you may have gotten in grade school. Most of us have been exposed to this particular Herpes virus; once exposed, traces of it stay in our bodies for the rest of our lives. Anyone who has gone through an attack of shingles can tell you it is not fun. What most of you may not know is that a bad case of postherpatic neuralgia (medical jargon for shingles pain) is totally mind numbing pain that can be very hard to bear, hard to control with even potent narcotic medications, anti-depressants and anti-convulsants. Shingles attacks can also happen in the eye and can cause blindness if left uncontrolled. Prevention is the name of the game.  Any one who has had an earlier attack of shingles is much more at risk of a second attack.  You should make sure your doctor is aware of the prior history so that you can be better protected with daily acyclovir,  famcyclovir or valacyclovir antiviral drug therapy as needed.  Many of these medications have been tested in millions of people taking them on a daily basis for years at a time, since they are also effective in controlling genital herpes.

What causes T-cell function to go down? CLL is a B-cell cancer, but since B-cells and T-cells work hand in hand in many ways, a cancerous B-cell system can bugger up the T-cells too, make them lazy, crazy and downright nasty. Lazy as in not doing a good job of taking care of viral invaders, crazy in not being able to tell good guys from bad, and downright nasty as in attacking perfectly good red blood cells and platelets and killing them. This last bit of nastiness can cause two autoimmune diseases common in CLL: namely, AIHA(autoimmune hemolytic anemia ) and ITP(Idiopathic thrombocytopenic purpura).

Another good reason for poor T-cell function is dropping T-cell counts, there are just too few of them around to do the job right. This could again be due to the CLL itself, because it hogs all the prime real estate in the bone marrow and lymph nodes and does not give the T-cells a chance to live long and prosper (multiply). But an increasingly important reason for dramatically decreased T-cell function is the effect of many of the modern drugs used to treat CLL. Campathand fludarabine are prime examples of T-cell killing drugs. Dr. Terry Hamblin is on record saying CLL patients treated with chemo cocktails containing these drugs have T-cell counts as low as AIDS patients. A well known CLL expert echoed this sentiment, he recently described Campath as “AIDS in an infusion bag”.

Wow, that is one harsh message for patients looking at these particular drugs as therapy options. But once again, I caution you to remember this mantra: DO NOT throw out the baby with the bathwater. DO NOT use fludarabine or Campath if you do not have an incurable cancer called CLL. But if you are facing aggressive disease that needs to be treated, and your choices are treatment with these or similar drugs or sickness / loss of quality of life / death, please do make sensible decisions. And that means doing what you have to do to live today, to fight another day.

What are “Normal” ALC counts?

It is hard to understand things out of the ordinary without first understanding what a noraml CBC looks like.  Here is an example of what a normal CBC report looks like.  Since this is my CBC report from a couple of months ago, we will not quibble about the implications of the term ”normal”.  A few of  my friends would disagree with that description, not unless you consider Don Quixote “normal” as well.

CBC lymphocytes report

I have abbreviated the CBC report to include just the stuff we discussed in this post.  I will expand it to its full glory as we discuss additional items in the later articles of this series.

Note this test is called a “CBC with differential and platelets“.  That means the test will report lymphocytes and neutrophils seperately, not just lumped together, and it will also report platelet counts.  Some of the labs doing a “quickie” CBC may not bother to break out the lymphocytes and neutrophils, may not bother to even measure platelest counts.

The first line is WBC at 6.9.  Next column tells you there is no flag on this item, nothing out of the ordinary here.  Next column gives you the units in which the count is measured, in this case it is 6.9 x 1,000 cells per microliter. Next column over gives the reference range of what is a “normal result” for this testing facility.  It is important to realize that different labs (and different countries) have different normal ranges and your own results are to be taken only in the context of what is normal for your particular lab.  In our example, the normal range for WBC is 4.0 through 10.5 and at 6.9 my WBC is comfortably within this normal band.  If I had an infection of some sort when the blood was drawn, it is very likely that my WBC would be over the normal limit.  It would also come down back into the normal range once the infection is resolved.

Going down the chart you will see the report gives the percent Lymphs and Neutrophils (at 29% and 62% respectively). Once again, nothing out of the ordinary and within normal ranges.

Next the report gives the ALC and ANC (absolute values for lymphocytes and neutrophils respectively).  Even if these two numbers are not given, I hope you know by now how to calculate them from the WBC and the percent Lymphs and Neutrophils, using the equations we discussed earlier in this article.

Adding up the Lymphs and Neutrophils falls short of the total WBC (29% + 62%  = 91%) and looking at absolute counts 2.0 + 4.3 = 6.3, a tad short of  the 6.9 WBC number .  The missing 9% (0.6 in terms of absolute counts) are made up of monocytes, eosinophils and basophils, the three cell types we have sadly neglected in this article.  We have also ignored “Natural killer cells” , think of them as sort of Rambo T-cells on steroids and without as many inhibitions about killing. I will address these cell types in more detail if any of our members raise the issue in the comments section.

That’s it for lymphocytes, probably more than you bargained for.  The idea is not for you to remember each and every detail we have spelled out here.  As long as you understood the general drift and you know where to find the information again when you need it, you are in good shape.  There will be no pop quiz, you don’t have to know this stuff by heart.  In our modern internet age, half the time knowledge is just knowing where to find the information you need, quickly. 

Next stop, we will look at neutrophils:  why they are important, what happens when there are too few of them (neutropenia), precautions to be taken if you are neutropenic, what can be done to shorten duration of neutropenia.

CBC cell lines