“Prognosis at Diagnosis”

That was the title of one of the most important papers I read during my early CLL tenure.  That (2004) paper from Mayo researchers discussed modern prognostic indicators and laid out the logic for why it is a good to develop some idea of the prognosis of the patient at the time of diagnosis.  A lot has changed, we know a great deal more about the how and why of these indicators.

This is going to be a long and detailed presentation.  Please do not worry if you don’t get every smidgen of information at the first reading.  This article is not going anywhere, the website will be here and you can always come back here and refresh your memory.  It took me years to learn all this stuff, and more than a couple of weeks to put together the presentation.  It is perfectly OK if you need a couple of sittings before you get all the juice from it.  Slow and steady is the way to learn this stuff.


Here you are, nice Saturday afternoon, to hear about CLL prognostic indicators. But what if you were smarter, chose instead to go on an outing with a bunch of your friends and try your luck at the horse races? You have a few dollars burning a hole in your pocket and you want to try your luck. Problem is, you know next to nothing about betting on the ponies. How do you pick a winner? Close your eyes, go eenie-meenie-mo and take a blind stab at one of the contestants? That is one way of doing it; but chances are excellent that using a purely random strategy you will not win. Random choices do pay off sometimes, but do so very infrequently.

The other option is to pore over the handicap information, learn as much as you can about the different horses running in the race, their track record, how often they won or lost in this type of weather on this type of track etc. You have a better chance of picking the winner if you know something about the background of the horses. There are no guarantees of course. The horse that had everything going for it may have an off day today. Maybe the jockey was hung over and not really trying. Maybe you are just plain unlucky.

Prognostic indicators give you a way of learning a bit about the lay of the land. Barring a few exceptions that we will be discussing later on, prognostics are not the modern version of crystal balls. Just as in the horse handicapping charts, they give you the odds on how your disease is likely to behave. They do not, repeat, do not give you a guaranteed vision of the future. But just as in betting on the horses, the savvy customer who does his homework is more likely to make better decisions than the guy who takes his chances and places his bets blind.

There is one other thing you need to consider, as we go through this presentation. I will be talking about statistical outcomes, based on how (reasonably) large groups of patients fared. There are statistics and then there is individual experience. A hundred patients with exactly your particular prognostic profile could have lived for decades after their CLL diagnosis. You, on the other hand, could have aggressive disease from the word go, or get hit by the bus as you crossed the street after your CLL diagnosis. In other words, notwithstanding all the prognostic indicators, your own mileage may vary. Large scale statistics give us the odds on how things may play out in a given situation. They do not 100% guarantee that in fact that is how things will work out in the case of a single patient.

Last but not least, researchers still have a lot to learn about what makes CLL tick. There has been an explosion of information since the 1990’s; new drugs, new therapy regimens, new approaches to keeping our guys healthy. Quality of life and overall survival figures keep getting better, there is no doubt about that. But a full fledged CURE of CLL with low risk of death-due-to-therapy is still out of our grasp. In the midst of all this confusion, what is a bewildered patient supposed to do? Spending a sunny Saturday afternoon learning about prognostic indicators is one way of gaining some control over your own healthcare.


The “good old days” were not that long ago. Just one generation ago, CLL was a fairly simple disease. I suspect all too often it was not even correctly diagnosed. CLL strikes older people more often – folks in their late 60’s and 70’s. There was no dramatic change in health, just a series of health problems that gradually got worse. Death was often due to infections, especially pneumonia. Even today, I wonder how many death certificates list pneumonia as the cause of death, rather than the underlying CLL. The actual incidence and death rates due to CLL may be significantly under-reported by cancer registries!

For the patient who was diagnosed with CLL, the first thing to do was to establish his / her Rai stage. Most cancers have staging systems, a short hand way of establishing where the patient happens to be, with respect to the full length of the cancer journey. In our case it is the Rai staging system (Binet staging system if you live in Europe), named after Dr. Kanti Rai of Long Island Jewish Hospital.

Since CLL is a cancer of the B-cells of our immune system, which in turn are part of the white blood cells (“lymphocytes”), how fast the lymphocyte counts are increasing is an obvious thing to measure. The yard stick used to measure the rate of increase of these pesky cancer cells is the lymphocyte doubling time. More on this later on.

Another classic pattern of CLL as it progresses are swollen lymph nodes.  Some patients have almost all of their CLL cells residing in their lymph nodes (and spleen, liver, bone marrow), with very few of them swimming around in blood circulation. There is a special name for this version of CLL – small lymphocytic lymphoma or SLL.  Never mind the different name, it is still CLL.  It may require slightly different approaches to how it is monitored and treated, but all in all the experts have decided that SLL and CLL are the same disease.  A rose by any name and so on.

When rubber meets the road, it is the disease symptoms that bother patients most. In the early stages of CLL there are often no symptoms at all. Patients are often bewildered when they are told they have CLL since they feel just fine! But as the disease progresses, they begin to notice changes in their health. There is a classic pattern of symptoms that have been observed in CLL patients, the so called B-symptoms. I have no idea why they are called that, why not the “A symptoms”?

Last but not least, CLL diagnosis does not happen in a vacuum, there is the rest of the patient to consider. How old is he? What is his general health? Are there other medical issues with shorter fuses, that are likely to do him in before the CLL gets going? Are there good reasons why certain drugs normally used in CLL therapy are contraindicated in his/her case?

While this list of “old” prognostic indicators are not as sexy as the modern ones we will be discussing, you are well advised to pay attention to them. Especially the onset of B-symptoms. Listen to your body. Only you can tell how you are feeling, how bad the fatigue is.  Most often, B-symptoms are the deciding factor when it comes to therapy timing.  We will be discussing these B-symptoms in greater detail later on.

Age at diagnosis plays a huge role in all medical situations and CLL is no exception. Older people have less robust immune systems to begin with. They have a harder time bouncing back after aggressive chemotherapy. They are more likely to have other medical conditions such as diabetes, hypertension, cardiac disease, liver or kidney malfunction. A life time of bad habits begin to catch up with you as you head into those so called golden years. All of these things limit the therapy choices open to older CLL patients.


Both the Rai and Binet staging systems depend on the same features for their staging algorithms.  Basically, they look at blood lymphocyte counts (ALC: absolute lymphocyte count), swollen lymph nodes that can be detected by physical examination, same thing for swollen liver and spleen, decreased amounts of red blood cells and platelets.
Notice all of the above criteria can be evaluated by nothing more than a careful physical examination and a simple blood test (CBC: complete blood counts).  There is no mention of CT scans, MRI scans, PET scans, Lymph node biopsies or bone marrow biopsies.  It is a crying shame that so many patients are subjected to some or all of these testing procedures when there is absolutely no need for any of them to adequately stage the CLL patient.  There are cost and medical risks associated with each of these unnecessary tests.
Rai and Binet staging still have many advantages, not the least of which is their simplicity.  But there is one important caveat, especially when it comes to late stages, and we will discuss that later on.

Both the Rai and Binet staging systems depend on the same features for their staging algorithms. Basically, they look at blood lymphocyte counts (ALC: absolute lymphocyte count); swollen lymph nodes that can be detected by physical examination; same thing for swollen liver and spleen; decreased amounts of red blood cells and platelets.

Notice all of the above criteria can be evaluated by nothing more than a careful physical examination and a simple blood test (CBC: complete blood counts). There is no mention of CT scans, MRI scans, PET scans, Lymph node biopsies or bone marrow biopsies. It is a crying shame that so many patients are subjected to some or all of these testing procedures when there is absolutely no need for any of them to adequately stage the CLL patient. There are cost and medical risks associated with each of these unnecessary tests.

Rai and Binet staging still have many advantages, not the least of which is their simplicity. But there is one important caveat, especially when it comes to late stages, and we will discuss that later on.


Rai staging comes in 5 flavors, going from stage 0 through stage 4. As you can imagine, the higher the stage, the more advanced the disease.

I have simplified the criteria required for each stage in this chart. Stage zero is when you have elevated counts of lymphocytes in your blood. ALC (absolute lymphocyte count) needs to be more than 5K before you can be diagnosed with CLL. Less than that and we are talking about MBL (monoclonal B-cell lymphocytosis), a precursor that may or may not develop into full fledged CLL some day.

Stage 1 means the patient has now graduated from just a blood abnormality of higher than 5K lymphocytes to having one or more palpable lymph nodes. No need for CT scans or other high tech methods, the swollen lymph nodes are felt by the talented finger tips of your oncologist.

Stage 2 means that in addition to elevated ALC and swollen lymph nodes, you are also the proud owner of a swollen spleen or liver. The technical term for swollen spleen is “spelnomegaly”. Your spleen is in the lower left hand corner of your abdomen, just under your diaphragm. When their spleens are enlarged, most patients report a sense of feeling full after having eaten only a small meal. When the spleen gets really swollen, you may look a tad pregnant. Your oncologist will dig deep just under your ribcage to feel the tip of your spleen. In a normal person, he should not able to feel this tip at all. A swollen spleen is often described as the tip being so many inches below the rib cage.

Your liver is  on the right hand side of your midsection. It too is just below the rib cage and can be palpitated when it is swollen. “Hepatomegaly” is just a fancy way of saying swollen liver.

Stage 3 and Stage 4 are defined as late stage CLL. Here the symptom is dropping red blood cell counts and platelet counts respectively. Both Rai and Binet staging systems look for this tell tale symptom, as an indication of failing bone marrow.

And therein is the caveat I would like to emphasize. You see, there are two very different reasons why platelet counts and / or red blood cell counts maybe low CLL patients. The first reason (and the only one that Rai and Binet staging systems consider) is a heavily infiltrated bone marrow. Your bone marrow is a very unique organ, the only place where new baby red blood cells and platelets can be formed, to replace the ones that have been lost to wear and tear. If the bone marrow is heavily infiltrated, it is no longer able to do its job of making red blood cells and platelets. Hence, anemia and thrombocytopenia (low platelets) are indications of the health of the bone marrow. If this is indeed the cause of low platelet counts and/or red blood cell counts, it is correctly defined as infiltrative late stage CLL.

But what if the bone marrow is doing just fine, there is still plenty of capacity in the marrow to make all the various cell lines, the reason for low platelet / red blood cell counts lies elsewhere? Autoimmune disease is well documented in CLL. AIHA (autoimmune hemolytic anemia) and ITP (idiopathic thrombocytopenic purpura) are autoimmune diseases where perfectly healthy red blood cells and platelets respectively are destroyed by an immune system gone crazy. Autoimmune disease is not fun, it can significantly impact your quality of life.  When it is aggressive it must be treated immediately. But autoimmune destruction has nothing to do with bone marrow health. As such, this reason for low platelets and/or red blood cells is called “immune late stage CLL”. The prognosis for the immune variety of late stage CLL is a lot better than that of infiltrative late stage CLL.


Barring the caveat we just discussed, how well does the Rai staging system predict overall survival?

Above is a graph showing how large numbers of patients diagnosed at various stages fared, in terms of their overall survival. This graph comes courtesy of an article in Medscape, authored by Dr. Michael Keating of M. D. Anderson.

As we discussed in prior workshops, it is not all that difficult making sense of these survival curves once you know how to do it.  For example, to get the median survival (the time point by which exactly half of the patients are alive and the other half are dead), just draw a horizontal straight line starting from the 0.5 point on the Y-axis (the vertical axis).  See where this line you have drawn cuts the different curves.  Folks diagnosed in Stage 0 (yellow curve) lived the longest, the horizontal line cuts the yellow curve at about the 12 year mark.  Next are stages 1 and 2 (green and pink) which have median survival of about 10 years and 7 1/2 respectively. There is not much to choose between stages 3 and 4, they had the shortest median survival of about 5 years.

A couple of things you should understand about these types of survival curves.  First, all of this reports data seen in the rear-view mirror.  Much of this data was collected based on patients seen at M. D. Anderson 10 or more years ago.  A lot has changed since then.  The good news is that we have better therapy options, we understand how to use the drugs we do have more effectively.  We have a better handle on what makes this disease tick and therefore better able to target the right therapies to the right patient type.  The biggest change has come in how we treat infections, the single biggest cause of death in CLL patients.  All of this means median survival statistics are significantly better.  There is still a lot to learn, CLL is still an incurable cancer.  But we are making progress and it is important to remember that.

Then there is the issue of how to view this information from the perspective of your own future.  Median survival just says by that time point half the patients are still alive, half are dead.  Which half will you be in?  There is no way to telling that, based on this graph. You may get lucky, you may be way out on right hand side tail end of the curve.

As you can see, Binet staging does pretty much the same thing as the Rai staging.  A roughly speaking, Rai stages 0 & 1 is Binet stage A; Rai Stage 2 = Binet stage B; and Rai stages 3 & 4 = Binet stage C.  As in the case of Rai Staging, there is a direct correlation between the proportion of patients surviving over time and their Binet stage.

Now we come to the caveat we discussed above.

Here are probability of survival plotted for Binet stages A, B and C (solid lines) – pretty similar to the previous graph.  But here we have broken down the late stage Binet C folks into two different groups.  The black solid line are the folks who are truly late stage.  These are patients who have low platelets or red blood cell counts because their bone marrows are not able to make these cell lines in sufficient quantity.  The cause for a malfunctioning bone marrow in late stage CLL is usually due to the marrow getting more and more infiltrated with CLL cells, leaving little room for the marrow to do its job properly.

The dotted black line on the other hand represents patients who would have been incorrectly staged as late stage (Binet stage C).  In their case the dropping red blood cell counts or platelets is due to autoimmune disease, nothing to do with malfunctioning bone marrow.  These guys have survival characteristics more in line with Stage B folks. In other words, infiltrative Stage C is different from immune Stage C.  It is important to know the reason why platelet counts and / or red blood cell counts are falling.

“Lymphocyte doubling time” looks at the ALC and judges how long it takes for the number to double.  This simple metric looks only at blood counts.  It makes no attempt to consider the CLL cells living in the lymph nodes and elsewhere.  Did you know that even in a straight forward CLL patient, as much as 90% of the CLL cells are tucked away in lymph nodes, spleen, bone marrow etc?  Only about 10% are swimming around in the blood at any given time.  In other words, using blood counts as a way of judging the total number of CLL cells in your body is a little bit like looking at the small bit of the iceberg that is poking over the surface of the water and using that to judge the much larger mass of it submerged under water.  The problem is even more striking when we consider SLL patients.  These guys may have substantial nodes and yet have very little to show for it in their blood counts!

Another thing to remember is that there is a built in variation in blood counts, depending on the lab you use, human error, and a bunch of other trivial reasons.  If you are just recovering from a minor cold or other infection, your lymphocyte counts are going to be higher – but the numbers will trend down to their normal track once the infection is fully dealt with.  In other words, it does not make sense to get totally fixated on every blip in your white blood cell count (WBC) or your absolute lymphocyte count (ALC) .  The regularly scheduled CBC is a good thing to keep track of, but it has its limitations.

In general, ALC doubling time of less than a year is considered aggressive disease.


There are nice mathematical equations for calculating doubling time based on any two ALC numbers.  Frankly, I find such equations of little use since the result depends almost entirely on you pick the two representative ALC numbers.  Far easier to plot your ALC data over time (it lets you eyeball how your ALC is progressing over time).  ALC doubling time calculated when the numbers are very small serves no purpose.  “Doubling” from 5K to 10K is not worth worrying about.  There is too much room for plain random error in the numbers.  But once the counts have grown a bit, and you draw a curve through all the data points that more or less represents the best fit, it is easier to compute the doubling time.  In the case above, ALC went from about 32 in July 01 to about 64 in Jan 02.  That is a doubling time of 6 months, an indication of progressive disease.


If you ever get a CT scan to look for swollen lymph nodes distributed through out your body, the lab report may describe the size and location of the lymph nodes using medical terminology to describe the various groups.  Jargon is intimidating only if you don’t know the words.  Here is picture of the major lymph node groups and their names.

In early stages and right after diagnosis, patients often get very worried when they feel the very first tiny little node in their arm pit, under their chin or groin.  Remember, swollen lymph nodes are now part of the new normal.  There is no reason to panic just because you can feel a pea-sized node someplace.


This is what massive lymph nodes can look like.  This lady has clearly identifiable chain of cervical  lymph nodes around her chin and up by her ears.  See if you can spot the supraclavicular nodes.  The axillary nodes under her arm pits are hard to miss.  This patient had 11q deletion (FISH), which is often accompanied by massive lymph nodes.  I thought I would put up this picture just so you can tell the difference between pea-size nodes and really enlarged nodes.


From the patient’s quality of life perspective, the most important indicator of progressive disease and time to start therapy is the onset of “B-symptoms”.  We have already discussed rapidly growing ALC and doubling time that is much shorter than a year as indicators of progressive CLL.

CLL is a cancer of the immune system.  Since the immune system’s function is to keep us safe from infections of various sorts, frequent infections (especially those that are severe enough to require hospitalizations) are a clear indicator that the immune system is not doing its job.  Obviously, patients that are extra careful about exposing themselves to infections are going to do better than those that take chances.  Given the general age of CLL patients, cute little grandkids with drippy noses are the number one risk factor for most of us.  Here is your chance to “delegate” chores such as diaper changing and litter box cleaning to some one else in the family.

Most women who have been through a rough patch of post menopausal hot flashes can tell you how uncomfortable it can be.  But that is not what we mean when we talk about night sweats as a B-symptom.  Patients who have night sweats cannot possibly mistake them for anything else.  Patients tell me that they often had to change their pajamas a couple of times a night because they became dripping wet – sometimes the bed sheets as well.

Garden variety fatigue because you had a bad day at work or you did too many things the day before – that is not what we are talking about here.  This is mind-numbing fatigue that makes it hard for you to get upstairs to bed, that makes it impossible for you to avoid a mid-day nap.  When it happens, you will know it.

Almost everyone I know is trying to lose a few pounds.  That is not it.  We are talking about patients losing five or often more pounds of weight without doing anything to bring about the weight loss.  There is a special word for the weight loss that happens in many different kinds of cancer – “cahexia”.  I am not sure anyone knows exactly why cahexia happens in cancer patients, but it is a well documented phenomenon.

We have already discussed enlarged lymph nodes and I will not belabor that point.


This is a short list of the more popular prognostic indicators. There are a bunch more that I will not go into.  We will discuss each of these indicators, what exactly they measure, what the results mean (or don’t mean).  Once again, let me emphasize that prognostic indicators are no more than somewhat cloudy crystal balls – you may get a glimpse of what to expect, a hazy look at the lay of the land. No guarantees of your medial future.


Beta-2-microglobulin (B2M) is measured by means of a simple blood test.  It is easy to do, most of the commercial labs do it and it is a cheap test.  Its use in monitoring CLL was initially popularized by M. D. Anderson.  The thing to remember about B2M is that it is not fixed in stone, it may (will) change over time.  Since it is easy to do, it may be a good idea to get it done every quarter or so, just to keep an eye on things.  Several things can cause it to spike, such as chemotherapy treatment!.  Since excess B2M is removed from the body by the kidneys, damage to kidney function can cause B2M elevation.  It is not exactly a well focused and specific CLL prognostic indicator, but it is worth monitoring – provided you don’t have a panic attack over minor blips.


As you can see, B2M level is a pretty good indicator of survival.  This graph comes from Dr. Michael Keating’s article in Medscape.  The data was collected over a number of years, from 1980 through 2002, I believe.  M. D. Anderson uses the cut-off of 2.0 for normal B2M, anything over that is abnormal.  The yellow line represents 445 patients whose B2M is normal, under 2.1.  Median survival for this bunch was about 13 years.  At the other extreme, the white curve is for 175 patients whose B2M was higher than 4.0.  Median survival for this group was less than 5 yers.

But once again in pays to remember that general statistics do not guarantee your own track record.  Also of note, this data was collected quite a while back, 1980 through 2002.  Here we are, almost a decade later than the latest patient in this group.  Believe me, a lot has changed – not the least of which is that overall median survival is getting longer in CLL patients!  Better drugs, better drug combinations, better understanding of when, who and how to treat patients, better ways of protecting them against infections, second cancers and autoimmune disease – all of this adds up to longer life and better quality of life.


Most often the FISH (Fluorescent in-situ hybridization) test is done on a sample of blood.  Sometimes it is also done on the mush sucked up during a bone marrow biopsy (“aspirate”). Don’t be surprised if the results from these two different samples do not always agree 100%.  Sometimes a particular clone prefers to live in the bone marrow, and it may not be picked up during a blood test.  But for most people, a simple blood test for FISH is all that is necessary.

FISH test is important in the sense that it looks for underlying chromosomal abnormalities.  The fact that you have CLL means you do have one or more of these abnormalities.  There are four common abnormalities and the run-of-the-mill FISH test uses four probes looking for these abnormalities.

It is important to remember that the FISH test can change over time – an indication that the CLL clone is gradually evolving over time, learning new tricks.  This is called “clonal evolution” and it is more likely to happen if the patient has been treated with mutagenic chemotherapy.  Drugs such as fludarabine, chlorambucil, cyclophosphamide, bendamustine etc attack the DNA double strand and cause damage.  If the damage is not enough to kill the cell outright, the damaged cell can linger on with even more bizarre chromosomal damage that it had before start of therapy.  Think of a wounded (but still alive) tiger, more dangerous than the healthy one before it got shot.


Chromosomes are what make us who we are.  Each and every cell in your body that has a nucleus in it has the same set of chromosomes.  There are 22 pairs, numbered one through 22.  You get one of each pair from your father and the other from your mother. In addition to these 22 pairs, men also have and “X” chromosome from their mother and a “Y” chromosome from their father.  If on the other hand, on that fateful moment 9 months before your birth when your father’s sperm kept a date with your mother’s ovum, your father’s contribution was also an “X” chromosome, you would have ended up with a pair of “X” chromosomes and you would have been a girl.

A small cultural aside:  there is still a strong preference for boy babies in many Asian cultures, including India.  There are periodic reports of Indian women being harassed by their husbands or in-laws because the new bride gave birth to a girl rather than the desired boy-child.  If only they knew.  The sex of the child is not determined by the mother.  If any one has any control over it at all (and they don’t), it is the guy who donated the “X” chromosome that made the child a baby-girl!  Ironic that women get blamed for something they had nothing to do with, not even at the the chromosomal level.

Getting back to our subject, what is the big deal with chromosomes?  Well, these tubes carry carefully coiled double strands of genetic material, your DNA.  And your DNA in turn controls everything about you.  The color of your eyes, your sex, everything about you – including the fact that your DNA has acquired some defects over the years and here you are, a CLL patient spending a nice Saturday afternoon learning about CLL prognostic indicators.


Let us look at one of these chromosomes up close and personal, say one of the pair of #17 chromosomes.  Looking at a cartoon version of the chromosome, it looks like a long sausage with a crimp in the middle.  Not quite the exact middle, one arm is longer than the other arm.  The short arm is called “p” and the long arm is called “q” (Don’s ask me why scientists decided to call them p and q, and not “s” for short and “l” for long!)

Looking more closely at the short “p” arm of the chromosome, we are in the right neighborhood but we still need the actual house address.  Let us say we are interested in who lives in the 13.1 house in the short arm of the 17th chromosome. Put it all together and we are talking about the resident of 17p13.1.  That is the full address.  Why are we interested in that particular address? Because that is the location where the TP53 gene lives. Each and every healthy cell of your body which has a nucleus has a TP53 gene at this particular address. Think of the TP53 gene as a sort of a fail-safe suicide switch.  When something damages the cell to the point where it is no longer able to do its job, when it has become positively dangerous to itself and its neighbors (think of the wounder tiger we talked about above), the TP53 gene kicks in and orders the cell to commit suicide.  No mess, no fuss, the damaged cell dies and life goes on.

That is what should happen, in healthy cells.  But what about cancerous cells? What happens in the case of a CLL patient, whose cancerous clonal cells have this very important bit of their 17p chromosome damaged?  With the TP53 gene broken off (“17p deletion” is the short-hand way of saying the TP53 gene at that location has broken off), the cell is no longer controlled by a master suicide switch.  Try killing such a cell with garden variety chemotherapy and even if the cell gets more damaged, it refuses to die.  The wounded tiger can sustain more and more wounds, gets more and more fierce and mean, but it refuses to die.  This is a dangerous situation, a badly damaged cell that refuses to die, continues to have babies that inherit all of its defects – and most chemotherapy drugs cannot do much about it.  This is the reason why patients with 17p defects are not likely to get good remissions from standard chemotherapy drugs.  All of these drugs depend on an active and functioning TP53 gene to deliver the killing blow, once the chemo has damaged the cell.  In the absence of the TP53 gene, there is no one present to pull the plug.  TP53 is one of the most important tumor suppressor genes, its absence can trigger many different kinds of cancers.


We talked about the importance of having a properly working TP53 gene.  FISH test using the right probe can tell whether or not the right bit of DNA is still intact on the 17th chromosome, at the 13.1 location of the short “p” arm of the chromosome.

But mere physical presence is only part of the story.  What if the TP53 gene is physically present but unable or unwilling to do its job? What if it is on an indefinite lunch break?  FISH test cannot tell the difference.  This is a bit like the Oracle of Delphi, it just answers the questions it is asked, it is up to you to figure out if the answer makes any sense.  So, it is entirely possible for the TP53 gene to be present and not doing its job, in which case you have no way of knowing that by just looking at the FISH test results.  Two reasons why genes can be asleep at the switch are mutation and silencing.  In the case of mutation, the gene is not quite configured right, there is a subtle damage not bit enough to be picked up by FISH probe, but enough to bugger up the gene and prevent it from working right.  “Silencing” is the term given to genes that are covered over with gunk such that the gene is blind and deaf for all practical purposes and has no idea what is going on around it.  (Please read an earlier article titled “Epigenetics” if you want to learn more about gene silencing) Same thing no difference, a deleted TP53 gene, a mutated TP53 gene or a silenced TP53 gene – none of them can get the job done: namely commanding a dangerously damaged cell to commit suicide.

How important is this TP53 gene?  Above is a graph of patients with or without a properly working TP53 gene.  If the gene is not doing its job, for whatever reason (deleted, mutated, silenced), the median survival of the patients from the point of diagnosis is little over 50 months.  Lucky patients with a properly working TP53 gene lived more than a couple of decades!  This is not a large study, and that puts some limits on its credibility.  But the take home lesson is absolutely correct:  A properly working TP53 gene is a hugely important prognostic indicator, indicating a slow moving and “smoldering” variety of CLL.

Some of you may ask, how about the fact that there are a pair of 17 chromosomes, so there are actually a pair of TP53 genes in each cell.  Does it help if one of the TP53 genes is present and working, even though the second one is damaged?  The answer is YES, it helps if there is at least one working TP53 gene.  But the sad news is that over time, if one of the TP53 genes is gone AWOL, gradually the good TP53 gene may also get overworked and damaged.  And chemotherapy will kill the easy pickings, the ones with at least one working TP53 gene, leaving behind the clones where both of the pair of genes are malfunctioning.

Someday, we will not stop at just looking at the presence or absence of genes.  As we have discussed, mere presence of genes is not the whole story, we need to know if they are working right.  TP53 gene produces a protein and it is this protein that does the actual work.  Someday, we will not depend on FISH test alone to see if the TP53 gene is present.  We will look for and measure the amount of the right protein this gene is supposed to produce, in order to do its job.  The day of genomics (study of genes) has truly dawned.  Let us hope the more important day or proteomics will dawn soon, the study of the critical proteins that the genes make, in order to carry about the business of the body.


Getting back to the nuts and bolts of the FISH test, most commercial labs use four probes in their CLL FISH panel.  They look for particular defects in the 17th chromosome (discussed at length above); a deletion on the 11th chromosome (where a gene called “ATM” lives. This gene is very good at repairing DNA damage. Its absence makes the cell more liable to sustain further chromosomal damage); a deletion on the 13th chromosome (we are not exactly sure what the particular gene is, but this is one of the most common chromosomal defects in CLL patients).  Last but not least, the FISH panel looks at the 12th chromosome.  Instead of the standard issue pair of 12 chromosomes, some patients have three of them. This is called 12 Trisomy (tri- refers to three).

What does it mean when your FISH report says none of the 4 common chromosomal defects are present and you have a “normal” FISH report? All it means is “none of the above”.  You have CLL, which means there is some chromosomal damage some place. It is just not one of these four common defects.  I wish labs would stop using “normal” as a way of describing this situation.  “Unknown” or “none of the above” or “we don’t know” are better ways of describing such a patient.


Here is a more comprehensive list of potential chromosomal defects seen in CLL patients.  Notice the top 4 (by percentage) are the usual ones examined by commercial CLL FISH panels – 13q, 11q, 17p and 12 trisomy.  Some labs have started using a fifth probe, looking for deletion on the long arm of the 6th chromosome (6q).  All in all, roughly 82% of the patients in this study had identifiable chromosomal defects.  There were 18% of patients with “normal” result, which just means they had defects that could not be seen by any of the probes used.

A more expensive test is something called a full karyotype examination, where each of the chromosomes if fully examined in turn, to see if there is damage.  This test obviously avoids the pitfalls of the usual FISH test.  Full karyotyping is not really necessary except under special circumstances and for high risk patients.


Professor Dohner developed this risk categorization based on FISH results.  Most dangerous is the deletion on the 17th chromosome, where the important tumor suppressor gene TP53 lives.  Next in line is the the 11q deletion, where the ATM gene lives. This gene is very good at repairing DNA damage.  Deletions at the 17p and 11q are considered high risk CLL

It is thought there is a tumor promoter gene on the 12th chromosome, and having three of these tumor promoter genes (instead of the standard issue 2 of them) makes things worse.  If you follow our “Bucket” classification, 12 trisomy puts patients in the middle bucket by way of risk.

The least dangerous of the lot is the deletion on the long arm of the 13th chromosome (13q). It is also the most common chromosomal defect, perhaps that is what makes CLL a “good cancer”.

By now you should be able to draw a horizontal line starting from the 50% percentile survival.  Where this horizontal line cuts the various curves, go down vertically to the survival axis and you can read off the median survival of the patients in this study with that particular chromosomal abnormality. If you have problems with this task, please go back to our second workshop where we discussed how to do this in greater detail.


Let us summarize what we have learned about the FISH test.

Since it is possible for cells to acquire additional chromosomal defects, clonal evolution can happen and your FISH status may change over time.  You may have started as nothing more than 13q deletion (Bucket A), but after percolating along for a few years you may be unpleasantly surprised to find you now have two FISH defects: the original 13q defect is joined by the more dangerous 11q deletion.  That was what happened to PC, husband. He had 13q as sole abnormality at the time of diagnosis.  A year later, they also identified 11q deletion and his disease took off at a rapid clip.  Since 11q deletion is usually accompanied by bulky lymph nodes without showing highly elevated ALC blood counts, it is important for these patients not to get fixated on the regularly scheduled CBC reports.  The real CLL crowds hang around elsewhere for these folks, in the lymph nodes.

Detection of 17p deletion (TP53 gene) has implications for therapy decisions.  For example, patients with high percentage of their CLL cells showing loss of this particular bit of their 17th chromosome are not likely to get much joy from conventional chemotherapy.  Not even FCR, the new “gold standard” chemoimmunotherapy.  What is the point in exposing patients to the obvious toxicity of these drug regimens, if they are not going to much benefit from it?  For this reason, for patients who show rapid clinical progression and may have high risk FISH abnormalities, it is a good idea to do a repeat FISH just prior to making therapy choices. There are only a few drugs that can deal with a clearly 17p deleted case. Among them are Campath, Revlimid (lenalidomide) and the experimental drug flavopiridol.


As we discussed above, FISH status does not capture genes that are not working right because they are mangled (mutated) in some fashion, or because they have been silenced through epigenetic mechanisms.  On the other side of the coin, even though a particular gene has been deleted, remember you have a pair of each kind of chromosome.  ATM gene deleted on on the 11th chromosomes may still mean you have a functioning ATM gene on the second of the pair.

How about situations where both chromosomes in a pair have sustained the same hit?  What happens when both of the 13th chromosomes have the same identical 13q deletion – called a double allele or bi-allele deletion?  A paper from Brazil (if I remember correctly) suggested bi-allele 13q deletion is more dangerous than single allele deletion of the same kind. There there was a Mayo paper (with larger patient group) that said exactly the opposite, that there is no additional risk in having the 13q bit deleted from both the pair of 13 chromosomes.  The jury is out on this one, but I put more credibility behind the Mayo paper, simply because it dealt with a larger group of patients.

How about if there is more than one FISH defect?  If the patient had, for example, a 13q deletion as well as a 11q deletion? Which one drives the prognostics bus? I am afraid the prognosis is mostly defined by the worse of the two defects, in this case this patient will progress as you would expect a 11q patient to progress.

Beware of strange sounding FISH abnormalities that surprise you.  For example, if your FISH report has in it words such as t(11;14) translocation – meaning a bit of the the 11th chromosome has broken off and attached itself to the 14th chromosome – that might be an indication that you may not even be a CLL patient, what you have may be one of the other blood cancers.  In this case, it may be mantle cell lymphoma, a decidedly more dangerous blood cancer.  It may need further testing to confirm diagnosis, perhaps detection of cyclin D1.  The moral of the story is that it is very important that you have a rock solid diagnosis of CLL before you can start worrying about it.  It is all too easy to confuse CLL with another blood cancer, MCL looks a lot like CLL in early stages.  You can read more about this particular confusion in an earlier article I wrote on the subject.


So, how does FISH status match up with the more old fashioned prognostic indicators we discussed at the start of this presentation?

There are five columns in the chart above, four of the common FISH abnormalities of 17p, 11q, 12 trisomy and 13q, along with the “normal” or “none of the above” categories.  You can see the most common of the FISH abnormalities is the 13q deletion.  117 patients had this one, by far the most common.  People with this abnormality were more likely to be in earlier Rai stage, half of them had no swollen spleen, only a quarter  had swollen lymph nodes, very few of them (6%) had B-symptoms at diagnosis and on average these guys trundled along without needing treatment for their  CLL for a whopping 92 months (more than 7 1/2 years!)

Compare that bunch with the more unlucky group, 23 of them, that had the dangerous 17p deletion.  None of these guys were in Rai Stage 0 at diagnosis, majority of them were in the higher stages of 3 and 4.  86% of them had swollen spleens, more than half had swollen lymph nodes at diagnosis, a third had B-symptoms and in a short 9 month period these guys were ready for start of therapy.  I think you will agree, there is good correlation between the FISH status of this group of patients and their clinical presentation at diagnosis.


In his recent article “How I treat CLL” Dr, John Gribben lays out the logic.

If the patient is asymptomatic at diagnosis, he / she goes into “Watch & Wait”, until he develops actual B-symptoms.  Once the patient has developed symptoms and it is time to start therapy, a hugely important question is the general health situation of the patient.  As we discussed in our earlier workshop “Everything you wanted to know about FCR”, modern day drug regimens – even the “gold standard” FCR – are no easy walk in the park.  Patients with other health conditions may have a hard time tolerating these high impact regimens.  General performance status is important to determine if such therapy options are contra-indicated in older and more frail patients.  Chlorambucil is a popular drug of choice in Europe for elderly patients.  Single agent Rituxan may be a more common option in this country – but I do not have statistics to confirm that.

If the patient is reasonably fit and able to handle high impact therapy, the next step is to determine his FISH status.  If there is no concern about 17p deletion, the choice of therapy is FCR or something akin to that. If however the patient has this FISH abnormality and is therefore not likely to benefit from standard chemotherapy regimens, it is best to consider options such as Campath (alemtuzumab), Revlimid (lenalidomide) or flavopiridol.

Knowing none of these drugs is going to hold the line very long, younger patients with 17p (TP53) defects may be best served by considering a mini allo (“reduced intensity conditioning” or RIC) stem cell transplant, soon after getting into remission following their Campath / Revlimid / flavopiridol therapy.


Let us know turn our attention to the most important of all the prognostic indicators we know of today, namely the IgVH gene mutation status.

I would like to de-mystify some of the jargon and science behind this prognostic indicator – but only at the expense of making a small cartoon version of it.  Please be aware that I am taking significant liberties with scientific accuracy here, in order to make the subject matter more comprehensible to the layperson.

The crux of the whole business is that cells like to communicate with their neighbors and the surrounding environment, just like people.  Without feedback and communication, cells die pretty quickly.  That is why a CLL cell placed in a glass petri dish in the lab dies so soon, why it is not really possible to do exactly meaningful testing of cells in the lab and hope the results are well matched when the cells live inside people.

Let us focus on the B-cells, since CLL is a cancer of the B-cells in our immune system.

B-cells have a structure on their surface called the B-cell receptor, which is very important in how the cell receives signals from other cells around it as well as the general surroundings.  This B-cell receptor is a “Y” shaped affair, anchored at the tail of the “Y” and the two arms of the “Y” pointing outwards.  Signals are received through the tips of the two arms.  If we can totally shut down the cells ability to “see” and “hear” through the arms of the B-cell receptor, the cell will soon die of loneliness.


Here is a cartoon version of a B-cell with 8 of the “Y” shaped B-cell receptors (BCR) on it.  In actual fact, there may a couple of thousand or so of such receptors on the surface of each B-cell.  And this number is rather on the low side!  In some other blood cancers, there may be as many more than just a mere couple of thousand of them.  Another name for the B-cell receptor is immunoglobulin.  You may have seen flow cytometry results back when you were diagnosed that said you had dim sIg.  What that phrase is saying is that you have only a small number (“dim”) of these surface (“s”) immunoglobulins (“Ig”).  In other words, dim sIg is one of the confirmations for CLL diagnosis.


Getting a bit closer to it, this is a rough sketch of what a  BCR unit looks like.  It is anchored to the B-cell by the tail of the “Y”, with the two arms of the Y flapping in the breeze.  Notice the “Heavy chain” and “Light chain” that make up the arms of the Y.  At the very tips of the arms is what is called the variable region.  This is the part that is sensitive to receiving messages, it is the part that changes when the B-cell becomes fixated on any particular antigen as its soulmate.

So, this is it in a nutshell.  We have the immunoglobulin (different name, same as BCR).  We have the variable region, the tips of the two arms of the “Y”.  We have the heavy chain.  Put it all together and we have IgVH.  So, next time you see something about the IgVH, remember they are talking about the tips of the arms of the Y, the variable region of the heavy chain, of the immunoglobulin on the surface of B-cells.  Easy, once you know how they came up with that particular acronym, right?


Young and foolish B-cells have the tips of their BCRs in a virginal state, unable to tell the difference between one antigen or another.  Somewhere along their maturation process they come across the one particular antigen that becomes their soul mate, the one and only antigen to which they respond.  Above is the picture of a BCR that has made up its mind. It has decided that it and its daughters will now and forever respond only to the particular (yellow one, in our example) that is shaped in a particular fashion. The variable region of the BCR changes its shape accordingly, to exactly match its soul mate. Notice that in our cartoon version the tips of the Y are now shaped so that they match only the yellow antigen, they will not fit any of the other differently shaped antigens.  This particular B-cell now has all of its B-cell receptors, all thousands of its surface immunoglolubins configured this way.  It has changed (“mutated“) its IgVH, the variable region of the heavy chain of its immunoglobulin.

If the very first CLL cell in your body, the very first great, great grand-daddy of them all had unmutated IgVH, it and every one of its daughter cells will continue to have unmutated IgVH genes. If on the other hand the very first CLL cell had mutated IgVH, mutated to match a particular antigen, this cell and all of its progeny down the generations will also have mutated IgVH, mutated exactly in the same fashion as the original CLL cell.  IgVH mutation status is fixed and remains unchanged from that distant beginning.


People who have CLL cells with mutated IgVH have much better prognosis than those without.  As you can see, the percent of patients surviving past 10 years is much higher for the folks with mutated IgVH gene than those that had the unmutated version of it.


Recently, this simple picture of “mutated IgVH = good prognosis” and “unmutated IgVH = bad prognosis” became a little more complicated.  We now know that there are certain types of mutations of the IgVH that act clinically as if they were unmutated.  Patients with this particular change in the tips of their BCR (VH3-21 variety) have clinical progression as if they were unmutated variety.  You can see that in the survival curves above.  The solid dark line represents patients who have mutated IgVH, but the wrong kind of IgVH mutation, the VH3-21 variety that behaves as if it were unmutated.  Complicated, but let me see if I can help you understand that with a slightly off-color analogy.


Three very nice and virginal young ladies go into a bar on CLover Lane.  They are fresh out of their convent school, never met any boys before then.

Mary, Betsy May and Ursula meet a variety of boys in that bar.  Each of them has a chance to meet their soul mate, the one and only true love of their lives.


Mary falls in love right away, and the guy she falls for happens to be a sailor that was scheduled to sail far away the very next day.  Poor Mary!  Being a loyal girl true to her heart, she would never look at another boy now that she has given her heart to Sam the sailor.  Sam is away for a long time and soon enough Mary dies of loneliness – no babies, no one to continue her line.


Betsy May too finds her one true love.  But she is a bit luckier in her choice.  She falls in love with a local guy, not a sailor going away for a long time.  Since her one true love is always around, she has plenty of company. She has many babies who are just like her and lives for a very long time.


Ursula, the third of our heroines, cannot make up her mind.  She is not sure exactly who she likes and decides she is going to be a town’s “bad girl” and flirt with all the boys.  What if a couple of them are already married, or a few of them are sailors who go away for a few months?  There are always enough boys around for her to have a good time.  She has a lot of babies, lives a fun-filled and happy life for a very long time.


I chose the names of our three heroines carefully.  Mary (M for mutated) is the good variety of IgVH.  It represents CLL cells with their IgVH mutated to accept input from only one kind of antigen, and more over an antigen that is rarely present.  Perhaps it was a bit of protein from the coat of a bacterial that is long since gone, never to return. This kind of IgVH gene mutation means the cell does not get much by way of signaling and it soon dies without having given birth to a lot of daughter cells.  As a patient, that is what you want, you want the CLL cell to die soon without having babies.

Betsy May (B M for bad kind of mutated) stands for the mutated IgVH but of the VH3-21 variety that acts as if it is unmutated.  Since the antigen that fits this particular variety of IgVH mutation is always present (“ubiquitous” antigen), CLL cells with this kind of IgVH gene mutation will survive a long time and continue procreating daughter cells just like themselves. Perhaps the “antigen” in question here is a snippet of a red blood cell or some other bit of cellular debris from the patient’s own body – and therefore likely to be around most of the time.  This variety of IgVH gene mutation predicts for a progressive variety of CLL

Ursula (U for unmutated) stands for unmutated IgVH.  This variety of IgVH will respond to a variety of antigens floating around, making it possible for the CLL cell to have plenty of cell signaling.  This variety of CLL cell lives for a long time, has many daughter cells just like it, and therefore predicts for a progressive variety of CLL.

Silly analogy, and it leaves out a lot of scientific detail, but I hope it will make it easier for you to understand and remember what this is all about.


Based on what we know as of today, IgVH gene mutation status is a very important prognostic indicator in CLL, if not THE most important one.  I have no doubt we will learn of more caveats and exceptions, more wrinkles like the VH3-21 type (bad mutated IgVH) as time progresses and our researchers uncover more about the all important B-cell receptor and how it “talks” to to other cells.

How much of the BCR is changed when the tip is mutated and the IgVH becomes fixated on one and only one kind of antigen?  About 2-3 percent. That is all the change that is needed to define the IgVH as a mutated variety.

As we discussed above, once the pattern is set in the IgVH of the very first CLL cell in your body, it does not change for the rest of your CLL career. That great- grand daddy cell and all of its  daughters down the generations will have the same exact IgVH.  In practical terms, once you have had your IgVH gene mutations status tested by a credible lab, there is no reason to repeat this expensive test again.


I think you get the picture by now.


Back about 10 years ago, when they first discovered CD38, a marker on the surface of CLL cells, there was a lot of excitement since they thought it was a good mirror for IgVH gene mutation status.  CD38 level is easily measured by flow cytometry, a relatively cheap blood test (unlike IgVH gene mutations status, which is both expensive and requires expertise to do correctly).  It was observed that high CD38 expression (20% is considered a cut off by most labs) indicated aggressive disease, while lower than 20% indicated a less aggressive disease.

Unfortunately, CD38 expression changes over time.  And it does not exactly parallel IgVH gene mutation status (which does NOT change over time).  So, while CD38 levels are still measured and it continues to be a valuable prognostic indicator, much of the excitement has worn off.  Some physicians may have the CD38 measured again, just to see if it has changed a great deal, especially in patients who have progressed rapidly and may be looking to make therapy decisions.


As you would expect, people with high CD 38 expression (in this case, the authors used 30% as the cut-off level) had disease that progressed rapidly.  Those with CD38 level less than 30% had slower progression.


The same trend is observed in overall survival as well.  CD38 level predicts for progression and survival.


ZAP70 was another of the prognostic markers that had high hopes of mimicking IgVH gene mutation status.  Usual cut-off was 20%, higher level indicated higher rate of progression of disease.  But once again hopes were dashed when it was observed that the match between IgVH gene mutation status and ZAP 70 levels was not always perfect. Like CD38, ZAP70 expression also changes over time.

But unlike CD38, the problem did not stop there.  Measuring ZAP70 is not easy, and after all these years we still do not have consensus on exactly how to do the test.  Frankly, unless your ZAP70 was measured at one of the expert CLL centers, I would not even bother with getting this test done at one of the commercial labs – it is a temperamental test and the results can be all over the place.


Significant predictive power of ZAP 70 on progressive disease


and survival too.


We talked about IgVH and how the B-cell receptor uses the tips of the Y shaped immunoglobulins to communicate with other cells and its broader environment.  CD38 and ZAP70 are also part of the same communication complex.  And very complex it is!! Above is a simplified picture of how the BCR (shown as Y shaped objects at the very top of the picture) is linked to a very complicated signaling system underneath it.  No doubt this will get even more complicated as research progresses.  Messing up any of these signaling pathways may be a good target, a way of shutting down the cell’s communication.  Some of the new kinase inhibitors (such as CAL-101) try to do just that.  The other side of the coin, if we manage to bugger up one or more of these pathways, will the cell develop ways around the road block and then go on its merry way?  Nothing about cancer is simple.  But the more we learn, the better we are able to target drug development.


Exactly how good are any of these prognostic indicators?

When rubber meets the road, what matters to patients is the length of their life, and the quality of that life.

As I have mentioned several times before, the single biggest cause of sickness and hospitalizations in CLL is due to infections.  Here is a set of graphs that illustrate how prognostic indicators influence the risk of getting major infections.  I apologize for the quality of the graph, it was the best I could do.  Graph A shows the risk of infection is significantly higher for patients in later Binet stages (B and C) compared to Stage A.  Graph B shows the same thing, using IgVH gene mutation status as the indicator.  People with unmutated IgVH had much higher chance of major infections.  Graph C looks at CD38 level and Graph D looks at presence of high risk FISH abnormalities.

As you can see, there is significant predictive power to each of these four prognostic indicators and the risk of major infections


The same article also looked at the risk of patients dying from major infections. It should come as no surprise, the risk of death due to infections increased in patients with higher Binet stage, unmutated IgVH, high CD38 or high risk FISH abnormalities.


I regret to say that life does not come in nice, well defined and clear packages.  Most patients have what I call “mix-and-match” set of prognostic indicators.  The first step is to make sure you have CLL, not some other blood cancer like MCL.  Second step is to see if you have garden variety of CLL and not what is called PLL (pro-lymphocytic leukemia).  PLL folks have a slightly different variant of CLL and if your labwork says you have more than 50% of your CLL cells look like PLL, you may be in for a rougher ride.  Not as much is known about PLL and it may be best if you go to an expert center to find out more about your PLL presentation.

All through this presentation we have discussed that patients sometimes have SLL presentation (small lymphocytic lymphoma) which is considered the same disease as CLL – with the big exception that they are likely to have most of their disease present in their enlarged lymph nodes and not much of it in their blood.  Routine blood tests are not likely to be as helpful to SLL patients.  Some drugs such as Campath are not useful to them since they cannot kill cancer cells buried deep inside bulky lymph nodes.

I think it is fair to say IgVH gene mutation status (with the caveat of VH3-21 type bad mutations we discussed above) is the single most important indicator and it trumps most other prognostic indicators.

But when it comes to therapy decisions, I think having (or not having) a properly working TP53 gene makes a huge difference.  17P deletion detected by FISH is important in determining this.  But bear in mind that physical presence of the TP53 gene does not guarantee it is working right (gene mutation or gene silencing can make for trouble!).  On the other side of the coin, some patients with a single allele deletion can still get along reasonably OK because the second gene of the same type on the other chromosome continues to do its job.


Here is a picture that tries to put all that we have discussed into one slide.


Allow me to finish on a high note.

The very good news is that patients are living longer today than they did a decade ago.  Here is the Keating article we used several times before in this presentation.  This slide looks at proportion of patients alive, against months since their diagnosis.  There is no doubt that patients diagnosed later on (say, in the time period of 2000 – 2002) lived a longer time than those diagnosed back in 1980- 1984 (yellow line).

That is good news, and I am willing to bet dollars to donuts that the results would look even better if we look at patients diagnosed in the last year or so.  Better drugs, better therapy regimens, better understanding of when, how and who is most likely to benefit from those therapy options – all of that goes into longer patient survival.


This is even more dramatic proof people are living longer with CLL.  This chart looks at people younger than 70 years old, who are in late stage Binet B or C.  Depending on whether they were in that stage in 1980 -1994 or more recently in 1995 – 2004, there is a huge difference in their relative survival.  In the older  group of patients, 50% of the patients were alive at the 4 year mark.  But looking at the more recent modern group, 50% of the patients were still alive at the 10 year mark!!!  Now that is something we can all cheer.


So we talked about a lot of prognostic indicators your doctor will mention (hopefully) and researchers will discuss in their learned papers.

There are also a bunch of politically incorrect prognostic indicators that we can all related to, but it is not considered kosher to talk about them in public.  When has that ever stopped me?

Family is important.  Whether it be your biologic family, or your cyber family right here, or the friends you make by choice, you will need support of various kinds as you go along on this journey.  CLL cells die of loneliness, as we discussed. Human beings do not thrive on loneliness either.

Not everyone has access to adequate medical care.  We talk of local oncologists and how they may or may not match the quality of care at expert centers. A member recently took me to task for false advertisement (my choice of description of her kinder description) because I said the NIH did state of the art prognostic testing and their recent budget cuts may slow down the rate at which they can do IgVH gene mutation status testing.  I was bemused, a little taken aback.  We get spoiled in this country.  When I hear from members in India, Nigeria, parts of the rest of the world that is not as affluent, the problem is not slightly delayed IgVH gene mutation status, the problem is being able to afford any kind of drug, even good old chlorambucil.  The problem is avoiding infection in the absence of clean water supply, basic community hygiene.  Don’r forget to count your blessings folks.  A lot of people are hurting a lot more than you!

Street smarts are important in every aspect of our lives, and that includes taking care of your health.  Try not to mistake wishful thinking for reality.  Good nutrition is important for everyone, especially for cancer patients.  But can you cure CLL by becoming a vegetarian or drinking many glasses of vegetable juice?  I do not think so.

Wishful thinking may actually hurt, if you do silly things.  At the very least it is going to disappoint you. It may waste your time and money that is better spent on more realistic therapy options.  Remember that the window of opportunity does not stay open forever.

When is it time to start therapy?  Should you fire your present doctor because he is not really up to speed on CLL?  How do you handle tough medical and financial issues?  None of these are easy questions and it takes a strong personality to make the right calls.  When the going gets tough, that is when you must stay strong.

I believe in patient participation in their own healthcare.  Your health means more to you than anyone else in the whole wide world.  Why should anyone else care about it, if you don’t?  Outsourcing CLL worry is an issue we discussed in a recent article.  Something to be done cautiously, if you get my drift.

Life style and the choices you make are important.  I am not even talking about shared needles, illicit drug usage or safe sex practices!  How about staying away from the grand kids when they are clearly sick and dripping a the nose? How about a little sensible “social distancing”? How about making sure everyone in your family gets the annual flu shot?  How about a little commonsense people?

Last but not least, there is the element of luck.  You can learn everything there is to know about CLL, do all the correct things, make smart therapy decision – and still come up empty.  That is what happened to my husband.  He was smart, brave, incredibly rational in how he dealt with his CLL diagnosis.  His luck ran out when he developed increasingly high risk CLL, followed by lack of well matched adult donors when he needed a transplant.  He almost made it through a cord blood transplant.  Almost, but not quite.

You too might do everything right and yet get hit by that proverbial bus with your name on it, as you cross the street.  As one wise philosopher put it, “shit happens” and there is not a whole heck of a lot you can do about it.  The best advice I can give you is to be good to yourself, enjoy the life you do have, and be good to those around you.  An equally wise philosopher put it like this:  what goes around, comes around.  You may feel a lot happier about yourself and your life, with or without good luck,  if you can take pride in the kind of a person you were in the face of adversity.  When the going gets tough, tough guys become gentle, caring and generous.  I know that from my own personal experience, watching my husband PC.  He did exactly that.


It is a miracle that after 4 hours of this stuff none of you have fallen asleep, no one left in disgust half way through.  The questions you asked as we went along tell me you are coming up the learning curve nicely!  Perhaps we need to rent the conference hall for more than four hours; they had to literally throw us out well past our time.

I am only able to publish my own presentation and comments – not your questions or discussion after the presentation. I hope you will participate in the comment section below, sharing your perspectives of the subject matter as well as the workshop.

Let me also take this opportunity to thank all the folks who brought delicious brownies, cookies and other yummy stuff to eat during the break.  Your generosity was reflected in how much food there still was left over at the end of the workshop.

Site news:

I amazed myself, getting through this four hour presentation plus questioning period that went quite a bit longer.  As someone pointed out, I looked a bit like Dr. House M.D, limping with a cane and all (including a Vicodin pill before I got started!)

My knee joint is shot, consequence of playing basketball while dressed in a saree and flip-flops back when I was in college four decades ago.  Most likely, it is now time for surgery. I have a consultation coming up to tell me exactly how extensive the repair work has to be.  I may be out of pocket for couple of months as I recover from surgery.  But I doubt I will be able to stay away from emails, so keep writing to me if you wish.  It may take a little bit longer for me to get back to you.