Grounds for re-staging to Rai Stage - IV?

The other day I heard from a good friend whose local oncologist had just changed his Rai Stage from a reassuring Stage - I to a scary Stage - IV.  The reason for the change? His latest CBC (complete blood test) done a couple of days earlier showed his platelet count was 96K. This is just shy of the 100K lower limit many labs use for healthy platelet counts.  All other counts were doing fine and there were no other symptoms - unless you count being a tad tired after putting in long hours planting trees.

True, definition for Rai Stage - IV is based on thrombocytopenia (reduced platelets). Going by the book (and brain not engaged!) the doctor promptly declared my friend had now graduated to Stage - IV and should start treatment (FCR) right away.  Which brings us to the important question:  are there other reasons besides late stage CLL that can cause platelet counts to drop?  Are some possible reasons for dropping platelet counts more serious than others?

Let me count the ways ..

There are many different reasons why my friend’s platelet counts came in below the “magic” threshold of 100K.  Some are trivial, some need attention, some can be downright alarming.  It is foolish to put all these causes in the same basket!  Call me picky, but I have serious problems with this shoot first and ask questions later approach to medicine.

Reliability of blood tests

Let’s get started with some of the more trivial reasons.  How accurate do you think the platelet count number is on your latest CBC?  What if it was 115K last month and this month it is “only” 96K? Should you get ready to write out your last will and testament because you are now at Rai Stage-4?

Not on your life, not without a bit more digging to understand the result.  For starters, platelet count measurements are notoriously poor at accuracy and reproducibility. If you gave two samples of blood on the same day and CBC was run twice on the two samples, same lab tech, same machine, same phase of the moon or whatever, the two platelet count results can still differ by as much as +/- 10 or more.  You see, platelets have a tendency to clump (which is why they are so important in proper clotting of blood).  They may clump a tad more in one sample and less in the other. The machine counts a clump of, say, 4 platelets as 1. You can see how that can be a problem right there.

How about tests done in two different labs, using different machines? The variation can be even more pronounced, depending on how well the machine is maintained and calibrated.  That is why we encourage our members to try and get their blood work done by the same lab each time, as far as possible. For women who are still menstruating, it is also important to get the test done during the same part of the cycle each month, in order not to bias red blood cell counts.

Now for a really trivial reason why platelet (and other cell) counts may drop in a given test:  try drinking a couple of glasses of water just before you drive over to the lab for your blood test. Your blood is “diluted” pretty much as you would expect with all that water sloshing inside of you, and all your counts would be lower!

How then do we make sense of CBC reports?

For starters, do not get fixated on any single number in one lab report.  That is why we encourage our members to plot their lab data on a graph and look for overall trends.  You can download a nifty spreadsheet template that you might find useful in monitoring your charts from our flagship website

The platelet counts for the past year are plotted below for a generic patinet, with a computer generated best-fit straight line (blue) through all the data points. Looking at the blue trend line it is clear there is a slow decline in the platelet counts, not unexpected in a patient with CLL.










While it is true that the latest point in February fell just a tad below 100K, looking at the scatter of the data points from the blue line, it might as well have been 110 and not 96.  The scatter of the points represents the errors inherent in the lab equipment and other such stuff we discussed above. A reasonable assessment of this data is that there is a gradual decline in platelet counts and it would be a good idea to keep an eye on it and not let it get a whole lot lower before considering therapy.

But tell me, do you still think the last platelet count number in February is a big red flag needing urgent action with the biggest gun available to you, no questions asked? You will be happy to know in my friend’s case, a second blood test done a couple of weeks later put his platelet count back where it normally is, in the low hundreds. No drama here, nothing to see, move on folks.

There are also some non-trivial reasons for drop in platelet counts that may still have nothing to do with CLL.  Certain medications can confuse the immune system and cause platelet destruction. Examples include heparin, quinidine, quinine, sulfa-containing antibiotics, as well as some oral diabetes drugs

CLL related causes for low platelet counts

The definition of the high risk group in both the Binet and the Rai systems of staging depend upon anemia and thrombocytopenia. But most experts now agree, it is important to consider the why of low red blood cells and platelets, not just the how low.

Bone marrow packed to the hilt with CLL cells

As your CLL progresses, there is a gradual accumulation of CLL cells in your body.  These useless cancer cells accumulate in your blood (you will see it as an increase in WBC and ALC), but many more will accumulate in swollen lymph nodes, spleen, liver and most importantly - your bone marrow.  Over time it is possible for the bone marrow to get infiltrated by so many CLL cells that there is little room left. A bone marrow biopsy can reveal the exact status.  I have seen bone marrow biopsy results showing as much as 90-95% infiltration of the bone marrow.

Why is this important?  Well, your bone marrow provides a very unique function.  It is the only place in your body where new blood cells (red blood cells and platelets, for example) can be created.  Millions upon millions of these cells die each and every day due to normal wear and tear and a healthy bone marrow replaces these lost troops with fresh new cells.  But if the bone marrow is thoroughly infiltrated with CLL cells it cannot perform its proper function and make new cells.  The result is a gradual dropping off of red blood cell and platelet counts (the drop off can be precipitously steep as the level of infiltration gets higher and higher).  Think of it as a factory with perfectly good machinery, but one that is packed to the rafters with garbage.  Until the garbage is cleaned out there is no way for production to start up again.  In CLL terms, this means start of appropriate therapy to clean out the bone marrow, kill as many of the CLL cells festering there and free up some space so that normal cell production can begin again.

Dead or dying bone marrow with damaged hematopoietic stem cells

A more dangerous reason for low counts across the board could be that the bone marrow is completely shot, either because of the cancer itself and/or the effect of prior harsh chemotherapy treatments. For these or other reasons, the stem cells have given up. No more production; crucial machinery is busted beyond repair and the factory is burned to the ground. A bone marrow biopsy would reveal a graveyard type of scenario, no new baby cells being produced, nothing happening. No new red blood cells or platelets or neutrophils being made.

There is no way to fix dead stem cells, except to replace them with healthy new stem cells from some one else, new stem cells to take over the job of producing all the vital cell lines. We are talking mini-allo stem cell transplant from a willing and healthy donor who matches the patient.  Bone marrow aplasia - when the bone marrow is no longer able to produce necessary cell lines - is serious business.  Without a stem cell transplant the patient would become dependent on frequent transfusions for all the necessary cell lines - just to stay alive.  This is not a good place to be, long term.

Role of the spleen

The other reason for low red blood cells and low platelets could be that although they are being produced normally back at the “factory”, (bone marrow), they are not being allowed to do their job properly and in fact they are getting destroyed before their time.

The destruction could be due to improper functioning of the spleen, for example. Your spleen acts as a filter of sorts.  If it is clogged (enlarged) with lots of CLL cells, it does what any clogged filter would do, it does not let stuff get through that is supposed to get through. People with large swollen spleens due to CLL infiltration could have good, perfectly normal platelets sequestered and destroyed by their spleens. In such cases, splenectomy (surgical removal of the spleen) is often recommended.

While this is major surgery, and no one wants to leave behind a piece of their original equipment in the operating room, splenectomy has surprisingly excellent results and few complications if done early enough. Surgeons have perfected laparoscopic methods where only tiny incisions are made and this speeds up the healing process. Many patients live just fine without a spleen; but be aware that patients without a spleen have to be a lot more careful about infections. You are advised to go the nearest emergency room at the first sign of a fever.

Autoimmune disease

Another reason for low platelets (or red blood cells) could be autoimmune disease. Even though CLL is a B-cell cancer, when your system is choke full of these malignant cells, they manage to corrupt a lot of other parts of the immune system as well. Under normal circumstances, the body depends on antibodies and killer cells such as T-cells and macrophages to protect itself from foreign invaders. When things go wrong, as in advanced stages of CLL, everything gets subverted to some degree.

Autoimmune disease is one face of this subtle corruption from within. Antibodies may be produced that attack red blood cells and platelets, tagging them unfairly as “foreign and dangerous”.  Killer cells then home-in on these unfortunate cells and kill them. In autoimmune disease the careful distinction between “self” and “non-self” breaks down, and the very defenses that should keep us safe start attacking various parts of the body. When platelets are the hapless targets, it is called ITP (idiopathic thrombocytopenic purpura).  When red blood cells are the targets, it is called AIHA (autoimmune hemolytic anemia). Patients with either ITP or AIHA can see sudden and frighteningly steep drop in platelet counts and red blood cells respectively.  Diagnosis of autoimmune disease as the root of the problem is confirmed by identifying the antibodies that are tagging the poor innocent cells and getting them killed. Autoimmune diseases is often treated with steroids (prednisone) with or without Rituxan. When steroids are no longer enough to control autoimmune disease, it may be necessary to treat the underlying CLL as the root cause of the problem.

Refractory AIHA and ITP can be very dangerous and not something to be taken lightly.

Putting it all together

Once we have eliminated the trivial reasons (such as variability in the lab test results) it becomes important to rule out the most dangerous reason for dropping counts - a dead or dying bone marrow. If this is the reason for dropping counts (red blood cells or platelets), that is bad news indeed.

If platelet counts are dropping due to untimely destruction of platelets in a clogged spleen, even though they are being produced OK in the bone marrow, this can be corrected by splenectomy, or CLL therapy to clean out the spleen. Similarly, bone marrow infiltration can be decreased by suitable therapay. Growth factors such as Procrit (which give the bone marrow marching orders to make more red blood cells) are often used to correct anemia in cancer patients.  Use of growth factors to correct low platelets is not quite as common.  At a pinch, patients can be stabilized by means of transfusions of red blood cells or packed platelets.  Be aware most hospitals do not transfuse unless the patient has hemoglobin less than 10, and platelets are rarely transfused until the patient’s counts drop below 10-20K!

If the problem lies in autoimmune destruction of platelets (or red blood cells), the usual approach is to use steroidal drugs such as prednisone or dexamethasone to calm down the immune system and tamp down the berserk killer cells. It is a very effective approach.  The downside is that long term use of steroids is very immune suppressive and can leave the patient more vulnerable to infections and the like.  Also, most patients become resistant to steroid therapy sooner or later.  Rituxan is often used in combination with steroids and this seems to give better results.  AIHA and ITP are complex beasts.  Please refer to our flagship website for full length articles on both of these conditions - we go into a lot more detail there.

Getting back to the Rai staging issue

Below are the criteria used in staging patients into the various Rai stages.  The Binet system of staging used in Europe and else where is not all that different.

Rai Staging System

Stage 0: Your CBC shows absolute lymphocyte count is too high, more than 5.0 K. You probably have no other symptoms, and the CLL was most likely diagnosed as a result of a routine blood test. Patients in Stage - 0 do not have swollen lymph nodes, spleen or liver. And you have hemoglobin, red blood cells and platelet numbers that are all in the normal ranges. Neutrophils are also “in the pink”, and you have not noticed any higher frequency in getting infections. 

Stage I: By this stage, some of your lymph nodes are swollen (lymphadenopathy), but that is the only thing that has changed from Stage - 0. Everything else is still within the normal limits, and the spleen and liver are doing fine too. 

Stage II: Besides the swollen lymph nodes of Stage - 1, you have now graduated to where either your liver is swollen (hepatomegaly) or the spleen is swollen (splenomegaly). The CLL has now started impacting other organs of the body, in addition to the peripheral blood, lymph nodes and most likely the bone marrow as well. 

Stage III: The pivotal indication of Stage - 3 in the Rai classification system is anemia, there are too few red blood cells and too little hemoglobin. Since red blood cells are the only carriers of oxygen, not having enough red blood cells is pretty hard to miss. You will start to feel out of breath, tired after exertion, and generally not up to your old feisty self. This is considered such an important criteria that a patient is defined as Stage - 3 if he/she has significant anemia, even if the lymph nodes are hardly swollen, and the liver and spleen are doing OK too. 

Stage IV: Like Stage - 3 discussed above, the crucial criteria for putting patients in Stage - 4 is not having enough platelets (thrombocytopenia). The lymph nodes, liver, or spleen may be swollen, and there may be too few red blood cells (anemia). Typically, patients in Stage - 4 have all the bells and whistles, swollen lymph nodes, high WBC, swollen spleen and liver, anemia and thrombocytopenia. 

Details missed by the Rai staging

As you can see from the definitions of the Stages III and IV above, the pivotal issues are anemia and thrombocytopenia.  Rai staging does not ask why red blood cells or platelets are low in order to make the call.  It is sufficient if the counts are below established norms.  But as we have discussed above, the why of the matter is very important indeed!

The abstract below reports on 132 patients with CLL/SLL. Careful analysis showed that if the anemia and thrombocytopenia were due to autoimmune disease, as in AIHA (autoimmune hemolytic anemia) and ITP (immune thrombocytopenia), there was no significant penalty in terms of overall survival. If these patients had been put in the high risk category based strictly on anemia and thrombocytopenia as per the Rai and Binet staging systems, they would have been miscast in the role. On the other hand, if the anemia and thrombocytopenia were due to bone marrow failure, then the risk of death was significantly higher and the “high risk” classification is justified. 

Am J Hematol. 2003 Sep;74(1):1-8. 

Autoimmune cytopenia does not predict poor prognosis in chronic lymphocytic leukemia/small lymphocytic lymphoma 

Kyasa MJ, Parrish RS, Schichman SA, Zent CS. 

Division of Hematology/Oncology, Department of Medicine, Central Arkansas Veterans Healthcare System (CAVHS) and University of Arkansas for Medical Sciences (UAMS), Little Rock, AR

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is characterized by an acquired immune defect that can cause autoimmune complications, including anemia and thrombocytopenia. We conducted an observational study of the epidemiology, clinical presentation and significance of autoimmune complications of CLL/SLL in 132 patients from a large population (>45,000 veterans), in which at least 90% of patients with CLL/SLL have been previously identified. Over a period of 12.5 years, 12 patients (9.1%) had autoimmune complications; of these, 6 (4.5%) had autoimmune hemolytic anemia (AIHA), 5 (3.8%) had immune thrombocytopenia (ITP), and 1 (0.8%) had pure red blood cell aplasia (PRBA). All 6 cases of AIHA had a positive direct immunoglobulin test for IgG and C3d. In 6 patients, CLL/SLL was an incidental finding at the time of presentation with autoimmune cytopenia. Nine out of 10 patients responded to immunosuppressive therapy, which was complicated by serious infection in 7 cases, one of which was fatal. The major cause of mortality in patients with autoimmune complications of CLL/SLL was secondary malignancy. Survival of patients with immune cytopenia was not significantly different from CLL/SLL patients without immune cytopenia. Among patients with anemia or thrombocytopenia, mortality was significantly higher in those with bone marrow failure compared to an autoimmune etiology. We show that in a non-referred population with a high incidence of CLL/SLL, autoimmune cytopenia can occur early in the natural history of the disease. These data suggest that the Rai and Binet classifications for CLL need to be modified for patients with autoimmune cytopenia.

PMID: 12949883