Oy VeyWe all use benchmarks in our everyday life, to make decisions without having to spend too much time thinking about things. Should you replace the tires on your car? Is it time to change the oil? There are reliable benchmarks for those decisions, making life easy for those of us who do not spend a lot of time thinking about our cars.

How about when to let your kids start driving? Now, that is a very much more nuanced decision and few good parents will rely solely on slam-dunk benchmarks. Age is one of the points that influence the decision, but most likely you will also consider whether the kid has sufficient maturity, whether you just found a stash of drugs in his bedroom, whether he/she is keeping up his grades in school etc. When to start CLL treatment falls into the second category, a little more important and complicated than when to change the oil in your car.

When is it time to start treatment?

Let us face it: local oncologists are very busy people. Majority of them treat a huge variety of cancers, including “solid” cancers like breast cancer, prostate cancer, lung cancer etc. With any luck your local guy sees a small number of blood cancers in his practice. Of these again many would be non-Hodgkin’s lymphoma, multiple myeloma etc. I doubt the average local oncology practice sees more than a couple of CLL patients on a regular basis.

What are the chances your local guy is going to use tried-and-true benchmarks to make therapy decisions quickly, rather than spend a lot of time worrying about subtle nuances that may be valid in your case? I think you get my drift, it is important that we understand the benchmarks a little better, dig down and get into the details so that we can make better choices when it comes to therapy time. Even if your local oncologist did not initially focus on the pesky details, perhaps you can get him interested if you ask the right questions, make therapy decisions that are a bit more tailored for your specific situation. Remember, in life and in CLL, the quality of care you get often depends on what you can knowledgably negotiate.

Rai and Binet Staging

No benchmark has more importance than staging, when it comes to CLL therapy decisions. Rai staging is used in the USA while Binet staging is used more often in Europe. Both are quite similar in the kind of things they focus on. Please refer to our earlier and detailed articles on the subject to get the exact features that go into defining the various stages in Rai and Binet systems. I strongly advise you to do so, since in this article I will focus entirely on late stage CLL.  For your convenience the links to earlier articles are given at the end of this review.

Stage 4 (Rai) or Stage C (Binet) CLL

Whether you are using Rai or Binet staging, it goes without saying that late stage patients have multiple swollen lymph nodes and elevated white blood counts; perhaps they also have swollen spleens and livers. All of that is baked in the cake for late stage (Rai Stage 4 or Binet Stage C) patients. The big deal about late stage CLL are reduced platelets and red blood cell counts. Late stage CLL, the kind that gets your oncologist talking about time to start therapy, focuses on health of your platelet counts and your red blood cell parameters.

New platelets and red blood cells are made by blood stem cells in your bone marrow and no place else. As CLL progresses, the bone marrow is gradually infiltrated by CLL cells. In late stage CLL, the bone marrow might get so clogged with the useless CLL cells that there is no place left for proper function of the stem cells residing in the bone marrow. The result is that the marrow begins to experience increasing difficulty in manufacturing platelets and red blood cells. Think of these cell lines as the canaries in the coal mine. When the canaries begin to drop dead, an indication or too many toxins in the air, it is time for the miners to get out.

Same logic goes for using platelet counts and red blood cell counts as the trigger point for defining late stage CLL, end of “Watch & Wait” and start of therapy to roll back the CLL. Low platelet counts means clogged marrow unable to function, which in turn means you are Rai Stage 4 (Stage C Binet) and you had better get moving with therapy soon. Makes sense, right?

Not always. What if the low platelets and red blood cell counts are not due to a bone marrow clogged by CLL cells, but some other reason? This is where it gets interesting, where the tried-and-true benchmarks of Rai and Binet fail. Unless your local oncologist is paying attention and looking beyond slam-dunk benchmarks and looking for the reason why your platelet counts are low, you may be initiating the wrong therapy, for the wrong reasons.

Devil is in the Details

Let us get rid of some of the trivial reasons for low platelet counts right up front.  Platelet counts are notoriously prone to measurement errors. Platelets tend to form clumps. That is their whole purpose in life, form clumps and clots, gradually slow down blood flow and prevent too much blood loss when you cut yourself shaving. That tendency to clump together makes it difficult for automated machines to count platelets accurately. A clump of platelets in the field of vision could be a single platelet, or it could be three or four platelets getting together and singing Kumbaya. How is a poor automated CBC machine to know the difference? Many labs follow up on an abnormal platelet count reported by automated machine with a manual check where a real live human being looks at the slide and counts the little suckers. As you can imagine, it is not all that hard for a trained tech to spot the clumps and make the proper adjustment to the counts reported.

We discuss this and many other trivial and not so trivial reasons why platelet counts may dip below the usual 100K specified for normal healthy range in our earlier articles.  Heaven protect us from thoughtless / lazy oncologists who believes in therapy by numbers, using benchmarks without putting brain in gear first. I just heard from one patient whose doctor said he would start therapy the first time he sees platelets in the 100-125K range.  How many ways is that plain stupid?

Excuse me Dr. Oncologist, but patients from some ethnicities have chronically low platelet counts. My husband was one such. Even prior to CLL diagnosis his platelet count was never much higher than 150K. The smart hematologist would pay attention to factors like that, look for robust and clear downward trend lines in platelet counts before making therapy decisions. If a patient started with healthy platelet counts and over a period of several months there was a clear and unmistakable trend downwards below healthy norms, then it is time to get excited. Please know that there is no immediate danger in low platelet counts. Chances are not high that you would immediately bleed to death if you get a small nick while shaving. No responsible doctor would initiate platelet transfusion unless the count goes below 25K or so, most often not until it gets into the teens. No experienced CLL expert would initiate therapy based solely on a single platelet count of between 100-125K, no other questions asked.

Autoimmune disease and CLL

Most of you know by now that there are two particular autoimmune diseases that happen frequently in CLL. The first and more common one is AIHA (autoimmune hemolytic anemia) – where perfectly good red blood cells are destroyed by your own immune system gone a little crazy and no longer able to tell the difference between friend and foe. The second is ITP (immune thrombocytopenic purpura) – where the immune system attacks and destroys good platelets before their time. Both of these autoimmune diseases are well documented in CLL and we have discussed them in earlier articles.

AIHA and ITP can cause devastatingly huge drops in red blood cell counts and platelet counts in a matter of days. AIHA is especially hard to miss. The sudden killing of all those red blood cells means an immediate onset of potentially deep anemia. You will no doubt experience some of the symptoms of your body struggling to get enough oxygen to the tissues without enough red blood cells to do the job properly: weakness, dizziness, difficulty going up the stairs, pounding of your heart and a startling deep reddish brown urine in the toilet bowl – colored by fragments of zillions of red blood cells killed – these are just some of the symptoms of sudden onset AIHA.

Both AIHA and ITP are serious issues that require careful intervention. No question about that. But here is the million dollar question: Do low platelet counts and/or red blood cell counts due to autoimmune disease have the same impact on CLL staging, compared to a clogged bone marrow unable to produce the platelets and red blood cells in the first place? Which is truly late stage CLL that generally requires initiation of therapy to control the CLL?

“Stage C or not Stage C”

That is the pithy title of the editorial in the recent issue of “Blood” journal, discussing the full length article on the same subject published in the same issue of the journal. You can read the editorial for free by clicking on the link. The abstract of the article it refers to is given below. Write to me if you wish to read it in full and I will show you how to get hold of it.

The authors had three major goals of this study: first, to get a handle on the prevalence of autoimmune disease (AIHA and ITP) in general CLL population; second, understand if patients with bad prognostic indicators are more likely to have autoimmune disease as well; last but not least, understand how cytopenias (low red blood cells and / or platelets) due to autoimmune disease compare with similarly low counts due to heavy infiltration of the bone marrow.

Blood. 2010 Aug 24. [Epub ahead of print]

Autoimmune cytopenias in chronic lymphocytic leukemia: prevalence, clinical associations, and prognostic significance.

Institute of Hematology and Oncology, Hematology Department, Hospital Clinic University of Barcelona, IDIBAPS, Barcelona, Spain;

We analyzed the prevalence, characteristics, clinical correlates, and prognostic significance of autoimmune cytopenia in patients with CLL. Seventy of 960 (7 %) unselected patients had autoimmune cytopenia, of whom nineteen were detected at diagnosis, three prior to diagnosis and 48 during the course of the disease. Forty-nine patients had autoimmune hemolytic anemia (AIHA), 20 immune thrombocytopenic purpura (ITP) and one both AIHA and ITP. A clear association was observed between autoimmune cytopenia and poor prognostic variables (i.e. high blood lymphocyte count, rapid blood lymphocyte doubling time, increased serum beta-2 microglobulin level, and high expression of ZAP-70 and CD38). Nevertheless, the outcome of patients with autoimmune cytopenia as a whole was not significantly different from that of patients without this complication. Furthermore, no differences were observed according to the time at which cytopenia was detected (i.e. at diagnosis, during the course of the disease). Importantly, patients with advanced (Binet C stage) disease due to an autoimmune mechanism had a significantly better survival than those in advanced stage related to a massive bone marrow infiltration (median survivals: 7.4 years vs. 3.7 years; p=0.02). These results emphasize the importance of determining the origin of cytopenia in patients with CLL for both treatment and prognostic purposes.

PMID: 20736453

For a change, this abstract is relatively easy to read and understand. That last couple of sentences in the abstract say it all.  Here is the annotated version, to make sure you get the important points.

  • Roughly 7% of CLL patients have to deal with autoimmune AIHA or ITP.  A very small percentage have both!
  • Patients with poor prognostic indicators (positive CD38, ZAP70; high B2M) are also more likely to have autoimmune disease during the course of their CLL career.
  • In general, autoimmune disease did not decrease overall survival statistics much. Median overall survival for Stage A patients who went on to develop autoimmune disease was 9-10 years, same as for patients who did not develop this complication. You guys out there with AIHA or ITP, breathe easy.  No extra penalty points for your autoimmune disease, according to these researchers.
  • The “why” of low platelet or red blood cell counts (“cytopenias”) is important in properly staging CLL. Low counts due to autoimmune disease is not the same thing as low counts due to significantly infiltrated marrow.
  • Patients who are “Stage C – autoimmune” are likely to live quite a bit longer than those with “Stage C – infiltrative”.
  • As the graph below points out, the median survival of “Stage C – autoimmune” is more than 7 years. For “Stage C – infiltrative”, median survival is less than 4 years. Of course, these are statistics based on this large cohort study. Your own mileage may vary, depending on your own specific situation.
  • In fact, a patient “Stage C – autoimmune” can be treated for that (with steroids such as prednisone, IVIG, Rituxan etc) and once the autoimmune disease is under control, the patient is often no longer in Stage C, may be kicked downstairs back to a more reassuring Stage B or even Stage A.

The graph below shows the survival probability of patients over time, depending on their staging.  For your convenience, they have drawn a horizontal line across at the 50% level.  Where it cuts the different curves gives the median survival (Median survival means 50% of the patients are alive at that point, 50% are dead).  As you can see, the blue line representing early Stage A patients cuts the median line at about 10 years.  Next in line are the Stage B folks, red curve in the graph below.

The shortest time (roughly 4 years) is for “Stage C – infiltrative group”, the full black curve right at the bottom.  This group is the truly late stage CLL folks.  Above that is the broken black curve, for “Stage C – autoimmune” folks.  They have below normal platelets or red blood cells due to autoimmune disease, not because they have infiltrated bone marrow.  These guys fare a lot better than the “Stage C – infiltrative” folks, with a median survival of more than 7 years.

Late Stage CLL

Treating autoimmune disease versus CLL control

Game plans for controlling autoimmune disease are very different than those for cleaning out a heavily infiltrated bone marrow.   Autoimmune disease is usually handled by daily doses of steroids such as prednisone.  Splenectomy (surgical removal of the spleen) is often surprisingly effective in reversing the ravages of autoimmune disease.  When (if) the patient develops resistance to prednisone therapy, it is usual to initiate Rituxan therapy as a single agent or in combination with dexamethasone (another steroid like prednisone) and / or cyclophosphamide, vincristine etc. Sometimes intravenous immunoglobulin infusions (IVIG) help.

While the onset of AIHA or ITP can be very sudden and the symptoms scary as all heck, we do have methods of handling them and their onset does not significantly influence overall survival odds. On the other hand,  low platelet counts and low red blood cell counts because the bone marrow is heavily infiltrated and the blood stem cells can no longer produce these cell lines – that is indeed the definition of late stage CLL requiring end of W&W and start of therapy.

For example, when the bone marrow is no longer working, there are only two ways of having enough red blood cells for your body to keep breathing.   A quick but very short term way of getting around the problem is a red blood cell transfusion, getting red blood cells from blood donors to do the job for you. Transfusions are not a long term solution. In a matter of days patients will need another transfusion because the previously infused cells have died on the job.  Patients who are transfusion dependent face huge difficulties of many sorts – trust me, you don’t want to walk in their shoes if you can possibly help it.

The second option is to clear out the bone marrow, kill most of the CLL cells messing it up, so that the marrow can get back to work. Since no one wants to become transfusion dependent, the real option for late stage CLL is just that: start therapy to get rid of the CLL cells in the bone marrow, so it can get back to work.

Getting the bone marrow up and working  is the major reason for start of therapy. The white blood counts in the CBC reports that patients get fixated on are not really all that important and even the ugly swollen lymph nodes can be ignored for a while. The bone marrow and the precious blood stem cells living there – these are the truly unique resource of your body and no one can live long without reasonably good functioning of the bone marrow.

Someone is bound to ask me the question, so I will address it right away.  How about when therapy fails and the bone marrow gets re-infiltrated? Does this not make therapy as an option of clearing the bone marrow just as temporary?  You bet.  Everything in life is temporary, my friends.  In the end, all of us die. That is the only real guarantee in life.  The real question is not whether it is temporary, the real question is how temporary. Running in front of a speeding truck is extremely temporary. Transfusion dependence is very temporary. Chemotherapy that gives you a deep and long remission is a whole lot less temporary.  Not doing anything when you are in late stage CLL, whether it be due to autoimmune disease or infiltrated bone marrow?  Now that falls into the category of very temporary indeed.  Not quite as quick as running in front of the truck, but a close second.

One approach does not fit all late stage CLL

I hope I have convinced you why proper staging of late stage CLL is important.  We have now learned there are two distinctly different versions of late stage (Rai Stage 4 or Binet Stage C) disease. Treating “Stage C – infiltrative” with daily doses of prednisone is hardly the right thing to do. It will not do much to relieve the over-crowding in the bone marrow and get it working properly again. Single agent Rituxan does not do a whole lot either for getting good marrow clearance. What will get the marrow clear is more heavy duty options such as chemoimmunotherapy combinations (FCR, FR, PCR etc) or newer therapy options such as Revlimid, CAL-101 etc.

On the other hand, autoimmune disease (AIHA, ITP) are  reasonably controlled in most patients with nothing more than prednisone or single agent Rituxan. Relapsed autoimmune disease that has become resistant to these two frontlines may need couple more things thrown at it.  But I hope you agree it is not reasonable to initiate full blown FCR therapy as primary control for taking care of “Stage C – autoimmune” disease. There is no doubt that autoimmune disease is scary and its long term control is complicated. But it is important that we do not confuse the low counts resulting from autoimmune disease with low counts due to heavily infiltrated marrow. Different reasons, different causes, different prognoses and different methods of best treating them. They why is important because it gives us a better handle on how to treat it, and with what.

Below are some links to previous articles on this subject that you may find interesting. I have given the dates of publication in parenthesis.  Oy vey! I have been writing this stuff for too many years! This lot should be enough to keep you busy reading for a while.

Staging Does Not Predict Survival (2003)

CLL Staging: Dawn of a New Era (2005)

CLL Staging: Devil is in the Details (2010)

When Platelet Counts Start Dropping (2009)

To Wait or Not to Wait (2009)

AIHA (2004)

ITP (2007)

Splenectomy to Control Autoimmune Disease (2009)