Friday, September 26, 2008


Earlier this year new guidelines on CLL were published by the IWCLL. I have to admit that despite being consulted about the paper before publication a change has slipped through that I did not notice – and it is a very controversial change. Previously the threshold for diagnosis was a lymphocyte count of 5000 per cu mm. This has been changed to a B lymphocyte count of 5000. The proportion of lymphocytes that are B cells is extremely variable, so in order to reach a B cell count of 5000 a person might need to have an absolute lymphocyte count of greater than 10,000.

This needs to be seen in the context of the diagnosis of monoclonal B lymphocytosis (MBL) in which the individual has circulating lymphocytes exactly like CLL cells, but the absolute lymphocyte count is less than 5000. Under the new definition what would previously have been called CLL would now be called MBL unless that total B-lymphocyte count is greater than 5000. A lot of patients who have been told that they have been told that they have CLL would suddenly have their diagnosis corrected to MBL. It has been estimated that 40% of patients with stage 0 CLL in fact have MBL.

There are real problems with this. First, it means that flow cytometry becomes essential for diagnosis and also for follow up. This is much more expensive than a simple cbc. Second, patients will fluctuate between MBL and CLL on successive visits to their doctor. Third, MBL turns into CLL at the rate of1% per year, so it does not mean that follow-up can be omitted. Fourth, a paper from Andy Rawstron in the NEJM earlier this year suggested that a threshold of 2000 B cells was necessary for MBL to progress – patients with lower levels were very unlikely to do so.

To some extent this new definition satisfies the problem that Victor Hoffbrand and I raised earlier this year, namely that patients were being told that they had leukemia, yet they would never need treatment for it, though even with the new definition that will still be the case for some patients (though for fewer than before).

I guess the major problem that I have with this change is that it has been made without the benefit of evidence to guide it, merely on the gut-instinct of the authors.


Vance said...


In cases where there is a mild lymphocytosis, I typically order flow cytometry to make a more precise diagnosis. I don't always personally feel this is necessary, but the patients and referring physicians want the information.

Anyway, I shudder to think about the idea of ordering the test each time I see the patient. How expensive!

On the other hand, does it really matter whether a person has very early stage CLL or MBL? The approach is still the same, isn't it? Namely, watch and wait?

Anonymous said...

It might matter to the patient. In the U.S. having been a dx of CLL will effect their ability to get life insurance and health insurance. Some other patients want the CLL tag because it will qualify them for disability benefits

john liston

Anonymous said...

Can absolute B-lymphocyte level be driven up by an active virus infection.. and can it get back yo normal when the infection calms down or treated by antiviral drugs? I understand that some viruses invade B cells.. if they invade B cells already corrupted by CLL, can they replicate CLL cells and thus bring the "safe" level of absolute B-lymphocyte count of 5,000 much higher??

Terry Hamblin said...

Viruses do not infect CLL cells, but EBV infects normal B cells. It is possible that this population might expand, but the more usual effect would be for the reactive T cells o increase. It is because the number of T cells is very variable that the new definitiojn is suggested.

Anonymous said...

Thank you! I guess I read this
and assumed that it could be true. Thank you for clearing this for me. It is the reactive T-lymphs that can bring up the level of ALC..

Terry Hamblin said...

Yes, a B-cell lymphoproliferative syndrome can be seen in CLL. It usually takes the form of Richter's syndrome. It is caused by immunodeficiency. When the T cells fail to control the EBV infected normal B cells, they are able to proliferate and can become cancerous.