Tuesday, December 27, 2005

Other prognostic factors - doubling time

Doubling time.

This is a simple measurement of how rapidly the CLL is growing. A lymphocyte count doubling every six months is an indication for treatment according to the NCI, though some trials have adopted a less stringent criterion - doubling every 12 months - as an indication for treatment (for example the British CLL4 trial).

How accurately does the doubling time reflect the true growth in the size of the leukemic clone? While the count is very low it does not really do so at all. Most of the growth takes place within the bone marrow, and the spillover element in the blood is variable. As the count increases it is more accurate, but it has to be remembered that within the lymphocyte count there is a variable number of T cells and NK cells. Only when the count is fairly high, say over 30k is it safe to neglect this.

It is important to exclude the other variables. Strange to say it should not be assumed that different laboratories will give the same answer. Even very famous epartment can get things wrong. The truth is that the famous head of department is usually traveling from meeting to meeting giving presentations or sitting on committees deciding on grants. You can certainly rely on his research laboratory, because the very best people will be competing to work for him (or her), but the routine laboratory in his hospital is unlikely to be under his day to day control. If the laboratory is in a large city, it may be difficult to find laboratory technicians to run the machines - it is not a well paid job, and there are plenty of jobs in the city that are well paid.

In one of the tasks I undertook when I was employed by the National Health Service I had to go around inspecting other people's laboratories. I usually got landed with the London Teaching Hospitals. Surprisingly, they were often worse than ordinary laboratories at ordinary hospitals. In one blood transfusion laboratory where the person who had written a well known text book worked, entirely the wrong concentration of suspended red cells was being used. In another, where a well known expert in laborartory technology was in charge, the condensors on the laboratory microscopes couldn't be adjusted because of all the crud on them. So it was no surprise to me when I was sent a sequence of lymphocyte counts which showed an apparent doubling thast was entirely due to a rogue result from a famous laboratory.

One technical problem is that the machines are callibrated to give an accurate count in the normal - high range , but when the count is very high it becomes progressively inaccurate. The sample then has to be diluted to get the count back into the accurate range. This dilution introduces a potential source of error.

It also has to be remembered that the lymphocyte count goes up an down according to other things than progression of the CLL. Following an infection the lymphocyte count rises as the immune response kicks in. this effect is emphasized by the crowding out of normal lymphocytes from the lymph nodes by the infiltrating CLL cells. Vaccination also induces an immune response, so it can also raise the lymphocyte count transiently.

For all these reasons it is important not to accept a single observation as evidence of progression. Unless the count is rising rapidly, I would expect to follow a patients for 3-6 months with several blood tests before being convinced of a rapid lymphocyte doubling time.


22years cll said...

I believe that the majority of cll patients incorrectly use their gross cbc values to calculate the doubling time which of course is incorrect when cbc values are below 25.

The other error made is to use %neutrophiles ;when low is not indicative of the absolute neutrophile count

Michele said...

I personally found this very interesting since I have been treated twice (2003 and 2005) for rapid doubling times. My question always has been about the significance of rapid doubling as opposed to # of lymphocytes. Why is it OK to have very high numbers of lymphocytes as long as they are increasing slowly whereas treatment starts at lower numbers if the doubling time is rapid.

Terry Hamblin said...


What is important is the pace of progression of the disease. The doubling time is another prognostic marker. A high white count may simply mean that the disease has been there a long time.