I am beginning to have a different view of beta-2 microglobulin as a prognostic factor in CLL. Hitherto, I have been suspicious of its value. It has been championed by the people at MD Anderson Cancer Center and it is practically the only factor they use. I have always contended that it is not so much a prognostic factor as a declaration of how much disease the patient has. I spoke to John Gribben yesterday and he agreed with me.
However, I saw some new data yesterday from the CLL4 trial. They have just done an analysis of the prognostic factors in that trial and for the first time included beta-2M. Sure enough in a multivariate analysis is does help to separate good risk from intermediate risk patients. However, it is interesting to note that when beta-2M is included the prognostic value of stage is eliminated.
Here's what I think is happening. Beta-2M is a measurement of disease bulk. It refines clinical staging. Earlier this year the German group demonstrated that stage A patients included patients with enlarged nodes in their abdomens that were not picked up by routine clinical examination. If these were moved into stage B, then the remaining stage A patients had a better prognosis. We have also known for some time that bone marrow biopsy histology is an important prognostic factor - a diffuse pattern of histology has a worse prognosis than any other. Rai or Binet stages do not show this. To reach stage C or stage III or IV requires a high degree of marrow infiltration. However, as CLL4 demonstrates, patients with 'progressive stage A' have the same prognosis as those with stage B. Progressive stage A comprised patients with s degree of anemia or thrombocytopenia that was insufficient to make them stage C, but was evidence that the marrow was filling up with CLL. If you have more disease you are further along the natural history of the disease.
Look at it this way: Supposing you are stage A (or Rai stage 0,I or II) but your beta-2M is 4.5 then you have either some hidden nodes or relatively large amounts of bone marrow disease. This means that you have had the disease longer than other stage A patients. Supposing the average survival of stage A patients is 12 years, you may well have had the disease for 4 or 5 years already rather than the one or two years of the rest of the cohort. In terms of natural history you have s shorter time left.
Beta-2M, therefore, is a prognostic factor of a different quality to VH genes, ZAP-70 or CD38, which tell you something about the rate of growth of the CLL, or from del 17p and perhaps del 11q, which say something about rate of turnover, something about loss of molecular control and something about drug resistance. Beta-2M is more like stage or marrow histology.
This is not to say it is not valuable. It may well be more useful than CT scanning and bone marrow biopsy, which are both more experimental and invasive.
Having changed my mind I will now interpret beta-2M levels in the light of this new concept.