We have known for many years that many people (about 6% of the over-60s) have a monoclonal protein in their serum, reminiscent of multiple myeloma, but without any of the malignant features of myeloma, and that about 1% a year of these turn into myeloma. The condition is known as monoclonal gammopathy of undetermined significance (MGUS). So it should not have been a surprise that a similar situation might exist for CLL. Still, nobody was expecting it when Andy Rawstron of Leeds published a paper in 2002 entitled "Monoclonal B lymphocytes with the characteristics of "indolent" chronic lymphocytic leukemia are present in 3.5% of adults with normal blood counts". 3.5% is about 1000 times commoner than CLL!
What they did was examine the dregs in the bottles of blood taken for routine CBCs from 910 outpatients at Leeds over the age of 40. They used 4-color flow cytometry testing for CD19/CD5/CD79b/CD20 expression, which detects the typical immunophenotype of CLL. In a subsequent paper they showed that in people with a family history of CLL there is an even higher prevalence of 13.5%.
There was some scepticism as to whether this really could be how CLL starts, but a subsequent longitudinal study demonstrated that of 185 subjects diagnosed as MBL from patients who presented with a lymphocyte count of greater than 4000 per microlitre, 28% developed progressive lymphocytosis when followed up for a median of 6.9 years (range 0.2- 11.5). There was little risk of progression for those with a B cells count of less than 1900 per microlitre. Of the 51 subjects with progressive lymphocytosis, further evidence of progressive CLL, predominantly lymphadenopathy, developed in 28, and 13 of these 51 subjects eventually required chemotherapy, starting a median of 4 years after the initial diagnosis.
The estimated rate of progression to CLL requiring treatment among subjects MBL presenting with lymphocytosis was 1.1% per year - about the same as those with MGUS progressing to myeloma. There were 62 deaths among the 185, but only 4 were due to CLL. Only age and non-CLL related anemia were prognostic factors, confirmation that these were deaths unrelated to CLL. None of the factors assessed — including age, sex, hemoglobin level, total lymphocyte count, T-cell count, B-cell count, and B-cell CD38 expression — predicted an increased risk of disease progression or the requirement for treatment. Unfortunately, not enough cases had IgVH genes tested to allow this to be evaluated as a prognostic factor. We do know that 87% of patients with MBL have mutated IgVH genes, which goes along with the idea that this is a very benign syndrome.
It even seems that progression from MBL is the usual way that CLL starts. A study from the NCI and Milano had available 77,000 blood samples among whom they found 45 cases of CLL for whom there was a previous blood sample stored. In 44 of these there was evidence of an MBL clone in the earlier specimen. Again most patients had mutated IgVH genes and most commonly used the V3-23 and V4-34 genes that are most commonly seen in mutated CLL.
Of course the vast majority of individuals with MBL will never develop CLL and there will be a few unlucky ones who will develop it despite having a B cell count of less than 1900 per microlitre, but this will be rare. What is clear is that we need to look again at stage A0 CLL and make the distinction between those with MBL and CLL.