Two groups, Leeds and NIH, have done most of the work on Monoclonal B-cell lymphocytosis (MBL) and I can report on papers from both of them.
There is a good article in this weeks B J Haem on MBL from NIH. Goldin et al BJH 2010; 151:152-8 and also a very good review by Rawstron and Hillmen in Best Practice and Research Clinical Haematology 2010; 23:61-69.
Remember how surprised we were when Andy Rawstron told us in 2002 that one person in 30 over the age of 40 had a population of cells indistinguishable from CLL cells in their blood, and that in those who had a family history of CLL or other lymphomas it was nearer to one in seven? Gerald Marti's group in this study updates the story. They remind us that this was all discovered using 4-color flow cytometry, a sensitive way at looking at small populations in the blood. Newer studies using 8-color flow are even more sensitive and have found that one in five over-60s have an MBL population in their blood.
It has also been demonstrated from studies of stored samples that virtually all cases of CLL start off as MBL and this can be detected up to 6 years before the CLL is diagnosed.
The discovery of MBL has meant that there needs to be a numerical threshold between MBL and CLL. IT is a count of 5000 B cells per microliter in the blood. Previously, such cases would have been called stage 0 CLL, so there are a lot of people out there who have stage 0 CLL who under today's definition would not be called leukemia at all. For a rule of thumb, if you total lymphocyte count is less than 10,000 then you probably have MBL not CLL - unless you have enlarged lymph nodes, when you probably have SLL.
In general, it has been found that if you have MBL with a B-lymphocyte count of between 1000 and 4,999 per mictoliter then your prognosis is the same as if you had stage 0 CLL - about 1.1% of cases will become CLL formerly every year and most will not require treatment throughout their lifespan. The range of mutated v unmutated will be the same and the same biased use of individual IGHV genes will occur - VH1-69, VH3-07, VH3-21, VH3-23, and VH4-34.. Again the same prognostic factors as for CLL will apply. So del 13q is a good prognostic factor and del 11q is a poor prognostic factor.
By contrast, those cases of MBL with much lower counts - <10 cells per microliter - tend to use different IGHV genes like VH4-59 and VH4-61. This suggests that only those 'CLL' cels with thr 'right' receptor receive a signal to expand.
So what should happen if you are discovered to have MBL? most hematologist feel obliged to do follow-up interval blood tests, but is this wise? The majority of individuals who fall into this sub-group are elderly with all the attendant problems, and although Quality of Life studies in CLL patients show no difference to published population norms, Emotional Quality of Life scores are significantly worse. In part this is anxiety related to uncertainty about progression, and reassurances about CLL being a 'good cancer' actually increase anxiety.
The Leeds programme relies on local blood sampling once a year accompanied by a questionnaire and central processing of the sample which includes flow cytometry, since a rise in B-cell numbers may make no impact on the straight cbc.
There is also a population of individuals who do not have CLL marker MBL, who are CD5- or CD5+ but CD23-. Such individuals are more likely to have bulkier disease and in them bone marrow biopsy and/or CT scanning should be considered. Bone marrow biopsy should also be performed in those with MBL who have cytopenias.
As flow cytometry becomes more sensitive small MBL populations will be picked up in BMBs used for routine staging of NHS. This should not be taken as indicating stage IV disease. A bone marrow donor might have a small population of MBL cells. Should he be rejected as a donor?
It is clear that the discovery of MBL is going to throw up a whole range of difficult decisions.
The Goldin paper concentrates mainly on the familial cases and comes up with the statistic that by the age of 90, 60% of family members will have detectable MBL in their blood. In familial CLL, the presence of an MBL clone is confirmation of the genetic tendency, but as yet we don't know the genetic lesion.