Monoclonal B-cell lymphocytosis

We have known about monoclonal B-cell lymphocytosis (MBL) for some time now. In order to have CLL you need to have two things; a lymphocyte count of greater than 5000 per cu mm and a specific immunophenotype showing positivity for CD5, CD19, CD23 and weak positivity for kappa (or lambda, but not both) and CD79b. If you have the immunophenotype but not the lymphocytosis, and you don’t have an enlarged lymph nodes or spleen, then you have MBL. The astonishing discovery that 3.5% of the over-40 population has this condition was made by Andy Rawstron from Leeds in 2002. Now his group have published a more comprehensive investigation into this condition in the New England Journal of Medicine. They studied two cohorts of individuals. The first comprised 890 women and 630 men between the ages of 60 and 80 with normal blood counts (including normal lymphocyte counts) attending hospital for conditions other than blood diseases, cancer and transplants. 78 of these (5.1%) had MBL. Another 27 (1.8%) had a non-CLL monoclonal B-cell population.

The second cohort comprised 2228 subjects referred for investigation of a lymphocytosis that had occurred some time between 1995 and 2000 – even if the lymphocytosis had subsequently resolved. Generally this meant a lymphocyte count greater than 4000 per cu mm, though for some referring centers this meant greater than 4800 per cu mm. 1031 of these (46.3%) had CLL at the time of diagnosis. 309 of these (13.9%) had MBL. The rest (39.9%) had either a non-CLL B-cell abnormality or a reactive lymphocytosis.

185 of the 309 MBLs were available for follow-up and these did not differ from the remaining 124 who weren’t followed up. The average length of follow up was 6.7 years (range: 0.2 – 11.8 years). Progressive lymphocytosis occurred in 51/185 (28%), 31 of these developing a lymphocyte count of >30,000 per cu mm. Of the 51, 28 developed lymphadenopathy and 13 eventually required chemotherapy. Time to first treatment following diagnosis varied greatly (1.1 – 10.1 years) in this group and the median of 4 years is probably meaningless with such small numbers. Of the 13 treated patients 6 have died. In this age group people are expected to die, and of the 309 individuals with MBL, 62 have died. Of these 13 had progressive CLL, but CLL was noted as the cause of death in only four.

What of prognostic markers, how did they perform? There was not really enough blood to do these investigations on many of the individuals. Of the first cohort of 78, 38 had a partial FISH study. 39% had del 13q14 and 18% trisomy 12, and none had del 17p13 or del 11q23. Of the second cohort of 309, 33 had a full FISH cohort. 58% had del 13q14, and 21% had trisomy 12. Two individuals had del 11q23 and one del 17p13. Even fewer had IGHV mutations estimated – 20 of the first cohort and 20 of the second cohort. All bar five were mutated. The V genes used, 3-07, 3-23 and 4-34 are the same as are used by mutated CLL. Of the 58 in the second cohort who had CD38 levels estimated, only two had levels higher than 30%.

It is clear therefore that too few individuals had poor prognostic markers for these to be assessed as prognostic markers for MBL. In fact the only measurement that predicted progression in a multivariate analysis was the absolute number of B lymphocytes – the threshold being 1900 per cu mm.
They conclude that MBL is indeed a precursor to CLL, much as MGUS is related to multiple myeloma. Just as with MGUS progressing to myeloma, the risk of MBL progressing to CLL is about 102% per year. Just like MGUS, the majority will die from an unrelated cause, and age and Hb levels are the only independent predictors of unrelated death – just as they would be for old people without MBL.

The one prognostic factor which informs on the risk of progression to CLL is the absolute B-lymphocyte count. Lymphocyte doubling time is unhelpful.

They also suggest that the definition of CLL based on an absolute count of 5000 per cu mm is unhelpful, and that the diagnosis should be related to the absolute B-lymphocyte count.