The clonal evolution and natural history of MBL

In this issue of Blood, Slager et al¹ describe the results of large-scale screening of more than 10 000 individuals from the Mayo Clinic Biobank for a monoclonal B-cell lymphocytosis (MBL). Eight-color flow cytometry was used with a sensitivity of 0.005% for the detection of 20 or more monoclonal B-cell events. The 3 previously defined immunophenotypes of CD5⁺ chronic lymphocytic leukemia (CLL)-like MBL, atypical MBL (bright CD20), and CD5^– MBL remain unchanged. The definitions of low-count MBL (LC-MBL; <500 cells per μL) and high-count MBL (HC-MBL; >500 cells per μL and <5000 cells per μL) are based on the absolute B-cell count. CLL is defined as an absolute B-cell count of >5000 cells per μL. In the absence of a complete blood count white blood cell and the absolute lymphocyte count, the estimated clone size can be used to designate LC-MBL (<15%) and HC-MBL (>85%). One final comment about nomenclature: LC-MBL sometimes is referred to as “population-based MBL,” whereas HC-MBL is referred to as “clinical MBL.”

Several findings emerge from this study that are confirmatory or constitute new findings that increase our understanding of MBL not only as a precursor to CLL, but also as a prognostic biomarker. First, the prevalence of MBL is 17%, of which 95% is LC-MBL. The pattern of increasing MBL with age and the male-to-female ratio was confirmed. The clone size based on the percentage of clonal B cells of the 3 immunophenotypes was 1.9%, 13%, and 28.2% for CLL-like MBL, atypical MBL, and CD5^– MBL, respectively. Shim et al² reported a similar pattern in MBL blood bank donors. The presence of more than one clone has been reported in individuals with MBL as well as in those with CLL. The clinical significance of this finding is not known. A 4.3-fold increased risk of lymphoid malignancy is present in LC-MBL and a 75-fold increased risk is present in HC-MBL.

Slager et al¹ note that in many cases, the lymphoid neoplasms that arise in the setting of MBL have an immunophenotype distinct from the pre-existing MBL clone. They further suggest “that it may represent origination of an independent clonal process rather than “progression” of the LC-MBL clone.” An early report by Tembhare et al³ supports this idea. Given the high prevalence of LC-MBL, more examples as described by Slager et al¹ are likely to be seen if they are sought at the diagnosis of other lymphoid neoplasms. An oligoclonal origin of MBL has been suggested.⁴ That the great majority of LC-MBL cases do not progress to CLL, but rather remain stable, has given rise to the idea of an aging immune system or immuno-senescence.⁵ Also, sporadic MBL is different from familial MBL.

Our understanding of the natural history of MBL depends on biorepositories, particularly those with 2 or more time points of stored samples before the diagnosis of CLL. This allows not only an estimate of prevalence, but also ascertainment of whether the MBL is stable, progressive, or transient. The striking finding in all these studies is the number of years that MBL may precede the diagnosis of CLL: literally decades in some cases.⁶ Further, it seems that this is independent of immunoglobulin gene heavy chain variable region mutational status and perhaps even fluorescence in situ hybridization results.

What about familial CLL and MBL? Mayo Clinic investigators and their National Cancer Institute colleagues have carried out a similar study screening for the prevalence and observing the natural history of MBL among first-degree relatives in several CLL kindreds.⁷ Of course, the prevalence is much higher. At baseline, the prevalence of MBL was 22% and the progression from healthy to LC-MBL to HC-MBL to CLL was documented at a 1.1% annual rate. The unaffected first-degree relatives provide an opportunity to investigate further the natural history of MBL. It would be of interest to learn more about the B-cell repertoire before and after the onset of MBL. Is it related to infection? What are the steps leading to MBL? Preunmutated MBL? Premutated MBL? Pre-13q14 del MBL? Pretrisomy 12 MBL? Many molecular findings in MBL also are found in early CLL.⁸ The number of susceptibility loci (single nucleotide polymorphisms [SNPs]) associated with CLL continue to increase. The number now stands at 41 SNPs observed in CLL among patients with CLL of European ancestry.⁹ A polygenic risk score (PRS) based on a weighted combination of individual loci linked to the risk of CLL PRS was developed. Using cryopreserved samples from the Mayo Clinic CLL Resource and Biobank, Kleinstern et al⁹ extended these studies to MBL, which seems to share approximately 50% of known CLL SNPs. More remarkable is that the progression of the PRS reported in this study increased from healthy to LC-MBL to HC-MBL to CLL (see Figure 1A in Kleinstern et al⁹). The authors suggest that “these loci may be associated with progression from MBL to CLL rather than associated with initiation of the B-cell clone.”

The study of familial CLL pedigrees adds another layer of complexity to the germline origin of MBL. Jønsson et al¹⁰ recently compared Danish and Norwegian families with unrelated parents and the inbred Faroese population with related parents to propose a model for the inheritance of malignant blood disorders. Compared with data in the Danish and Norwegian Cancer Registry, Jønsson et al’s data showed that CLL is increased significantly in both cohorts. Inferential visual pattern recognition was used to identify the mechanisms that might give rise to distribution seen in probands and affected relatives. Maternal and paternal lineages were described along with parental genomic imprinting and affected mother-son microchimerism. However, the male dominance in CLL remains unexplained, as does birth order effect, the pleotropic pattern of other lymphoproliferative disease in familial CLL, and why women have a better prognosis.

Slager et al estimated, given the high prevalence of MBL, that 8 to 10 million adults older than 40 years have this condition. The increased risk of lymphoid malignancy and serious infections in LC-MBL suggest the need for further study. Familial MBL offers an opportunity to unravel some of these questions further.

Conflict-of-interest disclosure: The author declares no competing financial interests.