Familial patterns of hematologic precursors

In this issue of Blood, Slager et al report novel results from a large familial screening study including 1045 relatives from 310 families that include a patient with chronic lymphocytic leukemia (CLL).¹ 

The aims of their study were to determine patterns of monoclonal B-cell lymphocytosis (MBL) and risk of progression from MBL to CLL. According to large population-based data sets, CLL has one of the highest familial risks among cancers,²  so it made sense for Slager et al to conduct a study to gain important clinical insights and to advance the field scientifically.

Two large prospective cohort studies, based on the large National Cancer Institute Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial cohort (from more than a decade ago), showed that 2 hematologic malignancies are preceded by precursor conditions. Specifically, prospective data showed that multiple myeloma is consistently preceded by monoclonal gammopathy of undetermined significance (MGUS)³  and CLL is similarly preceded by MBL.⁴  These are clinically and scientifically important observations in that they provide support for clinical monitoring of individuals affected by MGUS and MBL, respectively, and they define a framework for studying risk factors and underlying mechanisms of progressive vs stable precursor disease. Slager et al were motivated to extend current knowledge by studying patterns of progression from MBL to CLL among patients with MBL who are related to patients with CLL.

Slager et al used highly sensitive flow cytometry to prospectively follow relatives of patients with CLL and determined that the baseline prevalence of MBL among those relatives was 22%. After a median follow-up of 8 years among 449 relatives, 12 individuals progressed from MBL to CLL, yielding a 5-year cumulative incidence of about 2%. The authors further dissected their data, and when they considered only the 139 relatives with low-count MBL (absolute clonal B-cell count <500 cells per μL), the 5-year cumulative incidence increased to 6%. Furthermore, during follow-up of 264 individuals who had no MBL at baseline, 60 subsequently developed MBL (2 had high-count MBL [absolute clonal B-cell count ≥500 cells per μL] and 58 had low-count MBL). Overall, this screening cohort of relatives of CLL patients showed an excess of MBL in family members, which is similar to that in previous smaller studies.²  In addition, among family members of CLL patients, Slager et al found evidence in normal blood of progression from low-count MBL to high-count MBL and then to onset of CLL. The authors estimated that the average rate of progression from low-count MBL to CLL was ∼1% per year, which is high compared with the risk of progression in the general population.⁵ 

Similar to the pathogenesis of other lymphoproliferative disorders,^6-8  that for CLL is characterized by a long evolutionary history and early branching from the most common recent ancestor.⁹  In this scenario, most of the key drivers and genomic defining events are acquired several years before progression to CLL, and therefore they are potentially detectable irrespective of the low disease burden (ie, low-count MBL). A comprehensive characterization of these genomic and epigenomic events in CLL and other hematologic malignancies with evidence of early precursors and long evolutionary history^6-8,10  will allow differentiation between progressive and stable entities and potentially allow the development of early interception and preventive strategies.

The novel insights from the clinical epidemiology study by Slager et al suggest that additional molecular investigations are needed to characterize biological mechanisms of progression and to define early genomic signatures of progressors vs nonprogressors. For example, such information could be used to translate the observed statistically increased (average) risk of progression among MBL patients who are family members of patients with CLL (vs patients with MBL in the general population) to the absolute risk of progression to CLL in individual cases.