▎ WuXi AppTec content team editor
Chronic lymphocytic leukemia (CLL) is the most common type of leukemia and usually occurs in adults over the age of 60 and progresses slowly. Monoclonal B-cell lymphocytosis (MBL) is the prodrome state of CLL, usually detectable 6 years before CLL is confirmed, with a prevalence of up to 12% in older adults. However, the duration of MBL and the mechanism by which it evolved into CLL remain largely unknown.
A study recently published in the Journal BLood of the American Society of Hematology provides important information about the course of the onset and development of the disease. The study, from a team in the Department of Immunology at Erasmus Medical Center in the Netherlands, through sequencing blood samples from patients up to 22 years before diagnosis, suggested that the preclinical phase of CLL may be longer than previously thought, even in the case of poor prognosis.
Gerald Marti, M.D., of the National Institutes of Health's Heart, Lung, and Blood Institute (NHLBI), stressed in a related review that the findings "represent the earliest detection of clonal precursor cells in CLL."
Screenshot source: Blood
Participants in the study came from the well-known EPIC (European Prospective Survey on Cancer and Nutrition) cohort. To gain insight into the characteristics of B cell receptors in the early stages of CLL, the research team sequenced the B cell receptor (BcR) immunoglobulin heavy chain (IgH) gene bank (gene repertoire) in blood samples from 124 CLL patients and 118 matched controls, and the blood samples were sampled up to 22 years before the CLL or small lymphocytic leukemia (SLL) was diagnosed.
CLL has the same pathological and immunophenotypic characteristics as SLL, but CLL disease is mainly concentrated in the peripheral blood, while SLL disease is mainly concentrated in lymph nodes.
The researchers observed that significant changes in the BcR IgH gene pool were detected in most patients, with the frequency of dominant clonotypes in CLL patients differing significantly from the control group (54.9% vs 0.38%), even before lymphocytosis developed, and this feature was not associated with the somatic hypermutation state of cloned IgH variable region genes.
Of the 28 patients whose lymphocyte counts were measured at baseline, the data also suggested signs of pre-disease:
At 8 years before the diagnosis of CLL, samples from 10 patients showed evidence of lymphocytosis. The research team explained that this suggested that these patients were asymptomatic cases of CLL.
Second-generation sequencing results showed that changes in the IgH gene pool in 21 of the 28 patients were detectable at up to 15 years before CLL diagnosis, usually when lymphocyte counts were not elevated.
Notably, some CLL patients who need to be treated and clinically transition to aggressive B-cell lymphoma also show considerable changes in the IgH gene pool as early as 16 years before the CLL diagnosis.
In addition, in 14 patients with CLL, a specific type of dominant clone in the 16 years prior to diagnosis was associated with a poor prognosis.
Patients with IgHV unmutated dominant clonals prior to diagnosis had significantly shorter overall survival after CLL diagnosis than patients with IgHV mutant clonals.
50% to 60% of patients have somatic mutations in the immunoglobulin heavy chain variable region (IgHV) gene. CLL cells with IgHV gene mutations originate from memory B cells in post-growth centers, and such patients progress more slowly; CLL cells without IgHV gene mutations originate from proto-B cells in pre-emergence centers, and patients progress quickly, are more likely to respond poorly to immunotherapy, and have poor prognosis.
22 patients had samples from multiple different time points. The data showed that changes in the BcR IgH gene pool increased significantly over time or remained stable at high levels.
Image credit: 123RF
"To the best of our knowledge, the dynamics of progression to CLL in MML patients have never been captured in such a convincing way," the research team said, adding that the findings "expand current knowledge about the evolution of the IgH gene pool before the diagnosis of CLL, highlighting that even high-risk CLL subtypes may exhibit a long inert preclinical phase." ”
The research team further notes that "it would be valuable to clarify the difference between 'progressive' MBL and 'stable' MBL in greater depth." Nevertheless, we emphasize that early detection is only needed when there is a clear benefit to patient care. ”