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How Long Is the Indolent Preclinical Phase of High-Risk CLL?

December 6, 2021

December 2021

The indolent preclinical phase of chronic lymphocytic leukemia (CLL) may be longer than previously thought, with some high-risk subtypes of CLL occurring as many as 16 years prior to diagnosis, according to research published in Blood.

The study, led by Pieter Martijn Kolijn, PhD, of Utrecht University in the Netherlands, examined the composition of the B-cell receptor immunoglobulin (BcR IG) repertoire during early stages of CLL in samples obtained up to 22 years prior to diagnosis. According to the investigators, the stereotypy of the BcR IG is a prognostically relevant immunogenetic feature in CLL.

In the study, researchers selected 124 healthy individuals from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort who subsequently received a diagnosis of CLL or small lymphocytic leukemia. Another 188 controls matched for age, sex, blood draw date, and center were also included. In the primary cohort, there were 22 longitudinal samples and 32 post-diagnosis clinical data available for analysis.

Patients who ultimately received a CLL diagnosis did so between one month and 22 years following the initial blood sample. The median frequency of the dominant clonotype was significantly higher in the patients with CLL versus controls (54.9% vs. 0.38%, respectively; p<0.0001). Those with a shorter time to diagnosis had a significantly higher dominant clonotype frequency (p<0.0001).

Additionally, individuals who had a dominant clonotype frequency greater than 2% of the total repertoire had a shorter duration from blood sampling to CLL diagnosis. However, the researchers noted that the presence of a clonotype greater than 2% of the IGH gene repertoire prior to diagnosis did not exert a significant impact on post-diagnosis overall survival in patients with CLL.

Results from next-generation sequencing demonstrated detectable skewing of the IGH gene repertoire in 21 out of 28 patients with CLL at up to 15 years prior to diagnosis. This was observed even in the absence of increased lymphocyte counts. Additionally, some patients with CLL who had clinical transformation to aggressive B-cell lymphoma had noticeable skewing in the IGH gene repertoire up to 16 years prior to CLL diagnosis.

A total of 25 patients carried stereotyped BcR IG at up to 17 years before receiving a CLL diagnosis. There were 10 clonotypes that were assigned to minor CLL subsets and 15 assigned to major subsets, of which 14 of the later cases belonged in high-risk subsets. A trend for more rapid disease evolution was observed among most of these cases. In addition, high-risk stereotyped clonotypes observed as early as 16 years prior to diagnosis often exhibited a lower dominant clonotype frequency, or less than 20% of IGH gene repertoire.

In 21 out of the 22 patients with longitudinal samples, the researchers observed a strong increase over time in the frequency of the dominant clonotype (p<0.0001), or the frequency remained stable at a high frequency. In 14 out of 16 patients with longitudinal samples who had an available diagnostic sample, the CLL BcR IG clonotype was present at the earliest timepoint as the dominant clonotype (n=10) or in the background (n=4).

“We speculate that somatic genetic aberrations, (auto)stimulation, epigenetic and/or microenvironmental influences are required for the transformation into overt CLL,” the researchers wrote. “As the observed skewing in the IGH gene repertoire often occurs prior to B-cell lymphocytosis, we consider our findings as a novel extension to the characterization of monoclonal B-cell lymphocytosis (MBL).”

The investigators added that additional studies are needed to distinguish between progressing versus stable MBL. Additionally, the researchers emphasized the importance of early detection only in cases where it offers “clear benefits” to patients. Early therapy is not indicated for patients with CLL who lack symptoms, as it doesn’t provide a clear survival benefit, the researchers explained. “Therefore, screening through BCR repertoire sequencing for the early detection of MBL/CLL in relatives of [patients with] CLL or the general population is not currently indicated.”

The authors report no relevant conflicts of interest.


Kolijn PMM, Saberi Hosnijeh F, Späth F, et al. High-risk subtypes of chronic lymphocytic leukemia are detectable as early as 16 years prior to diagnosis [published online ahead of print, 2021 Oct 18]. Blood. doi:10.1182/blood.2021012890.


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