# Normal Residual Lymphoid Cell Populations in Blood as Surrogate Biomarker of the Leukemia Cell Kinetics in CLL BinetA/Rai 0

## TL;DR

This study explores how changes in blood cell populations can predict disease progression in early-stage chronic lymphocytic leukemia.

## Contribution

The study identifies immune cell profiles as potential biomarkers for predicting CLL progression in early-stage patients.

## Key findings

- Patients with rapidly increasing CLL clones had worse prognosis and shorter time to treatment.
- Lower Tαβ CD4+CD8lo cell counts and higher plasma cell counts were linked to faster CLL clone expansion.
- IGHV mutational status and clonal B-cell count are independent predictors of CLL progression.

## Abstract

The current prognostic index for chronic lymphocytic leukemia does not account for the dynamic changes in the B-cell clone over time. This study aims to investigate the association between the tumor microenvironment and the kinetics of clonal B-cells in early-stage CLL patients. By categorizing patients based on the rate of clonal B-cell increase, we identified significant differences in immune cell profiles and clinical outcomes. Patients with rapidly increasing clones exhibited poorer prognosis and shorter time to treatment, but notably, lower Tαβ CD4+CD8lo cell counts, altered B-cell subsets, and higher plasma cell counts were associated with highly proliferative clones. Multivariate analysis confirmed that the number of clonal B-cells, Tαβ CD4+CD8lo cells, and the IGHV mutational status were independent predictors of clonal expansion. These findings suggest that the interplay between CLL cells and the immune microenvironment might play a relevant role in disease progression, potentially leading to the development of novel prognostic markers.

Background/Objectives: Despite the current international prognostic index for chronic lymphocytic leukemia (CLL) being widely accepted and broadly used, it does not consider the kinetics of the B-cell clone over time. Here, we investigated the potential association between distinct features of leukemic cells and other immune cells in blood and the kinetics of clonal B-cells in CLL stage Binet A/Rai 0 (A/0) patients; Methods: Based on the leukemia cell kinetics, 69 CLL A/0 cases followed for a median of 105 months were classified as carrying stable (n = 53) vs. rapidly increasing in size (n = 16) CLL clones; Results: Patients with increasing CLL clones had a significantly higher risk of disease progression and shortened time to first therapy vs. those carrying stable B-cell clones (p ≤ 0.001). Strikingly, the distribution of various immune-cell populations in blood at diagnosis also differed significantly between the two groups, with lower Tαβ CD4+CD8lo cell counts (p = 0.03), a greater switched/unswitched memory B-cell ratio (p = 0.01), and higher plasma cell counts (p = 0.05) in CLL with increasing vs. stable clones. Multivariate analysis revealed that the number of circulating clonal B-cells (≥15 × 109/L) and Tαβ CD4+CD8lo cells (≤35 cells/µL), together with an IGHV unmutated gene status at diagnosis, were independent predictors of an increasing CLL clone; Conclusions: Altogether, these data suggest that the expansion of the CLL clone in stage A/0 patients may depend on both the intrinsic characteristics of CLL cells and the surrounding immune microenvironment.