# Longitudinal Whole-Exome Sequencing Identifies Clonal Hematopoiesis and Genomic Heterogeneity as a Predictor of Treatment Outcome in Patients with Newly Diagnosed, Elderly Chronic Lymphocytic Leukemia

## TL;DR

Long-term genetic analysis of elderly CLL patients in Korea reveals that genomic diversity and blood cell mutations can predict treatment success.

## Contribution

The study introduces longitudinal whole-exome sequencing to identify genomic heterogeneity and clonal hematopoiesis as predictors of treatment outcomes in elderly CLL patients.

## Key findings

- Baseline PCA showed compact clusters in patients with complete response but dispersed clusters in those with partial or progressive disease.
- Clustering revealed that CHIP-associated mutations were enriched in dispersed clusters (55.6% vs. 8.3%).
- Serial WES detected changes in CHIP status in some patients 3–5 months after treatment.

## Abstract

Chronic lymphocytic leukemia (CLL) is uncommon in Asia, and longitudinal genomic data from Asian cohorts are limited. We conducted serial whole-exome sequencing (WES) in a multicenter Korean cohort of newly diagnosed, elderly CLL treated with chlorambucil–obinutuzumab to evaluate mutational heterogeneity and clonal hematopoiesis of indeterminate potential (CHIP) during treatment and follow-up. Tumor-only variants were filtered, restricted to nonsynonymous or loss-of-function coding/splice-site mutations, and summarized as a binary patient-by-gene matrix for principal component analysis (PCA), trajectory analysis, and k-means clustering. CHIP was defined as ≥1 qualifying mutation in a prespecified CHIP gene set. Baseline PCA was more compact in patients with complete response at end of treatment, whereas partial response or progressive disease cases were more dispersed. PCA trajectories were compact and directionally consistent in complete responders, more dispersed in partial responders, and highly heterogeneous without a dominant direction in progressive disease. Clustering identified dispersed and compact clusters, and CHIP-associated mutations were enriched in the dispersed cluster (55.6% vs. 8.3%, Fisher’s exact p = 0.0086). In paired samples collected 3–5 months after end of treatment, CHIP status changed in some patients. Serial WES may provide complementary information to treatment response, although these observations require confirmation in larger cohorts.