# Low Cell Bioenergetic Metabolism Characterizes Chronic Lymphocytic Leukemia Patients with Unfavorable Genetic Factors and with a Better Response to BTK Inhibition

## TL;DR

This study finds that CLL patients with lower cell metabolism have worse genetic factors but respond better to BTK inhibitor treatment.

## Contribution

Identifies a novel bioenergetic metabolic subgroup in CLL with distinct clinical outcomes and treatment response to BTK inhibitors.

## Key findings

- CLL patients with low bioenergetic metabolism have higher white blood cell counts and unfavorable genetics.
- Low metabolic rate CLL patients show better and more durable response to ibrutinib treatment.
- Bioenergetic profiling can identify a subgroup of CLL patients who benefit most from BTK inhibition.

## Abstract

Chronic Lymphocytic Leukemia (CLL) is an indolent malignancy characterized by the accumulation of quiescent mature B cells. However, these cells are transcriptionally and translationally active, implicating an active metabolism. The recent literature suggests that CLL cells have an oxidative-type phenotype. Given the role of cell metabolism, which is able to influence the outcome of treatments, in other neoplasms, we aimed to assess its prognostic role in CLL patients by determining the ex vivo bioenergetic metabolic profile of CLL cells, evaluating the correlation with the patient clinical/biological characteristics and the in vivo response to BTK inhibitor treatment. Clustering analysis of primary samples identified two groups, characterized by low (CLL low) or high (CLL high) bioenergetic metabolic rates. Compared to the CLL high, CLL with lower bioenergetic metabolic rates belonged to patients characterized by a statistically significant higher white blood cell count and by unfavorable molecular genetics. More importantly, patients in the CLL low cluster displayed a better and more durable response to the BTK inhibitor ibrutinib, thus defining a bioenergetic metabolic subgroup that can benefit the most from this therapy.