Abstract
PURPOSE: Patients with chronic lymphocytic leukemia (CLL) have increased risk of severe infections. Although adaptive immune dysfunction is well described, clinical tools for identifying patients at risk are lacking, warranting investigation of additional immune components. In contrast to chemotherapy, targeted agents could spare or even improve innate immune function. Therefore, we investigated innate immune phenotypes and function in patients with CLL before and during targeted treatment.
EXPERIMENTAL DESIGN: Baseline and consecutive blood samples were collected from patients with CLL treated with acalabrutinib (n = 17) or ibrutinib+venetoclax (n = 18) in clinical trials. Innate immune function was assessed by TruCulture, a whole-blood ligand-stimulation assay quantifying cytokine release in response to standardized stimuli. Innate immune phenotypes were characterized by flow cytometry. As a proxy for infections, we mapped antimicrobial use before and during treatment.
RESULTS: At baseline, patients with CLL displayed impaired stimulated cytokine responses to the endotoxin lipopolysaccharide (LPS) along with deactivated monocytes, enrichment of myeloid-derived suppressor cells and metamyelocytes, and elevated (unstimulated) proinflammatory cytokines. Two/three cycles of acalabrutinib or ibrutinib normalized LPS-stimulated responses, in parallel with decreased duration of infections. Innate immune profiles and elevated proinflammatory cytokines further normalized during longer-term acalabrutinib or ibrutinib+venetoclax, paralleled by decreased infection frequency.
CONCLUSIONS: Innate immune impairment and infection susceptibility in patients with CLL were restored in parallel during targeted therapy. Thus, targeted treatment may reduce the risk of infections in CLL, as currently under investigation in the PreVent-ACaLL phase 2 trial of acalabrutinib+venetoclax for high-risk CLL (NCT03868722).
| Original language | English |
|---|---|
| Pages (from-to) | 1959-1971 |
| Number of pages | 13 |
| Journal | Clinical Cancer Research |
| Volume | 30 |
| Issue number | 9 |
| Early online date | 23 Feb 2024 |
| DOIs | |
| Publication status | Published - 1 May 2024 |
Funding
The authors would first and foremost like to acknowledge all the patients participating in this study. Furthermore, the authors acknowledge all clinical investigators, clinical-trial unit personnel, and laboratory technicians involved in this study for their efforts and contributions to this work. This work was supported by the Danish National Research Foundation (Grant 126) and EU ERA PERMED (to R. Svanberg Teglgaard), the Novo Nordisk Foundation (grant NNF16OC0019302), The Alfred Benzon Foundation, and the Danish Cancer Society Research Center (to C.U. Niemann). AstraZeneca, AbbVie, and Janssen provided financial support related to the clinical trials, had the chance to comment on the article but no further influence on the final content, and did not approve the final article.
| Funders | Funder number |
|---|---|
| Danish Cancer Society | 126 |
| Danish National Research Foundation | |
| European Partnership for Personalised Medicine | NNF16OC0019302 |
| Novo Nordisk Foundation | |
| Alfred Benzon Foundation | |
| Danish Cancer Society |
Keywords
- Adenine/analogs & derivatives
- Aged
- Aged, 80 and over
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Benzamides/therapeutic use
- Cytokines/metabolism
- Female
- Humans
- Immunity, Innate/drug effects
- Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy
- Male
- Middle Aged
- Molecular Targeted Therapy
- Piperidines/therapeutic use
- Pyrazines/therapeutic use
- Stimulation
- Ibrutinib
- Blood
- Failure
- Cll patients
- Suppressor-cells
- Survival
- Infection
- Monocytes
- Differentiation
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