Improved Innate Immune Function in Patients with Chronic Lymphocytic Leukemia Treated with Targeted Therapy in Clinical Trials

Author:

Svanberg Teglgaard Rebecca1ORCID,Marquart Hanne Vibeke2ORCID,Hartling Hans Jakob2ORCID,Bay Jakob Thaning3ORCID,da Cunha-Bang Caspar1ORCID,Brieghel Christian1ORCID,Faitová Tereza1ORCID,Enggaard Lisbeth1ORCID,Kater Arnon P.4ORCID,Levin Mark-David5ORCID,Kersting Sabina6ORCID,Ostrowski Sisse Rye27ORCID,Niemann Carsten U.17ORCID

Affiliation:

1. 1Department of Hematology, Rigshospitalet, Copenhagen, Denmark.

2. 2Department of Clinical Immunology, Rigshospitalet, Copenhagen, Denmark.

3. 3Department of Clinical Immunology, Zealand University Hospital, Køge, Denmark.

4. 4Department of Hematology, Cancer Center Amsterdam, Amsterdam University Medical Centers, University of Amsterdam, Cancer Center Amsterdam, Lymphoma and Myeloma Center Amsterdam, Amsterdam, the Netherlands.

5. 5Department of Internal Medicine, Albert Schweitzer Hospital, Dordrecht, the Netherlands.

6. 6Department of Hematology, Haga Ziekenhuis, Den Haag, the Netherlands.

7. 7Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Abstract

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).

Funder

Danish Cancer Society Research Center

Alfred Benzon Foundation

EU ERA PERMED

Danish National Research Foundation

Novo Nordisk Foundation

Publisher

American Association for Cancer Research (AACR)

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