Chronic lymphocytic leukemia

CXCL13 plasma levels function as a biomarker for disease activity in patients with chronic lymphocytic leukemia

Abstract

The chemoattractant CXCL13 organizes the cellular architecture of B-cell follicles and germinal centers. During adaptive immune responses, CXCL13 plasma concentrations transiently increase and function as a biomarker for normal germinal center activity. Chronic lymphocytic leukemia (CLL) cells express high levels of CXCR5, the receptor for CXCL13, and proliferate in pseudofollicles within secondary lymphoid organs (SLO). Given the morphologic and functional similarities between normal and CLL B-cell expansion in SLO, we hypothesized that CXCL13 plasma concentrations would correlate with CLL disease activity and progression. We analyzed CXCL13 plasma concentrations in 400 CLL patients and correlated the findings with other prognostic markers, time to treatment (TTT), CCL3 and CCL4 plasma concentrations, and in vivo CLL cell proliferation. We found that CXCL13 plasma concentrations were higher in CLL patients with active and advanced stage disease, resulting in a significantly shorter TTT. Accordingly, high CXCL13 levels correlated with other markers of disease activity and CCL3 levels. Higher CLL cell birth rates in vivo also associated with higher CXCL13 plasma concentrations. Interestingly, elevated CXCL13 plasma levels normalized during ibrutinib therapy, and increased in ibrutinib resistance patients. Collectively, these studies emphasize the importance of CXCL13 in crosstalk between CLL cells and the SLO microenvironment.

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Fig. 1: CXCL13 plasma concentrations in CLL patients with lower- or higher-risk disease features.
Fig. 2: Distribution of CXCL13 plasma levels and probability of treatment free survival.
Fig. 3: CXCL13 plasma concentrations in CLL patients treated with ibrutinib.
Fig. 4: Correlation between SPD in the lymph nodes, percentage of CLL in bone marrow and in vivo CLL cell birth rate.

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Acknowledgements

The authors are grateful to all the patients who provided samples for this study. We thank Claire Pacelli for assistance with tissue bank. This work was supported by MD Anderson’s CLL Moonshot program (JAB), and in part by the MD Anderson Cancer Center Support Grant CA016672.

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MS performed chemokine measurements, collected clinical information, analyzed the data and results, designed the figures, and wrote the paper. LX and XH performed the statistical analysis and assisted with the data interpretation. EK and AV contributed with sample collection and storage. S-SC and NC analyzed birth rate data. MJK, AF, ZE, NJ, and WGW contributed to clinical patient management. JAB designed and supervised the study, and wrote the paper together with MS. All authors reviewed the manuscript and approved the final version.

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Correspondence to Jan A. Burger.

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JAB, NJ, and WGW received research funding from Pharmacyclics, an AbbVie company. The remaining authors declared no competing financial interests.

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Sivina, M., Xiao, L., Kim, E. et al. CXCL13 plasma levels function as a biomarker for disease activity in patients with chronic lymphocytic leukemia. Leukemia (2020). https://doi.org/10.1038/s41375-020-01063-7

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