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Clinical implications of CSF-ctDNA positivity in newly diagnosed diffuse large B cell lymphoma

Leukemia (2024)Cite this article

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Abstract

The clinical implications of CSF-ctDNA positivity in newly diagnosed diffuse large B cell lymphoma (ND-DLBCL) remains largely unexplored. One hundred ND-DLBCL patients were consecutively enrolled as training cohort and another 26 ND-DLBCL patients were prospectively enrolled in validation cohort. CSF-ctDNA positivity (CSF(+)) was identified in 25 patients (25.0%) in the training cohort and 7 patients (26.9%) in the validation cohort, extremely higher than CNS involvement rate detected by conventional methods. Patients with mutations of CARD11, JAK2, ID3, and PLCG2 were more predominant with CSF(+) while FAT4 mutations were negatively correlated with CSF(+). The downregulation of PI3K-AKT signaling, focal adhesion, actin cytoskeleton, and tight junction pathways were enriched in CSF(+) ND-DLBCL. Furthermore, pretreatment CSF(+) was significantly associated with poor outcomes. Three risk factors, including high CSF protein level, high plasma ctDNA burden, and involvement of high-risk sites were used to predict the risk of CSF(+) in ND-DLBCL. The sensitivity and specificity of pretreatment CSF-ctDNA to predict CNS relapse were 100% and 77.3%. Taken together, we firstly present the prevalence and the genomic and transcriptomic landscape for CSF-ctDNA(+) DLBCL and highlight the importance of CSF-ctDNA as a noninvasive biomarker in detecting and monitoring of CSF infiltration and predicting CNS relapse in DLBCL.

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Fig. 1: Clinicopathological features of pretreatment CSF-ctDNA in newly diagnosed DLBCL.
Fig. 2: Differences of genomic landscapes between CSF(+) ND-DLBCL and PCNSL.
Fig. 3: The establishment of CSFi-IPI for CSFi prediction in ND-DLBCL patients.
Fig. 4: Predominant gene alterations in CSF(+) DLBCL patients.
Fig. 5: Transcriptomic alterations between CSF(+) and CSF(−) DLBCL patients.
Fig. 6: Molecular responses in CSF-ctDNA during therapy.

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Data availability

We agree to share publication-related data. The raw sequence data reported in this paper have been deposited in the Genome Sequence Archive (Genomics, Proteomics & Bioinformatics 2021) in National Genomics Data Center (Nucleic Acids Res 2022), China National Center for Bioinformation/Beijing Institute of Genomics, Chinese Academy of Sciences (GSA-Human) that are publicly accessible at https://ngdc.cncb.ac.cn/gsa-human. Part of DNA sequencing data has been shared in a data supplement available with the online version of this article.

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Funding

This research was funded by the National Natural Science Foundation of China (grant number 82200887 and 82370194), Jiangsu Science and Technology Department (grant number BK20220716 and BE2023780), and China Postdoctoral Science Foundation (grant number 2022M711404 and 2023M741463).

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Author notes

  1. These authors contributed equally: Jin-Hua Liang, Yi-Fan Wu.

Authors and Affiliations

  1. Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, 210029, China

    Jin-Hua Liang, Yi-Fan Wu, Hao-Rui Shen, Yue Li, Wei Hua, Chun-Yu Shang, Kai-Xin Du, Tong-Yao Xing, Xin-Yu Zhang, Jian-Yong Li, Jia-Zhu Wu, Hua Yin, Li Wang & Wei Xu

  2. Key Laboratory of Hematology of Nanjing Medical University, Nanjing, 210029, China

    Jin-Hua Liang, Yi-Fan Wu, Hao-Rui Shen, Yue Li, Wei Hua, Chun-Yu Shang, Kai-Xin Du, Tong-Yao Xing, Xin-Yu Zhang, Jian-Yong Li, Jia-Zhu Wu, Hua Yin, Li Wang & Wei Xu

  3. Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing, 210029, China

    Jin-Hua Liang, Yi-Fan Wu, Hao-Rui Shen, Yue Li, Wei Hua, Chun-Yu Shang, Kai-Xin Du, Tong-Yao Xing, Xin-Yu Zhang, Jian-Yong Li, Jia-Zhu Wu, Hua Yin, Li Wang & Wei Xu

  4. Nanjing Geneseeq Technology Inc., Nanjing, Jiangsu, China

    Jun-Heng Liang, Chen-Xuan Wang, Liu-Qing Zhu & Yang W. Shao

  5. Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, 210029, China

    Rui Gao

  6. Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, OX3 7LE, UK

    Rui Gao

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  1. Jin-Hua Liang
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Contributions

Conception and design: Jin-Hua Liang and Wei Xu. Collection of study materials or patients’ data: All authors. Assembly of data and data analysis: Jin-Hua Liang, Yi-Fan Wu, and Jun-Heng Liang. Manuscript writing and editing: Jin-Hua Liang, Yi-Fan Wu, Jun-Heng Liang, Chen-Xuan Wang, Liu-Qing Zhu and Wei Xu. Final approval of manuscript: All authors. Accountable for all aspects of the work: All authors.

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Correspondence to Wei Xu.

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This study was conducted in accordance with the Declaration of Helsinki, and the study protocol was approved by the Ethics Committee of the Institutional Review Broad of Jiangsu Province Hospital (No. 2023-SR-190) and informed consent was retrieved from subjects involved in this study. We have also obtained informed consent for publication of the involved images with anonymization.

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Liang, JH., Wu, YF., Shen, HR. et al. Clinical implications of CSF-ctDNA positivity in newly diagnosed diffuse large B cell lymphoma. Leukemia (2024). https://doi.org/10.1038/s41375-024-02279-7

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