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CHRONIC LYMPHOCYTIC LEUKEMIA

Progressive T cell defects correlate with disease outcome in high-count monoclonal B-cell lymphocytosis

Leukemia volume 39, pages 2551–2554 (2025)Cite this article

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Monoclonal B-cell lymphocytosis (MBL), defined as absolute B-cell count <5 × 109/L in the absence of organomegaly/lymphadenopathy and cytopenia, is the precursor state to CLL, and affects 3–5% of the general population >40 years of age [1]. Recent studies have shown that individuals with MBL have a higher risk of serious infections requiring hospitalization and non-hematologic malignancy compared to age- and sex- matched healthy controls, similar to CLL patients [2,3,4]. In a retrospective study of 56 individuals with MBL, 7/22 (32%) had hypogammaglobulinemia, and they were more likely to have infections (ascertained by the number of antibiotic prescriptions) compared to those with normal immunoglobulin levels [5]. T cells from CLL patients have increased expression of exhaustion markers CD244, CD160 and PD-1, with concomitant defects in proliferation and cytotoxicity, likely secondary to chronic antigenic stimulation [6]. This dysfunction is linked to a defective ability of CLL patient T cells to form immunological synapses [7]. and may contribute to the immunodeficiency. Recent studies have shown ibrutinib, a Bruton tyrosine kinase inhibitor, can augment formation of polarized F-actin synapses, thereby reversing the immune deficits associated with progressive CLL [8]. It is unknown if these T cell defects are present at the time of MBL diagnosis and if these immune changes progress over time.

Since 2000, patients with a clonal B-cell population of the CLL immunophenotype evaluated at Mayo Clinic, Rochester, MN have been offered participation in a longitudinal study of CLL B-cell biology. We used these samples to assess absolute CD8+ count, absolute CD4+ count, and the major CD8+ and CD4+ subsets (including naïve, effector, effector memory, and central memory). Individuals with high count MBL who submitted samples at the time of study entry and at least one subsequent time period (untreated sample) were considered eligible for this study. Individuals with MBL who experienced at least a two-fold increase in the absolute lymphocyte count (ALC) from the baseline sample were considered to have a significant expansion of the B-cell clone (defined as progressive MBL). We also obtained PBMCs from healthy controls (n = 10). Detailed methodology of flow cytometric analyses, immunological T cell synapse studies, and statistical analyses can be found in Supplementary Appendix and Supplemental Table 1.

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Fig. 1: Immune synapse studies.

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Acknowledgements

This work was supported in part by funding from the National Cancer Institute K12CA090628 (SAP), K12CA090628 (SSK), and CA95241 (TDS and NEK); Henry J. Predolin Foundation; and Division of Hematology Small Grants Program (SAP). This work was also supported in part by Janssen Pharmaceuticals. The authors thank the Nikon Imaging Facility at King’s College London.

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Authors and Affiliations

  1. Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, USA

    Sameer A. Parikh, Justin C. Boysen, Saad S. Kenderian, Sutapa Sinha, Susan L. Slager & Neil E. Kay

  2. School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences & Medicine, King’s College London, London, UK

    Nikolaos Ioannou & Alan G. Ramsay

  3. Division of Clinical Trials and Biostatistics, Mayo Clinic, Rochester, MN, USA

    Kari G. Rabe

  4. Department of Hematology and Oncology, Mayo Clinic, Phoenix, AZ, USA

    Esteban Braggio

  5. Department of Immunology, Mayo Clinic, Rochester, MN, USA

    Kay L. Medina & Neil E. Kay

  6. Division of Computational Biology, Mayo Clinic, Rochester, MN, USA

    Susan L. Slager

  7. Department of Medicine, Stanford Medicine, Palo Alto, CA, USA

    Tait D. Shanafelt

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  1. Sameer A. Parikh
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Contributions

Conceptualization of the project: SAP, AGR, TDS, and NEK; Data collection and analysis: SAP, NI, AGR, JCB, SSK, KGR, SS, EB, KLM, SLS, TDS, and NEK; Discussion and interpretation of results: SAP, NI, AGR, JCB, SSK, KGR, SS, EB, KLM, SLS, TDS, and NEK; Drafting of manuscript: SAP, AGR, and NEK; All authors reviewed the final manuscript.

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Correspondence to Sameer A. Parikh.

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Competing interests

SAP: Research funding has been provided to the institution from Janssen, AstraZeneca, Merck, and Genentech for clinical studies in which SAP is a principal investigator. Honoraria has been provided to the institution from Pharmacyclics, Merck, AstraZeneca, Janssen, BeiGene, Genentech, Amgen, MingSight Pharmaceuticals, TG Therapeutics, Novalgen Limited, Kite Pharma, and AbbVie for SAP’s participation in consulting activities/advisory board meetings. NEK: Research funding has been provided to the institution from AbbVie, Acerta Pharma, Astra Zeneca, Merck, Vincerx for which NEK is a principal investigator. NEK has also participated as a member of the Data and Safety Monitoring Board for AstraZeneca, BMS-Celgene, Dren Bio. He has also participated in Advisory Board meetings of AbbVie, Astra Zeneca, Beigene, Dava Oncology, Janssen, Pharmacyclics. SSK: is an inventor on patents in the field of CAR immunotherapy that are licensed to Novartis (through an agreement between Mayo Clinic, University of Pennsylvania, and Novartis), Humanigen (through Mayo Clinic), Mettaforge (through Mayo Clinic), and MustangBio (through Mayo Clinic), and Chymal therapeutics (through Mayo Clinic). SSK is an inventor on patents that are licensed to Immix Biopharma. Sponsored Research Funding provided to the from Kite, Gilead, Juno, BMS, Novartis, Humanigen, MorphoSys, Tolero, Sunesis/Viracta, LifEngine Animal Health Laboratories Inc., and Lentigen. SSK has participated in advisory meetings with Kite/Gilead, Calibr, Luminary Therapeutics, Humanigen, Juno/BMS, Capstan Bio, and Novartis. SSK has served on the data safety and monitoring board with Humanigen and Carisma. SSK has severed a consultant for Torque, Calibr, Novartis, Capstan Bio, BMS, Carisma, and Humanigen. TDS: Research funding has been provided to the institution from Pharmacyclics, Janssen, Genentech, Glaxo-SmithKline, Celgene, Cephalon, and Hospira for which TDS is a principal investigator. All others report no conflict of interest.

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Parikh, S.A., Ioannou, N., Ramsay, A.G. et al. Progressive T cell defects correlate with disease outcome in high-count monoclonal B-cell lymphocytosis. Leukemia 39, 2551–2554 (2025). https://doi.org/10.1038/s41375-025-02689-1

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