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MYELODYSPLASTIC NEOPLASM

Clonal hematopoiesis in large granular lymphocytic leukemia

Leukemia volume 39, pages 451–459 (2025)Cite this article

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Abstract

Past studies described occasional patients with myeloid neoplasms (MN) and coexistent large granular lymphocytic leukemia (LGLL) or T-cell clonopathy of unknown significance (TCUS), which may represent expansion of myeloid clonal hematopoiesis (CH) as triggers or targets of clonal cytotoxic T cell reactions. We retrospectively analyzed 349 LGLL/TCUS patients, 672 MN patients, and 1443 CH individuals to establish the incidence, genetic landscape, and clinical phenotypes of CH in LGLL. We identified 8% of cases overlapping with MN, while CH was found in an additional 19% of cases (CH + /LGLL) of which TET2 (23%) and DNMT3A (14%) were the most common. In MN cohort, 3% of cases showed coexistent LGLL. The incidence of CH in LGLL was exceedingly higher than age-matched CH controls (P < 0.0001). By multivariate analysis, the presence of CH in LGLL (P = 0.026) was an independent risk factor for cytopenia in addition to older age (P = 0.003), splenomegaly (P = 0.015) and STAT3/5B mutations (P = 0.001). CH + /LGLL cases also showed a higher progression rate to MN than CH-/LGLL (10% vs. 2% at 5 years; P = 0.02). A close relationship between CH and LGLL suggests that cytopenia in LGLL may be not only related to LGLL but be also secondary to coexisting clonal cytopenia of unclear significance.

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Fig. 1: Cytopenia according to CH in LGLL.
Fig. 2: Comparison of molecular patterns of CH and MN in LGLL and typical CHIP individuals.
Fig. 3: Impact of CH in LGLL on clinical outcomes.
Fig. 4: Schematic summary.

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All data to reproduce our study are presented in the manuscript and supplemental material. Additional information can be requested, if needed, by e-mailing the corresponding author.

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Acknowledgements

This work was supported by the R35HL135795 (to J.P.M.); the Edward P. Evans Foundation (to C.G.); Case Comprehensive Cancer Center and VeloSano Bike to Cure Award (to C.G. & A.D.) and AA&MDSIF (to C.B-P., V.V., J.P.M); VeloSano 9 Pilot Award (to V.V.). N.K. has a postdoctoral fellowship from Astellas Foundation for Research on Metabolic Disorders and the Uehara Memorial Foundation. C.B-P. has a postdoctoral fellowship from Instituto de Salud Carlos III (JR22/00041).

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Authors and Affiliations

  1. Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA

    Naomi Kawashima, Carmelo Gurnari, Carlos Bravo-Perez, Yasuo Kubota, Simona Pagliuca, Luca Guarnera, Nakisha D. Williams, Arda Durmaz, Arooj Ahmed, Danai Dima, Fauzia Ullah, Valeria Visconte & Jaroslaw P. Maciejewski

  2. Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy

    Carmelo Gurnari & Luca Guarnera

  3. Department of Hematology and Medical Oncology, Hospital Universitario Morales Meseguer, University of Murcia, IMIB-Pascual Parrilla, CIBERER - Instituto de Salud Carlos III, Murcia, Spain

    Carlos Bravo-Perez

  4. Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

    Yasuo Kubota

  5. Department of Clinical Hematology, CHRU de Nancy, Nancy, France

    Simona Pagliuca

  6. Department of Hematology Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA

    Hetty E. Carraway & Abhay Singh

Authors
  1. Naomi Kawashima
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Contributions

N.K. supervised the study, collected, analyzed, interpreted clinical and molecular data and wrote the manuscript; C.G., C.B-P. L.G. and V.V. collected, analyzed, interpreted clinical and molecular data and edited the manuscript. Y.K. and A.D. analyzed molecular data, S.P., N.W., A.A., D.D. and F.U. collected clinical and molecular data. H.E.C. and A.S interpreted clinical and molecular data and edited the manuscript. J.P.M. provided invaluable help with the manuscript preparation, generated and conceived the study design, designed figures and tables, and wrote the manuscript. All authors participated in the critical review of the final paper and submission.

Corresponding author

Correspondence to Jaroslaw P. Maciejewski.

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Kawashima, N., Gurnari, C., Bravo-Perez, C. et al. Clonal hematopoiesis in large granular lymphocytic leukemia. Leukemia 39, 451–459 (2025). https://doi.org/10.1038/s41375-024-02460-y

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