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Myelodysplastic syndrome

Large granular lymphocytic leukemia coexists with myeloid clones and myelodysplastic syndrome

Leukemia volume 34, pages 957–962 (2020)Cite this article

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Large granular lymphocytic leukemia (LGL) is a lymphoproliferation of cytotoxic T cells (CTL) typically occurring in the elderly. LGL encompasses a spectrum of manifestations from semireactive oligoclonal to clonal CTL expansions, the latter frequently associated with the somatic STAT3 mutations. Clinical symptomatology ranges from silent to an indolent to chronic leukemia with cytopenias as a paraneoplastic manifestation. Asymptomatic LGL may represent an equivalent of T cell clonopathy of unclear significance (TCUS). Indeed, the demographics of LGL resembles that of TCUS, B cell clonopathy of unclear significance, clonal hematopoiesis of indeterminate potential (CHIP) and even monoclonal gammopathy of unclear significance (MGUS). As previously described, LGL is associated with B cell dyscrasias including MGUS [1], myelodysplastic syndrome (MDS; Table S1) [2,3,4], and various other neoplastic conditions [1, 5]. However, historical reports lack uniform diagnostic criteria, and most of them precede the advent of next generation sequencing to detect pathogenic somatic mutations. Nevertheless, a peculiar relationship between MDS and LGL does exist and may correspond to a common pathogenic role of aging in these disorders. Alternatively, the presence of LGL in MDS may indicate an overshooting cellular tumor surveillance response rather than a coincidental demographic relationship [2].

For diagnosis of LGL, our strict diagnostic criteria (>3/5) included: (i) presence of large granular lymphocytes (>500/μL, by differential counts from complete blood count) for >6 months; (ii) abnormal cytotoxic T lymphocytes expressing CD2, CD56, and CD57 and lacking CD28; (iii) preferential usage of a TCR Vb family by flow cytometry; (iv) TCR gene rearrangement by PCR; and (v) Bone marrow infiltration with LGL is another diagnostic criterion but a designated marrow biopsy is often not performed in clear LGL which are otherwise asymptomatic. These criteria have been applied over the last 10 years and as a result we have compiled a large cohort of uniformly diagnosed and analyzed patients, n = 240, Tables S2–S4). In an earlier analysis of 204 patients (included in the current 240 patients), therapeutic options and outcomes were discussed in detail; 90% of the cases were successfully treated with at least >1 modalities, ~10% of the patients required salvage therapies (Table S3) [6].

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Acknowledgements

This work was supported by the National Institutes of Health, National Heart, Lung, and Blood Institute grants R01HL118281, R01HL123904, R01HL132071, and R35HL135795.

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Authors and Affiliations

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

    Jibran Durrani, Hassan Awada, Ashwin Kishtagari, Valeria Visconte, Cassandra Kerr, Vera Adema, Yasunobu Nagata, Teodora Kuzmanovic, Sanghee Hong, Bhumika Patel, Aziz Nazha, Yogen Saunthararajah & Jaroslaw P. Maciejewski

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

    Ashwin Kishtagari, Bhumika Patel, Aziz Nazha, Alan Lichtin, Sudipto Mukherjee, Yogen Saunthararajah, Hetty Carraway, Mikkael Sekeres & Jaroslaw P. Maciejewski

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  1. Jibran Durrani
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Durrani, J., Awada, H., Kishtagari, A. et al. Large granular lymphocytic leukemia coexists with myeloid clones and myelodysplastic syndrome. Leukemia 34, 957–962 (2020). https://doi.org/10.1038/s41375-019-0601-y

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