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Advances in the Diagnosis and Treatment of Large Granular Lymphocytic Leukemia


Purpose of Review

The past decade in LGL leukemia research has seen increased pairing of clinical data with molecular markers, shedding new insights on LGL leukemia pathogenesis and heterogeneity. This review summarizes the current standard of care of LGL leukemia, updates from clinical trials, and our congruent improved understanding of LGL pathogenesis.

Recent Findings

Various clinical reports have identified associations between stem, bone marrow, and solid organ transplants and incidence of LGL leukemia. There is also a potential for underdiagnosis of LGL leukemia within the rheumatoid arthritis patient population, emphasizing our need for continued study. Preliminary results from the BNZ-1 clinical trial, which targets IL-15 along with IL-2 and IL-9 signaling pathways, show some evidence of clinical response.


With advances in our understanding of LGL pathogenesis from both the bench and the clinic, exciting avenues for investigations lie ahead for LGL leukemia.

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Fig. 1


Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. 1.

    Lamy T, Moignet A, Loughran TP. LGL leukemia: from pathogenesis to treatment. Blood. 2017;129:1082–94.

  2. 2.

    Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127:2375–90.

  3. 3.

    Loughran TP, Kadin ME, Starkebaum G, Abkowitz JL, Clark EA, Disteche C, et al. Leukemia of large granular lymphocytes: association with clonal chromosomal abnormalities and autoimmune neutropenia, thrombocytopenia, and hemolytic anemia. Ann Intern Med. 1985;102:169–75.

  4. 4.

    Jerez A, Clemente MJ, Makishima H, Koskela H, Leblanc F, Peng Ng K, et al. STAT3 mutations unify the pathogenesis of chronic lymphoproliferative disorders of NK cells and T-cell large granular lymphocyte leukemia. Blood. 2012;120:3048–57.

  5. 5.

    Rajala HLM, Eldfors S, Kuusanmäki H, van Adrichem A, Olson T, Lagström S, et al. Discovery of somatic STAT5b mutations in large granular lymphocytic leukemia. Blood. 2013;121:4541–50.

  6. 6.

    Koskela HLM, Eldfors S, Ellonen P, van Adrichem A, Kuusanmäki H, Andersson EI, et al. Somatic STAT3 mutations in large granular lymphocytic leukemia. N Engl J Med. 2012;366:1905–13.

  7. 7.

    Loughran TP. Clonal diseases of large granular lymphocytes. Blood. 1993;82:1–14.

  8. 8.

    Dinmohamed AG, Brink M, Visser O, Jongen-Lavrencic M. Population-based analyses among 184 patients diagnosed with large granular lymphocyte leukemia in the Netherlands between 2001 and 2013. Leukemia. 2016;30:1449–51.

  9. 9.

    Shah MV, Hook CC, Call TG, Go RS. A population-based study of large granular lymphocyte leukemia. Blood Cancer J. 2016;6:e455.

  10. 10.

    Bareau B, Rey J, Hamidou M, Donadieu J, Morcet J, Reman O, et al. Analysis of a French cohort of patients with large granular lymphocyte leukemia: a report on 229 cases. Haematologica. 2010;95:1534–41.

  11. 11.

    Suzuki R, Suzumiya J, Nakamura S, Aoki S, Notoya A, Ozaki S, et al. Aggressive natural killer-cell leukemia revisited: large granular lymphocyte leukemia of cytotoxic NK cells. Leukemia. 2004;18:763–70.

  12. 12.

    Moignet A, Lamy T. Latest advances in the diagnosis and treatment of large granular lymphocytic leukemia. Am Soc Clin Oncol Educ Book. 2018;38:616–25.

  13. 13.

    Lamy T, Loughran TP. How I treat LGL leukemia. Blood. 2011;117:2764–74.

  14. 14.

    Bockorny B, Dasanu CA. Autoimmune manifestations in large granular lymphocyte leukemia. Clin Lymphoma Myeloma Leuk. 2012;12:400–5.

  15. 15.

    Liu X, Loughran TP. The spectrum of large granular lymphocyte leukemia and Felty’s syndrome. Curr Opin Hematol. 2011;18:254–9.

  16. 16.

    Qiu Z-Y, Qin R, Tian G-Y, Wang Y, Zhang Y-Q. Pathophysiologic mechanisms and management of large granular lymphocytic leukemia associated pure red cell aplasia. Onco Targets Ther. 2019;12:8229–40.

  17. 17.

    Kawakami T, Sekiguchi N, Kobayashi J, Imi T, Matsuda K, Yamane T, et al. Frequent STAT3 mutations in CD8+ T cells from patients with pure red cell aplasia. Blood Adv. 2018;2:2704–12.

  18. 18.

    Gentile TC, Uner AH, Hutchison RE, Wright J, Ben-Ezra J, Russell EC, et al. CD3+, CD56+ aggressive variant of large granular lymphocyte leukemia. Blood. 1994;84:2315–21.

  19. 19.

    Morice WG, Jevremovic D, Hanson CA. The expression of the novel cytotoxic protein granzyme M by large granular lymphocytic leukaemias of both T-cell and NK-cell lineage: an unexpected finding with implications regarding the pathobiology of these disorders. Br J Haematol. 2007;137:237–9.

  20. 20.

    Loughran TP, Zickl L, Olson TL, et al. Immunosuppressive therapy of LGL leukemia: prospective multicenter phase II study by the Eastern Cooperative Oncology Group (E5998). Leukemia. 2015;29:886–94.

  21. 21.

    Loughran TP, Kidd PG, Starkebaum G. Treatment of large granular lymphocyte leukemia with oral low-dose methotrexate. Blood. 1994;84:2164–70.

  22. 22.

    • Lamy T, Pastoret C, Houot R, et al. Prospective, multicentric phase II randomized trial comparing the efficacy of methotrexate or cyclophosphamide in large granular lymphocytic leukemia: a french national study. Report on the interim analysis. Blood. 2019;134:1545–5 This is the current ongoing prospective study comparing the efficacy of methotrexate or cyclophosphamide in LGL leukemia.

  23. 23.

    Fraiser LH, Kanekal S, Kehrer JP. Cyclophosphamide toxicity. Characterising and avoiding the problem Drugs. 1991;42:781–95.

  24. 24.

    Smith RE, Bryant J, De Cillis A, Anderson S, National Surgical Adjuvant Breast and Bowel Project Experience. Acute myeloid leukemia and myelodysplastic syndrome after doxorubicin-cyclophosphamide adjuvant therapy for operable breast cancer: the National Surgical Adjuvant Breast and Bowel Project Experience. J Clin Oncol. 2003;21:1195–204.

  25. 25.

    Moignet A, Hasanali Z, Zambello R, Pavan L, Bareau B, Tournilhac O, et al. Cyclophosphamide as a first-line therapy in LGL leukemia. Leukemia. 2014;28:1134–6.

  26. 26.

    Graham RM. Cyclosporine: mechanisms of action and toxicity. Cleve Clin J Med. 1994;61:308–13.

  27. 27.

    Zhang R, Shah MV, Yang J, Nyland SB, Liu X, Yun JK, et al. Network model of survival signaling in large granular lymphocyte leukemia. Proc Natl Acad Sci U S A. 2008;105:16308–13.

  28. 28.

    Sun H, Wei S, Yang L. Dysfunction of immune system in the development of large granular lymphocyte leukemia. Hematology Am Soc Hematol Educ Program. 2019;24:139–47.

  29. 29.

    Kallemeijn MJ, de Ridder D, Schilperoord-Vermeulen J, van der Klift MY, Sandberg Y, van Dongen JJM, et al. Dysregulated signaling, proliferation and apoptosis impact on the pathogenesis of TCRγδ+ T cell large granular lymphocyte leukemia. PLoS One. 2017;12:e0175670.

  30. 30.

    Leblanc F, Zhang D, Liu X, Loughran TP. Large granular lymphocyte leukemia: from dysregulated pathways to therapeutic targets. Future Oncol. 2012;8:787–801.

  31. 31.

    Viny AD, Maciejewski JP. High rate of both hematopoietic and solid tumors associated with large granular lymphocyte leukemia. Leuk Lymphoma. 2015;56:503–4.

  32. 32.

    Nyland SB, Feith DJ, Poss M, Olson TL, Krissinger DJ, Poiesz BJ, et al. Retroviral sero-reactivity in LGL leukaemia patients and family members. Br J Haematol. 2019. https://doi.org/10.1111/bjh.16223.

  33. 33.

    Wlodarski MW, Nearman Z, Jankowska A, Babel N, Powers J, Leahy P, et al. Phenotypic differences between healthy effector CTL and leukemic LGL cells support the notion of antigen-triggered clonal transformation in T-LGL leukemia. J Leukoc Biol. 2008;83:589–601.

  34. 34.

    Viny AD, Lichtin A, Pohlman B, Loughran T, Maciejewski J. Chronic B-cell dyscrasias are an important clinical feature of T-LGL leukemia. Leuk Lymphoma. 2008;49:932–8.

  35. 35.

    Skarbnik APZ, Portell CA, Maciejewski JP, et al. Association of large granular lymphocytic leukemia (LGL) with B-cell lymphoproliferative disorders. Blood. 2013;122:1387–7.

  36. 36.

    Starkebaum G, Loughran TP, Kalyanaraman VS, Kadin ME, Kidd PG, Singer JW, et al. Serum reactivity to human T-cell leukaemia/lymphoma virus type I proteins in patients with large granular lymphocytic leukaemia. Lancet. 1987;1:596–9.

  37. 37.

    Loughran T, Coyle T, Sherman M, Starkebaum G, Ehrlich G, Ruscetti F, Poiesz B Detection of human T-cell leukemia/lymphoma virus, type 11, in a patient with large granular lymphocyte leukemia.

  38. 38.

    Pulik M, Lionnet F, Genet P, Petitdidier C, Jary L, Fourcade C. CD3+ CD8+ CD56- clonal large granular lymphocyte leukaemia and HIV infection. Br J Haematol. 1997;98:444–5.

  39. 39.

    Perzova R, Graziano E, Sanghi S, et al. Increased seroreactivity to HERV-K10 peptides in patients with HTLV myelopathy. Virol J. 2013;10:360.

  40. 40.

    • Li W, Yang L, Harris RS, Lin L, Olson TL, Hamele CE, et al. Retrovirus insertion site analysis of LGL leukemia patient genomes. BMC Med Genet. 2019;12:88 This recent paper has shown that there are no new retrovirus insertions in LGL leukemia.

  41. 41.

    Chang H, Kamel-Reid S, Hussain N, Lipton J, Messner HA. T-cell large granular lymphocytic leukemia of donor origin occurring after allogeneic bone marrow transplantation for B-cell lymphoproliferative disorders. Am J Clin Pathol. 2005;123:196–9.

  42. 42.

    Gill H, Ip AHW, Leung R, So JCC, Pang AWK, Tse E, et al. Indolent T-cell large granular lymphocyte leukaemia after haematopoietic SCT: a clinicopathologic and molecular analysis. Bone Marrow Transplant. 2012;47:952–6.

  43. 43.

    Gentile TC, Hadlock KG, Uner AH, Delal B, Squiers E, Crowley S, et al. Large granular lymphocyte leukaemia occurring after renal transplantation. Br J Haematol. 1998;101:507–12.

  44. 44.

    • Alfano G, Fontana F, Colaci E, Mori G, Cerami C, Messerotti A, et al. T-cell large granular lymphocyte leukemia in solid organ transplant recipients: case series and review of the literature. Int J Hematol. 2019;110:313–21 This recent paper has identified T-LGL leukemia in patients who received solid organ transplantation.

  45. 45.

    Epling-Burnette PK, Liu JH, Catlett-Falcone R, et al. Inhibition of STAT3 signaling leads to apoptosis of leukemic large granular lymphocytes and decreased Mcl-1 expression. J Clin Invest. 2001;107:351–62.

  46. 46.

    Clemente MJ, Wlodarski MW, Makishima H, Viny AD, Bretschneider I, Shaik M, et al. Clonal drift demonstrates unexpected dynamics of the T-cell repertoire in T-large granular lymphocyte leukemia. Blood. 2011;118:4384–93.

  47. 47.

    Kerr CM, Clemente MJ, Chomczynski PW, Przychodzen B, Nagata Y, Adema V, et al. Subclonal STAT3 mutations solidify clonal dominance. Blood Adv. 2019;3:917–21.

  48. 48.

    Shvidel L, Duksin C, Tzimanis A, Shtalrid M, Klepfish A, Sigler E, et al. Cytokine release by activated T-cells in large granular lymphocytic leukemia associated with autoimmune disorders. Hematol J. 2002;3:32–7.

  49. 49.

    Kothapalli R, Nyland SB, Kusmartseva I, Bailey RD, McKeown TM, Loughran TP. Constitutive production of proinflammatory cytokines RANTES, MIP-1beta and IL-18 characterizes LGL leukemia. Int J Oncol. 2005;26:529–35.

  50. 50.

    Teramo A, Gattazzo C, Passeri F, et al. Intrinsic and extrinsic mechanisms contribute to maintain the JAK/STAT pathway aberrantly activated in T-type large granular lymphocyte leukemia. Blood. 2013;121(3843–54):S1.

  51. 51.

    Yang J, Liu X, Nyland SB, Zhang R, Ryland LK, Broeg K, et al. Platelet-derived growth factor mediates survival of leukemic large granular lymphocytes via an autocrine regulatory pathway. Blood. 2010;115:51–60.

  52. 52.

    Zambello R, Facco M, Trentin L, et al. Interleukin-15 triggers the proliferation and cytotoxicity of granular lymphocytes in patients with lymphoproliferative disease of granular lymphocytes. Blood. 1997;89:201–11.

  53. 53.

    Chen J, Petrus M, Bamford R, Shih JH, Morris JC, Janik JE, et al. Increased serum soluble IL-15Rα levels in T-cell large granular lymphocyte leukemia. Blood. 2012;119:137–43.

  54. 54.

    Hodge DL, Yang J, Buschman MD, Schaughency PM, Dang H, Bere W, et al. Interleukin-15 enhances proteasomal degradation of bid in normal lymphocytes: implications for large granular lymphocyte leukemias. Cancer Res. 2009;69:3986–94.

  55. 55.

    • Wang TT, Yang J, Zhang Y, Zhang M, Dubois S, Conlon KC, et al. IL-2 and IL-15 blockade by BNZ-1, an inhibitor of selective γ-chain cytokines, decreases leukemic T-cell viability. Leukemia. 2019;33:1243–55 This paper describes ex vivo efficacy of BNZ-1 on LGL leukemia cells.

  56. 56.

    • Brammer JE, Sokol L, Tagaya Y, et al. Blockade of IL-15 utilizing Bnz-1, a selective γ-chain inhibiting peptide, is safe and has clinical activity in patients with T-cell large granular lymphocytic leukemia (T-LGLL): results of a phase I/II multi-center clinical trial. Blood. 2019;134:2835–5 This abstract describes the preliminary results of a phase I/II BNZ-1 clinical trial.

  57. 57.

    Mishra A, Liu S, Sams GH, Curphey DP, Santhanam R, Rush LJ, et al. Aberrant overexpression of IL-15 initiates large granular lymphocyte leukemia through chromosomal instability and DNA hypermethylation. Cancer Cell. 2012;22:645–55.

  58. 58.

    Raess PW, Cascio MJ, Fan G, Press R, Druker BJ, Brewer D, et al. Concurrent STAT3, DNMT3A, and TET2 mutations in T-LGL leukemia with molecularly distinct clonal hematopoiesis of indeterminate potential. Am J Hematol. 2017;92:E6–8.

  59. 59.

    LeBlanc FR, Liu X, Hengst J, Fox T, Calvert V, Petricoin EF, et al. Sphingosine kinase inhibitors decrease viability and induce cell death in natural killer-large granular lymphocyte leukemia. Cancer Biol Ther. 2015;16:1830–40.

  60. 60.

    Kaelin WG. Common pitfalls in preclinical cancer target validation. Nat Rev Cancer. 2017;17:425–40.

  61. 61.

    Wong CH, Siah KW, Lo AW. Estimation of clinical trial success rates and related parameters. Biostatistics. 2019;20:273–86.

  62. 62.

    Lin A, Giuliano CJ, Palladino A, et al. Off-target toxicity is a common mechanism of action of cancer drugs undergoing clinical trials. Sci Transl Med. 2019. https://doi.org/10.1126/scitranslmed.aaw8412.

  63. 63.

    Thomas S, Fisher KH, Snowden JA, Danson SJ, Brown S, Zeidler MP. Methotrexate is a JAK/STAT pathway inhibitor. PLoS One. 2015;10:e0130078.

  64. 64.

    Bedoui Y, Guillot X, Sélambarom J, Guiraud P, Giry C, Jaffar-Bandjee MC, et al. Methotrexate an old drug with new tricks. Int J Mol Sci. 2019. https://doi.org/10.3390/ijms20205023.

  65. 65.

    Farber S, Diamond LK. Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamic acid. N Engl J Med. 1948;238:787–93.

  66. 66.

    Hunger SP, Lu X, Devidas M, Camitta BM, Gaynon PS, Winick NJ, et al. Improved survival for children and adolescents with acute lymphoblastic leukemia between 1990 and 2005: a report from the children’s oncology group. J Clin Oncol. 2012;30:1663–9.

  67. 67.

    Gamis AS, Alonzo TA, Perentesis JP, Meshinchi S, COG Acute Myeloid Leukemia Committee. Children’s Oncology Group’s 2013 blueprint for research: acute myeloid leukemia. Pediatr Blood Cancer. 2013;60:964–71.

  68. 68.

    Hunger SP, Loh ML, Whitlock JA, Winick NJ, Carroll WL, Devidas M, et al. Children’s Oncology Group’s 2013 blueprint for research: acute lymphoblastic leukemia. Pediatr Blood Cancer. 2013;60:957–63.

  69. 69.

    Vitanza NA. 50 years ago in TheJournal ofPediatrics: induction of remission in acute leukemia of childhood by combination of prednisone and either 6-mercaptopurine or methotrexate. J Pediatr. 2016;173:100.

  70. 70.

    O’Connor OA, Marchi E, Volinn W, Shi J, Mehrling T, Kim WS (2018) Strategy for assessing new drug value in orphan diseases: an international case match control analysis of the PROPEL study. JNCI Cancer Spectr 2:pky038.

  71. 71.

    Moosic KB, Paila U, Olson KC, Dziewulska K, Wang TT, Xing JC, et al. Genomics of LGL leukemia and select other rare leukemia/lymphomas. Best Pract Res Clin Haematol. 2019;32:196–206.

  72. 72.

    Andersson EI, Rajala HLM, Eldfors S, et al. Novel somatic mutations in large granular lymphocytic leukemia affecting the STAT-pathway and T-cell activation. Blood Cancer J. 2013;3:e168.

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We thank Bryna Shemo and Rachel Stidham for LGL Leukemia Registry support. We wish to extend a special thanks to the LGL Leukemia Registry patients for their enthusiastic support and interest in our research.


LGL leukemia research in the Loughran lab is supported by the National Cancer Institute of the National Institutes of Health under award number R01CA178393 and P30CA044579 (to TPL) and the NIH Cancer Research Training in Molecular Biology Award T32CA009109 (to KBM). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Additional support was provided by the Bess Family Charitable Fund, the LGL Leukemia Foundation, and a generous anonymous donor.

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Correspondence to Thomas P. Loughran Jr..

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Thomas P. Loughran, Jr. is on the Scientific Advisory Board and has stock options for Keystone Nano and Bioniz Therapeutics. Thomas P. Loughran and David J. Feith have received honoraria from Kymera Therapeutics. There are no conflicts of interest with the work presented in this manuscript.

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Cheon, H., Dziewulska, K.H., Moosic, K.B. et al. Advances in the Diagnosis and Treatment of Large Granular Lymphocytic Leukemia. Curr Hematol Malig Rep (2020). https://doi.org/10.1007/s11899-020-00565-6

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  • Large granular lymphocyte leukemia
  • STAT3
  • Autoimmunity
  • Organ transplant
  • BNZ-1