International Journal of Hematology

, Volume 110, Issue 3, pp 313–321 | Cite as

T-cell large granular lymphocyte leukemia in solid organ transplant recipients: case series and review of the literature

  • Gaetano AlfanoEmail author
  • Francesco Fontana
  • Elisabetta Colaci
  • Giacomo Mori
  • Caterina Cerami
  • Andrea Messerotti
  • Leonardo Potenza
  • Mario Luppi
  • Gianni Cappelli
Original Article


T-cell large granular lymphocyte (T-LGL) leukemia is a rare clonal proliferation of cytotoxic lymphocytes rarely described in solid organ transplant (SOT). We reviewed records from 656 kidney transplant recipients in follow-up at our Center from January 1998 to July 2017. In addition, we researched, through PubMed, further reports of T-LGL leukemia in SOT from March 1981 to December 2017. We identified six cases of T-LGL leukemia in our cohort of patients and 10 in the literature. This lymphoproliferative disorder was detected in one combined liver–kidney, one liver and 14–kidney transplant recipients. Median age at presentation was 46.5 years (IQR 39.2–56.9). The disease developed after a median age of 10 years (IQR 4.9–12) from transplantation. Anemia was the most common presentation (62.5%) followed by lymphocytosis (43.7%) and thrombocytopenia (31.2%). Splenomegaly was reported in 43.7% of the patients. Eight patients (50%) who experienced severe symptoms were treated with non-specific immunosuppressive agents. Six of them (75%) had a good outcome, whereas two (25%) remained red blood cell transfusion dependent. No cases progressed to aggressive T-LGL leukemia or died of cancer at the end of follow-up. These results suggest that T-LGL leukemia is a rare but potentially disruptive hematological disorder in the post-transplant period.


T-cell large granular lymphocyte leukemia T-LGL Post-transplant lymphoproliferative disorder Anemia Solid organ transplantation 



Autoimmune hemolytic anemia


Anti-double-stranded DNA


Parvovirus B19




Epstein Barr virus


Glomerular filtration rate


T cell lymphotropic virus


Interquartile range


Kidney transplant


Large granular lymphocyte


Large granular lymphocytes


Monoclonal B cell lymphocytosis


Monoclonal gammopathy of undetermined significance


Inhibitor of mammalian target of rapamycin


Pure red cell aplasia


Post-transplant lymphoproliferative disorder


Solid organ transplant


T-cell receptor


T-cell large granular lymphocyte


Author contributions

All the Authors listed above met the following criteria recommended by International Committee of Medical Journal Editors. In particular: AG designed study. AG, FF and CE performed the study and wrote the paper. MA, MG, CC collected data. PL, LM and CG analyzed data and reviewed the paper. All Authors approved the final version of the manuscript to be published and were accountable for any part of the work.


The authors declare no funding sources.

Compliance with ethical standards

Conflict of interest

The authors declare no conflicts of interest.


  1. 1.
    Swerdllow SH, Harris NL. WHO classification of tumours of haematopoietic and lymphoid tissues. France: IARC Press; 2008.Google Scholar
  2. 2.
    Timonen T, Ortaldo JR, Herberman RB. Characteristics of human large granular lymphocytes and relationship to natural killer and K cells. J Exp Med. 1981;153(3):569–82.Google Scholar
  3. 3.
    Sokol L, Loughran TP. Large granular lymphocyte leukemia. Oncologist. 2006;11(3):263–73.Google Scholar
  4. 4.
    Lamy T, Moignet A, Loughran TP. LGL leukemia: from pathogenesis to treatment. Blood. 2017;129(9):1082–94.Google Scholar
  5. 5.
    Lima M, et al. TCRαβ+/CD4+ large granular lymphocytosis. Am J Pathol. 2003;163(2):763–71.Google Scholar
  6. 6.
    Sandberg Y, et al. TCRγδ+ large granular lymphocyte leukemias reflect the spectrum of normal antigen-selected TCRγδ+ T cells. Leukemia. 2006;20(3):505–13.Google Scholar
  7. 7.
    Semenzato G, Zambello R, Starkebaum G, Oshimi K, Loughran TP. The lymphoproliferative disease of granular lymphocytes: updated criteria for diagnosis. Blood. 1997;89(1):256–60.Google Scholar
  8. 8.
    Bareau B, et al. Analysis of a French cohort of patients with large granular lymphocyte leukemia: a report on 229 cases. Haematologica. 2010;95(9):1534–41.Google Scholar
  9. 9.
    Mohan SR, Maciejewski JP. Diagnosis and therapy of neutropenia in large granular lymphocyte leukemia. Curr Opin Hematol. 2009;16(1):27–34.Google Scholar
  10. 10.
    Hodges E, Krishna MT, Pickard C, Smith JL. Diagnostic role of tests for T cell receptor (TCR) genes. J Clin Pathol. 2003;56(1):1–11.Google Scholar
  11. 11.
    Berliner N, et al. T cell receptor gene rearrangements define a monoclonal T cell proliferation in patients with T cell lymphocytosis and cytopenia. Blood. 1986;67(4):914–8.Google Scholar
  12. 12.
    Lamy T, Liu JH, Landowski TH, Dalton WS, Loughran TP. Dysregulation of CD95/CD95 ligand-apoptotic pathway in CD3(+) large granular lymphocyte leukemia. Blood. 1998;92(12):4771–7.Google Scholar
  13. 13.
    Epling-Burnette PK, et al. ERK couples chronic survival of NK cells to constitutively activated Ras in lymphoproliferative disease of granular lymphocytes (LDGL). Oncogene. 2004;23(57):9220–9.Google Scholar
  14. 14.
    Teramo A, et al. STAT3 mutation impacts biological and clinical features of T-LGL leukemia. Oncotarget. 2017;8(37):61876–89.Google Scholar
  15. 15.
    Loughran P, Thomas P, et al. Epitope mapping of HTLV envelope seroreactivity in LGL leukaemia. Br. J. Haematol. 1998;101(2):318–24.Google Scholar
  16. 16.
    Sokol L, Agrawal D, Loughran TP. Characterization of HTLV envelope seroreactivity in large granular lymphocyte leukemia. Leuk Res. 2005;29(4):381–7.Google Scholar
  17. 17.
    Wlodarski MW, et al. Pathologic clonal cytotoxic T cell responses: nonrandom nature of the T cell–receptor restriction in large granular lymphocyte leukemia. Blood. 2005;106(8):2769–80.Google Scholar
  18. 18.
    Lamy T, Loughran TP. Clinical features of large granular lymphocyte leukemia. Semin Hematol. 2003;40(3):185–95.Google Scholar
  19. 19.
    Bowman SJ, et al. The large granular lymphocyte syndrome with rheumatoid arthritis. Immunogenetic evidence for a broader definition of Felty’s syndrome. Arthritis Rheum. 1994;37(9):1326–30.Google Scholar
  20. 20.
    Loughran TP. Clonal diseases of large granular lymphocytes. Blood. 1993;82(1):1–14.Google Scholar
  21. 21.
    Zhang R, Shah MV, Loughran TP. The root of many evils: indolent large granular lymphocyte leukaemia and associated disorders. Hematol Oncol. 2010;28(3):105–17.Google Scholar
  22. 22.
    Gentile TC, et al. CD3+ , CD56+ aggressive variant of large granular lymphocyte leukemia [see comments]. Blood. 1994;84(7):2315–21.Google Scholar
  23. 23.
    Alekshun TJ, Tao J, Sokol L. Aggressive T cell large granular lymphocyte leukemia: a case report and review of the literature. Am J Hematol. 2007;82(6):481–5.Google Scholar
  24. 24.
    Steinway SN, LeBlanc F, Loughran TP. The pathogenesis and treatment of large granular lymphocyte leukemia. Blood Rev. 2014;28(3):87–94.Google Scholar
  25. 25.
    Feher O, Barilla D, Locker J, Oliveri D, Melhem M, Winkelstein A. T cell large granular lymphocytic leukemia following orthotopic liver transplantation. Am J Hematol. 1995;49(3):216–20.Google Scholar
  26. 26.
    Masuda M, Arai Y, Nishina H, Fuchinoue S, Mizoguchi H. Large granular lymphocyte leukemia with pure red cell aplasia in a renal transplant recipient. Am J Hematol. 1998;57(1):72–6.Google Scholar
  27. 27.
    Stamatopoulos K, et al. Large granular lymphocyte leukemia after renal transplantation: an immunologic, immunohistochemical, and genotypic study. Transplantation. 2007;83(1):102–3.Google Scholar
  28. 28.
    Gentile TC, et al. Large granular lymphocyte leukaemia occurring after renal transplantation. Br J Haematol. 1998;101(3):507–12.Google Scholar
  29. 29.
    Sabnani I, Zucker MJ, Tsang P, Palekar S. Clonal T-large granular lymphocyte proliferation in solid organ transplant recipients. Transplant. Proc. 2006;38(10):3437–40.Google Scholar
  30. 30.
    Kataria A, Cohen E, Saad E, Atallah E, Bresnahan B. Large granular lymphocytic leukemia presenting late after solid organ transplantation: a case series of four patients and review of the literature. Transplant. Proc. 2014;46(10):3278–81.Google Scholar
  31. 31.
    Schiff J, Cole E, Cantarovich M. Therapeutic monitoring of calcineurin inhibitors for the nephrologist. Clin. J. Am. Soc. Nephrol. CJASN. 2007;2(2):374–84.Google Scholar
  32. 32.
    Cattaneo D, et al. Therapeutic drug monitoring of sirolimus: effect of concomitant immunosuppressive therapy and optimization of drug dosing. Am J Transplant. 2004;4(8):1345–51.Google Scholar
  33. 33.
    Scotet E, et al. Frequent enrichment for CD8 T cells reactive against common herpes viruses in chronic inflammatory lesions: towards a reassessment of the physiopathological significance of T cell clonal expansions found in autoimmune inflammatory processes. Eur J Immunol. 1999;29(3):973–85.Google Scholar
  34. 34.
    Rose MG, Berliner N. T cell large granular lymphocyte leukemia and related disorders. Oncologist. 2004;9(3):247–58.Google Scholar
  35. 35.
    Yabe M, et al. Clinicopathologic, immunophenotypic, cytogenetic, and molecular features of γδ T cell large granular lymphocytic leukemia: an analysis of 14 patients suggests biologic differences with αβ T cell large granular lymphocytic leukemia. Am J Clin Pathol. 2015;144(4):607–19 (corrected).Google Scholar
  36. 36.
    Fujishima N, et al. Long-term responses and outcomes following immunosuppressive therapy in large granular lymphocyte leukemia-associated pure red cell aplasia: a Nationwide Cohort Study in Japan for the PRCA Collaborative Study Group. Haematologica. 2008;93(10):1555–9.Google Scholar
  37. 37.
    Bible KC, Tefferi A. Cyclosporine A alleviates severe anaemia associated with refractory large granular lymphocytic leukaemia and chronic natural killer cell lymphocytosis. Br J Haematol. 1996;93(2):406–8.Google Scholar
  38. 38.
    Shah MV, Hook CC, Call TG, Go RS. A population-based study of large granular lymphocyte leukemia. Blood Cancer J. 2016;6(8):e455.Google Scholar
  39. 39.
    Yamamoto JF, Goodman MT. Patterns of leukemia incidence in the United States by subtype and demographic characteristics, 1997–2002. Cancer Causes Control. 2008;19(4):379–90.Google Scholar
  40. 40.
    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(6):1449–51.Google Scholar
  41. 41.
    Dearden C. Large granular lymphocytic leukaemia pathogenesis and management. Br J Haematol. 2011;152(3):273–83.Google Scholar
  42. 42.
    Qiu Z-Y, Xu W, Li J-Y. Large granular lymphocytosis during dasatinib therapy. Cancer Biol Ther. 2014;15(3):247–55.Google Scholar
  43. 43.
    Sosin MD, Handa SI. Spontaneous remission of large granular lymphocytic leukaemia. Int J Clin Pract. 2003;57(6):551–2.Google Scholar
  44. 44.
    Scornik JC, Meier-Kriesche H-U. Blood transfusions in organ transplant patients: mechanisms of sensitization and implications for prevention. Am. J. Transplant. 2011;11(9):1785–91.Google Scholar
  45. 45.
    Zafrani L, et al. Incidence, risk factors and clinical consequences of neutropenia following kidney transplantation: a retrospective study. Am. J. Transplant. 2009;9(8):1816–25.Google Scholar
  46. 46.
    Brown AE. Neutropenia, fever, and infection. Am J Med. 1984;76(3):421–8.Google Scholar
  47. 47.
    Swerdlow SH. T cell and NK-cell posttransplantation lymphoproliferative disorders. Am J Clin Pathol. 2007;127(6):887–95.Google Scholar
  48. 48.
    Herreman A, et al. Clinicopathological characteristics of posttransplant lymphoproliferative disorders of T cell origin: single-center series of nine cases and meta-analysis of 147 reported cases. Leuk Lymphoma. 2013;54(10):2190–9.Google Scholar
  49. 49.
    Margolskee E, et al. Genetic landscape of T- and NK-cell post-transplant lymphoproliferative disorders. Oncotarget. 2016;7(25):37636–48.Google Scholar

Copyright information

© Japanese Society of Hematology 2019

Authors and Affiliations

  1. 1.Surgical, Medical and Dental Department of Morphological Sciences, Section of NephrologyUniversity of Modena and Reggio EmiliaModenaItaly
  2. 2.Nephrology Dialysis and Transplant UnitUniversity Hospital of ModenaModenaItaly
  3. 3.Section of Hematology, Surgical, Medical and Dental Department of Morphological SciencesUniversity of Modena and Reggio Emilia, University Hospital of ModenaModenaItaly

Personalised recommendations