Large granular lymphocytic leukemia

Large granular lymphocytic (LGL) leukemia is a chronic lymphoproliferative disorder that exhibits an unexplained, chronic (> 6 months) elevation in large granular lymphocytes (LGLs) in the peripheral blood.[1]

Large granular lymphocytic leukemia
SpecialtyHematology, oncology

It is divided in two main categories: T-cell LGL leukemia (T-LGLL) and natural-killer (NK)-cell LGL leukemia (NK-LGLL). As the name suggests, T-cell large granular lymphocyte leukemia is characterized by involvement of cytotoxic-T cells).[2]

In a study based in the US, the average age of diagnosis was 66.5 years[3] whereas in a French study the median age at diagnosis was 59 years (with an age range of 12-87 years old).[4] In the French study, only 26% of patients were younger than 50 years which suggests that this disorder is associated with older age at diagnosis.[4] Due to lack of presenting symptoms, the disorder is likely to be underdiagnosed in the general population.[5]

Signs and symptoms

This disease is known for an indolent clinical course and incidental discovery.[1] The most common physical finding is moderate splenomegaly. B symptoms are seen in a third of cases, and recurrent infections due to anaemia and/or neutropenia[6] are seen in almost half of cases.[7][8][9][10]

Rheumatoid arthritis is commonly observed in people with T-LGLL, leading to a clinical presentation similar to Felty's syndrome.[11] Signs and symptoms of anemia are commonly found, due to the association between T-LGLL and erythroid hypoplasia.[12]

Sites of involvement

The leukemic cells of T-LGLL can be found in peripheral blood, bone marrow, spleen, and liver. Nodal involvement is rare.[1][7]

Cause

The postulated cells of origin of T-LGLL leukemia are transformed CD8+ T-cell with clonal rearrangements of β chain T-cell receptor genes for the majority of cases and a CD8- T-cell with clonal rearrangements of γ chain T-cell receptor genes for a minority of cases.[1]

Diagnosis

Laboratory findings

The requisite lymphocytosis of this disease is typically 2-20x109/L.[12]

Immunoglobulin derangements including hypergammaglobulinemia, autoantibodies, and circulating immune complexes are commonly seen.[10][13][14][15]

Peripheral blood

The neoplastic lymphocytes seen in this disease are large in size with azurophilic granules that contains proteins involved in cell lysis such as perforin and granzyme B.[16] Flow cytometry is also commonly used.[17]

Bone marrow

Bone marrow involvement in this disease is often present, but to a variable extent. Bone marrow biopsy is commonly used for diagnosis. The lymphocytic infiltrate is usually interstitial, but a nodular pattern rarely occurs.[1]

Immunophenotype

The neoplastic cells of this disease display a mature T-cell immunophenotype, with the majority of cases showing a CD4-/CD8+ T-cell subset immunophenotype versus other permutations of those markers.[8][9] Variable expression of CD11b, CD56, and CD57[10] are observed. Immunohistochemistry for perforin, TIA-1, and granzyme B are usually positive.[1]

TypeImmunophenotype
Common type (80% of cases) CD3+, TCRαβ+, CD4-, CD8+
Rare variants CD3+, TCRαβ+, CD4+, CD8-
CD3+, TCRαβ+, CD4+, CD8+
CD3+, TCRγδ+, CD4 and CD8 variable

Genetic findings

Clonal rearrangements of the T-cell receptor (TCR) genes are a necessary condition for the diagnosis of this disease. The gene for the β chain of the TCR is found to be rearranged more often than the γ chain. of the TCR.[14][18]

Current evidence suggests that patients with STAT3 mutations are more likely to respond to methotrexate therapy.[19]

Treatment

First line treatment is immunosuppressive therapy. A weekly dosage of Methotrexate (with or without daily Prednisone) may induce partial or complete response in some patients while others may require Cyclosporine or Cyclophosphamide.[20]

Alemtuzumab has been investigated for use in treatment of refractory T-cell large granular lymphocytic leukemia.[21]

Experimental data suggests that treatment with calcitrol (the active form of vitamin D) may be useful in treating T-cell LGL due to its ability to decrease pro-inflammatory cytokines.[22]

Prognosis

The 5 year survival has been noted as 89% in at least one study from France of 201 patients with T-LGL leukemia.[4]

Epidemiology

T-LGLL is a rare form of leukemia, comprising 2-3% of all cases of chronic lymphoproliferative disorders.

History

LGLL was discovered in 1985 by Thomas P. Loughran Jr. while working at Fred Hutchinson Cancer Research Center.[23] Specimens from patients with LGLL are banked at the University of Virginia for research purposes, the only bank for such purposes.[24]

References
  1. Elaine Sarkin Jaffe; Nancy Lee Harris; World Health Organization; International Agency for Research on Cancer; Harald Stein; J.W. Vardiman (2001). Pathology and genetics of tumours of haematopoietic and lymphoid tissues. World Health Organization Classification of Tumors. 3. Lyon: IARC Press. ISBN 978-92-832-2411-2.
  2. Epling-Burnette PK, Sokol L, Chen X, et al. (December 2008). "Clinical improvement by farnesyltransferase inhibition in NK large granular lymphocyte leukemia associated with imbalanced NK receptor signaling". Blood. 112 (12): 4694–8. doi:10.1182/blood-2008-02-136382. PMC 2597136. PMID 18791165.
  3. Shah, M V; Hook, C C; Call, T G; Go, R S (August 2016). "A population-based study of large granular lymphocyte leukemia". Blood Cancer Journal. 6 (8): e455. doi:10.1038/bcj.2016.59. ISSN 2044-5385. PMC 5022177. PMID 27494824.
  4. Bareau, B; Rey, J; Hamidou, M; Donadieu, J; Morcet, J; Reman, O; Schleinitz, N; Tournilhac, O; et al. (2010). "Analysis of a French cohort of patients with large granular lymphocyte leukemia: A report on 229 cases". Haematologica. 95 (9): 1534–41. doi:10.3324/haematol.2009.018481. PMC 2930955. PMID 20378561.
  5. Kojić Katović, Sandra (2018). "T-Cell Large Granular Lymphocytic Leukemia – Case Report". Acta Clinica Croatica. 57 (2): 362–365. doi:10.20471/acc.2018.57.02.18. ISSN 0353-9466. PMC 6531996. PMID 30431731.
  6. Sanikommu, Srinivasa R.; Clemente, Michael J.; Chomczynski, Peter; Afable, Manuel G.; Jerez, Andres; Thota, Swapna; Patel, Bhumika; Hirsch, Cassandra; Nazha, Aziz (2017-06-20). "Clinical features and treatment outcomes in large granular lymphocytic leukemia (LGLL)". Leukemia & Lymphoma. 59 (2): 416–422. doi:10.1080/10428194.2017.1339880. ISSN 1042-8194. PMID 28633612.
  7. Lamy T, Loughran TP (January 1998). "Large Granular Lymphocyte Leukemia". Cancer Control. 5 (1): 25–33. doi:10.1177/107327489800500103. PMID 10761014.
  8. Chan WC, Link S, Mawle A, Check I, Brynes RK, Winton EF (November 1986). "Heterogeneity of large granular lymphocyte proliferations: delineation of two major subtypes". Blood. 68 (5): 1142–53. PMID 3490288.
  9. Pandolfi F, Loughran TP, Starkebaum G, et al. (January 1990). "Clinical course and prognosis of the lymphoproliferative disease of granular lymphocytes. A multicenter study". Cancer. 65 (2): 341–8. doi:10.1002/1097-0142(19900115)65:2<341::AID-CNCR2820650227>3.0.CO;2-2. PMID 2403836.
  10. Lamy T, Loughran TP (July 2003). "Clinical features of large granular lymphocyte leukemia". Semin. Hematol. 40 (3): 185–95. doi:10.1016/S0037-1963(03)00133-1. PMID 12876667.
  11. Loughran TP, Starkebaum G, Kidd P, Neiman P (January 1988). "Clonal proliferation of large granular lymphocytes in rheumatoid arthritis". Arthritis Rheum. 31 (1): 31–6. doi:10.1002/art.1780310105. PMID 3345230.
  12. Kwong YL, Wong KF (September 1998). "Association of pure red cell aplasia with T large granular lymphocyte leukaemia". J. Clin. Pathol. 51 (9): 672–5. doi:10.1136/jcp.51.9.672. PMC 500904. PMID 9930071.
  13. Oshimi K, Yamada O, Kaneko T, et al. (June 1993). "Laboratory findings and clinical courses of 33 patients with granular lymphocyte-proliferative disorders". Leukemia. 7 (6): 782–8. PMID 8388971.
  14. Loughran TP, Starkebaum G, Aprile JA (March 1988). "Rearrangement and expression of T-cell receptor genes in large granular lymphocyte leukemia". Blood. 71 (3): 822–4. PMID 3345349.
  15. Loughran TP, Kadin ME, Starkebaum G, et al. (February 1985). "Leukemia of large granular lymphocytes: association with clonal chromosomal abnormalities and autoimmune neutropenia, thrombocytopenia, and hemolytic anemia". Ann. Intern. Med. 102 (2): 169–75. doi:10.7326/0003-4819-102-2-169. PMID 3966754.
  16. Semenzato G, Zambello R, Starkebaum G, Oshimi K, Loughran TP (January 1997). "The lymphoproliferative disease of granular lymphocytes: updated criteria for diagnosis". Blood. 89 (1): 256–60. PMID 8978299.
  17. Lamy, Thierry; Loughran, Thomas P. (2011-03-10). "How I treat LGL leukemia". Blood. 117 (10): 2764–2774. doi:10.1182/blood-2010-07-296962. ISSN 0006-4971. PMC 3062292. PMID 21190991.
  18. Vie H, Chevalier S, Garand R, et al. (July 1989). "Clonal expansion of lymphocytes bearing the gamma delta T-cell receptor in a patient with large granular lymphocyte disorder". Blood. 74 (1): 285–90. PMID 2546620.
  19. Shi, Min; He, Rong; Feldman, Andrew L.; Viswanatha, David S.; Jevremovic, Dragan; Chen, Dong; Morice, William G. (March 2018). "STAT3 mutation and its clinical and histopathologic correlation in T-cell large granular lymphocytic leukemia". Human Pathology. 73: 74–81. doi:10.1016/j.humpath.2017.12.014. ISSN 0046-8177. PMID 29288042.
  20. Sanikommu, Srinivasa R.; Clemente, Michael J.; Chomczynski, Peter; Afable, Manuel G.; Jerez, Andres; Thota, Swapna; Patel, Bhumika; Hirsch, Cassandra; Nazha, Aziz (2017-06-20). "Clinical features and treatment outcomes in large granular lymphocytic leukemia (LGLL)". Leukemia & Lymphoma. 59 (2): 416–422. doi:10.1080/10428194.2017.1339880. ISSN 1042-8194. PMID 28633612.
  21. Rosenblum MD, LaBelle JL, Chang CC, Margolis DA, Schauer DW, Vesole DH (March 2004). "Efficacy of alemtuzumab treatment for refractory T-cell large granular lymphocytic leukemia". Blood. 103 (5): 1969–71. doi:10.1182/blood-2003-11-3951. PMID 14976065.
  22. Olson, Kristine C.; Kulling, Paige M.; Olson, Thomas L.; Tan, Su-Fern; Rainbow, Rebecca J.; Feith, David J.; Loughran, Thomas P. (2016-10-07). "Vitamin D decreases STAT phosphorylation and inflammatory cytokine output in T-LGL leukemia". Cancer Biology & Therapy. 18 (5): 290–303. doi:10.1080/15384047.2016.1235669. ISSN 1538-4047. PMC 5499847. PMID 27715403.
  23. https://cancer.uvahealth.com/LGLLeBookNew.pdf
  24. "LGL Leukemia Program | UVA Health System".
Classification
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