Clinical features of large granular lymphocyte leukemia

https://doi.org/10.1016/S0037-1963(03)00133-1Get rights and content

Abstract

The spectrum of large granular lymphocyte (LGL) proliferations consists of four distinct entities: reactive/transient LGL expansion, chronic LGL lymphocytosis, classical indolent LGL leukemia, and aggressive LGL leukemia. LGL leukemias are classified as lymphoid malignancies. They are divided into CD3+/T-cell LGL (85% of cases) and CD3/natural killer (NK) cell LGL leukemia (15% of cases). Recent progress in the comprehension of the leukemogenesis has shown a dysregulation of survival signals in leukemic cells. Identification of LGL expansion has been improved using T-cell receptor (TCR)β/γ polymerase chain reaction (PCR) analysis and a combination of Vβ and killer cell immunoglobulin-like receptor (KIR)-specific monoclonal antibodies. LGL leukemias are characterized by a clonal LGL infiltration of the bone marrow, spleen, and liver. Monoclonality is recognized by phenotypic, molecular, and karyotypic analysis. T-LGL leukemias affect the elderly and display a relatively indolent behavior. Approximately 60% to 70% of patients are symptomatic: recurrent infections secondary to chronic neutropenia, anemia, and autoimmune disease such as rheumatoid arthritis are the main clinical manifestations. Long-lasting remission can be obtained with low-dose methotrexate, cyclosporine A, or cyclophosphamide. Conversely, NK LGL leukemias behave aggressively, and most patients do not respond to chemotherapy.

Section snippets

Spectrum of LGL proliferations: problem of nomenclature

Several terms have been used to describe LGL disorders including: lymphoproliferative disease of granular lymphocytes (LDGL), granular lymphocyte proliferative disorder (GLPD), and LGL leukemia. At least four distinct clinical syndromes can be identified (Fig 1), ranging from a reactive to an aggressive/life-threatening form.9, 42, 58, 59, 69, 70 The different entities may overlap, suggesting that a chronic benign form may possibly transform into an aggressive form.

. Spectrum of LGL

Problems of definition

It is important to distinguish authentic LGL leukemia from the other forms of LGL lymphoproliferations. We originally described LGL leukemia as a disease characterized by clonal LGL expansion as documented by clonal cytogenetic abnormalities44 or T-cell receptor (TCR) gene rearrangement studies.42 The diagnosis of LDGL was initially based on LGL expansion greater than 2 × 109/L lasting more than 6 months.42 The definition needs some clarification: (1) Some patients have significant leukopenia

Clinical manifestations of T-LGL leukemia

There is no specific predilection for either men or women, and the elderly are mainly affected, with a median age of 60 years (range, 4 to 88).9, 35, 42, 58, 59, 69 Only 10% of patients are younger than 40 and pediatric cases are rare. About one third are asymptomatic at diagnosis. The frequency of symptoms is different among studies depending on the criteria used for patient selection. Initial manifestations are mainly related to neutropenia and include fever with recurrent bacterial

CD3 NK leukemia

About 15% of LGL proliferations have a CD3 NK phenotype.

Reactive and transient LGL proliferations

Different clinical situations may be associated with a transient excess of circulating LGL. Viral infections (EBV, hepatitis, cytomegalovirus), various skin disorders, idiopathic thrombocytopenic purpura, connectivitis, post-transplantation for organ or hematopoietic stem cells grafts, solid tumors, or non-Hodgkin’s lymphomas, and hemophagocytic syndromes are the main clinical situations where such LGL proliferations can be observed. Usually, the LGL count does not exceed 3 to 4 × 109/L, and

Conclusions

In summary, this review has highlighted the clinicobiological features of LGL leukemia and delineated the different forms of LGL proliferations. Progress has been made in the phenotypic and molecular analysis of LGL clones. However, the border between benign and malignant LGL expansion is not yet fully understood. Ongoing prospective clinical studies should optimize therapeutic approaches to T-LGL leukemia. The prognosis of NK LGL leukemia remains poor and further clinical trials are warranted.

References (80)

  • AW Langerak et al.

    Molecular and flow cytometric analysis of the Vbeta repertoire for clonality assessment in mature TCR alpha T-cell proliferations

    Blood

    (2001)
  • M Lima et al.

    Immunophenotypic analysis of the TCR-Vbeta repertoire in 98 persistent expansions of CD3(+) /TCR-alphabeta(+) large granular lymphocyte: Utility in assessing clonality and insights into the pathogenesis of the disease

    Am J Pathol

    (2001)
  • JH Liu et al.

    Chronic neutropenia mediated by Fas-ligand

    Blood

    (2000)
  • JH Liu et al.

    Blockade of fas dependent apoptosis by soluble Fas in LGL leukemia

    Blood

    (2002)
  • TP Loughran et al.

    Adult onset cyclic neutropenia is associated with increased large granular lymphocytes

    Blood

    (1986)
  • TP Loughran et al.

    Treatment of large granular lymphocyte leukemia with oral low-dose methotrexate

    Blood

    (1994)
  • C Man et al.

    Deletion 6q as a recurrent chromosomal aberration in T-cell large granular lymphocyte leukemia

    Cancer Genet Cytogenet

    (2002)
  • JL Molitor et al.

    Large granular lymphocytic leukemia disclosed by bilateral uveitis: Association with celiac disease

    Rev Med Intern

    (1997)
  • WG Morice et al.

    Distinct bone marrow findings in T-cell granular lymphocytic leukemia revealed by paraffin section immunoperoxydase for CD8, TIA-1, and granzyme

    Blood

    (2002)
  • K Morikawa et al.

    Functional analysis of clonally expanded CD8, TCR γδ T cells in a patient with chronic T-gamma lymphoproliferative disease

    Leuk Res

    (1990)
  • K Oshimi et al.

    Perforin gene expression in granular lymphocyte proliferative disorders

    Blood

    (1990)
  • T Papadaki et al.

    A unique case of splenic zone-cell lymphoma with synchronous clonal T-cell large granular lymphocyte proliferation: An immunologic, immunohistochemical and genotypic study

    Leuk Res

    (2003)
  • G Semenzato et al.

    The lymphoproliferative disease of granular lymphocytes: Updated criteria for diagnosis

    Blood

    (1997)
  • R Sood et al.

    Neutropenia associated with T-cell large granular lymphocyte leukemia: Long-term response to cyclosporine therapy despite persistence of abnormal cells

    Blood

    (1998)
  • A Tefferi et al.

    Chronic natural killer cell lymphocytosis: A descriptive clinical study

    Blood

    (1994)
  • R Bassan et al.

    Autoimmunity and B-cell dysfunction in chronic proliferative disorders of large granular lymphocytes/natural killer cells

    Cancer

    (1989)
  • M Battiwalla et al.

    Treatment of T-LGL (large granular lymphocytic disease) with cyclosporine A. Long term follow-up

    Blood

    (2002)
  • JM Bennet et al.

    1989 Proposals for the classification of chronic (mature) B and T lymphoid leukemias: French-American-British (FAB) cooperative group

    J Clin Oncol

    (1989)
  • JJ Bleesing et al.

    Common expression of an unusual CD45 isoform on T cells from patients with large granular lymphocyte leukaemia and autoimmune lymphoproliferative syndrome

    Br J Haematol

    (2003)
  • SJ Bowman et al.

    The large granular lymphocyte syndrome with rheumatoid arthritis: Immunogenetic evidence for a broader definition of Felty’s syndrome

    Arthritis Rheum

    (1994)
  • H Der Simonian et al.

    Clonal Vα12.1+ T cell expansions in the peripheral blood of rheumatoid arthritis patients

    J Exp Med

    (1993)
  • HJ Ditzel et al.

    Cloning and expression of a novel human antibody-antigen pair associated with Felty’s syndrome

    Proc Natl Acad Sci USA

    (2000)
  • H Dolstra et al.

    Expansion of CD8+ CD57+ T cells after allogeneic BMT is related with a low incidence of relapse and with cytomegalovirus infection

    Br J Haematol

    (1995)
  • O Fehrer et al.

    T-cell large granular lymphocytic leukemia following orthotopic liver transplantation

    Am J Hematol

    (1995)
  • L Genestier et al.

    Immunosuppressive properties of methotrexate: Apoptosis and clonal deletion of activated peripheral T cells

    J Clin Invest

    (1998)
  • TC Gentile et al.

    Humoral immune abnormalities in T-cell large granular lymphocyte leukemia

    Leuk Lymphoma

    (1996)
  • TC Gentile et al.

    Resolution of autoimmune hemolytic anemia following splenectomy in CD3+ large granular lymphocyte leukemia

    Leuk Lymphoma

    (1996)
  • TC Gentile et al.

    Large granular lymphocyte leukemia occurring after renal transplantation

    Br J Haematol

    (1998)
  • R Gonzales-Chambers et al.

    Lymphocyte subsets associated with T cell receptor beta-chain gene rearrangement in patients with rheumatoid arthritis and neutropenia

    Arthritis Rheum

    (1992)
  • AM Hamidou et al.

    Low-dose methotrexate for the treatment of patients with large granular lymphocyte leukemia associated with rheumatoid arthritis

    Am J Med

    (2000)
  • Cited by (0)

    NO LABEL

    *Address correspondence to Thierry Lamy, MD, PhD, Department of Hematology, Service d’Hématologie, Hôpital Pontchaillou, CHU de Rennes, 35033, Rennes, France

    View full text