The Oncologist, Vol. 9, No. 3, 247–258,
June 2004
© 2004 AlphaMed Press
T-Cell Large Granular Lymphocyte Leukemia and Related Disorders
Michal G. Rosea,
Nancy Berlinerb
a Yale University School of Medicine, The Comprehensive Cancer Center (IIID), VA Connecticut Healthcare System, West Haven, Connecticut, USA;
b Section of Hematology, Yale University School of Medicine, New Haven, Connecticut, USA
Correspondence: Michal G. Rose, M.D., The Comprehensive Cancer Center (IIID), VA Connecticut Healthcare System, 950 Campbell Avenue, West Haven, Connecticut 06516, USA. Telephone: 203-937-3421; Fax: 203-937-3803; e-mail: Michal.Rose{at}med.va.gov, michalrose{at}sbcglobal.net
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LEARNING OBJECTIVES
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After completing this course, the reader will be able to:
- Discuss the clinical manifestations of large granular lymphocyte leukemia and related disorders, including their association with autoimmune conditions.
- Describe recent developments in the understanding of the pathogenesis of large granular lymphocyte leukemia.
- Explain the treatment approach to large granular lymphocyte leukemia and its related disorders.
Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com
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ABSTRACT
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T-cell large granular lymphocyte (LGL) leukemia is a clonal proliferation of cytotoxic T cells, which causes neutropenia, anemia, and/or thrombocytopenia. This condition is often associated with autoimmune disorders, especially rheumatoid arthritis, and other lymphoproliferative disorders. The diagnosis is suggested by flow cytometry demonstrating an expansion of CD8+CD57+ T cells and is confirmed by T-cell receptor gene rearrangement studies. Mounting evidence suggests that LGL leukemia is a disorder of dysregulation of apoptosis through abnormalities in the Fas/Fas ligand pathway. In most patients, this is an indolent disorder, and significant improvement of cytopenias can be achieved with immunosuppressive agents such as steroids, methotrexate, cyclophosphamide, and cyclosporin A. This review provides a concise, up-to-date summary of LGL leukemia and the related, more aggressive, malignancies of cytotoxic T cells and natural killer cells.
Key Words. Chronic T-cell leukemia • Felty’s syndrome • Neutropenia • Natural killer cell
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INTRODUCTION
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T-cell large granular lymphocyte (LGL) leukemia is caused by a clonal proliferation of cytotoxic (CD8+) T cells and is characterized clinically by neutropenia, anemia and/or thrombocytopenia, and a modest lymphocytosis. It can occur in association with multiple autoimmune conditions. In most cases, it follows an indolent clinical course. Since the first description of this syndrome by McKenna et al. in 1977 [1], our understanding of the natural history, immunophenotype, pathophysiology, and treatment of this disorder has greatly expanded, and LGL leukemia is now recognized as a well-defined clinical entity. This disorder has been described by many terms over the years (Table 1
), but in modern literature, including the most recent World Health Organization (WHO) classification of the hematologic malignancies [2], the term T-cell LGL leukemia has been used and is used in this review. The purposes of this review are to provide a concise, up-to-date summary of this uncommon, but probably underdiagnosed, malignancy and to describe the current approach to its diagnosis and management. Other suppressor T-cell and natural killer (NK) cell malignancies are reviewed briefly.
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NORMAL DEVELOPMENT AND MATURATION OF CYTOTOXIC (SUPPRESSOR) T CELLS
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T lymphocytes develop from bone marrow progenitors that migrate to the thymus. In the thymus, they undergo somatic rearrangements of the V, D, and J elements of their T-cell receptor (TCR) genes [3, 4]. The TCR is a heterodimer consisting of two polypeptides, which are usually 
and ß chains. A minority of T cells express a related receptor composed of 
and 
chains. During T-cell maturation in the thymus, after the developing T cell has rearranged the ß and chains, it expresses both CD4 and CD8. The interaction of TCRs with antigens bound to major histocompatibility complex (MHC) molecules causes the dual-positive T cell to commit to either the CD4 (helper, regulatory) or CD8 (cytotoxic, suppressor) lineage. Mature CD3+CD4+CD8– lymphocytes are associated with helper/inducer activities, and mature CD3+CD4–CD8+ T cells show cytotoxic suppressor cell functions.
Upon stimulation of CD8+ T cells by antigens and cytokines, they differentiate into effector cytotoxic cells. The primary role of these cells is to eradicate viral infections. This involves the synthesis of lytic molecules such as perforin and granzymes, which cause direct lysis and death of target cells infected by viruses [4]. Effector cytotoxic T cells also express Fas ligand, a member of the tumor necrosis factor receptor family. Fas ligand can bind Fas, which has a broad distribution in normal tissue, and initiate apoptosis in the target cell through this pathway [4].
Less is known about the function of the cytotoxic T cells that express the TCR. These cells display strong, rapid, MHC-unrestricted cytotoxic activity, similar to NK cells. They tend to localize to mucosal epithelium and are thought to provide a first line of defense in the epithelial linings of the body [4, 5].
NK cells and T cells develop from a common precursor, distinct from the progenitor that gives rise to B cells. NK cells share many properties with cytotoxic T cells, including the expression of lytic molecules, the expression of CD8, and the expression of NK receptors [6, 7]. However, they do not express CD3 or the TCR, their TCR genes are not rearranged, and they do not require stimulation and clonal expansion to acquire their effector function. They lyse target cells in a non-MHC-restricted fashion, including tumor cells and cells infected with viruses [7]. Substantial progress has been made in the last several years in identifying receptors on NK cells that either trigger or inhibit their cytolytic activity [7].
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GRANULAR LYMPHOCYTES
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Normally, around 10%–15% of peripheral blood mononuclear cells are granular lymphocytes, which are typically large, with abundant cytoplasms and azurophilic granules (Fig. 1). Immunophenotypic markers (see below) have demonstrated that, in normal peripheral blood, the majority of these cells are NK cells (CD3–CD8+) and the minority are T cell suppressor cells (CD3+CD8+). However, in 85% of the leukemias of these granular lymphocytes, the malignant cell is a suppressor T cell, and these T-cell proliferations are the main focus of this review. With the widespread availability of flow cytometry, we are now aware that not all cells that have the immunophenotypic markers of suppressor T cells or NK cells in blood and bone marrow have the typical morphology of LGLs. Thus, if the diagnosis is suspected clinically, it should be pursued using flow cytometry, even if review of the peripheral blood smear does not demonstrate classic LGLs.
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CLINICAL MANIFESTATIONS OF LGL LEUKEMIA
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Epidemiology and Clinical Manifestations
LGL leukemia is a disease of the elderly, with a median age at diagnosis of 60 years. However, it has been described in all age groups, including in the pediatric population. Males and females are affected equally. Approximately half the patients are diagnosed because of recurrent bacterial infections secondary to neutropenia, which typically include cellulitis, perirectal abscesses, or respiratory infections [8–16]. Rarely, patients may demonstrate adult-onset cyclic neutropenia [17]. Other presenting symptoms include fatigue, usually secondary to anemia, and rarely, B symptoms (fever, night sweats, weight loss). About a third of patients come to medical attention because of asymptomatic cytopenias. On exam, about half the patients are found to have a modest splenomegaly, and 25% have hepatomegaly. Enlarged lymph nodes are rarely found [9, 18].
Laboratory investigation demonstrates neutropenia in 85% of cases, with an absolute neutrophil count of less than 500/µl in 50% of patients. Approximately half the patients have anemia, and moderate thrombocytopenia is found in 20%. Severe thrombocytopenia is rare. In most patients, examination of the peripheral blood smear demonstrates a large number of granular lymphocytes, although patients usually have either a normal absolute lymphocyte count or a mild lymphocytosis (median lymphocyte count at presentation 7,800/µl) [8]. The number of circulating granular lymphocytes is elevated, with a median number at presentation of 4,000/µl (normal number of circulating granular lymphocytes is 223 ± 99/µl) [8, 10, 13, 14].
Patients often have multiple serological abnormalities (Table 2), including rheumatoid factor, antinuclear antibody, antiplatelet antibodies, antineutrophil antibodies, positive direct Coombs test, hyper- or hypogammaglobulinemia, monoclonal gammopathies, and elevated ß2-microglobulin [9].
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DIAGNOSIS
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The diagnosis of LGL leukemia should be suspected in all patients with unexplained cytopenias and high numbers of LGLs by morphology and/or by flow cytometry. However, not all expansions of LGLs are malignant, and benign LGL proliferations are seen in several clinical conditions (Table 3), including patients with HIV infections [19], postsplenectomy patients [20], and in patients after allogeneic bone marrow transplantation [21] or solid organ transplantation [22].
In order to establish the diagnosis of LGL leukemia, the abnormal proliferation of CD8+ T cells has to be demonstrated to be clonal. A minority of patients has clonal cytogenetic abnormalities [23, 24], but in most patients, clonality is established by gene rearrangement studies. As T cells rearrange their TCR genes during normal development, all cells arising from a malignant, transformed T cell will have the same sequence of TCR genes. This can be demonstrated either by Southern blotting or by polymerase chain reaction (PCR). PCR is currently the technique most widely used in the clinical setting, although its sensitivity is only 70%–80%. False-negative results occur commonly because of the use of suboptimal consensus primers to variable regions of the TCR. Southern blotting has fewer false-negative and fewer false-positive results; however, it is labor intensive and requires a large amount of good quality DNA [25].
Flow cytometry using monoclonal antibodies against TCR variable region family gene segments can also aid in the establishment of clonality in T-cell disorders. Monoclonal antibodies are available for more than 80% of the variable region families of the ß chain (Vß). TCR Vß antibody studies can be used as an initial screening method for the detection of unbalanced use of ß chain gene families [25, 26].
As tests for the determination of clonality of T cells are becoming a standard part of our evaluation in these patients, it is also emerging that not all clonal T-cell proliferations are clinically significant. Minor T-cell clones can be found in the elderly [27, 28], in patients with autoimmune disorders, and in patients with viral infections [25].
In summary, the minimum criteria necessary to make the diagnosis of LGL leukemia include the presence of cytopenias of one or more cell lines with evidence of a clonal T-cell population by either PCR or Southern blotting (Table 4). The role of flow cytometry in determining clonality of T cells has not yet been established.
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PATHOLOGY AND IMMUNOPHENOTYPIC FINDINGS IN LGL LEUKEMIA
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Review of a peripheral blood smear in LGL leukemia demonstrates the cytopenia(s) that leads to the clinical suspicion of the disorder. The morphologies of the pathological lymphocytes are highly variable. Some patients manifest classic large lymphocytes with a condensed round or oval nucleus, abundant pale basophilic cytoplasm, and small azurophilic granules (Fig. 1
). However, in some patients, the granules are subtle or absent or large and coarse [29].
In a study of 36 patients with LGL leukemia, the bone marrow was hypercellular in 56%, hypocellular in 14%, and normocellular in 31% of the patients [30]. There were fewer myeloid precursors and a left shift in patients with neutropenia, and fewer erythroid precursors in patients who presented with anemia. Megakaryocyte numbers and morphologies are usually normal. A lymphocytic infiltrate is usually found, although it may be subtle, and may be evident only upon immunohistochemical staining (Fig. 2). It is usually a nonparatrabecular infiltrate that is either nodular or diffuse [29–31]. Large lymphoid aggregates are rare. Morice et al. also described a linear accumulation of cytotoxic T cells within marrow microvascular structures [30], a finding with a high specificity for LGL leukemia. These lymphocytic infiltrates can be demonstrated by immunohistochemistry using antibodies against T lymphocytes (CD3) or preferable antibodies against cytotoxic lymphocytes, such as CD8, CD56, CD57, and the cytotoxic granule proteins TIA-1 and granzyme B [29, 30]. The spleen in LGL leukemia shows red pulp infiltration by malignant lymphocytes, follicular hyperplasia, and infiltration of the sinuses [31, 32].
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Figure 2. CD3 immunoperoxidase staining of bone marrow biopsy in a patient with LGL leukemia and pure red cell aplasia, demonstrating lack of erythroid precursors and a lymphocytic infiltrate.
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IMMUNOPHENOTYPING IN LGL LEUKEMIA
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The classic immunophenotype of the malignant T cell in LGL leukemia is CD3+CD4–CD8+CD16+CD27– CD45R0–CD57+CD94+ [8]. Case reports have described patients with CD4+CD8– LGL leukemia, dual-positive CD4+CD8+ LGL leukemia [33], and CD4–CD8– cases. CD56, an NK cell marker, is occasionally found in these patients and tends to be associated with a more aggressive clinical course (see below). In the vast majority of cases, the TCR is of the ß subtype, but cases of TCRs have been reported [34].
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PATHOGENESIS OF LGL DISORDERS
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Malignant LGLs display many of the features of antigen-activated effector T cells, including expression of perforin, granzyme, and Fas ligand. Microarray technology has demonstrated that, in LGL leukemia, multiple genes involved in cytotoxic functions are upregulated, including granzymes, cathepsin, calpain, perforin, and caspase-8, in a pattern similar to that seen in activated cytotoxic T cells [35]. The target antigen activating these T cells has not been identified, but serologic data have demonstrated that some patients have antibodies against proteins homologous to human T lymphotropic virus I antigens, suggesting that a retroviral infection may play a role in the activation process [36].
The normal process of elimination of activated cytotoxic T cells is through Fas-mediated apoptosis. However, LGL leukemia cells are resistant to Fas-mediated apoptosis [37]. Furthermore, leukemic LGLs express high levels of both Fas and Fas ligand [37, 38], and the sera of patients with LGL leukemia contain high levels of soluble Fas. Supernatants from cells transfected with Fas variants cloned from leukemic LGLs have been shown to block Fas-dependent apoptosis of leukemic LGLs [39]. That study suggests that the high levels of "decoy" soluble Fas produced by the leukemic LGLs may block Fas-mediated apoptosis of the malignant cells and contribute to the pathogenesis of this disorder. Two studies have demonstrated a correlation between disease activity and Fas-ligand levels, with a reduction of Fas-ligand levels in patients treated successfully with immunosuppressive agents [37, 40].
Thus, mounting evidence suggests that LGL leukemia is a disorder of dysregulation of apoptosis through abnormalities in the Fas/Fas ligand pathway. Animal studies have shown that mice with Fas and Fas-ligand mutations have lymphadenopathy, autoimmune manifestations, and expansion of activated T lymphocytes [41]. A genetic human disease, autoimmune lymphoproliferative syndrome, in which patients have adenopathy, expansion of CD4–CD8– T cells, and autoimmune conditions, has also been shown to be caused by Fas mutations [42].
The mechanisms underlying the cytopenias in LGL leukemia have not been elucidated. However, Liu et al. demonstrated that sera from LGL leukemia patients causes apoptosis of normal neutrophils [37].
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THE ASSOCIATIONS BETWEEN LGL LEUKEMIA AND OTHER DISORDERS
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One of the unique features of this malignancy is its common associations with other clinical conditions, including autoimmune diseases, other hematologic disorders, and other malignancies. Up to one-third of patients with LGL leukemia have rheumatoid arthritis (RA), and concomitant autoimmune thrombocytopenia, autoimmune hemolytic anemia, and other autoimmune diseases have been reported frequently. LGL leukemia is the most common cause of pure red cell aplasia in adults and can also be associated with aplastic anemia, myelodysplasia, and paroxysmal nocturnal hemoglobinuria. LGL leukemia has also been associated with many B-cell lymphoproliferative disorders (Table 5 and Table 6).
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LGL LEUKEMIA AND OTHER HEMATOLOGIC CONDITIONS
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LGL Leukemia and Pure Red Cell Aplasia
Several studies report the association between LGL leukemia and pure red cell aplasia (PRCA) [43–46]. In the largest study, by Go et al. [45] from the Mayo Clinic, among 203 patients with LGL leukemia, 15 (7%) presented with PRCA. Less than half the patients with PRCA in that series had absolute lymphocytosis (median lymphocyte count 2,310/µl), and the median granular lymphocyte count was only 450/µl (range 300–7,210/µl). All patients were transfusion dependent. Of the 15 patients in the study, eight had associated conditions including non-Hodgkin’s lymphoma, chronic lymphocytic leukemia (CLL), thymoma, rheumatoid arthritis, inflammatory bowel disease, and polyendocrine failure.
Masuda et al. reported four patients with PRCA and thymoma, three of whom had an LGL lymphocytosis, and two of those patients demonstrated TCR rearrangement by Southern blotting [47]. Other studies have shown that parvovirus B19 infection can precipitate PRCA in patients with LGL leukemia [47–49].
The diagnosis of LGL leukemia can easily be missed in PRCA, as most patients do not have a lymphocytosis in their blood or bone marrow. Thus, an evaluation for LGL leukemia, including flow cytometry and T-cell gene rearrangement studies should be part of the routine work-up in adults with PRCA, even when another cause for the PRCA, such as parvovirus infection or thymoma, has been identified.
Treatment approaches for PRCA associated with LGL leukemia have most commonly included steroids, cyclophosphamide, and cyclosporine. In a series by Go et al. [45], three of seven patients had complete responses (CRs) to prednisone alone, four of five patients had CRs with cyclophosphamide alone, and one of three patients responded to cyclophosphamide with prednisone.
Although multiple immunological mechanisms have been proposed to explain the destruction of red blood cell precursors in PRCA, cytotoxic T cells and, less frequently, NK cells, appear to play prominent roles. In LGL leukemia, the destruction of red cell precursors may be triggered by antibodies directed against erythroblasts that bind to the Fc receptor on malignant cells, or by the expression of an abnormal antigen on the erythroid precursor that is recognized by the TCR. LGLs express killer-cell inhibitory receptors, which prevent their cytotoxicity against cells that express specific MHC class 1 antigens. Since erythroblasts express low levels of MHC class 1 molecules, they are more vulnerable to LGL-mediated lysis [50].
Aplastic Anemia and LGL Leukemia
The association between aplastic anemia and LGL leukemia has been reported less frequently than that between PRCA and LGL leukemia, although, as with PRCA, LGL may be underdiagnosed in this setting. In another study from the Mayo Clinic, 9 of 203 patients with LGL leukemia presented with aplastic anemia [51]. None of the patients had an absolute lymphocytosis, although most had high levels of granular lymphocytes in the peripheral blood and bone marrow, as demonstrated by flow cytometry and immunohistochemical staining. Bone marrow findings were otherwise typical for aplastic anemia. Partial or complete remissions were obtained in patients who were treated with agents known to be effective in aplastic anemia, including cyclosporine, antithymocyte globulin (ATG), and prednisone. None of the patients treated with chemotherapeutic agents known to be active against LGL proliferation, including methotrexate, azathioprine, and cyclophosphamide, responded to therapy in that study [51].
No published studies specifically address the pathogenesis of LGL-associated aplastic anemia, but it is now clear that, in most patients with aplastic anemia, activated T lymphocytes induce the destruction of blood-forming cells by the secretion of lymphokines (interferon-, tumor necrosis factor, and interleukin-2). The death of hematopoietic stem cells has been shown to be Fas mediated [52, 53], as has been demonstrated in LGL-mediated cytopenias.
LGL Leukemia and Myelodysplasia
Saunthararajah et al. described nine patients who had myelodysplastic features in their bone marrow (either a clonal karyotype, megakaryocytic dysplasia and/or myeloid dysplasia, and/or >15% ringed sideroblasts) and a clonal expansion of LGLs [54]. Three of those patients responded to immunosuppression, with improvements in their blood counts. In a study by Dhodapkar et al. [15], 5 of 68 patients with LGL leukemia had evidence of myelodysplasia.
Oligoclonal T-cell expansions have been found in patients with myelodysplastic syndrome (MDS) [55], and the recent report of a 30% improvement in cytopenias in 61 patients with MDS treated with ATG further supports an immune-mediated suppression of hematopoiesis in this disorder [56].
LGL Leukemia and Lymphoproliferative Disorders
Papadaki et al. described eight patients with clonal LGL proliferations associated with clonal B-cell diseases, including small lymphocytic disorders, myeloma, hairy cell leukemia, monoclonal gammopathies, and lymphoplasmacytic lymphoma [57]. Other researchers have described associations between LGL leukemia and CLL [58], marginal zone lymphoma [59], and Hodgkin’s disease [60]. In most cases described in the literature, both lymphoproliferative disorders were diagnosed simultaneously. The causal relationship between these two malignancies has not been proven, but it is unlikely that the two clonal lymphoid processes share a common stem cell origin. The prevailing theory is that the immune dysregulation present in LGL leukemia enables the emergence of clonal B-cell disorders.
LGL Leukemia and Autoimmune Conditions
LGL leukemia is associated with many autoimmune disorders (Table 5), including RA, autoimmune thrombocytopenia and hemolytic anemia, Sjogren’s syndrome, Hashimoto’s thyroiditis, autoimmune polyglandular syndrome, and others [61–67]. Multiple serologic abnormalities have been described in this disorder, including rheumatoid factor, antinuclear antibody, either hyper- or hypogammaglobulinemia, monoclonal gammopathy, antiplatelet antibodies, and antineutrophil antibodies.
RA, Felty’s Syndrome, and LGL Leukemia
RA is found in up to one-third of patients with LGL leukemia. In 1924, Felty described five patients with RA, leukopenia, and splenomegaly, a triad now known as Felty’s syndrome [67]. Patients with RA who develop Felty’s syndrome tend to have had chronic, deforming disease for many years, with high frequencies of extra-articular features such as subcutaneous nodules, hepatomegaly, leg ulcers, and vasculitis [62, 63, 68, 69].
There is considerable clinical overlap between Felty’s syndrome and LGL leukemia with RA. Both disorders are associated with RA, neutropenia, and splenomegaly. T cells are thought to play an important role in joint destruction in RA [70]. Approximately one-third of patients with Felty’s syndrome has clonal proliferations of T cells [62, 71]—for example, 8 of 23 patients in a study by Gonzales-Chambers et al. [72] and 4 of 12 patients in a series by Loughran et al. [73]. In a study of 32 patients with RA, 50% had evidence of CD8+ oligoclonality as assessed by PCR, compared with 4% of 25 age-matched controls [74]. More than 85% of patients with Felty’s syndrome have HLA-DR4, as do the majority of patients with RA with LGL leukemia. However, the incidence of HLA-DR4 in patients with LGL leukemia that is not associated with RA is only 33%, which is the incidence in the general population [75], and the incidence of HLA-DR4 in unselected RA patients is 60%–70%. Thus, LGL leukemia with RA and Felty’s syndrome are related disorders that appear to share some pathogenetic mechanisms.
LGL Leukemia Posttransplantation
Most of the lymphoproliferative disorders that occur following transplantation of both solid organs and hematopoietic stem cells are B-cell malignancies associated with Epstein-Barr virus (EBV) infection. Of the T-cell lymphoproliferative disorders reported, the majority of studies describes an aggressive NK-like malignancy, in which most patients die from the lymphoma within a few months, despite withdrawal of immunosuppressive therapy and combination chemotherapy [76, 77]. However, classic, indolent LGL leukemia has been described following renal [78] and liver transplantations [79]. Gentile et al. [78] described three patients who developed expansions of LGLs after renal allografting that was clonal by TCR gene rearrangement studies. All patients were receiving multiple immunosuppressive medications at the time of diagnosis and had indolent clinical courses, not requiring therapy for their lymphoproliferative disorder.
LGL Expansions after Stem Cell Transplant
LGL expansions following stem cell transplantation have been reported in several series, although a malignant, clonal disorder has not been clearly documented. Gorochov et al. [80] studied nine bone marrow transplant recipients with expansions of CD8+CD57+ cells to >15% of their total peripheral blood lymphocytes. They found a restricted use of Vß segments (Vß16 and Vß17 were overexpressed in the CD8+CD57+ population in six of the patients) with an oligoclonal pattern of the ß TCR gene. Dolstra et al. [81] reported that, in recipients of lymphocyte-depleted bone marrow allografts, the early repopulation of the peripheral blood with CD8+CD57+ T cells expressing the ß TCR was associated with a lower incidence of leukemic relapse and a higher incidence of cytomegalovirus (CMV) infection. Mohty et al. [21] found that 6 of 201 patients who underwent allogeneic stem cell transplantations over a period of 7 years had LGL expansions. The LGL proliferations were more frequent in patients with low-intensity preparative regimens, were associated with recurrent viral infections, especially CMV, and were temporally related to the achievement of complete remission of the patient’s primary hematologic malignancy. Two of these patients developed severe neutropenia, and one had significant autoimmune hemolytic anemia, necessitating treatment. However, TCR gene rearrangement studies were not performed in the latter two studies and, thus, it is not clear if these patients had a polyclonal or oligoclonal LGL expansion or a true LGL leukemia.
Natural History, Prognosis, and Therapy of LGL Leukemia
LGL leukemia is usually an indolent disorder, with a median survival time of over 10 years in some studies [15]. Some patients are diagnosed because of mild cytopenias and/or lymphocytosis and remain asymptomatic for a long period of time without therapy. Rare spontaneous remissions have been reported [82, 83]. However, the majority of patients require treatment at some point in their disease [9, 11, 12, 15, 18, 84].
No prospective clinical trials have been reported in this rare malignancy and, thus, treatment recommendations are based on case reports and retrospective studies (Table 7). The most common indication for therapy is recurrent infections secondary to neutropenia. Both G-CSF and GM-CSF improve neutropenia in these patients and are especially beneficial in patients with severe infections [85, 86]. Patients with Felty’s syndrome may develop autoimmune complications from G-CSF, including vasculitis, arthralgias, and thrombocytopenia, necessitating discontinuation of therapy or lowering of the dose [87].
Immunosuppressive agents directed against the malignant T cell are the mainstay of therapy in LGL leukemia and have been used successfully in patients with both neutropenia and anemia. Methotrexate, cyclophosphamide, and cyclosporine have all been shown to be effective in small series of patients, often in combination with prednisone. Although prednisone alone improves cytopenias in most patients, it rarely induces a sustained remission [88]. Loughran et al. reported on 10 patients with LGL leukemia and neutropenia treated with low-dose weekly oral methotrexate at 10 mg/m2 after having failed prednisone. Five patients had complete hematologic responses and, in three of these, gene rearrangement studies demonstrated the disappearance of the malignant clone after therapy [88]. The efficacy of methotrexate in patients with RA suggests that this drug should probably be used in patients in which LGL leukemia is associated with Felty’s syndrome [89]. Successful use of oral cyclophosphamide has been reported predominantly in patients with pure red cell aplasia (see above) [45, 90].
More recently, several studies have reported the successful use of cyclosporine for this condition, and responses were seen in patients who had failed other immunosuppressive agents. Sood et al. [91] treated five patients with LGL leukemia and neutropenia, with resolution of the low counts in all. Maintenance cyclosporine was required to sustain the counts, and the abnormal population of T-LGL cells persisted in all patients [91]. The doses of cyclosporine required to induce response in that study were 100–300 mg every 12 hours. In a recent study of 25 patients with LGL leukemia and cytopenias treated with cyclosporine 10 mg/kg/day for 3 months followed by a taper, 13 responded, although most required low-dose maintenance cyclosporine [92].
Purine analogues may have a role in the treatment of resistant patients. Sternberg et al. reported the reversal of severe neutropenia and/or anemia in four patients treated with fludarabine [93], although the malignant clone persisted. Similar success has been reported in case reports using pentostatin [94, 95].
Alemtuzumab, the humanized anti-CD52 monoclonal antibody, has efficacy against T-cell lymphoproliferative disorders, and a recent report describes the successful treatment of LGL-associated refractory PRCA with this agent [96].
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AGGRESSIVE FORMS OF LGL LEUKEMIA (CD3+CD56+)
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In most patients with aggressive LGL leukemia, the malignant, CD3+ T cells express CD56, an NK cell marker. Gentile et al. [97] described three patients who presented with severe systemic illness characterized by B symptoms, a rapidly enlarging spleen, extensive lymphadenopathy, and resistance to therapy. Patients had very high circulating levels of LGLs, which were CD3+CD8+ CD16+CD56+. Matutes et al. [98] described a patient with CD3+CD56+CD57– LGL leukemia who developed a Richter transformation of her LGL leukemia 11 years after diagnosis. Molecular analysis demonstrated that the aggressive lymphoma in that case arose from the indolent clone.
T-Cell Lymphomas
T cells are found mainly in mucosal surfaces and splenic red pulp and are part of the innate immune response, providing first-line defense in the mucosal linings. Malignancies of these cells are rare and, of these, the most common is the hepatosplenic T-cell lymphoma. Less frequently T-cell lymphomas can involve the skin and mucosal surfaces. Hepatosplenic lymphoma typically affects young men and is characterized by massive splenomegaly and hepatomegaly, but without lymphadenopathy [5, 99]. Flow cytometry usually demonstrates CD3+CD4–CD8–CD56+ CD57+ cells. Cytogenetic studies have shown that most hepatosplenic lymphomas demonstrate the presence of an isochromosome 7q [100]. The clinical course is usually aggressive, and although most patients have an initial response to combination chemotherapy, the majority of patients relapse early and die of their disease. Rarely, in patients with an otherwise classic indolent LGL leukemia, the leukemic cells display the TCR instead of the more common ß receptor [34].
NK Cell Leukemia/Lymphoma
Malignancies of NK cells are rare, aggressive disorders that cause both leukemia and extranodal infiltrations, with a predilection for the nasal cavity. In previous lymphoma classifications they were known by multiple terms, such as "angiocentric T-cell lymphoma" and "lethal midline granuloma," but in the current WHO classification they are recognized as predominantly NK cell malignancies [101, 102].
Both forms of this malignancy are strongly associated with EBV infection and are more common among Asians, Mexicans, and South Americans [103–107]. Immunophenotypically, the majority of these lymphomas express the NK-cell-related antigen CD56, do not express T-cell markers such as CD3, and do not rearrange their TCR genes.
Extranodal NK Cell Lymphoma
The most common site of involvement in patients with extranodal NK cell lymphoma is the nasal cavity. Patients present with symptoms of nasal obstruction, discharge, and bleeding, and, untreated, develop extension to the nasopharynx and sinuses, bone destruction, and systemic disease [106]. Organs involved in patients with extranasal disease include the gastrointestinal tract, the skin, the testis, and soft tissues. B symptoms are common, as is an association with hemophagocytic syndrome. Pathologically, specimens show extensive necrosis and ulceration, angiocentric growth, and infiltration of granular lymphocytes. Overall prognosis is poor, although in some studies, patients with early-stage disease achieved remissions with high-dose radiation therapy with or without combination chemotherapy [107, 108].
NK Cell Leukemia
Patients with NK cell leukemia tend to be younger than patients with extranodal disease and usually present with B symptoms, bone marrow involvement, organomegaly, high white blood cell counts, and, in some patients, hemophagocytic syndrome. Response to chemotherapy is usually poor and most patients succumb within days to months to their disease [102].
Chronic, indolent NK lymphocytosis, similar to T-cell LGL leukemia, has also been described. Most of these patients are asymptomatic, but they may develop cytopenias, splenomegaly, vasculitic skin lesions, and peripheral neuropathy [109].
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ACKNOWLEDGMENT
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We would like to thank Dr. Nelofar Q. Shafi for the pictures of peripheral blood and bone marrow.
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Learning Objectives
Abstract
