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Keywords:

  • T-PLL;
  • T-LGL;
  • ATLL;
  • biology;
  • therapy

Abstract

  1. Top of page
  2. Abstract
  3. T-Cell Prolymphocytic Leukemia
  4. Adult T-Cell Leukemia/Lymphoma
  5. T-Cell Large Granular Lymphocyte Leukemia
  6. Molecular Features and Pathogenesis
  7. Therapy
  8. Conclusions
  9. REFERENCES

Mature T-cell and NK-cell leukemias are a group of relatively uncommon neoplasms derived from mature or postthymic T-cells accounting for a relatively small percentage of lymphoid malignancies. The recent availability of modern immunophenotypic and molecular tools has allowed a better distinction of these disorders from their B-cell counterparts. Similarly, identification of recurrent cytogenetic abnormalities, as well as plausible mechanisms through which these molecular events influence cellular signaling pathways, have created further insight into the pathogenesis of these disorders. Furthermore, the availability of new agents such as alemtuzumab has generated significant interest in devising specific therapeutic strategies for these malignancies. Herein, we review the clinical and pathological features of mature T-cell leukemias. Cancer 2005. © 2005 American Cancer Society.


T-Cell Prolymphocytic Leukemia

  1. Top of page
  2. Abstract
  3. T-Cell Prolymphocytic Leukemia
  4. Adult T-Cell Leukemia/Lymphoma
  5. T-Cell Large Granular Lymphocyte Leukemia
  6. Molecular Features and Pathogenesis
  7. Therapy
  8. Conclusions
  9. REFERENCES

Clinical features

In 1973 Catovsky et al.1 were the first to describe a patient with prolymphocytic leukemia. T-cell prolymphocytic leukemia (T-PLL) is characterized by the proliferation of prolymphocytes with a mature postthymic phenotype (Fig. 1A).2 The median age at presentation is 63 years (range 33–91 years).3 Common presenting features of T-PLL include splenomegaly, generalized lymphadenopathy, skin infiltration, and serous effusions, particularly pleural.2, 3 The majority of patients present with widespread disease and an elevated lymphocyte count often over 100 × 109/L.4 Anemia and thrombocytopenia occur less frequently than in B-PLL.1 Human T-lymphotrophic viruses I and II (HTLV-I/II) are invariably negative by both serology and polymerase chain reaction (PCR) and a positive result for these viruses excludes this diagnosis.4–6

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Figure 1. Peripheral blood smear demonstrating the leukemia cells in (A) T-prolymphocytic leukemia, (B) adult T-cell leukemia/lymphoma, (C) T-large granular lymphocyte leukemia.

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In the majority of patients there is a predominance of small- to medium-sized lymphoid cells with prominent nucleoli and a nongranular basophilic cytoplasm in the peripheral blood.2 The small cell variant of T-PLL occurs in approximately 20% of patients. In this form the cells are small, have condensed chromatin, and a small nucleolus.7 Another morphological variant of T-PLL, the cerebriform (or Sézary cell-like) variant, has also been described and accounts for 5% of patients.3, 7, 8

The mature T-PLL cells are by definition negative for terminal deoxynucleotidyl transferase (TdT) and CD1a and express the pan-T-cell markers CD2, CD5, and CD7.2, 3 CD7 expression is bright and CD3 expression can be absent or weak, suggesting that T-prolymphocytes may be at an intermediate stage of differentiation between thymic and postthymic T-cells.3, 9 The majority of patients (60%) have the CD4+, CD8− phenotype, with CD4+/CD8+ coexpression in 25%, and fewer cases (15%) having the CD4−/CD8+ immunophenotype.3 CD52 expression is commonly bright and TCR γ and β chains are clonally rearranged.3 A lower incidence of the memory T-cell pattern of CD45 expression (i.e., CD45RO+/CD45RA−) has been reported in the more indolent variety of T-PLL.10

Molecular features

T-PLL patients often have a complex karyotype with recurrent alterations including chromosomes 14, 11, and 8. Rearrangements of chromosome 14q32.1 through inversion [inv(14)(q11;q32)] and translocation [t(14;14)(q11;q32)] are the most common cytogenetic abnormalities reported in T-PLL (Fig. 2).11, 12 As a result of these rearrangements, TCL1, a gene that is physiologically expressed in CD4/CD8 double-negative thymocytes, is deregulated.13, 14 Typically, the TCL1 locus rearranges with the T-cell receptor (TCR) α/δ chain locus in the above mentioned rearrangements, but it can also rearrange with the TCR-β chain locus on chromosome 7 in another translocation [t(7;14)(q35;q32.1)].14–17 Furthermore, several patients with mature T-cell leukemias have the translocation [t(X;14)(q28;q11)], which results in the rearrangement of the MTCP1 gene (a member of the TCL1 gene family) located at Xq28.18, 19 Therefore, chromosomal rearrangements in T-PLL juxtapose TCL1 and MTCP1 to the TCR loci and lead to their activation. Recent genomic analyses of the 14q32.1 breakpoint region has revealed three additional genes, TCL1b, TNG1 (T-CL1 neighboring gene 1), and TNG2, which have an expression pattern similar to TCL1 in that they are not expressed in normal T-cells, but are expressed in T-PLL cell lines and cells from patients with T-PLL.20–22 Activation of TCL1 through hypomethylation of its promoter has also been described.23

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Figure 2. Common cytogenetic abnormalities in T-PLL involving the TCL-1 gene.

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The molecular events related to the above chromosomal aberrations are believed to be causal in the pathogenesis of T-PLL.24 The protein product of TCL1 (Tcl-1) can interact in vitro with Akt kinase, a component of the PI3-kinase signaling pathway, which is important in the survival and proliferative functions of T-cells.25, 26 Through this interaction, Tcl-1 may promote the nuclear translocation of Akt and enhance its kinase activity. The oncogenic effect of Akt is through phosphorylation and activation of prosurvival molecules such as raf, bad, and IKKα and Tcl-1 appears to further promote this activity (Fig. 3).25 Recently, another nuclear target for Akt has been described that appears to be important in the oncogenic effects of Tcl-1. Nuclear receptor Nur77 is an important transcription factor in T-cell receptor-mediated apoptosis in immature thymocytes undergoing selection.27 Akt can interact with Nur77 in a PI3K-dependent manner and inhibit the proapoptotic function of Nur-77.28, 29 This effect can be further accentuated through the interaction of Akt and Tcl-1 (Fig. 3).

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Figure 3. Molecular consequences of TCL-1 dysregulation.

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Patients with the autosomal recessive disorder ataxia telangiectasia (AT) have biallelic inactivation of the ataxia telangiectasia mutated (ATM) gene. The association of AT with a clonal T-cell proliferation has been well described.30 Clonal cytogenetic abnormalities are present in the peripheral T-lymphocytes in 10% of patients with AT.31, 32 The abnormal lymphocytes in patients with AT share many features with the malignant cells in patients with T-PLL. Furthermore, in some patients with AT this clonal T-proliferation (known as AT clonal proliferation or ATCP) can progress into T-PLL, arguing that ATCP may represent the preleukemic stage of T-PLL.33 This is supported further by the observation that ATM-deficient knockout mice consistently develop an immature T-cell malignancy.34, 35 Furthermore, a subgroup of patients with T-PLL with an initial indolent course has been reported.10, 30, 33 Moreover, biallelic inactivation of the ATM gene at 11q23 has been demonstrated in sporadic T-PLL.36–38 This finding suggests that ATM aberrations can occur at a somatic level and play a role in malignant transformation of T-cells in patients with T-PLL.37

Therapy

T-PLL is often resistant to conventional chemotherapy, with survival duration in the region of 7 months.4, 39 Nucleoside analogs such as deoxycoformycin (DCF) have been used with limited success. In an early study, 68 patients with postthymic mature T-cell malignancies including 31 patients with T-PLL were treated with DCF 4 mg/m2 weekly for the first 4 weeks, then every 2 weeks until maximal response.40 Toxicity was very low, with only one death from prolonged neutropenia. Forty-eight percent of patients with T-PLL responded, including 3 patients who achieved a CR and 12 patients a PR.40 More recently, Mercieca et al.41 updated their results of 145 patients treated using the above regimen, with the last 30 patients receiving weekly pentostatin until maximal response; an overall response rate of 32% was reported.

Dearden et al.42 treated 39 patients with T-PLL (including 2 previously untreated patients) with alemtuzumab and reported an overall response rate of 76%, with 60% CR and 16% PR. The median disease-free interval was 7 months (range 4–45 mos). Survival was significantly longer in patients achieving a CR, with 9 patients remaining alive up to 29 months after the completion of therapy.42 Seven patients underwent an autologous stem cell transplant after therapy with alemtuzumab, with three remaining alive and in CR up to 15 months after the transplant. Four patients had an allogeneic transplant and three remained alive in CR up to 20 months after the transplant.42 Although the majority of patients responded to alemtuzumab, all but two patients who were followed up for more than 1 year had relapsed at the time of reporting.

In a follow-up study, Dearden et al.43 administered a standard regimen of alemtuzumab to 11 previously untreated patients with T-PLL. All patients achieved a CR. Response duration was 2–25 months (median 10+ mos). After a median follow-up of 12 months (range 4–27 mos), 7 patients remained alive and 4 had undergone an autologous stem cell transplant. One patient died from sepsis in CR; 4 patients relapsed at 4–25 months (median 13 mos) and died from progressive disease. More recently, Keating et al.44 treated 66 patients (4 previously untreated) with alemtuzumab and reported a response rate of 51% (39.5% CR). The median duration of CR was 8.7 months (range, 0.13+ to 44.4 mos) and the median time to progression was 4.5 months (range 0.1–45.4 mos).44 The median overall survival was 7.5 months (14.8 mos for patients achieving CR). The most common adverse events were infusion reactions. Fifteen infectious episodes occurred in 10 patients. Activity of alemtuzumab in T-PLL may be superior to that seen in patients with CLL probably due to the higher expression of CD52 on normal and leukemic T-cells as compared with B-cells.45

Therefore, alemtuzumab is currently considered the treatment of choice in patients with T-PLL. However, in a significant proportion of patients the responses are not durable, and strategies to further prolong the time to progression and overall survival are needed. Combination of alemtuzumab with nucleoside analogs such as DCF is one such strategy, which should be investigated prospectively. Patients with an available donor should be considered for an allogeneic stem cell transplant using standard or nonmyeloablative regimens.

Adult T-Cell Leukemia/Lymphoma

  1. Top of page
  2. Abstract
  3. T-Cell Prolymphocytic Leukemia
  4. Adult T-Cell Leukemia/Lymphoma
  5. T-Cell Large Granular Lymphocyte Leukemia
  6. Molecular Features and Pathogenesis
  7. Therapy
  8. Conclusions
  9. REFERENCES

Clinical features

Adult T-cell leukemia/lymphoma (ATLL) was first identified in Japan in 1977.46 The causative agent, human T-cell leukemia virus Type I (HTLV-I), is the first oncogenic retrovirus discovered in man.47 The virus is endemic in southwest Japan, the Caribbean basin, the southeastern United States, and Central and South America.48, 49 Overall, it is estimated that 20–30 million individuals are infected with the virus worldwide. In endemic areas of Japan, antibodies to HTLV-I are present in 6–37% of healthy adults, but only 2–4% of the carriers develop ATLL during a 70-year lifespan.50 Three main routes of HTLV-I transmission have been recognized, including transmission from mother to child through breast feeding, sexual transmission, and parenteral transmission through infected whole blood or blood components or by infected needles.51, 52 Transplacental transfer has also been rarely reported.53

The median age at diagnosis is 58 years, partly explained by the long latency period between infection and development of ATLL, ranging from 10–30 years.54 As a consequence, the disease is very rare in children. However, transfusion-related disease has been reported to occur earlier.52 The median age of onset is lower for African and Caribbean patients (43 years) than for the Japanese patients.49, 50

The clinical features of ATLL are diverse and four clinicopathologic subtypes have been recognized: acute, lymphoma, chronic, and smoldering.55 The majority of patients (57%) present with the acute form, whereas approximately 19% present in the chronic stage, 19% with nodal or extranodal disease (lymphoma subtype) with very little peripheral blood involvement, and 5% with the smoldering form.55 The chronic and smoldering forms of the disease have an indolent early course but progress to the acute form after a variable period of time.55

The main clinical manifestations of ATLL include lymphadenopathy, hepatosplenomegaly, skin lesions, osteolytic lesions, central nervous lesions, and hypercalcemia.56–58 In the acute and lymphomatous forms of the disease patients are immunocompromised and may develop a number of opportunistic infections.49, 58 The prognosis for acute and lymphoma subtypes is poor, with a median survival of only 6.2 and 10.2 months, respectively.48, 59 The smoldering form of the disease is characterized by a normal peripheral blood leukocyte count but with tumor infiltration of skin and/or lung.59 Four-year survival times have been reported to be 5% for the acute type, 5.7% for the lymphoma type, 26.9% for the chronic type, and 62.8% for the smoldering type.55

Opportunistic infections occur commonly in patients with ATLL. Infection with strongyloidiasis has been reported in all clinical subtypes of ATLL as well as the carriers of the virus.60 Interestingly, opportunistic infections have also been reported in healthy carriers.49, 58 This has been attributed to lymphotropic effects of HTLV-I as well as immunosuppressive factors released from ATLL cells.49, 55, 60

Diagnosis of ATLL is usually based on morphological and immunophenotypic assessment of peripheral blood lymphocytes as well as serological testing for HTLV-I antibodies.61 In the acute and lymphomatous subtypes, the peripheral blood malignant cells are often medium-sized to large and commonly have marked nuclear pleomorphism with polylobulated nuclei or ‘flower cells’ being a common feature (Fig. 1B).61 The nuclear chromatin is coarse, with distinct nucleoli. Marrow involvement can be patchy and lymph node involvement is paracortical to diffuse. The pattern of skin infiltration is variable, with some cases demonstrating epidermotropism with Pautrier-like microabscesses resembling classic mycosis fungoides.49, 61

The immunophenotype of ATLL is consistent with the postthymic nature of the neoplastic T-cells, with expression of T-cell-associated antigens such as CD2, CD3, and CD5 and an absence of TdT and CD1a.61, 62 CD7 is commonly negative and the majority of patients' cells are CD4+/CD8−, with only rare patients having the double-positive or double-negative phenotype.63 The lymphocytic activation markers HLA-DP, DQ, DR, and the interleukin (IL)-2 alpha chain receptor, CD25, are expressed in nearly all cases of ATLL.61

Molecular features

An increased understanding of the interactions between the HTLV-I viral products and cellular molecules has shed light on the mechanisms underlying the pathogenesis of the disease.48 The HTLV-I provirus genome includes gag, pol, and env genes encoding the viral matrix, capsid, nucleocapsid, and envelope proteins, as well as enzymes such as reverse transcriptase and integrase.48, 64 In addition, the HTLV-I genome contains unique genes encoded by sequences at the 3′ end of the genome, referred to as pX.64 The proteins encoded by these genes are regulatory proteins and are known as Tax, Rex, p12, p30, and p21.65 Transacting transcriptional activation by Tax through its interaction with cellular transcription factors such as NF-κB and the members of the cAMP responsive element binding proteins (CREB)/activating transcription factor (ATF) family has been demonstrated.66 Many heterologous promoters such as those for the genes for interleukin-2 (IL-2), IL-2Rα chain, IL-13, IL-15, tumor growth factor-β (TGF-β), granulocyte/macrophage colony-stimulating factor (GM-CSF), c-myc, and tumor necrosis factor-β (TNF-β) contain NF-κB binding sites and are transactivated through an interaction between Tax protein and NF-κB/Rel proteins.67–69 Other genes such as those for IL-1, IL-6, major histocompatibility complex class I (MHC-I), and parathyroid hormone-related protein (PTHrP) are activated by Tax through unknown mechanisms.70, 71 Transcriptional repression of some genes such as DNA polymerase-β, p18, and p53 by Tax protein has also been described.72, 73 Other effects of Tax include interaction with the cyclin-dependent kinase (CDK) inhibitor p16INK4A resulting in activation of CDK4, interaction with and inhibition of checkpoint kinase-1 (Chk1), and promotion of nuclear translocation of NF-κB through binding its cytoplasmic inhibitor, IKK.74, 75 The dysregulated expression of these genes with important roles in cell-cycle regulation, apoptosis, and proliferation leads to the development of HTLV-I-related diseases and contributes to their clinical features (Fig. 4).48, 76–78

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Figure 4. Oncogenic effects of viral tax protein.

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Constitutive activation of the Jak-Stat pathway has also been demonstrated in HTLV-1-transformed, IL-2-independent T-cells.79, 80 Takemoto et al.80 evaluated the activation/phosphorylation status of the Jak-Stat pathway as well as DNA-binding of Stat proteins in cell extracts of leukemic cells from patients with ATLL. They demonstrated the constitutive DNA-binding of one or more Stat proteins as well as an association between Stat activation and cell-cycle progression. More recently, Mohapatra et al.81 demonstrated induction of apoptosis in the HTLV-1-transformed cell line MT-2 through inhibition of Stat activation. These results may suggest a role for inhibition of the Jak-Stat pathway for the treatment of patients with ATLL.

Therapy

Despite significant advances in understanding the pathogenesis of ATLL, treatment of patients with ATLL remains disappointing. Combination chemotherapy regimens have been of limited success, possibly due to the intrinsic resistance of ATLL cells, the associated immunosuppression, and the frequent poor performance status of the patients. Overexpression of the multidrug resistance gene and mutations of the p53 gene have been described and probably contribute to this drug resistance.59, 82

Single-agent chemotherapy has produced low response rates and nucleoside analogs such as deoxycoformycin and cladribine have been of limited value.40, 83 Several trials have investigated the feasibility and efficacy of combination regimens.59, 84, 85 Although these regimens are generally associated with an increased response rate, response duration and overall survival remain short.86 Autologous and allogeneic transplant have been performed in a few patients, with little success.84, 87 Combination of the antiretroviral drug zidovudine (AZT) and interferon-α (IFN-α) was reported to have significant activity, with an overall response rate of 58% in patients with ATLL including those who had failed prior cytotoxic chemotherapy.88 Other reports of this combination in ATLL suggested variable response rates up to 92%, with a median overall survival of 11 months.89, 90

Several new approaches to the treatment of patients with ATLL have been proposed.91 The combination of arsenic trioxide and IFN-α reduced tax expression and reversed the tax-induced constitutive NF-κB activation, and has demonstrated activity in some patients.92, 93 The proteasome inhibitor PS-341 affects multiple survival pathways in HTLV-I-positive T-cells and may have a potential therapeutic role.94, 95 Immune-based therapy with Tax-directed vaccines as well as antibody therapy directed at leukemia cell antigens may also have a therapeutic role in the future.96, 97 ATLL cells have a high expression of CD25 (IL-2Rα) on their cell surfaces and humanized anti-Tac antibody (daclizumab) is currently under evaluation. In an early study, anti-Tac monoclonal antibody produced responses in 7 of 18 patients.98 More recently, responses were reported in 9 of 16 evaluable patients treated with anti-Tac labeled with yttrium-90.99 The duration of remission was longer when compared with previous results with unmodified anti-Tac antibody.99 Further studies evaluating combinations of monoclonal antibodies with chemotherapy are ongoing.

T-Cell Large Granular Lymphocyte Leukemia

  1. Top of page
  2. Abstract
  3. T-Cell Prolymphocytic Leukemia
  4. Adult T-Cell Leukemia/Lymphoma
  5. T-Cell Large Granular Lymphocyte Leukemia
  6. Molecular Features and Pathogenesis
  7. Therapy
  8. Conclusions
  9. REFERENCES

Clinical features

The first detailed description of a syndrome with increased numbers of circulating large granular lymphocytes (LGLs) associated with chronic neutropenia dates back to 1977.100 The first definition of this entity as LGL-leukemia was the result of a description of the clonal nature of the disease.101 Normally, LGLs account for approximately 10–15% of peripheral blood mononuclear cells and include suppressor T-cells as well as natural killer (NK) cells. Similarly, neoplastic proliferations of LGLs may also be characterized as T- or NK-LGL leukemias based on the expression or absence of T-cell markers such as surface CD3.102 T-LGL leukemia usually expresses surface CD3, CD8, CD16, and CD57, whereas NK-LGL leukemia express CD2 and cytoplasmic but not surface CD3 and are variably positive for CD16, CD56, and CD57.102

T-LGL leukemia is characterized by a persistent increase in the number of peripheral blood LGLs and is commonly associated with neutropenia and anemia.103–105 Traditionally, an increase in the peripheral blood LGLs to greater than 2.0 × 109/L lasting for more than 6 months was used as the necessary criterion for the diagnosis.106–108 However, more recently evidence of clonality of the T-cell proliferation is required.104 The median age at diagnosis for T-LGL leukemia is 55–60 years, but the disease has been reported in all age groups.105, 109 Approximately one-third of patients are asymptomatic but the majority present with recurrent bacterial infections. Splenomegaly is present in about half of patients and 25% have an enlarged liver. Lymphadenopathy is uncommon. Neutropenia is present in about 85% of patients and is severe in about 50%. Anemia and thrombocytopenia occur in about 50% and 20% of patients, respectively.109 These cytopenias are due to an inhibitory effect of the leukemic cells on normal hematopoiesis and not as a result of marrow infiltration or hypersplenism.110 Neutropenia is secondary to neutrophil destruction resulting from Fas-mediated apoptosis by direct contact of LGL cells expressing Fas ligand (FasL) or through paracrine effects of soluble FasL.110–113 Neutropenia may be accentuated by increased margination as a result of activation of neutrophils by precipitated immune complexes.110

T-LGL leukemia is commonly associated with autoimmune disorders including immune thrombocytopenia, autoimmune hemolytic anemia, pure erythrocyte aplasia, rheumatoid arthritis, and Felty syndrome.105 Serological abnormalities are also common and include polyclonal hypergammaglobulinemia, hypogammaglobulinemia, circulating immune complexes, antineutrophil and antiplatelet antibodies, and a positive test for rheumatoid factor (RA) and antinuclear antibody (ANA).102, 105 Defective cellular immunity with a decrease in the number and function of NK cells has also been reported.114

Diagnosis of T-LGL should be entertained in patients presenting with pure erythrocyte aplasia as well as those with chronic or adult-onset cyclic neutropenia. The predominant cells in peripheral blood and bone marrow films are LGLs with abundant cytoplasm and fine and coarse azurophilic granules (Fig. 1C).100, 106 The extent of bone marrow involvement is variable; there is often an interstitial infiltrate with the lymphocytes accounting for approximately 50% of marrow cellular elements.103 A minority of patients have cytogenetic abnormalities.101, 115, 116 However, in most patients T-cell receptor (TCR) gene rearrangement analysis by PCR or Southern blot analysis is used to establish the clonal nature of the malignant LGL population.104 Flow cytometry can also be used to evaluate the presence of a discrete population of neoplastic LGLs, although its role has not yet been established. Monoclonal antibodies against the TCR variable region β chain gene segments can be used to screen for unbalanced use of β chain gene families.117

T-LGL leukemia cells have a mature T-cell immunophenotype and commonly express CD3, TCRαβ, CD8, CD16, and CD57.103, 105, 109 The expression of CD56 is variable and tends to be associated with a more aggressive clinical course.118 The common variant of T-LGL leukemia lacks the expression of CD4, but rare variants have been reported to be CD4+/CD8−, CD4+/CD8+, CD4−/CD8−.103, 119 In the majority of cases the TCR is of the αβ subtype, but rare TCRγδ+ variants have also been reported.120 Expression of CD26 has been reported to be indicative of clinically aggressive disease.121

Molecular Features and Pathogenesis

  1. Top of page
  2. Abstract
  3. T-Cell Prolymphocytic Leukemia
  4. Adult T-Cell Leukemia/Lymphoma
  5. T-Cell Large Granular Lymphocyte Leukemia
  6. Molecular Features and Pathogenesis
  7. Therapy
  8. Conclusions
  9. REFERENCES

Leukemic LGLs are the neoplastic counterparts of antigen-driven and activated cytotoxic T-lymphocytes (CTLs) that contain several cytolytic proteins such as perforin, granzyme, and FasL. Constitutive expression of high levels of perforin and FasL by leukemic LGL cells has been described.111, 122 This is further corroborated by the recent microarray data demonstrating the up-regulation of these genes in T-LGL cells in a pattern similar to activated cytotoxic T-cells.123 Further evidence for antigenic selection is based on analysis of TCR gene rearrangement and TCR Vβ repertoire.124, 125 The antigen responsible for activation of these CTLs has not been identified. However, antibodies against proteins homologous to human T-lymphotropic virus I (HTLV-1) and HTLV-II have been reported in some patients, suggesting the possible role of a retroviral infection.126–128

Abnormalities in the Fas/Fas ligand pathway resulting in dysregulated apoptosis are thought to play an important role in the pathogenesis of LGL leukemias.113 Activated CTLs are normally eliminated through Fas-mediated apoptosis. However, LGL leukemic cells are resistant to Fas-mediated cell death.113 Furthermore, leukemic LGLs express high levels of Fas and Fas ligand and high levels of soluble Fas has been reported in the sera of patients with LGL leukemia.113 These high levels of soluble Fas may block the Fas-mediated apoptosis of LGL leukemic cells and contribute to the neoplastic process.129 Recent reports have demonstrated a correlation between the serum level of Fas ligand and disease activity and normalization of these levels with successful therapy.113, 130

Other mechanisms of LGL leukemia-mediated suppression of hematopoiesis have also been proposed. Inhibitory receptors in the immunoglobulin gene superfamily normally expressed by NK cells and a subset of memory cytotoxic T-cells have been described. These killing inhibitory receptors (KIRs) recognize the specific human leukocyte antigen (HLA)-I allotypes to promote self-tolerance.131 T-LGL cells are frequently KIR-positive and usually express a single, or rarely two, KIR isoforms in a clonotypic pattern.132 As the genes encoding the KIR receptors and HLA-I molecules are not linked, it is possible that the KIR expressed by the LGL may not recognize any of the self HLA-I alleles, resulting in KIR/HLA-I mismatch.133 This KIR/HLA-I mismatch could contribute to the ability of the neoplastic cells to inappropriately destroy self cells and suppress hematopoiesis.133 Such incompatibility between clonal KIR expression profile and host HLA class I has been reported in T-LGL.133

Therapy

  1. Top of page
  2. Abstract
  3. T-Cell Prolymphocytic Leukemia
  4. Adult T-Cell Leukemia/Lymphoma
  5. T-Cell Large Granular Lymphocyte Leukemia
  6. Molecular Features and Pathogenesis
  7. Therapy
  8. Conclusions
  9. REFERENCES

The median survival of patients with T-LGL is generally on the order of 10 years and occasionally spontaneous remissions have been reported.134, 135 However, the majority of patients will eventually require therapy.106, 116, 134, 136 Unfortunately, because of the rarity of the disorder, no prospective clinical trials have been reported and current treatment strategies are based on anecdotal case reports and small retrospective studies. Indications for treatment include neutropenia and anemia. Several drugs are known to have activity and include immunosuppressive agents such as low-dose methotrexate, cyclosporine, low-dose cyclophosphamide, and prednisone.134, 137–139 Treatment with weekly oral low-dose methotrexate can result in the disappearance of the abnormal clone at least in some patients.137 Prednisone alone is not recommended as the disease generally relapses after its taper and its use may increase risk of infections.134 Successful therapy with cyclophosphamide has been reported in patients with pure erythrocyte aplasia.139

The primary objective of therapy in T-LGL is to improve the associated cytopenias. As such, not all patients with T-LGL need therapy. Furthermore, it may not be necessary to eliminate the T-cell clone for a clinical response.138 In fact, the neoplastic clone rarely disappears even after high-dose therapy. Other treatment modalities including growth factors such as granulocyte colony-stimulating factor and erythropoietin, as well as splenectomy, can occasionally be used to improve the cytopenias.

Patients with a more aggressive clinical course have been treated with regimens designed for treating lymphomas, although these do not appear to be highly effective.118 This may be related to the high expression of the multidrug resistance (MDR) genes in the leukemic LGLs.140 Purine analogs such as fludarabine, pentostatin, and 2-chlorodeoxyadenosine have been used with some success, either alone or in combination with other agents.41, 141, 142 Recently, alemtuzumab has been reported to be effective in treating patients with refractory T-LGL.143

Conclusions

  1. Top of page
  2. Abstract
  3. T-Cell Prolymphocytic Leukemia
  4. Adult T-Cell Leukemia/Lymphoma
  5. T-Cell Large Granular Lymphocyte Leukemia
  6. Molecular Features and Pathogenesis
  7. Therapy
  8. Conclusions
  9. REFERENCES

Mature, postthymic T-cell leukemias comprise a small fraction of patients with leukemia. Traditionally, therapeutic strategies have been dictated by anecdotal reports and retrospective studies in small patient groups. With increased understanding of the biology of these disorders, as well as introduction of better diagnostic tools, we will likely be able to provide more effective treatment options to this patient population. Enrollment into ongoing clinical trials should be encouraged.

REFERENCES

  1. Top of page
  2. Abstract
  3. T-Cell Prolymphocytic Leukemia
  4. Adult T-Cell Leukemia/Lymphoma
  5. T-Cell Large Granular Lymphocyte Leukemia
  6. Molecular Features and Pathogenesis
  7. Therapy
  8. Conclusions
  9. REFERENCES