American Journal of Hematology 82:481485 (2007)

Aggressive T-cell Large Granular Lymphocyte Leukemia: A Case Report and Review of the Literature
Todd J. Alekshun,1 Jianguo Tao,2 and Lubomir Sokol3 *
1

Division of Hematology and Oncology, H. Lee Moftt Cancer Center and Research Institute, University of South Florida, Tampa, Florida 2 Department of Interdisciplinary Oncology, Division of Hematopathology and Laboratory Medicine, H. Lee Moftt Cancer Center and Research Institute, University of South Florida, Tampa, Florida 3 Department of Interdisciplinary Oncology, Division of Malignant Hematology, H. Lee Moftt Cancer Center and Research Institute, University of South Florida, Tampa, Florida

The majority of patients with T-cell large granular lymphocyte (LGL) leukemia will have an indolent clinical course. Herein, we report a case of an aggressive T-cell LGL leukemia in a previously healthy 42-year-old Caucasian male who presented with acute onset of Bsymptoms, hepatosplenomegaly, lymphocytosis, moderate anemia, and thrombocytopenia. Immunophenotypically, the malignant cells co-expressed CD3+CD8+CD56+ markers and the T-cell receptor beta (TCR b) gene demonstrated clonal rearrangement. The patient was treated with an intensive chemotherapeutic regimen (hyper-CVAD) and he achieved a complete remission. A systematic review of all available English literature revealed 12 welldescribed cases of aggressive T-cell LGL leukemia suggesting that this variant is a new and distinct entity in the spectrum of LGL disorders. Am. J. Hematol. 82:481485, 2007.
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Key words: aggressive T-cell LGL leukemia; diagnosis; therapy

INTRODUCTION

Large granular lymphocyte leukemia (LGL) represents a spectrum of lymphoproliferative disorders arising either from T-cell (CD3+) or NK-cell (CD3) lineages [1]. The World Health Organization (WHO) classication of lymphoid malignancies recognizes only two distinct entities derived from large granular lymphocytes (LGLs): indolent T-cell LGL leukemia and aggressive NK cell leukemia [2,3]. However, several cases of aggressive T-cell LGL leukemia have been reported using different terms including CD3+CD56+ aggressive variant T-cell LGL leukemia, aggressive lymphoma of T-cell large granular lymphocytes, and aggressive acute LGL leukemia [36]. The majority of patients described in these reports presented with symptoms of acute illness, hepatosplenomegaly, lymphadenopathy, lymphocytosis, and variable degrees of anemia or thrombocytopenia. Leukemic LGLs typically displayed a CD3+CD8+CD56+ immunophenotype along with variable expression of other T-cell or NK-cell markers. In particular, this hematologic entity primarily affected younger people, with a median age of 41 years (range 964 years), without ethnic predilection.
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In general, these patients had poor prognoses and their survival ranged from several months to 2 years. In this report, we summarize the published literature that is relevant to aggressive T-cell LGL leukemia using a PubMed search through March 2006. Furthermore, we also discuss our own experience and suggest diagnostic criteria and therapies for aggressive T-cell LGL leukemia.
CASE REPORT

A previously healthy 42-year-old Caucasian male was referred to our center for further evaluation
*Correspondence to: Lubomir Sokol, M.D., Ph.D., Department of Interdisciplinary Oncology, Division of Malignant Hematology, H. Lee Moftt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612. E-mail: sokolL@moftt.usf.edu Received for publication 18 April 2006; Revised 25 September 2006; Accepted 12 October 2006 Published online 4 January 2007 in Wiley InterScience (www. interscience.wiley.com). DOI: 10.1002/ajh.20853

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Fig. 1. Peripheral blood smear demonstrates circulating atypical cells with an irregular nuclear contour, coarse chromatin, distinct nucleoli, and azurophilic granules consistent with large granular lymphocytes (arrow). [Color gure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

Fig. 2. Bone marrow biopsy demonstrates diffuse involvement by atypical large granular lymphocytic cells. [Color gure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

and management of his lymphocytosis, which was associated with acute abdominal pain, fevers, and hepatosplenomegaly. Additional symptoms included a 3-week history of generalized malaise, anorexia, and vomiting without associated weight loss. His physical examination revealed a well developed, uncomfortable appearing male with a temperature of 100.58F, normal hemodynamics and respirations. He had no palpable peripheral lymphadenopathy, however, splenomegaly and hepatomegaly were evident. His complete blood prole revealed: a WBC of 53.3 109/l, with 90% atypical lymphocytes, 5% neutrophils, 2% monocytes, hemoglobin of 14 g/dl, and a platelet count of 59 109/l. Pertinent chemistries revealed: LDH of 1,082 U/l, total bilirubin of 4.6 mg/dl that was predominantly conjugated, alkaline phosphatase of 261 U/l, ALT of 67 U/l, total protein of 5.3 g/dl, albumin of 2.6 g/dl. The serology for human T-cell lymphotrophic virus (HTLV) type I and II, HIV-1 and 2, Hepatitis A, B, and C were negative. CMV IgG was positive but CMV IgM and CMV DNA were negative. Epstein-Barr virus (EBV) DNA was demonstrated in peripheral blood but no clonal episomal EBV was detected in leukemic cells. All blood cultures were negative. The peripheral blood smear (see Fig. 1) revealed atypical lymphocytes that constituted 90% of the white blood cell population. A bone marrow biopsy with aspirate (see Fig. 2) revealed a hypercellular marrow with diffuse replacement by an atypical lymphoid inltrate accounting for 70% of the overall cellularity. The karyotype was 46, XY. MultiparaAmerican Journal of Hematology DOI 10.1002/ajh

meter ow cytometry demonstrated a TdTCD3+ CD8+CD56+CD57 immunophenotype. The T-cell receptor was positive for rearrangement of the b gene. Computerized axial tomography (CAT) scan of the thorax did not reveal any pulmonary parenchymal abnormalities or mediastinal lymphadenopathy. CAT scan of the abdomen demonstrated hepatosplenomegaly and multiple lymph nodes within the periaortic and aortocaval regions. The spleen contained multiple areas of hypoattenuation suspicious of splenic infarcts. The liver contained no focal masses or ductal dilation. Upon conrming his diagnosis of aggressive T-cell LGL leukemia, he was initiated on the hyper-CVAD protocol consisting of four cycles of fractionated cyclophosphamide with vincristine, doxorubicin, and dexamethasone alternating with four cycles of high-dose methotrexate (MTX) and cytarabine (ara-C) [7]. Each cycle was administered every 21 days with growth factor support. He tolerated this treatment without complications, and developed resolution of his systemic symptoms, hepatosplenomegaly, and normalization of his CBC and liver function tests. A repeat bone marrow biopsy was consistent with complete hematologic remission. Since there is no data supporting the administration of prophylactic intrathecal (IT) chemotherapy for the treatment of LGL leukemia, IT chemotherapy was not administered with his induction protocol. However, during an evaluation for hematopoietic cell transplantation (HCT) our patient was found to have leukemic cells within his cerebrospinal uid (CSF) that required IT therapy with MTX and ara-C via an Ommaya reservoir. After sterilization of his CSF, he underwent mobili-

Case Report: Agressive T-cell LGL Leukemia

TABLE I. Features of Reported Cases of Aggressive T-cell LGL Leukemia Patient 1 2 3 4 5 6 7 8 9 10 11 12 13 Absolute WBC (1 109/l) 14.8 29.9 19.0 17.9 2.0 18.2 6.0 3.0 2.6 55.0 9.0 106.0 53.3
+

483

Immunophenotype CD3 CD8 CD56 CD57 CD3+CD8+CD56+CD57 CD3+CD8+CD56+CD57 CD3+CD8+CD56+CD57 CD3+CD8+CD56+CD57 CD3CD8+CD56+CD57 CD3+CD8+CD56+CD57 CD3+CD8+CD56+CD57 CD3+CD8+CD56+CD57 CD3+CD4CD8CD56+CD57 CD3+CD8+CD56CD57 sCD3cCD3+CD8+CD56CD57a sCD3cCD3+CD4+CD8+CD56CD57b CD3+CD8+CD56+CD57
+ +

Karyotype 46XX 46XY NS 46XY 46XY,i(7),t(8;14),+13 46XX,t(2;17),+14 46XY,i(7),+12 NS NS i(7q) NS NS 46XY

Reference nos. 3 3 3 4 4 4 4 4 4 4 5 6

NS, not stated; WBC, white blood cell. Peripheral blood. b Lymph node.
a

zation of peripheral blood hematopoietic cells with a G-CSF and alemtuzumab regimen. High dose chemotherapy with BEAM (BCNU, etoposide, cytarabine, and melphalan) was used as a conditioning regimen for autologous hematopoietic cell transplantation. The patient tolerated HCT without signicant complications.
DISCUSSION

Since the rst description of aggressive variant T-cell LGL leukemia by Gentile et al. [3], Macon et al. reported seven cases of natural killer (NK)like T-cell lymphoma manifesting a similar phenotype and clinical behavior [4]. Additionally, Tordjman et al. [6] and Falcao et al. [5] each reported one case of an aggressive T-cell LGL leukemia with differing immunophenotypes. In the series reported by Gentile et al., all three cases appeared to arise in immunocompetent individuals [3]. These patients manifested systemic B symptoms, splenomegaly, peripheral lymphadenopathy, and lymphocytosis within 3 months of presentation (Table I and Table II). The malignant cells in all three cases displayed a CD3+CD8+CD56+CD57 immunophenotype and clonally rearranged TCR b gene. Each patient developed disease progression despite treatment with varying regimens, which are summarized in Table II. Two patients received salvage chemotherapy with high-dose cyclophosphamide and a pediatric acute lymphoblastic leukemia (ALL) chemotherapeutic regimen, respectively. Both patients underwent evaluation for allogeneic hematopoietic cell transplantation at the time of the publication. The third patient died following a splenectomy. Similarly, Macon et al. [4] described seven cases of aggressive lymphoma of T-cell large granular lym-

phocytes. Five patients displayed identical immunophenotypes as displayed in our patient, while one patient lacked expression of surface CD3 (sCD3) but expressed cytoplasmic CD3 (Table I). However, all patients had TCR b gene rearrangements. Unique among four patients were pre-existing chronic immunosuppression. Three patients had received a solid organ allograft and one was treated with immunosuppressive therapy for ulcerative colitis. All four patients died within 5 months of presentation despite treatment with systemic chemotherapy. There was only one complete response, lasting 22 months, in a 9-year-old who received the Memorial Sloan-Kettering-New York-II Protocol [8]. Tordjman et al. reported one case of an aggressive T-cell LGL leukemia in an 18-year-old Caucasian female who presented with systemic B symptoms, hepatosplenomegaly, and peripheral lymphadenopathy [6]. Two distinct immunophenotypic cell populations were detected by ow cytometry from malignant cells obtained from her peripheral blood and a lymph node (Table I). Treatment with an intensive regimen designed for adult ALL induced a complete response for 18 months, however she subsequently relapsed. Passetto et al. published one case of an aggressive T-cell LGL leukemia arising in a patient with sarcoidosis [5]. She developed mediastinal lymphadenopathy, a pleural effusion, systemic B symptoms, and a lymphocytosis. Cells from her peripheral blood and pleural effusion demonstrated a CD3+CD8+CD56CD57 immunophenotype with T-cell receptor gamma (TCR g) gene rearrangement. She was treated with corticosteroids and cyclophosphamide but did succumb to complications. Upon developing a differential diagnosis for an aggressive T-cell LGL leukemia, three distinct
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TABLE II. Clinical Characteristics and Treatment of Reported Cases of Aggressive T-cell LGL Leukemia Patient 1 2 3 4 5 6 7 8 9 10 11 12 13 Age/sex 14/F 52/M 41/M 64/M 32/M 9/F 16/M 62/M 64/M 62/F 46/F 18/F 42/M Symptoms SM, anemia, LAN, B symptoms SM, LAN, B symptoms SM, anemia, LAN, B symptoms Anemia, B symptoms SM, anemia, B symptoms SM, anemia, LAN, B symptoms SM, anemia, B symptoms SM, SM, SM, SM, SM, anemia, B symptoms anemia, LAN, B symptoms anemia, LAN, B symptoms B symptoms anemia, LAN, B symptoms Therapy ALL induction regimen, consolidation 1. CHOP 2. High-dose Cy 1. Oral Cy 2. 2-CdA None Mega IV MSK-NY-II MSK-NY-II None CHOP CHOP Prednisone + Cy 1. ALL-type regimen 2. Salvage therapy (NS) HyperCVAD Outcome Alive at time of report Alive at time of report Died after 6 months. Died after 20 days Died after 2 months without evidence of disease CR for 22 months Died after 3 months without evidence of disease Died after 20 days Died after 5 months Died after 2 months Died after 3 months CR for 18 months, then relapsed Alive at time of report CR alive at time of report Reference nos. 3 3 3 4 4 4 4 4 4 4 5 6

SM, anemia, B symptoms

ALL, acute lymphoblastic leukemia; 2-CdA, cladribine; CR, complete response; Cy, cyclophosphamide; F, female; LAN, lymphadenopathy; M, male; NS, not stated; SM, splenomegaly. TABLE III. Characteristics of Distinct T/NK-Cell Entities T-cell LGL leukemia (indolent) Most common immunophenotype TCR gene rearrangement Clinical presentation CD3+CD8+CD57+ TCRab + 1. One third asymptomatic 2. Two thirds symptomatic with recurrent infections, splenomegaly, rheumatoid arthritis 1. Clinical trial preferred or 2. Immunosuppressive therapies Aggressive T-cell LGL leukemia CD3+CD8+CD56+ TCRab + All patients are symptomatic with acute B-symptoms, HSM, LAN, cytopenias 1. ALL-like induction regimens 2. Consolidation with HCT Aggressive NK-cell leukemia CD3CD8CD56+ All patients are symptomatic with acute B-symptoms, HSM, LAN, cytopenias

HSTL CD3+CD4CD8CD56+ TCR gd + All are patients are symptomatic with B-symptoms, HSM, cytopenias

Therapy

1. ALL-like induction regimens 2. Consolidation with HCT

1. CHOP-like therapies 2. Alemtuzumab 3. Consolidation with HCT

ALL, acute lymphoblastic leukemia; HCT, hematopoietic cell transplantation; HSM, hepatosplenomegaly; HSTL, hepatosplenic T-cell lymphoma; LAN, lymphadenopathy; TCR, T-cell receptor.

T/NK-cell entities must be considered (Table III). Indolent T-cell LGL leukemia cytologically resembles and shares a similar immunophenotype with aggressive T-cell LGL leukemia. However, indolent T-cell LGL leukemia lacks expression of the NK-cell marker, CD56, but expresses CD57. This leukemia frequently manifests with neutropenia and is associated with underlying autoimmune diseases. Furthermore, these patients may also present with splenomegaly, but hepatomegaly, lymphadenopathy, and acute onset of B symptoms are not common. Careful surveillance or treatments with immunosuppressive therapies are the mainstays of managing this condition [1]. Molecular mechanisms responsible for
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biological differences between indolent and aggressive T-cell LGL leukemia are not well understood. However, it was postulated elsewhere that production of distinct arrays of proinammatory and proapoptotic cytokines by leukemic cells could correlate with disease behavior [9]. A comparison of gene expression proling of two cell lines derived from indolent and aggressive phases of LGL leukemia revealed distinct gene proles suggesting a role of different pathogenic mechanisms in these two entities [10]. Aggressive NK-cell leukemia resembles aggressive T-cell LGL leukemia as both conditions present in an acute manner and manifest with B symptoms,

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organomegaly, and cytopenias. The morphology of leukemic cells in both hematologic conditions is similar. The prognosis from either entity is poor. In contrast, at least four characteristics distinguish aggressive NK-cell LGL leukemia from aggressive T-cell LGL leukemia. Aggressive NK-cell LGL leukemic cells are: (1) sCD3 with (2) TCR genes in a germinal conguration, along with (3) clonal episomal EBV within leukemic cells. Additionally, the fourth characteristic is that aggressive NK-cell LGL leukemia appears to be more prevalent in the Asian population. Hepatosplenic T-cell lymphoma (HSTL) can also mimic aggressive T-cell LGL leukemia. Patients with HSTL are typically young and often present with hepatosplenomegaly and peripheral cytopenias. The majority of malignant cells display a CD3+ CD4CD8CD56+ and TCR gamma delta (TCR gd) immunophenotype. However, in a minority of cases the malignant cells may display a TCR alpha beta (TCR ab) and CD8+ immunophenotype. The most common cytogenetic abnormality is isochromosome 7q (i7q), but this abnormality is not unique to HSTL. Our review suggests that a diagnosis of aggressive T-cell LGL leukemia can be unequivocally established based upon four clinical and laboratory features: (1) an absolute LGL count in the peripheral blood >500 cells/ml (frequently >10,000 cells/ml) (2) presence of a characteristic immunophenotype: CD3+CD8+CD56+ or variants (refer to Table I) (3) demonstration of clonally rearranged TCR genes, and (4) development of acute onset of systemic B symptoms, hepatosplenomegaly, peripheral cytopenias, and lymphadenopathy.
CONCLUSION

leukemia and recognize the clinical manifestations and laboratory features that differentiate this condition from other T/NK-cell malignancies. Furthermore, our review suggests that patients who develop aggressive T-cell LGL leukemia will have a poor prognosis if treated with conventional doses of systemic chemotherapy. Despite limited data, treatment with intensive ALL-like induction chemotherapy regimens containing IT prophylaxis followed by consolidation with high dose chemotherapy and hematopoietic stem cell rescue possibly renders better responses and outcomes.
REFERENCES
1. Loughran TP Jr. Clonal diseases of large granular lymphocytes. Blood 1993;82:114. 2. Chan JKC, Wong KF, Jaffe ES, et al. Aggressive NK-cell leukemia. In: Jaffe E, Harris N, Stein H, Vardiman J, editors. Pathology and Genetics of Tumours of the Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2001. pp 198 200. World Health Organization Classication of Tumours. 3. Gentile TC, Uner AH, Hutchison RE, et al. CD3+, CD56+ aggressive variant of large granular lymphocyte leukemia. Blood 1994;84:23152321. 4. Macon WR, Williams ME, Greer JP, et al. Natural killer-like T-cell lymphomas: Aggressive lymphomas of T-large granular lymphocytes. Blood 1996;87:14741483. 5. Falcao RP, Simoes BP, Garcia AB, et al. Aggressive variant of morphologically typical T large granular lymphocyte leukemia/ lymphoma lacking NK cell markers. Acta Haematol 2000;104(2/3):110114. 6. Tordjman R, Macintyre E, Emile JF, et al. Aggressive acute CD3+. Leukemia 1996;10:15141519. 7. Kantarjian HM, OBrien S, Smith TL, et al. Results of treatment with hyper-CVAD, a dose-intensive regimen, in adult acute lymphocytic leukemia. J Clin Oncol 2000;18:547561. 8. Steinherz PG, Redner A, Steinherz L, et al. Development of a new intensive therapy for acute lymphoblastic leukemia in children at increased risk of early relapse. The Memorial SloanKettering-New York-II Protocol. Cancer 1993;72:31203130. 9. Kothapalli R, Nyland SB, Kusmartseva I, et al. Constitutive production of proinammatory cytokines RANTES, MIP-1b and IL-18 characterizes LGL leukemia. Int J Oncol 2005;26: 529535. 10. Daibata M, Matsuo Y, Machida H, Taguchi T, Ohtsuki Y, Taguchi H. Differential gene-expression proling in the leukemia cell lines derived from indolent and aggressive phases of CD56+ T-cell large granula lymphocyte leukemia. Int J Cancer 2004;108:845851.

Our description of a case of an aggressive T-cell LGL leukemia adds to the small number of previously reported cases. Since this disorder is not recognized within the WHO classication it might be underreported. The practicing hematologist should be aware of the existence of aggressive T-cell LGL

American Journal of Hematology DOI 10.1002/ajh