The case of T-cell large granular lyphocyte leukemia presented as transfusion dependent anemia with sustained response to cyclosporine a therapy: case report/T-celijska leukemija velikih granulisanih limfocita sa klinickom slikom transfuziono zavisne anemije i protrahovanim terapijskim odgovorom na ciklosporin a: prikaz slucaja.
T-large granular lymphocyte (T-LGL) leukemia is a rare lymphoprol iterative disorder that comprises 2%-5% of all T-cell/natural killer (NK)-cell malignancies [1, 2]. The diagnosis is suggested by flow cytometry and demonstrates an expansion of CD3 + [CD8.sup.+][CD57.sup.+] Tcells that is confirmed by T-cell receptor gene rearrangement studies [2-4]. In most patients, this is an indolent disorder with a median survival time >10 years [1, 2, 4]. Approximately two thirds of all patients with indolent T-LGL leukemia develop cytopenias, recurrent bacterial infections, autoimmune disorders, and/or splenomegaly over the course of their disease. Thus, more than half of these patients require treatment . Immunosuppressive therapy, including single agent corticosteroids, methotrexate, cyclophosphamide and cyclosporine (CsA), is effective in controlling symptoms and cytopenia [3, 4]. In this report, we discuss our own experience and report a complete response to CsA.
A previously healthy 41-year-old man was admitted to our department for the investigation of symptomatic anemia. He did not have palpable peripheral lymphadenopathy, splenomegaly or hepatomegaly. His complete blood count showed anemia (hemoglobin (Hgb) of 80 g/1, erythroid indices: MCV 109.7 fl, MCHC 33.73 g/dl, RDW 19.6%) and lymphocytosis (white blood count--WBC) of 12.2 x [10.sup.9]/L, with a differential count of 51% lymphocytes, total lymphocyte count: 4.816 x [10.sup.9]/l). The lymphocytes were small to intermediate with discrete but visible granules in cytoplasma (Figure 1). Other laboratory test results were as follows: reticulocytes 1x[10.sup.-3]/L. negative direct and indirect Coombs" test, liver enzymes, creatinine, blood urea nitrogen, and iron within the normal range. Hepatitis B surface antibody (HB-sAg), anti hepatitis C virsu (HCV), anti human immunodeficiency virus (HIV), Cytomegalo and Epstein-Barr virus were negative, whereas Mycoplasma pneumoniae and Adeno virus IgM were slightly positive. Bone marrow (BM) cytology showed moderate erythroid hypoplasia. The small to intermediate lymphocytic cells comprised 25% of the BM cells. Ultrasonography showed a slightly enlarged spleen. Treatment with corticosteroids was started (prednisone 20 mg/day). However, transfusions with erythrocytes were needed to address a persistent drop in Hgb to 67 g/L.
Subsequent diagnostic investigation excluded antinuclear, antimitochondrial, antismooth-muscle, anti-parietal cell, antithyroid and anticardiac antibodies. Quantitative Igs were within the reference ranges. The Coombs direct (IgG and c3d) and indirect tests were positive. A 51Cr red cell survival study showed reduced survival times for erythrocytes (17 days). Flow cytometry of peripheral blood demonstrated a [(CD3, TCR a/b, CD2, CD7, CD5, CD8, CD16, CD57, HLA DR.).sup.+] and (CDla, CD4, TCRg/d)" lymphocyte immunophenotype. A BM biopsy showed a moderate interstitial infiltration with CD3+, CD8+, CD57+, Granzyme B+ T-lymphocytes (Figure 2). The T-cell receptor [delta] was positive for gene rearrangement and showed the presence of two rearranged clones. Therefore, T-LGL leukemia was diagnosed. The patient was started on CsA 250 mg/d, which was increased to 300 mg/d within two months. Due to the possible CsA side effects, the CsA blood level, blood pressure, kidney and liver function were monitored. All of the parameters were within the reference range, except the creatinine levels, which reached a maximum of 136 mmol/1. However, 10 months of CsA therapy resulted in only a partial response according to the criteria of a French group (Hgb >8 g/dL, platelets >50x[l0.sup.9]/L, and neutrophils >0.5x[10.sup.9]/L, no transfusion requirements), with a total WBC of 18,5x[10.sup.9]/L, Hgb 84 g/1, platelets 356 x [10.sup.9] and LGL still present in peripheral blood smears. Repeated immunophenotyping and T-cell gene rearrangement confirmed persistent T-LGL leukemie. He was started on low-dose oral methotrexate, with a total dose of 10 mg/d weekly. He was on methotrexate therapy, exhibiting only a partial response, for two and half years (30 months). He was not transfusion dependent, but he was symptomatic due to anemia. Complete remission was not achieved, as demonstrated in the complete blood count values (WBC 13,7x [10.sup.9]/L, Hgb 96 g/L) and the dominant cell population in peripheral blood immuno-cytochemistry (90% CD3+, CD8+ lymphocytes). The CsA treatment was reintroduced. The initial and maintenance dose was 300 mg/d. Within only a few months, the patient achieved complete remission. After [equivalent to] 3 years, the CsA was tapered down and excluded. The toxic effects of CsA were evident in the elevated creatinine levels (maximum 156 mmol/1). The patient was off CsA therapy for 4 years, and thus far he has been in complete hematological remission, and has repaired kidney function. A molecular response was missing. Although it was substantially decreased, an abnormal T-cell clone was detected by immunophenotyping and the presence of a T-cell receptor [gamma] rearrangement in one clone.
T-large granular lymphocyte leukemia is a rare lymphoproliferative disorder that is characterized by the clonal proliferation of CD3+ T-cytotoxic cells. It is an indolent disorder. However, its clinical course is quite uncertain. Its mortality may be as high as 20% in four years . Most patients (50-82%) are symptomatic at presentation . Although neutropenia and recurrent bacterial infections are frequent and are considered to be a main cause of morbidity and mortality in patients with T-LGL leukemia, this was not the case with our patient. He had transfusion-dependent anemia, which is reported to occur in only 6% of patients [3, 4]. In addition to neutropenia (severe or moderate with recurrent infections) and associated autoimmune conditions that require therapy (most often rheumatoid arthritis), anemia (symptomatic or transfusion-dependent) is considered to be a therapy indication [3, 4, 6].
It is believed that sustained immune stimulation and a dysregulation of apoptosis underlies T-LGL leukemia pathogenesis, which is why immunosuppressive therapy remains the mainstay of treatment . No standard therapy algorithm has been established, and the current recommendations are based on small case studies and a recently published large French cohort study . Lamy and Loughran  proposed methotrexate with/without prednisone and cyclo-phosphamide as a first-line therapy. However, they suggested that CsA could be used as an alternative first-line, particularly in patients with anemia, because in those cases, the overall response rate was 100%. It was first-line therapy in our patient. However, it initially led to only a partial response.
Methotrexate has been used with varying success with overall response rates of 44 to 87%, but generally it has obtained only a partial response [3,4,7]. Unfortunately, our patient only had a partial response. Few studies reported the use of purine analogs, polyche-motherapy, antithymocyte globulin and other regimens in refractory or relapsed T-LGL leukemia [1,2].
Because our patient did achieve a partial response during CsA therapy, we reintroduced the therapy; upon its reintroduction, it resulted in a favorable outcome. A complete clinical and hematological response was achieved. However, it did not result in an eradication of the leukemic LGL clone. The current opinion is that CsA should be given indefinitely to maintain a response . However, after a 3-year CsA treatment in our patient, we excluded CsA due to slightly impaired kidney function. Osuji et al.  also reported that they were able to discontinue CsA treatment in three patients without any recurrence of cytopenias.
Our case confirms that cyclosporine therapy is effective in treating T-cell laige granular lymhocytc leukemia but with a persistant underlying T-cell large granular lymhocyte clone. It also suggests that indefinite treatment may not be needed to maintain response.
Abbreviations BM --bone marrow CsA --cyclosporine Hgb --hemoglobin T-LGL --T-large granular lymphocyte WBC --white blood count
[1.] Sokol L, Loughran TP Jr. Large granular lymphocyte leukemia. Oncologist 2006; 11:263-73.
[2.] Chan WC, Foucar K, Morice WG, Catovky D. T-cell large granular lymphocytic leukaemia. In: Swerdlow SH, Campo E, Harris NL, et al., editors. WHO classification of tumours of hae-matopoietic and lymphoid tissues. 4th ed. Lyon: IARC; 2008. p. 272-5.
[3.] Bareau B, Rey J, Hamidou M, Donadieu J, Morcet J, Reman O, et al. Analysis of a French cohort of patients with large granular lymphocyte leukemia: a report on 229 cases. Haematologica. 2010-95:1534-41.
[4.] Lamy T, Loughran TP Jr. How I treat LGL leukemia. Blood. 2011-117; 2764-74.
[5.] Battiwalla M, Melenhorst J, Saunthararajah Y Nakamura R, Molldrem J, Young NS, et al. HLA-DR4 predicts haematological response to cyclosporine in T-large granular lymphocyte lymp-hoproliferative disorders. Br J Haematol. 2003; 123(3):449-53.
[6.] Brinkman K, van Dongen JJ, van Lom K, Groeneveld K, Misere JF, van der Heul C. Induction of clinical remission in T-large granular lymphocyte leukemia with cyclosporin A, monitored by use of immunophenotyping with Vb antibodies. Leukemia. 1998-12; 150-4.
[7.] Osuji N, Matutes E, Tjonnfjord G, et al. T-Cell large granular lymphocyte leukemia: a report on the treatment of 29 patients and a review of the literature. Cancer. 2006; 107:570-8.
Radje primljen25. IV 2016.
Recenziran 11. VII2016.
Prihvacen za stampu 25. VIII 2016.
Vanja ZEREMSKI (1), Aleksandar SAVIC (2, 3), Vesna CEMERIKIC MARTINOVIC (4), Ivana MILOSEVIC (2, 3), Marina DRAGICEVIC (2) and Amir El FARRA (2)
University Hospital Magdeburg, Department of Hematology and Oncology,
Magdeburg, Germany (1)
Clinical Center of Vojvodina, Novi Sad, Department of Hematology (2)
University of Novi Sad, Novi Sad, Faculty of Medicine (3)
Pathohistology Laboratory Beolab, Belgrade, Serbia (4)
Corresponding Author: Dr Vanja Zeremski, University Hospital Magdeburg, Department of Hematology and Oncology, D-39120 Magdeburg, Germany, Leipziger Str. 44, E-mail: email@example.com
Caption: Figure 1. Large granular lymphocyte in peripheral blood Slika 1. Veliki granulisani limfociti u perifernoj krvi
Caption: Figure 2. Bone marrow, magnification x 20 (A) Hematoxylin and eosin staining (B) CD3 expression (C) CD8 expression (D) CD 57 expression Slika 2. (A) Kostana srz, uvecanje x 20 (A) hematoxilin-eozin bojenje (B) CD3 ekspresija (C) CD8 ekspresija (D) CD57 ekspresija
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|Title Annotation:||Case report/Prikaz slucaja|
|Author:||Zeremski, Vanja; Savic, Aleksandar; Martinovic, Vesna Cemerikic; Milosevic, Ivana; Dragicevic, Marin|
|Date:||Nov 1, 2016|
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