AGGRESSIVE NK-CELL LEUKEMIA: A REPORT OF SIX CASES AND LITERATURE REVIEW

Transcription

1 Acta Medica Mediterranea, 2014, 30: 1017 AGGRESSIVE NK-CELL LEUKEMIA: A REPORT OF SIX CASES AND LITERATURE REVIEW YUAN FANG, LINNA XIE, ZHE YU, FANSHENG KONG, XIMIN LIU, FANG ZHOU Department of Hematology, Jinan Military General Hospital Jinan, Shandong, China ABSTRACT Background: It is imperative to develop new therapeutic strategies to improve the diagnostic accuracy of aggressive NK cell leukemia (ANKL) and improve the outcome of ANKL patients. Methods: Herein, we reported 6 ANKL patients who were treated in our institution within of the past 5 years and reviewed the literatures. Results: The common symptoms and signs of ANKL were fever (100%), hepatosplenomegaly (83.3%) and hemophagocytosis (33.3%). These cells were characterized by CD56, CD16, ccd3, scd3-, as well as CD2, CD7, CD11c and CD38 expression to different extents. Four patients had abnormalities in the cytogenetics. Epstein Barr virus (EBV) in situ hybridization showed negative. Response to clinical treatment was observed in 16.7% of patients, and the median survival time was 63 days. Conclusion: ANKL often has a fulminant course with a poor response to chemotherapy and predicts a short survival time. Hematopoietic stem cell transplantation (HSCT) is a promising strategy for the treatment of ANKL. Key words: Natural killer cells, Leukemia, Diagnosis, Therapy. Received February 18, 2014; Accepted June 19, 2014 Introduction Aggressive natural killer cell leukemia (ANKL) is a malignant lymphoproliferative disorder and has close relationship with EBV in the pathogenesis. ANKL is characterized by systemic infiltration of NK cells and usually has an aggressive clinical course. ANKL was first reported in 1990 by Imamura et al (1). For the first time classification was made in 1994 for Lymphoid Neoplasms (REAL) as Large Granular Lymphocyte (LGL) Leukemia, NK-cell type; LGL Leukemia, T-cell type (2).The ANKL is named in the World Health Organization Classification which first recognizes its dramatic clinical behavior and separated it from the T cell large granular lymphocyte leukemia (3). Clinically, ANKL patients present with fever, constitutional symptoms, liver dysfunction, hemophagocytic syndrome and leukemia. This disease usually displays a fulminant clinical course with a median survival time of <2 months. Studies have shown that this disease has a strong association with EBV infection. The majority of patients harbor EBV in the tumors, and, on rare occasions, patients manifest features of hypersensitivity to mosquito bites or chronic active EBV infection (3). This disease is more prevalent in Asians (71% of reported cases) than in Caucasians (25% of cases) (4). Material and method Case Series ANKL was diagnosed in six consecutive patients older than 18 years who visited Jinan Military General Hospital between January 2008 and December Peripheral blood, bone marrow, and biopsy samples were obtained from all the individuals with standardized procedures and subjected to morphologic, immunophenotypic, molecular, and cytogenetic examinations in our hospital. The diagnosis was done according to the bone mar-

2 1018 Yuan Fang, Linna Xie et Al row infiltration of malignant cells, which were immunohistochemically and clinically determined. Hematological examination and Flow Cytometry Finger- stick smears also were obtained. Large granular lymphocytes were counted under a light microscope after Wright-Giemsa staining. Blood samples were collected from the vein and processed for routine complete blood cell counting (SYSMEX XE-2100 Hematology Analyzer, Japan), clinical chemical assay of liver enzymes (lactate dehydrogenase [LDH], alanine aminotransferase [ALT], and aspartate aminotransferase [AST]) (Hitachi bio-chemical analyzer, Japan). Flow cytometry of bone marrow was conducted using a panel of lymphoid cell-associated monoclonal antibodies for CD2, surface CD3, cytoplasmic CD3, CD5, CD7, CD19, CD20, CD4, CD8, CD2, CD16, CD11c, CD38, CD117, CD5, HLA-DR and nuclear TdT (FACS Cabilum Becton Dickinson, USA). Detection of EBV EBV RNA was detected by using the in situ hybridization (ISH) technique. Bone marrow samples were fixed in neutral-buffered formalin and decalcified in formic acid. Paraffin-embedded sections (5 μm) were deparaffinized with xylene, treated with proteinase K and hybridized with FITCconjugated EBER oligonucleotide probes (Novocastra). After incubation with anti-fitc antibody conjugated with alkaline phosphatase (ALP), sections were treated with nitro blue tetrazolium, 5- bromo-4-chloro-3-indolyl phosphate and 1 M levamisole. EBV-negative lymphoid tissues were processed using the hybridization mixture without EBV oligonucleotides in the negative control group. Molecular Studies For the PCR amplification of the TCR- γ locus, DNA was prepared by standard proteinase K digestion and phenol/chloroform extraction. PCR followed by single-stranded conformational polymorphism assay was performed as previously described (5). Results Clinical Features There were 4 men and 2 women with the age ranging from 18 years to 41 years (median, 30.5 years). All the 6 patients complained B symptoms (fever, night sweat, loss of weight), and fever was the most common B symptom (n=6), followed by weight loss (3/6) and sleep hyperhidrosis (1/6). Five patients had splenomegaly, 3 had hepatomegaly, 4 had an elevated LDH (max: 2997 U/L). All the patients had an elevated β2-mg (max: 8.2 mg/l). Three patients (50%) had highintermediate and high risk according to the International Prognostic Index (6, 7). EBV in situ hybridization showed negative in 3 patients (0%). Hemophagocytosis was common in the bone marrow (33.3%). There was bone marrow involvement of ANKL blasts to different extents. The clinical characteristics of these 6 patients are given in Table 1. Characteristics No. 6 Median age (y) 30.5 (range: 18-41) Male: Female 2:01 ECOG grade (50%) (50%) Initial presentation Fever 6 (100%) Dyspnea 2 (33.3%) Abdominal pain 3 (50%) B symptoms (+) 6 (100%) Increased LDH 4 (66.7%) Increased β2-mg 6 (100%) Internal prognostic index (IPI) Low-intermediate 3 (50%) High-intermediate 2 (33.3%) High 1 (16.7%) Hepatomegaly 3 (50%) Splenomegaly 5 (83.3%) EBV ISH (+) (n=3) 0 pancytopenia 4 (66.7%) Hemophagocytic syndrome (HPS) 2 (33.3%) Table 1: Patient s characteristics. Of 6 patients, 4 had a pancytopenia, 3 had a hemoglobin concentration of <110 g/l (range, g/L; median, 108 g/l), 5 had a platelet count of < /L (range, /L; median, /L), and 1 had a neutrophil count of <1 109/L (range, /L; median, 2.95

3 Aggressive NK-cell leukemia: a report of six cases and literature review 109/L). The peripheral hemogram of 6 patients are given in Table 2. Case No. WBC ( 109/L) Hb (g/l) Platelet ( 109/L) NK cells ( 109/L) _ _ Table 2: Peripheral hemogram of 6 patients. Footnote: No.=number; WBC= white blood cell; Hb=hemoglobin; NK cells=nature killer cells NK Cells and Bone Marrow Features The number of NK cells in the peripheral blood ranged from 0 to /L (median, /L), and NK cells accounted for 7-72% (median, 25.5%) of nucleated cells in the bone marrow. In addition, the cytologic characteristics of NK cells were quite variable (Figure 1) Other cells exhibited a mature, large granular morphology of lymphocytes/nk cells, but were larger than normal and frequently binucleated. Moreover, hemophagocytosis was common in bone marrow (Figure 2) Immunophenotype, and Cytogenetic and Molecular Features Findings from immunohistochemistry of neoplastic cells are summarized in Table 2. Previous reports indicated that the neoplastic cells of ANKL are positive for CD2, CD56, and, often ccd3. In the present report, the neoplastic cells were positive for CD16, ccd3 and CD56 in all the 6 patients, CD2 in 2, CD7 in 5, HLA-DR in 3, CD38 in 4 and CD11c in 4. Cytogenetic assay revealed that 2 patients (33.3%) had normal karyotypes, and complex chromosomal abnormalities were seen in 2 patients (33.3%). No clonal rearrangements of γ TCR were found in 3 patients (Table 3). Case Immunophenotype Cytogenetics TCRγ 1 CD2, ccd3, CD7, CD16, CD56, HLA-DR 46, xy 2 Fig. 1: Morphology of aggressive natural killer blast cells. Large cells with large cytoplasmic granules (some with bilobulated nuclei) and dysplastic erythroid cells. CD2, ccd3, CD16, CD56, CD11c, 47, xx, 3p+, +10, 15q+, +i(17q), CD8, HLA-DR 22[20] 3 ccd3, CD16, CD56, CD7, CD38 46, xy NO 4 ccd3, CD4, CD5, CD7, CD11c, CD38, CD16, CD56 46, xy, +19, -21[4]/46, xy[8] 5 CD7, CD38, CD11c, CD16CD56, HLA-DR 48, xy, +10, +20[6]/46, xy[4] NO 6 CD16CD56, CD7, CD38, CD11c 54-59, xx, +1, +2, +3, +5, +6, +7, +10, +11, +14, +14, +15, +16, +19[cp4]/46,xx[21] NO Table 3: Immunophenotype, genotype and cytogenetics. Fig. 2: Bone marrow smear: hematophagocytes. Bone marrow smear: hematophagocytes. In some cases, there were large, comet-like cells with oval nuclei, slightly condensed chromatin, and trailing sky-blue cytoplasm with one or more azurophilic granules. Nucleoli were normal, but had indistinct margins. In other cases, the abnormal NK cells had tortuous and twisted shapes with hyperchromic and irregular nuclei that contained different small round nucleoli and featured basophilic cytoplasm with short trail. Outcome and survival A complete response to treatment was observed in 1 of 6 patients (16.7%). The response was maintained for 90 days (Table 4). However, disease progressed after 3 courses of chemotherapy with etoposide, ifosfamide, and pharmorubicin. The remaining 5 patients received chemotherapy, but none experienced remission, and all eventually died within 2 months. The median survival time of these patients was 63 days (range: days). The long survival time of patient 1 might be attributed to the normal karyotype. Discussion NK cell tumors are an uncommon and heterogeneous group of disorders. The World Health

4 1020 Yuan Fang, Linna Xie et Al Organization (WHO) classifies mature NK cell neoplasms into 3 types: 1) extranodal NK cell lymphoma, nasal type, 2) aggressive NK cell leukemia, 3) chronic NK cell lymphocytosis (3). Case No Age/Sex PS Major Involvement HPS EBV BM (FAX,%) Initial treatment Response Response duration Survival 1 24/M 2 BM, liver/spleen NO 7% CHOPE4, HyperCVADL d 334d+ 2 18/F 4 BM, liver/spleen, lung 9.50% CHOP1, COPE1 55d 3 37/M 2 BM, spleen, lung NO 72% FND2 60d+ 4 41/M 3 BM,liver/spleen, lung NO 30% VP+IDA1 63d 5 18/M 2 BM, spleen 21% * 68d 6 38/F 3 BM, lung 50% VDCP1 48d Table 4: Outcome and survival of six patients. Footnote: performance status (ECOG), BM: bone marrow, NO: not done, ; +Censored Data, CHOP: D1 Cytoxan 750 mg/m2 i.v., D1 Pharmorubicin 80 mg/m2 i.v., D1 Vincristine 1.4 mg/m2 (max. 2 mg) i.v., D1-D5 Prednisolone 100 mg/d p.o. q 3 wks;chope:chop+d1-d5 Etoposide100mg/d iv q3wks;hypercvad: D1 -D3 Cytoxan 300 mg/m2 1/12h i.v., D4 Pharmorubicin 80 mg/m2 i.v., D4,D11Vincristine 1.4 mg/m2 (max. 2 mg) i.v., D1-D4,D11-D14 Dexamethasone 40 mg/d i.v. q 3wks;COPE: D1 Cytoxan 750 mg/m2 i.v., D1 Vincristine 1.4 mg/m2 (max. 2 mg) i.v., D1-D5 Prednisolone 100 mg/d p.o. D1-D5 Etoposide100mg/d iv q 3wks;FND:D1-D3 Fludarabine25mg/m2 /d i.v., D1 Mitoxantrone 15 mg/d i.v, D1-D5 Dexamethasone 20 mg/d i.v. q 3wks;VP+IDA: D1 Vincristine 1.4 mg/m2 (max. 2 mg) i.v., D1-D14 Dexamethasone 15mg/d i.v. D1-D3 Idarubicin 8mg/m2 /d i.v., D1-D7 Cytarabine 100 mg /m2/d i.v. q 3wks;VDCP: D1 Cytoxan 750 mg/m2 i.v., D1-D14 Dexamethasone 15mg/d i.v., D1 Vincristine 1.4 mg/m2 (max. 2 mg) i.v., D1-D3 Idarubicin 8mg/m2 /d i.v., q 3wks.*The patient 5 had not been treated in our hospital,so he has not acography. These tumors show polymorphic neoplastic infiltration with angioinvasion and/or angiodestruction, cytoplasmic azurophilic granules, CD2+/CD3- /ccd3ε+/cd56+ phenotype, and strong association with EBV infection. Cytogenetic and molecular analyses have shown DNA losses at chromosomes 6q, 11q, 13q, and 17p to be recurrent aberrations. Extranodal NK/T-cell lymphoma, nasal type, is characterized by a proliferation of cells that vary in cytologic characteristics from one case to another. The immunophenotypic profile of these neoplastic cells of this disorder includes the expression of cytoplasmic CD3ε, CD56, and CD2 and a lack of expression of surface CD3, CD57, and CD16. TCR genes are usually not rearranged. Evidence of EBV infection is almost invariably found. As indicated by the name of this disorder, the most common site of presentation is the nasal cavity. However, symptoms may also present in the skin, gastrointestinal tract, respiratory tract, testis, and other sites. There is a tendency for this malignancy to be angiocentric, and it is frequently associated with extensive areas of necrosis (8, 9). Chronic NK lymphocytosis is defined as a chronic expansion of mature looking NK cells ( 600/μL) in the peripheral blood for 6 months (8). A study showed the median age of 16 patients was 60.5 years (range, 7-77 years) (10). Most patients present with a chronic, indolent course with severe neutropenia, and pure red cell aplasia. ANKL is a catastrophic, systemic disease and characterized by the presence of neoplastic NK cells mainly in the peripheral blood and bone marrow and by a rapidly progressive clinical course. There is no effective treatment for this disease at present. However, because of the extranodal presentation, widely varying numbers of NK cells and bone marrow pathology, ANKL is often confused with a reactive process. These characteristics, coupled with the rapid and fulminating disease course, pose a challenge for the accurate diagnosis of ANKL, and thus further studies on its pathogenesis and the development of cogent therapeutic modalities are required. ANKL has a high prevalence in young adults, with 60% of cases occurring in individuals aged 40 years or younger. In a review, 107 cases were analyzed in the available literatures, and only 3 of 107 cases were from China mainland. More than half (58.5%) of these cases were found in patients aged years (11). In the present report, the median age was 30.5 yeas, and more males were noted (4 men and 2 women). Together with cases reported previously (M: F=1.18:1.) (11), the incidence of this disease is slightly higher in males. In 1989, Kawa-Ha et al for the first time reported that NK cells in both chronic NK-cell lymphocytosis and ANKL were infected by EBV (12). In some cases, investigators demonstrated that the EBV proliferation was clonal, suggesting that the

5 Aggressive NK-cell leukemia: a report of six cases and literature review 1021 infection of the NK cells by EBV preceded the malignant transformation and possibly played an etiological role in this process (13-15). However, in the present series, EBV in situ hybridization showed negative 3 (0%). ANKL is more prevalent in Asians than in Caucasians. We reviewed 24 ANKL cases from China mainland which have previously been described in the Chinese-language literatures (16-23). Herein, we presented 6 ANKL cases and analyzed them together with 24 previously published cases. Our findings may provide a better characterization of this rare entity. Table 5 summarizes the clinical and molecular characteristics of these 30 ANKL cases. B symptoms reported in previous cases have usually not specified. These symptoms refer to the triad of fever, weight loss and sleep hyperhidrosis. In 30 cases reported in China, at least one of the symptoms was complained in all the cases, with a cumulative frequency of B symptoms of 96.7% (29/30). In respect of organ involvement, bone marrow involvement was noted in 30 (100%), spleen involvement in 22 (73.3%), liver involvement in 14 (46.7%), and lymph node involvement in 15 (50%). In addition, the LDH was usually elevated, which was observed in 25 (83.3%) of 30 patients undergoing LDH detection. EBV in situ hybridization was positive in 14 of 30 (46.7%). Of the available 107 cases, the EBV genome in the tumor cells was documented in 66 cases, and EBV infection was noted in 55 cases (11). The prevalence f EBV infection in 107 cases was higher than that in cases from China mainland. The immunophenotype of ANKL is usually determined, and frequently used in the differential diagnosis. Neoplastic cells are consistently positive for CD2, CD56, and HLA-DR and negative for surface CD3. Of 30 cases, cells were positive for CD2 in 30 (100%) of 30 cases, CD56 in 30 (100%) of 30 cases, and HLA-DR in 30 (100%) of 30 cases. None (0%) were positive for surface CD3 in 30cases, although 30 (100%) of 30 cases were positive for CD3ε. Several other antigens are also noted: CD38 in 28 (93.3%) of 30 cases, CD7 in 29 (96.7%) of 30 cases, and CD16 in 30 (100%) of 30cases. Cytogenetic assay has been performed in 26 ANKL cases, and clonal cytogenetic abnormalities are reported in 17 cases (65.4%). Consistent with the poor prognosis of this disease, complex abnormalities are found in 11 (42.3%) of 26 cases. Consistent with our current understanding of NK cell ontogeny, no clonal TCR rearrangements are found in the 15 ANKL cases that have been reviewed. Survival was defined as the time to death in days after establishing the diagnosis of ANKL. Because of its rare incidence, there is no known effective therapeutic strategy. This disease is usually refractory to chemotherapy and often exhibits a relentless progressive course with a poor prognosis. Characteristic Sex Positive/Reported Cases, n Male 22/30 (73.3%) Female 8/30 (26.6%) B symptoms 29/30 (96.7%) Hematology Hemoglobin <10 g/dl 21/30 (70%) Platelets < /L 24/30 (80%) Neutrophils <109/L 9/30(30%) Organ involvement Bone marrow 30/30 (100%) Spleen 22/30 (73.3%) Liver 14/30(46.7%) Lymph node 15/30 (50%) Lactate dehydrogenase index 25/30 (83.3%) Epstein-Barr virus 14/30 (46.7%) NK cells Peripheral blood 26 Bone marrow 30 Immunophenotye of neoplastic NK cells CD2+ 30/30 (100%) CD56+ 30/30 (100%) HLA-DR+ 30/30(100%) CD3+ 0/30(0%) CD38+ 28/30 (93.3%) CD3ε+ 30/30 (100%) CD7+ 29/30 (96.7%) CD16+ 30/30(100%) Cytogenetics Normal karyotypes 9/26(34.6%) Complex chromosomal abnormalities 11/26(42.3%) TCRγ 0/15(0%) Survival 60d(4-378d) Table 5: Clinical and Molecular Characteristics of 30 ANKL Cases Reported in China mainland.

6 1022 Yuan Fang, Linna Xie et Al The patient who was still alive at the time of publication was excluded from the analysis. The exact survival time was available for 28 cases. The median survival time was 60 days. The shortest survival time after diagnosis was 4 days and the longest was 378 days. Only one patient underwent hematopoietic stem cell transplantation (HSCT) and had the longest survival time (20). NK-cell Tumor Study Group performed a survey in Japan in which 228 patients were recruited for analysis. Of these patients, 40 underwent HSCT (15 with allografts and 25 with autografts), and 3 patients had aggressive NK-cell leukemia (2 with allografts and 1 with autografts). The patient who received autologous transplantation survived for 16 months after transplantation and died of this disease. The other two patients receiving allogeneic transplantation survived for 7 months and 5 months, respectively, after transplantation, one died of graft-versus-host disease (GVHD) after complete remission (CR), and the other died of this disease. The survival time of these patients was significantly longer than that of patients without HSCT (24). In the study by Ito et al (25), 3 patients with ANKL received allogeneic transplant and 7 had no HSCT. No patients were in CR at the time of conditioning. After allo-hct, all the 3 patients achieved and maintained CR. One died from sepsis and the other developed relapse of this disease, received a second transplantation and achieved a second CR. Although their backgrounds were similar to those without allo-hct, patients with allo-hct had a better outcome (25). These findings suggest that HSCT is a promising strategy for the treatment of NK-cell lineage. The mechanisms underlying the resistance of NK-cell tumors to chemotherapy are not fully understood, and the molecules responsible for pro-apoptosis and anti-apoptosis should be characterized as well as drug-resistance genes. Novel combined chemotherapy without anthracyclines for NK cell lymphoma and ANKL is under investigation (26). Improvement of the prior chemotherapy for ANKL is necessary to enable more patients to receive allo-hct. Finally, new therapies targeting the abnormal molecules should be extensively investigated. References 1) Imamura N, Kusunoki Y, Kawa-Ha K, Yumura K, Hara J, Oda K, Abe K, Dohy H, Inada T, Kajihara H, et al. Aggressive natural killer cell leukaemia/lymphoma: report of four cases and review of the literature. Possible existence of a new clinical entity originating from the third lineage of lymphoid cells. Br J Haematol 1990; 75: ) Harris NL, Jaffe ES, Stein H, Banks PM, Chan JK, Cleary ML, Delsol G, De Wolf-Peeters C, Falini B, Gatter KC, et al. A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood 1994; 84: ) Chan JKC, Wong KF, Jaffe ES, Ralfkiaer E. Aggressive NK-Cell Leukemia. Lyon: IARC Press, ) Ruskova A, Thula R, Chan G. Aggressive Natural Killer-Cell Leukemia: report of five cases and review of the literature. Leuk Lymphoma 2004; 45: ) Signoretti S, Murphy M, Cangi MG, Puddu P, Kadin ME, Loda M. Detection of clonal T-cell receptor gamma gene rearrangements in paraffin-embedded tissue by polymerase chain reaction and nonradioactive single-strand conformational polymorphism analysis. Am J Pathol 1999; 154: ) Jaffe ES. Classification of natural killer (NK) cell and NK-like T-cell malignancies. Blood 1996; 87: ) Kwong YL, Chan AC, Liang R, Chiang AK, Chim CS, Chan TK, Todd D, Ho FC. CD56+ NK lymphomas: clinicopathological features and prognosis. Br J Haematol 1997; 97: ) Oshimi K. Leukemia and lymphoma of natural killer lineage cells. Int J Hematol 2003; 78: ) Jaffe ES, Krenacs L, Kumar S, Kingma DW, Raffeld M. Extranodal peripheral T-cell and NK-cell neoplasms. Am J Clin Pathol 1999; 111: S ) Morice WG, Leibson PJ, Tefferi A. Natural killer cells and the syndrome of chronic natural killer cell lymphocytosis. Leuk Lymphoma 2001; 41: ) Ryder J, Wang X, Bao L, Gross SA, Hua F, Irons RD. Aggressive natural killer cell leukemia: report of a Chinese series and review of the literature. Int J Hematol 2007; 85: ) Kawa-Ha K, Ishihara S, Ninomiya T, Yumura-Yagi K, Hara J, Murayama F, Tawa A, Hirai K. CD3-negative lymphoproliferative disease of granular lymphocytes containing Epstein-Barr viral DNA. J Clin Invest 1989; 84: ) Hart DN, Baker BW, Inglis MJ, Nimmo JC, Starling GC, Deacon E, Rowe M, Beard ME. Epstein-Barr viral DNA in acute large granular lymphocyte (natural killer) leukemic cells. Blood 1992; 79: ) Akashi K, Mizuno S. Epstein-Barr virus-infected natural killer cell leukemia. Leuk Lymphoma 2000; 40: ) Ohshima K, Kikuchi M, Mizuno S, Akashi K, Moriyama K, Yoneda S, Takeshita M, Shibata T. Hepatosinusoidal leukaemia/lymphoma consisting of Epstein-Barr virus-containing natural killer cell leukaemia/lymphoma and T-cell lymphoma; mimicking malignant histiocytosis. Hematol Oncol 1995; 13:

7 Aggressive NK-cell leukemia: a report of six cases and literature review ) Zhou XZ, Huang ZL, Mo XL. One case report of aggressive NK cell Leukemia. Chinese Journal of Clinical Oncology 2009; 36: ) Wei Z, Xu JM, Zou SH, Cheng LY. One case report of aggressive NK cell leukemia and review of the literature. Journal of Clinical Hematology 2007; 20: ) Aggressive NK-cell leukemia: report of nine cases and review of literature. Zhonghua Xue Ye Xue Za Zhi 2006; 27: ) Ji O, Lu H, Zhang JF, Wu YJ, Zhang JS. One case report of aggressive NK cell leukemia and review of the literature. Acta Universitatis Medicinalis Nanjing 2005; 25: ) An G, Zou DH, Wang Y, F., Zhao YZ, Qiu LG, Qi JY. Report of nine cases of aggressive natural killer-cell leukemia. Journal of Leukemia & Lymphoma 2009; 18: ) Zhu WB, Zhai ZM, Ding KY, Wan X, Ding BS, Li Q. Report of two cases of aggressive natural killer-cell leukemia. Journal of Clinical Internal Medicine 2009; 26: ) Liu XF, Mi YC, Bai J, Jing LP, Bian SG, Wang JX. Aggressive NK-cell Leukemia Complicating Tumour Lysis Syndrome,One Case Report and Review of Literaturs. Journal of Internal Intensive Medicine 2006; 12: 26-28,36. 23) Wang Z, He GQ, Zhu L, Zhang N, Zhang H, Xu HZ, Meng L, Zhang YC, Liu WL. Aggressive Natural Killer-cell Leukemia Associated With Complicated and Compounded Chromosomal Aberrations: A Case Report and Renew of Literatures. Journal of Internal Intensive Medicine 2009; 15: , ) Suzuki R, Suzumiya J, Nakamura S, Kagami Y, Kameoka JI, Sakai C, Mukai H, Takenaka K, Yoshino T, Tsuzuki T, Sugimori H, Kawa K, Kodera Y, Oshimi K. Hematopoietic stem cell transplantation for natural killer-cell lineage neoplasms. Bone Marrow Transplant 2006; 37: ) Ito T, Makishima H, Nakazawa H, Kobayashi H, Shimodaira S, Nakazawa Y, Kitano K, Matsuda K, Hidaka E, Ishida F. Promising approach for aggressive NK cell leukaemia with allogeneic haematopoietic cell transplantation. Eur J Haematol 2008; 81: ) Yamaguchi M, Suzuki R, Kwong YL, Kim WS, Hasegawa Y, Izutsu K, Suzumiya J, Okamura T, Nakamura S, Kawa K, Oshimi K. Phase I study of dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) chemotherapy for advancedstage, relapsed or refractory extranodal natural killer (NK)/T-cell lymphoma and leukemia. Cancer Sci 2008; 99: Corresponding Author DR. FANG ZHOU Department of Hematology, Jinan Military General Hospital 25 Shifan Road Jinan Shandong (China)