- Email: [email protected]
NK-cell lymphoproliferative disease
Critical Reviews in Oncology/Hematology 44 (2002) 251 /257 www.elsevier.com/locate/critrevonc
Allogeneic hematopoietic stem cell transplantation for Epstein Barr virus-associated T/NK-cell lymphoproliferative disease /
Keisei Kawa , Takayuki Okamura, Masahiro Yasui, Emiko Sato, Masami Inoue Department of Pediatrics, Osaka Medical Center and Research Institute for Maternal and Child Health, 840 Murodo, Izumi City, Osaka 594-1101, Japan Accepted 14 February 2002
Contents 1.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
251
2.
X-linked lymphoproliferative disease (LPD) . . . . . . . . . . . . . . . . . . . . . . . . . .
252
3.
EBV-associated hemophagocytic syndrome (EBV-AHS)
. . . . . . . . . . . . . . . . . . .
252
4.
Chronic active EBV infection (CAEBV)
. . . . . . . . . . . . . . . . . . . . . . . . . . . .
252
5.
Nasal and nasal-type NK-cell lymphomas . . . . . . . . . . . . . . . . . . . . . . . . . . .
253
6.
‘EBV-associated T/NK-cell LPD’ as a distinct disease entity . . . . . . . . . . . . . . . . .
253
7.
Treatment strategy for EBV-associated T/NK-cell LPD . . . . . . . . . . . . . . . . . . . . 7.1. Lymphoma type . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2. Systemic type . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
254 254 255
Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
256
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
256
Biography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
257
Abstract Epstein /Barr virus (EBV) is implicated in a variety of human diseases, some of which have fatal outcomes. Some EBV related diseases are considered to be candidates for the treatment of hematopoietic stem cell transplantation (HSCT). X-linked lymphoproliferative (XLP) syndrome is one of the representative diseases in which more than half of affected males die of infectious mononucleosis (IM) within a few weeks of primary infection, whereas the minority who survive have an increased risk of acquired hypogammaglobulinemia and lymphoma. Patients with XLP usually die by the age 40. Similarly, the majority of patients with chronic active EBV infection develop hemophagocytic syndrome, organ failure, opportunistic infection, and/or lymphoma and die within 5 /10 years from onset. Recently, HSCT has provided successful outcomes in these patients. In this review, progress in the new therapeutic strategy is summarized, focusing on EBV-associated T/NK-cell lymphoproliferative disease (LPD), which is one of the heterogeneous EBV-associated disorder. # 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: XLP; HPS; Mosquito allergy; Hydroa vacciniforme; LPD (lymphoproliferative disease); EBV-associated T/NK-cell LPD; Hematopoietic SCT
1. Introduction Corresponding author. Tel.: /81-725-56-1220; fax: /81-725-565682 E-mail address: [email protected] (K. Kawa).
Allogeneic hematopoietic stem cell transplantation (HSCT) from an HLA-identical related or unrelated
1040-8428/02/$ - see front matter # 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 1 0 4 0 - 8 4 2 8 ( 0 2 ) 0 0 1 1 6 - 6
252
K. Kawa et al. / Critical Reviews in Oncology/Hematology 44 (2002) 251 /257
donor has been established as a curative therapy for a variety of hematological malignancies, bone marrow failure syndromes, and immunological disorders. In addition, HSCT from HLA-mismatched related donor with T cell depletion has also been performed for patients who require allogeneic HSCT but lack an available HLA-matched donor [1]. Among Epstein / Barr virus (EBV)-associated diseases, allogeneic HSCT was first applied for the treatment of X-linked lymphoproliferative (XLP) disease [2]. More recently, other patients with EBV-associated diseases such as EBVassociated hemophagocytic syndrome (EBV-AHS), EBV-associated natural killer (NK) cell lymphoma, and chronic active EBV infection have been treated using this treatment method, resulting in encouraging results [3 /5]. In this brief review, representative reported cases of HSCT for the treatment of EBV-associated diseases are described and our current strategy for the treatment of EBV-associated T/NK-cell LPD is also discussed.
2. X-linked lymphoproliferative disease (LPD) Purtilo et al. first reported this disease, and now the XLP International registry consists of over 300 affected patients. The diagnosis of XLP is based on clinical criteria requiring two or more maternally related males manifesting one or more of the characteristic phenotypes: fulminant infectious mononucleosis (IM), malignant lymphoma or LPD, and dysgammaglobulinemia [6]. Recently, the gene responsible for XLP was identified [7 /9], and its product interacts with signaling lymphocyte activation molecule (SLAM), and mediates the expansion of activated T cells during immune responses. Mutations in the XLP gene disrupt the interactions, and is considered to be responsible for the development of the XLP phenotype. In 1996, Gross et al. reported seven male patients with XLP who had undergone allogeneic HSCT [10]. All patients received HSCT from HLA-identical donors: related six (BM 5, cord blood 1), unrelated BM one. Conditioning regimens consisted of TBI containing regimens (n/4) and non-TBI containing regimens (n/3). All patients successfully engrafted and four are alive and well with normal immune function more than 3 years after HSCT. Although the number of patients was small, the authors suggested that age at HSCT (/ 15 years), TBI-containing regimen and a significant history for pre-HSCT infections were critical risk factors for success. Based on these findings they recommend that all possible efforts should be made to resolve active and/or subclinical infection, and that HSCT should be performed as soon as a suitable donor is identified.
3. EBV-associated hemophagocytic syndrome (EBVAHS) Virus-associated hemophagocytic syndrome (VAHS) is a lymphoproliferative disorder associated with viral infection [11]. Among various infectious agents, herpesviruses, particularly EBV, have been implicated in the pathogenesis of VAHS. Clinically, patients with EBVAHS have prolonged fever, hepatosplenomegaly, pancytopenia, and coagulopathy. Morphologic examination of lymph nodes and bone marrow shows marked phagocytosis of erythrocytes and nucleated blood cells. In infants and children, hypertriglyceridemia is often observed. Until recently, the pathogenesis of EBV-AHS was poorly understood, but recent studies have indicated that the proliferation of EBV-infected T cells may be a primary feature of the disease, and unrestricted release of inflammatory cytokines (hypercytokinemia), such as interferon-g and tumor necrosis factor-a, is a prominent feature of EBV-AHS. Since some cases of EBV-AHS have a fatal outcome, rapid diagnosis and initiation of newly established immunochemotherapy, such as prednisolone/dexamethasone, cyclosporin A, and etoposide, are recommended. HSCT should be considered if the patient responds poorly to immunochemotherapy or combined cytotoxic drugs [12]. Currently, HSCT has been performed for six patients with EBV-AHS including two with EBV-associated NK-cell LPD in Japan [3], of which there were four related HLA-matched donors and two unrelated HLA-matched donors. Preconditioning regimens consisted of TBIcontaining regimen (n /5) and non-TBI regimen (n/ 1). Four patients with EBV-AHS were in remission (3.5 /29 m/), but two patients with EBV-associated NK-cell LPD who received transplants from siblings relapsed at 14 and 15 m post HSCT, suggesting resistance to the therapy.
4. Chronic active EBV infection (CAEBV) In the early 1980s, the presence of so-called chronic (or persistent) or recurrent EBV infectious disease was recognized. CAEBV is characterized by chronic or recurrent IM-like symptoms, an abnormal pattern of anti-EBV antibodies (increased anti-VCA and early antigens, absence of anti-EBNA), and no evidence of prior immunologic abnormality or recent infection that could explain the condition [12,13]. Initially, CAEBV was considered to be a very rare disorder, and its pathogenesis was not well understood. More recently, our understanding has improved, and the clinical features and pathogenesis of CAEBV have been elucidated. CAEBV occurs at any age and in both sexes. No obvious immunodeficiency or hereditary background is
K. Kawa et al. / Critical Reviews in Oncology/Hematology 44 (2002) 251 /257
observed in family members, distinguishing it from XLP. Interestingly, one third of pediatric patients had a history of mosquito allergy. Although atypical lymphocytosis is a characteristic finding of IM, results of complete blood counts are variable. In addition, nearly one fourth of patients showed granular LPD in their clinical course, and the increased granular lymphocytes were exclusively EBV-infected NK cells [14]. Imai et al. succeeded in establishing T-cell lines containing the EBV genome from patients with CAEBV [15]. Similarly, we used PCR to demonstrate the existence of EBV DNA in CD3/ T cells from peripheral blood lymphocytes of CAEBV patients [13]. Thus, EBV-infected T cells and NK cells seem to play an important role in the pathogenesis of CAEBV, and it can be possible to divide into 2 groups, T-cell type and NK-cell type, based on the predominant infected cell population found in the peripheral blood [16]. Importantly, however, one should pay attention for identifying the predominant infected cell population that may shift from T-cell to NK-cell during the clinical course [5]. On the basis of these findings, it is understandable that CAEBV patients are more likely to develop T/NK-cell LPD. Typical clinical symptoms are fever, hepatomegaly, splenomegaly, anemia, and lymphadenopathy. The prognosis of patients with CAEBV is very poor in both pediatric and adult patients, and about half of them die within 4/5 years from onset. Hepatic and cardiac failure, various kinds of LPD, opportunistic infections, and EBV-AHS are the main causes of death [13]. Recently, we have reported a successful case of allogeneic HSCT in a 7-year-old boy who initially presented with EBV-infected T-cell LPD, and subsequently developed bilateral exophthalmos due to infiltration of EBV-infected NK cells into extraocular muscles during chemotherapy [5].
5. Nasal and nasal-type NK-cell lymphomas Nasal and nasal-type NK-cell lymphomas represent a distinct clinicopathologic entity almost always associated with EBV. Mostly, this type of lymphoma presents as a nasal destructive disease often extending to the palate, commonly accompanied by nasal obstruction, erythema, and orbital swelling. In addition to the most common nasal lesion, the larynx and upper respiratory and digestive tracts can be affected. Occasionally, the disease is initially localized in the skin and subcutaneous tissue as well as the digestive tract but then spreads to other sites including the lung (referred to as nasal-type lymphoma). Histologic characteristics are the presence of pleomorphic lymphoid cells, ischemic
253
Table 1 Hypersensitivity to mosquito bites (HMB) conceals clonal lymphoproliferation of Epstein /Barr viral DNA-positive natural killer cells More than half of the patients with HMB died of HPS Among six patients with HMB only two patients were diagnosed with increased LGL in the PBL. However, four of the five studied cases showed increment of CD56CD3-lymphocytes All but one of the patients showed abnormal patterns of antibodies against EBV All of the patients showed high levels of lgE (1000 /20 854 IU/ml) EBV-DNA was detected in the PBMCs in all six patients and in the serum in three of four examined patients. In addition, four cases were monoclonal and one case was biclonal
Table 2 The association of latent EBV infection with HV Patients with HV-like eruptions and malignant potential have been reported from Asia and Mexico A diagnostic histological feature of HV is a dense perivascular infiltrate of T cells, and angiodestructive infiltration is also seen Biopsy specimens from cutaneous lesions of six children with typical HV demonstrated EBERcells (3 /10% of the dermal infiltrates) The presence of EBV-DNA was also confirmed in five of six biopsy specimens by PCR Immunophenotype of the infiltrating cells was CD45RO and CD20 (two examined cases were CD56) Atypical HV is a smouldering stage potentially leading to an EBVassociated lymphoid malignancy
necrosis, and angiocentric or angioinvasive infiltration in the lesions [17]. According to Nakamura et al. [18], the overall survival rate for patients with nasal NK (or T)-cell lymphoma in Japan was 49% at 5 years, and all patients with stage IV disease died within 6 months. Although the number of reports is limited, successful treatments with autologous HSCT have been reported [19,20].
6. ‘EBV-associated T/NK-cell LPD’ as a distinct disease entity Mosquito allergy is characterized by intense local skin symptoms, which consist of not only erythema or bulla, but also ulcer or scar, and general symptoms such as high fever following mosquito bites. Until recently, the pathogenesis of mosquito allergy was unclear; however, we first demonstrated a close relationship between mosquito allergy and EBV-infected NK-cell LPD in six patients with mosquito allergy (Table 1) [21]. In addition, we clearly demonstrated that EBV-infected Tcell LPD had preceded the onset of mosquito allergy in an interesting case [22]. Because no hereditary background in family members and preceding immunodefi-
K. Kawa et al. / Critical Reviews in Oncology/Hematology 44 (2002) 251 /257
254
Fig. 1. Prognosis of EBV-associated T/NK-cell LPD. LPD, lymphoproliferative disease; CAEBV, chronic active EBV infection; HPS, hemophagocytic syndrome; D, death; (EBV-associated T/NK-cell
Table 3 M.S. 17 years/M, CAEBVHV Eleven years Twelve years Thirteen years Fifteen years Seventeen years, on admission
Eruptions on the face and extremities for several months Fever, cervical lymphoadenopathy, liver dysfunction CAEBV, HV-like eruption HV (angiocentric lymphoma, EBERNKcells), NK-LPD in PBL EBV-infected NK-LPD (monoclonal); eruptions on the face (HV)
ciencies were observed among these patients, EBV infection to T or NK cells may happen by chance and in some instances latently infected T/NK cells may develop LPD under unknown co-factors. Hydroa vacciniforme (HV) is characterized by the childhood onset of necrotic vesiculopapules on sunexposed areas and epidermal necrosis with lymphatic infiltration. Recently, Iwatsuki et al. showed that atypical HV is closely related to infiltration of EBVinfected T cells in the lesions (Table 2) [23]. More recently, we examined a patient who was diagnosed with CAEBV and HV (Table 3). His clinical course is discussed later, but taken together, we hypothesize that there is a close relationship between EBV infection and mosquito allergy/HV. In addition, EBV-associated T/NK-cell LPD seems to be a common pathogenesis for all these disorders, and the prognosis is very poor (Fig. 1). Table 4 EBV-associated T/NK */cell LPD Chronic active EBV infection (CAEBV) EBV-associated hemophagocytic syndrome (EBV-AHS) Peripheral T-cell lymphoma Mosquito allergy Hydroa vacciniforme Chronic granular LPD Aggressive NK-cell leukemia Nasal/nasal type NK-cell lymphoma
In parallel with the concept of HTLV-1-asociated T cell leukemia/lymphoma (ATL), thus far, EBV-associated T/NK-cell LPD comprises chronic active EBV infection, EBV-AHS, peripheral T-cell lymphoma, mosquito allergy, HV, chronic granular LPD, aggressive NK-cell leukemia, and nasal/nasal type NK-cell lymphoma (Table 4). Contrary to EBV-associated T/NK-cell LPD, EBVassociated B-cell LPD consists of Burkitt’s lymphoma, posttransplant LPD, AIDS-related LPD, XLP, and pyothorax-associated lymphoma [12]. With the use of more profound immunosuppressive therapy, the incidence of posttransplant B-cell LPD has recently increased. In the case of posttransplant B-cell LPD, reduction of the immunosuppressants is the first choice of the treatment. AIDS-related lymphoma shares many features with posttransplant LPD, and more recently with the successful use of anti-viral agents autologous HSCT is employed for its treatment [24]. Therefore, treatments including HSCT should be specified in each patient according to the cell lineage of LPD and the clinical status of the patients (Table 5).
7. Treatment strategy for EBV-associated T/NK-cell LPD 7.1. Lymphoma type In the case of localized lymphoma, conventional surgical approach and local radiotherapy with systemic Table 5 Treatment strategy for EBV infection 1 Prolonged infectious mononucleosis or mild form of chronic active EBV infection: Conventional therapy such as steroids and antiviral drugs 2 Silent lymphoproliferative disease: Early detection of the presence of lymphoproliferative disorder by diagnostic imaging and of increased EBV DNA in peripheral blood lymphocytes Treatment is almost the same as for posttransplant lymphoproliferative disorder 3 EBV-associated hemophagocytic syndrome: Plasma exchange to reduce the increased cytokines Immunosuppression of activated T cells, reduction of EBV-infected T cells Similar treatment to that for T-cell lymphoproliferative disorder 4 Posttransplant lymphoproliferative disorder: Reduction of immunosuppressants EBV-specific cytotoxic T lymphocytes Steroids and cytotoxic drugs when graft vs. host disease is present Combined chemotherapy 5 T/NK-cell lymphoproliferative disorder: Immunochemotherapy to suppress activated T cells and macrophages Reduction of EBV infected T cells Combined chemotherapy Stem cell transplantation EBV-specific cytotoxic T lymphocytes in the future
K. Kawa et al. / Critical Reviews in Oncology/Hematology 44 (2002) 251 /257
chemotherapy such as CHOP (vincristine, cyclophosphamide, doxorubicin, and prednisolone) are the choice of the treatment. However, EBV-associated T/ NK-cell LPD frequently expresses a P-glycoprotein that extrudes anti-cancer drugs such as vincristine and doxorubicin from the cell against a concentration gradient. This can explain one of the reasons for becoming resistance to chemotherapy in the majority of the T/NK-cell LPD [25,26]. More recently, the effect of L-asparaginase has been reported in resistant or relapsed patients [27]. Therefore, a front-line chemotherapy regimen containing L-asparaginase should be considered in the future study. In case of relapse or advanced stage autologous or allogeneic HSCTs seems to be a promising avenue similar to other types of lymphomas [4,5,19]. 7.2. Systemic type After making an accurate diagnosis based on EBVspecific serology, detection of EBV-infected cells, and monoclonality of proliferating cells, immunosuppressive and cytoreductive therapy such as prednisolone/cyclosporine A/etoposide are currently used for EBVAHS and CAEBV. More intensive combination chemotherapy should be applied for resistant cases and more advanced leukemia/lymphoma cases, and the final goal seems to eradicate EBV-infected T/NK cells (Table 6). However, since the complete eradication of EBVinfected T/NK cells by conventional chemotherapy is often very difficult at present the application of allogeneic HSCT should be considered for all patients when minimum residual disease is not disappeared. Autologous HSCT is also a feasible treatment. But without purging, contamination of EBV-infected T/NK-cells in the graft is always the risk of relapse. As mentioned before (Table 3), the clinical course and laboratory findings of our patient with CAEBV and HV are shown in Fig. 2. After starting chemotherapy the patient’s skin lesions gradually improved, and although EBV-DNA levels in plasma soon decreased under the detection level, EBV-DNA in the mononuclear cells did not disappear until administration of high-dose Ara C Table 6 Diagnosis and treatment for EBV-associated T/NK */cell LPD 1 EBV-specific serologic test (anti-VCAs, EAs and EBNAs) 2 Detection of EBV-related proteins and genome in proliferating cells. Subset of lymphocytes, cell sorting and PCR, immunostaining0 double staining, in situ hybridization 3 Determination of monoclonality, TCR/Ig gene rearrangements, EBV-terminal region, chromosomal abnormality 4 Immunosuppressive/cytoreductive therapy 5 Combination chemotherapy 6 Stem cell transplantation 7 Immunotherapy/cell therapy
255
(HDCA). After three courses of HDCA the patient received HSCT from an HLA-matched unrelated donor with preconditioning of TBI (12 Gy)/etoposide (900 mg/m2)/cyclophosphamide (120 mg/kg). Prophylaxis for graft-versus-host disease (GVHD) consisted of tacrolimus and a short course of methotrexate. Posttransplant clinical course was uneventful and EBVDNA in the peripheral blood mononuclear cells became undetectable. The patient is well in complete remission at the time of writing (UPN 252). Thus far, we have performed allogeneic HSCT for eight patients with EBV-associated T/NK-cell LPD as shown in Table 7. Age at diagnosis ranged from 3 to 28 years. Among six patients with CAEBV, two had hypersensitivity to mosquito allergy (UPN209, 250) and one had hydroa vacciniforme (UPN252). UPN185 had nasal NK-cell lymphoma with disseminated metastases, and UPN224 developed fulminant IM to lymphoma-associated hemophagocytic syndrome (LAHS) [28]. Three patients (UPN146, 209, 224) had EBVinfected T-cell LPD and four patients (UPN185, 247, 249, 251) had EBV-infected NK-cell LPD. In UPN184, EBV-infected T-cells and NK-cells were detected at different time during the patient’s clinical course. All studied cases (seven cases) showed monoclonal expansion of EBV-infected T/NK-cells. Three types of HSCT were performed: two with CD34 positive cell selection (HLA-haploidentical), two with HLA-matched related BMT, and four with unrelated BMT; three with HLA matching and one with HLA one locus mismatching. Except for UPN247 in which cyclophosphamide was replaced by melphalan due to cardiotoxicity, all other patients received a preconditioning regimen consisting of TBI, etoposide, and cyclophosphamide. As GVHD prophylaxis, tacrolimus was used for CD3 positive cell transplant, cyclosporin A was used for related BMT, and tacrolimus/short term MTX were used for unrelated BMT. Although UPN209 developed grade III GVHD, all other patients had less than grade II GVHD. Posttransplant clinical course of UPN185 was uneventful, but the patient died suddenly of undetermined causes and permission for autopsy was not obtained. At the time of transplant in UPN146 the disease state was progressive and UPN258 had organ failures. Both patients subsequently died, which suggests that disease status and the patient’s condition just prior to transplant influence the outcome. Five patients are alive and well with no EBV-infected T/NK-cells. Based on the above findings, we suggest that allogeneic HSCT is a feasible and promising method to cure EBV-associated T/NK-cell LPD. In addition, reports of successful autologous HSCT for the treatment of EBVassociated T/NK-cell LPD have also been published [19,20]. Since T-cell-based therapies (CTLs, cytotoxic Tcells) are being applied for the treatment of posttransplant B-cell LPD in which target EB viral antigens such
K. Kawa et al. / Critical Reviews in Oncology/Hematology 44 (2002) 251 /257
256
Fig. 2. Clinical course (M.S., UPN252). Pred, prednisolone; CyA, cyclosporin A; CHOP, (combination of vincristine, cyclophosphamide, doxorubicin, and prednisolone); HDCA, high dose Ara C; U-BMT, unrelated BMT; MNC, mononuclear cells; w, weak.
Table 7 SCT for EBV-associated T/NK-cell LPD Type of SCT
UPN Age/sex
Diagnosis
Pre SCT
Complication
Outcome
CD34
146 209 184 185 224 258 250 252
CAEBV CAEBV HMB CAEBV Nasal lymphoma IM0 LAHS CAEBV NK-LPD CAEBV HMB NK-LPD HV CAEBV
3 years/Progressive 4 years/PR 3 years/PR 7 ms/Stable disease 11 ms/CR 11 years/PR 4 years/Stable disease 8 years/CR
VOD relapse aGVHD(GIII) convulsion sepsis / Convulsion effusion cGVHD (limited) VOD infection renal failure aGVHD (GII) aGVHD (GI)
Dead (day 26) CR (28 msB ) CR (38 msB ) Dead (day 48) CR (23 msB ) Dead (day 14) CR (14 msB ) CR (14 msB )
RBMT URBMT
8 years/M 5 years/M 7 years/M 28 years/F 17 years/F 4 years/M 3 years/F 11 years/M
as EBV nuclear antigens (EBNAs) and latent membrane protein (LMP) are expressed, similar approach seems to be possible if specific CTLs against LMP which is expressed on the EBV-infected T/NK-cells are exploited [12,29]. Until more sophisticated approach become available, due to the poor outcome of this disorder, the early application of HSCT for the treatment of EBVassociated T/NK-cell LPD is recommended to avoid the development of a fatal clinical course.
Reviewers Thomas G. Gross, Division of Hematology/Oncology, Director, Blood Marrow Transplant Program, Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA. Raymond Liang, Department of Medicine, University of Hong Kong, K417, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong.
Tibor Kovacsovics, Hematology Division, Chuv (University Hospital), CH-1011 Lausanne, Switzerland.
References [1] Kato S, Yabe H, Yasui M, et al. Allogeneic hematopoietic transplantation of CD34/ selected cells from an HLA haploidentical related donor. A long-term follow-up of 135 patients and a comparison of stem cell source between the bone marrow and the peripheral blood. Bone Marrow Transplant 2000;26:1281 /90. [2] Filipovich AH, Blazar BR, Ramsay NKC, et al. Allogeneic bone marrow transplantation for X-linked lymphoproliferative syndrome. Transplantation 1986;42:222 /4. [3] Imashuku S, Hibi S, Todo S, et al. Allogeneic hematopoietic stem cell transplantation for patients with hemophagocytic syndrome (HPS) in Japan. Bone Marrow Transplant 1999;23:569 /72. [4] Teshima T, Miyaji R, Fukuda M, Ohshima K. Bone marrow transplantation for Epstein /Barr-virus-associated natural killer cell large granular lymphocytic leukemia. Lancet 1996;347:1124. [5] Okamura T, Hatsukawa Y, Arai H, Inoue M, Kawa K. Blood stem-cell transplantation for chronic active Epstein /Barr virus with lymphoproliferation. Lancet 2000;356:223 /4.
K. Kawa et al. / Critical Reviews in Oncology/Hematology 44 (2002) 251 /257 [6] Okano M. Epstein /Barr virus infection and its role in the expanding spectrum of human diseases. Acta Paediatr 1998;87:11 /8. [7] Coffey AJ, Brooksbank RA, Brandan O, et al. Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene. Nat Genet 1998;20:129 /35. [8] Sayos J, Wu C, Morra M, et al. The X-linked lymphoproliferative disease gene product SAP regulates signals induced through the co-receptor SLAM. Nature 1998;395:462 /9. [9] Nichols KE, Harkin DP, Levitz S, et al. Inactivating mutations in an SH2 domain-encoding gene in X-linked lymphoproliferative syndrome. Proc Natl Acad Sci USA 1998;95:13765 /70. [10] Gross TG, Filipovich AH, Conley ME, et al. Cure of X-linked lymphoproliferative disease (XLP) with allogeneic hematopoietic stem cell transplantation (HSCT): report from the XLP registry. Bone Marrow Transplant 1996;17:741 /4. [11] Risdall RJ, Mckenna RW, Nesbit ME, et al. Virus associated hemophagocytic syndrome: a benign histiocytic proliferation distinct from malignant histiocytosis. Cancer 1979;44:993 /1002. [12] Kawa K. Epstein /Barr virus-associated diseases in humans. Int J Hematol 2000;71:108 /17. [13] Kawa K, Ishihara S, Okamura T, Inoue M. Chronic active Epstein /Barr virus infection and lymphoproliferative diseases. In: Osato T, Takada K, Tokunaga M, editors. Epstein /Barr virus and human cancer: Gann monograph on cancer research no. 45. Tokyo: Japan Scientific Societies Press, 1998:139 /47. [14] Kawa-Ha K, Ishihara S, Ninomiya T, et al. CD3-negative lymphoproliferative disease of granular lymphocytes containing Epstein /Barr viral DNA. J Clin Invest 1989;84:52 /5. [15] Imai S, Sugiura M, Oikawa S, et al. Epstein /Barr virus (EBV)carrying and expressing T-cell lines established from severe chronic active EBV infection. Blood 1996;87:1446 /57. [16] Kimura H, Hoshino Y, Kanegane H, et al. Clinical and virologic characteristics of chronic active Epstein /Barr virus infection. Blood 2001;98:280 /6. [17] Jaffe ES. Classification of natural killer (NK) cell and NK-like Tcell malignancies. Blood 1996;87:1207 /10. [18] Nakamura S, Katoh E, Koshikawa T, et al. Clinicopathologic study of nasal T/NK-cell lymphoma among the Japanese. Pathol Int 1997;47:38 /53. [19] Liang R, Chen F, Lee CY, et al. Autologous bone marrow transplantation for primary nasal T/NK cell lymphoma. Bone Marrow Transplant 1997;19:91 /3. [20] Sasaki M, Matsue K, Takeuchi M, et al. Successful treatment of disseminated nasal NK/T-cell lymphoma using double autologous peripheral blood stem cell transplantation. Int J Hematol 2000;71:75 /8.
257
[21] Ishihara S, Ohshima K, Tokura Y, et al. Hypersensitivity to mosquito bites conceals clonal lymphoproliferation of Epstein / Barr viral DNA-positive natural killer cells. Jpn J Cancer Res 1997;88:82 /7. [22] Kawa K, Okamura T, Yagi K, Takeuchi M, Nakayama M, Inoue M. Mosquito allergy and Epstein /Barr virus-associated T/natural killer-cell lymphoproliferative disease. Blood 2001;98:3173 /4. [23] Iwatsuki K, Xu Z, Takata M, et al. The association of latent Epstein /Barr virus infection with hydroa vacciniforme. Br J Dermatol 1999;140:715 /21. [24] Zaia JA, Krishnan. Progenitor cell transplantation for AIDSrelated lymphoma: response in terms of lymphoma and HIV, In: Schechter GP, Broudy VC, Williams M, editors. Hematology 2001. pp. 470 /78. [25] Yamaguchi M, Kita K, Miwa H, et al. Frequent expression of Pglycoprotein/MDR1 by nasal T-cell lymphoma cells. Cancer 1995;76:2351 /6. [26] Egashira M, Kawamata N, Sugimoto K, et al. P-glycoprotein expression on normal and abnormally expanded natural killer cells and inhibition of P-glycoprotein function by cyclosporin A and its analogue. Blood 1999;93:599 /606. [27] Nagafuji K, Fujisaki T, Arima F, Ohshima K. L-asparaginase induced durable remission of relapsed nasal NK/T-cell lymphoma after autologous peripheral blood stem cell transplantation. Int J Hematol 2001;74:447 /50. [28] Yagita M, Iwakura H, Kishimoto T, et al. Successful allogeneic stem cell transplantation from an unrelated donor for aggressive Epstein /Barr virus-associated clonal T-cell proliferation with hemophagocytosis. Int J Hematol 2001;74:451 /4. [29] Rooney CM, Heslop HE, Brenner MK. EBV specific CTL: a model for immune therapy. Vox Sanguinis 1998;74:497 /8.
Biography In March 1970: Keisei Kawa graduated from Osaka University Medical School. Until June 1982: Pediatric clinical work at Osaka University Hospital and at affiliated hospitals. From July 1982 to June 1984: Terry Fox Research Fellowship at Hospital for Sick Children in Toronto. In October 1989: Assistant Professor at Osaka University Hospital. In July 1990: Associate Professor at Osaka University Hospital. From July 1991 to present: Director of Department of Pediatrics, Osaka Medical Center and Research Institute for Maternal and Child Health.
Allogeneic hematopoietic stem cell transplantation for Epstein Barr virus-associated T/NK-cell lymphoproliferative disease /
Keisei Kawa , Takayuki Okamura, Masahiro Yasui, Emiko Sato, Masami Inoue Department of Pediatrics, Osaka Medical Center and Research Institute for Maternal and Child Health, 840 Murodo, Izumi City, Osaka 594-1101, Japan Accepted 14 February 2002
Contents 1.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
251
2.
X-linked lymphoproliferative disease (LPD) . . . . . . . . . . . . . . . . . . . . . . . . . .
252
3.
EBV-associated hemophagocytic syndrome (EBV-AHS)
. . . . . . . . . . . . . . . . . . .
252
4.
Chronic active EBV infection (CAEBV)
. . . . . . . . . . . . . . . . . . . . . . . . . . . .
252
5.
Nasal and nasal-type NK-cell lymphomas . . . . . . . . . . . . . . . . . . . . . . . . . . .
253
6.
‘EBV-associated T/NK-cell LPD’ as a distinct disease entity . . . . . . . . . . . . . . . . .
253
7.
Treatment strategy for EBV-associated T/NK-cell LPD . . . . . . . . . . . . . . . . . . . . 7.1. Lymphoma type . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2. Systemic type . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
254 254 255
Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
256
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
256
Biography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
257
Abstract Epstein /Barr virus (EBV) is implicated in a variety of human diseases, some of which have fatal outcomes. Some EBV related diseases are considered to be candidates for the treatment of hematopoietic stem cell transplantation (HSCT). X-linked lymphoproliferative (XLP) syndrome is one of the representative diseases in which more than half of affected males die of infectious mononucleosis (IM) within a few weeks of primary infection, whereas the minority who survive have an increased risk of acquired hypogammaglobulinemia and lymphoma. Patients with XLP usually die by the age 40. Similarly, the majority of patients with chronic active EBV infection develop hemophagocytic syndrome, organ failure, opportunistic infection, and/or lymphoma and die within 5 /10 years from onset. Recently, HSCT has provided successful outcomes in these patients. In this review, progress in the new therapeutic strategy is summarized, focusing on EBV-associated T/NK-cell lymphoproliferative disease (LPD), which is one of the heterogeneous EBV-associated disorder. # 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: XLP; HPS; Mosquito allergy; Hydroa vacciniforme; LPD (lymphoproliferative disease); EBV-associated T/NK-cell LPD; Hematopoietic SCT
1. Introduction Corresponding author. Tel.: /81-725-56-1220; fax: /81-725-565682 E-mail address: [email protected] (K. Kawa).
Allogeneic hematopoietic stem cell transplantation (HSCT) from an HLA-identical related or unrelated
1040-8428/02/$ - see front matter # 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 1 0 4 0 - 8 4 2 8 ( 0 2 ) 0 0 1 1 6 - 6
252
K. Kawa et al. / Critical Reviews in Oncology/Hematology 44 (2002) 251 /257
donor has been established as a curative therapy for a variety of hematological malignancies, bone marrow failure syndromes, and immunological disorders. In addition, HSCT from HLA-mismatched related donor with T cell depletion has also been performed for patients who require allogeneic HSCT but lack an available HLA-matched donor [1]. Among Epstein / Barr virus (EBV)-associated diseases, allogeneic HSCT was first applied for the treatment of X-linked lymphoproliferative (XLP) disease [2]. More recently, other patients with EBV-associated diseases such as EBVassociated hemophagocytic syndrome (EBV-AHS), EBV-associated natural killer (NK) cell lymphoma, and chronic active EBV infection have been treated using this treatment method, resulting in encouraging results [3 /5]. In this brief review, representative reported cases of HSCT for the treatment of EBV-associated diseases are described and our current strategy for the treatment of EBV-associated T/NK-cell LPD is also discussed.
2. X-linked lymphoproliferative disease (LPD) Purtilo et al. first reported this disease, and now the XLP International registry consists of over 300 affected patients. The diagnosis of XLP is based on clinical criteria requiring two or more maternally related males manifesting one or more of the characteristic phenotypes: fulminant infectious mononucleosis (IM), malignant lymphoma or LPD, and dysgammaglobulinemia [6]. Recently, the gene responsible for XLP was identified [7 /9], and its product interacts with signaling lymphocyte activation molecule (SLAM), and mediates the expansion of activated T cells during immune responses. Mutations in the XLP gene disrupt the interactions, and is considered to be responsible for the development of the XLP phenotype. In 1996, Gross et al. reported seven male patients with XLP who had undergone allogeneic HSCT [10]. All patients received HSCT from HLA-identical donors: related six (BM 5, cord blood 1), unrelated BM one. Conditioning regimens consisted of TBI containing regimens (n/4) and non-TBI containing regimens (n/3). All patients successfully engrafted and four are alive and well with normal immune function more than 3 years after HSCT. Although the number of patients was small, the authors suggested that age at HSCT (/ 15 years), TBI-containing regimen and a significant history for pre-HSCT infections were critical risk factors for success. Based on these findings they recommend that all possible efforts should be made to resolve active and/or subclinical infection, and that HSCT should be performed as soon as a suitable donor is identified.
3. EBV-associated hemophagocytic syndrome (EBVAHS) Virus-associated hemophagocytic syndrome (VAHS) is a lymphoproliferative disorder associated with viral infection [11]. Among various infectious agents, herpesviruses, particularly EBV, have been implicated in the pathogenesis of VAHS. Clinically, patients with EBVAHS have prolonged fever, hepatosplenomegaly, pancytopenia, and coagulopathy. Morphologic examination of lymph nodes and bone marrow shows marked phagocytosis of erythrocytes and nucleated blood cells. In infants and children, hypertriglyceridemia is often observed. Until recently, the pathogenesis of EBV-AHS was poorly understood, but recent studies have indicated that the proliferation of EBV-infected T cells may be a primary feature of the disease, and unrestricted release of inflammatory cytokines (hypercytokinemia), such as interferon-g and tumor necrosis factor-a, is a prominent feature of EBV-AHS. Since some cases of EBV-AHS have a fatal outcome, rapid diagnosis and initiation of newly established immunochemotherapy, such as prednisolone/dexamethasone, cyclosporin A, and etoposide, are recommended. HSCT should be considered if the patient responds poorly to immunochemotherapy or combined cytotoxic drugs [12]. Currently, HSCT has been performed for six patients with EBV-AHS including two with EBV-associated NK-cell LPD in Japan [3], of which there were four related HLA-matched donors and two unrelated HLA-matched donors. Preconditioning regimens consisted of TBIcontaining regimen (n /5) and non-TBI regimen (n/ 1). Four patients with EBV-AHS were in remission (3.5 /29 m/), but two patients with EBV-associated NK-cell LPD who received transplants from siblings relapsed at 14 and 15 m post HSCT, suggesting resistance to the therapy.
4. Chronic active EBV infection (CAEBV) In the early 1980s, the presence of so-called chronic (or persistent) or recurrent EBV infectious disease was recognized. CAEBV is characterized by chronic or recurrent IM-like symptoms, an abnormal pattern of anti-EBV antibodies (increased anti-VCA and early antigens, absence of anti-EBNA), and no evidence of prior immunologic abnormality or recent infection that could explain the condition [12,13]. Initially, CAEBV was considered to be a very rare disorder, and its pathogenesis was not well understood. More recently, our understanding has improved, and the clinical features and pathogenesis of CAEBV have been elucidated. CAEBV occurs at any age and in both sexes. No obvious immunodeficiency or hereditary background is
K. Kawa et al. / Critical Reviews in Oncology/Hematology 44 (2002) 251 /257
observed in family members, distinguishing it from XLP. Interestingly, one third of pediatric patients had a history of mosquito allergy. Although atypical lymphocytosis is a characteristic finding of IM, results of complete blood counts are variable. In addition, nearly one fourth of patients showed granular LPD in their clinical course, and the increased granular lymphocytes were exclusively EBV-infected NK cells [14]. Imai et al. succeeded in establishing T-cell lines containing the EBV genome from patients with CAEBV [15]. Similarly, we used PCR to demonstrate the existence of EBV DNA in CD3/ T cells from peripheral blood lymphocytes of CAEBV patients [13]. Thus, EBV-infected T cells and NK cells seem to play an important role in the pathogenesis of CAEBV, and it can be possible to divide into 2 groups, T-cell type and NK-cell type, based on the predominant infected cell population found in the peripheral blood [16]. Importantly, however, one should pay attention for identifying the predominant infected cell population that may shift from T-cell to NK-cell during the clinical course [5]. On the basis of these findings, it is understandable that CAEBV patients are more likely to develop T/NK-cell LPD. Typical clinical symptoms are fever, hepatomegaly, splenomegaly, anemia, and lymphadenopathy. The prognosis of patients with CAEBV is very poor in both pediatric and adult patients, and about half of them die within 4/5 years from onset. Hepatic and cardiac failure, various kinds of LPD, opportunistic infections, and EBV-AHS are the main causes of death [13]. Recently, we have reported a successful case of allogeneic HSCT in a 7-year-old boy who initially presented with EBV-infected T-cell LPD, and subsequently developed bilateral exophthalmos due to infiltration of EBV-infected NK cells into extraocular muscles during chemotherapy [5].
5. Nasal and nasal-type NK-cell lymphomas Nasal and nasal-type NK-cell lymphomas represent a distinct clinicopathologic entity almost always associated with EBV. Mostly, this type of lymphoma presents as a nasal destructive disease often extending to the palate, commonly accompanied by nasal obstruction, erythema, and orbital swelling. In addition to the most common nasal lesion, the larynx and upper respiratory and digestive tracts can be affected. Occasionally, the disease is initially localized in the skin and subcutaneous tissue as well as the digestive tract but then spreads to other sites including the lung (referred to as nasal-type lymphoma). Histologic characteristics are the presence of pleomorphic lymphoid cells, ischemic
253
Table 1 Hypersensitivity to mosquito bites (HMB) conceals clonal lymphoproliferation of Epstein /Barr viral DNA-positive natural killer cells More than half of the patients with HMB died of HPS Among six patients with HMB only two patients were diagnosed with increased LGL in the PBL. However, four of the five studied cases showed increment of CD56CD3-lymphocytes All but one of the patients showed abnormal patterns of antibodies against EBV All of the patients showed high levels of lgE (1000 /20 854 IU/ml) EBV-DNA was detected in the PBMCs in all six patients and in the serum in three of four examined patients. In addition, four cases were monoclonal and one case was biclonal
Table 2 The association of latent EBV infection with HV Patients with HV-like eruptions and malignant potential have been reported from Asia and Mexico A diagnostic histological feature of HV is a dense perivascular infiltrate of T cells, and angiodestructive infiltration is also seen Biopsy specimens from cutaneous lesions of six children with typical HV demonstrated EBERcells (3 /10% of the dermal infiltrates) The presence of EBV-DNA was also confirmed in five of six biopsy specimens by PCR Immunophenotype of the infiltrating cells was CD45RO and CD20 (two examined cases were CD56) Atypical HV is a smouldering stage potentially leading to an EBVassociated lymphoid malignancy
necrosis, and angiocentric or angioinvasive infiltration in the lesions [17]. According to Nakamura et al. [18], the overall survival rate for patients with nasal NK (or T)-cell lymphoma in Japan was 49% at 5 years, and all patients with stage IV disease died within 6 months. Although the number of reports is limited, successful treatments with autologous HSCT have been reported [19,20].
6. ‘EBV-associated T/NK-cell LPD’ as a distinct disease entity Mosquito allergy is characterized by intense local skin symptoms, which consist of not only erythema or bulla, but also ulcer or scar, and general symptoms such as high fever following mosquito bites. Until recently, the pathogenesis of mosquito allergy was unclear; however, we first demonstrated a close relationship between mosquito allergy and EBV-infected NK-cell LPD in six patients with mosquito allergy (Table 1) [21]. In addition, we clearly demonstrated that EBV-infected Tcell LPD had preceded the onset of mosquito allergy in an interesting case [22]. Because no hereditary background in family members and preceding immunodefi-
K. Kawa et al. / Critical Reviews in Oncology/Hematology 44 (2002) 251 /257
254
Fig. 1. Prognosis of EBV-associated T/NK-cell LPD. LPD, lymphoproliferative disease; CAEBV, chronic active EBV infection; HPS, hemophagocytic syndrome; D, death; (EBV-associated T/NK-cell
Table 3 M.S. 17 years/M, CAEBVHV Eleven years Twelve years Thirteen years Fifteen years Seventeen years, on admission
Eruptions on the face and extremities for several months Fever, cervical lymphoadenopathy, liver dysfunction CAEBV, HV-like eruption HV (angiocentric lymphoma, EBERNKcells), NK-LPD in PBL EBV-infected NK-LPD (monoclonal); eruptions on the face (HV)
ciencies were observed among these patients, EBV infection to T or NK cells may happen by chance and in some instances latently infected T/NK cells may develop LPD under unknown co-factors. Hydroa vacciniforme (HV) is characterized by the childhood onset of necrotic vesiculopapules on sunexposed areas and epidermal necrosis with lymphatic infiltration. Recently, Iwatsuki et al. showed that atypical HV is closely related to infiltration of EBVinfected T cells in the lesions (Table 2) [23]. More recently, we examined a patient who was diagnosed with CAEBV and HV (Table 3). His clinical course is discussed later, but taken together, we hypothesize that there is a close relationship between EBV infection and mosquito allergy/HV. In addition, EBV-associated T/NK-cell LPD seems to be a common pathogenesis for all these disorders, and the prognosis is very poor (Fig. 1). Table 4 EBV-associated T/NK */cell LPD Chronic active EBV infection (CAEBV) EBV-associated hemophagocytic syndrome (EBV-AHS) Peripheral T-cell lymphoma Mosquito allergy Hydroa vacciniforme Chronic granular LPD Aggressive NK-cell leukemia Nasal/nasal type NK-cell lymphoma
In parallel with the concept of HTLV-1-asociated T cell leukemia/lymphoma (ATL), thus far, EBV-associated T/NK-cell LPD comprises chronic active EBV infection, EBV-AHS, peripheral T-cell lymphoma, mosquito allergy, HV, chronic granular LPD, aggressive NK-cell leukemia, and nasal/nasal type NK-cell lymphoma (Table 4). Contrary to EBV-associated T/NK-cell LPD, EBVassociated B-cell LPD consists of Burkitt’s lymphoma, posttransplant LPD, AIDS-related LPD, XLP, and pyothorax-associated lymphoma [12]. With the use of more profound immunosuppressive therapy, the incidence of posttransplant B-cell LPD has recently increased. In the case of posttransplant B-cell LPD, reduction of the immunosuppressants is the first choice of the treatment. AIDS-related lymphoma shares many features with posttransplant LPD, and more recently with the successful use of anti-viral agents autologous HSCT is employed for its treatment [24]. Therefore, treatments including HSCT should be specified in each patient according to the cell lineage of LPD and the clinical status of the patients (Table 5).
7. Treatment strategy for EBV-associated T/NK-cell LPD 7.1. Lymphoma type In the case of localized lymphoma, conventional surgical approach and local radiotherapy with systemic Table 5 Treatment strategy for EBV infection 1 Prolonged infectious mononucleosis or mild form of chronic active EBV infection: Conventional therapy such as steroids and antiviral drugs 2 Silent lymphoproliferative disease: Early detection of the presence of lymphoproliferative disorder by diagnostic imaging and of increased EBV DNA in peripheral blood lymphocytes Treatment is almost the same as for posttransplant lymphoproliferative disorder 3 EBV-associated hemophagocytic syndrome: Plasma exchange to reduce the increased cytokines Immunosuppression of activated T cells, reduction of EBV-infected T cells Similar treatment to that for T-cell lymphoproliferative disorder 4 Posttransplant lymphoproliferative disorder: Reduction of immunosuppressants EBV-specific cytotoxic T lymphocytes Steroids and cytotoxic drugs when graft vs. host disease is present Combined chemotherapy 5 T/NK-cell lymphoproliferative disorder: Immunochemotherapy to suppress activated T cells and macrophages Reduction of EBV infected T cells Combined chemotherapy Stem cell transplantation EBV-specific cytotoxic T lymphocytes in the future
K. Kawa et al. / Critical Reviews in Oncology/Hematology 44 (2002) 251 /257
chemotherapy such as CHOP (vincristine, cyclophosphamide, doxorubicin, and prednisolone) are the choice of the treatment. However, EBV-associated T/ NK-cell LPD frequently expresses a P-glycoprotein that extrudes anti-cancer drugs such as vincristine and doxorubicin from the cell against a concentration gradient. This can explain one of the reasons for becoming resistance to chemotherapy in the majority of the T/NK-cell LPD [25,26]. More recently, the effect of L-asparaginase has been reported in resistant or relapsed patients [27]. Therefore, a front-line chemotherapy regimen containing L-asparaginase should be considered in the future study. In case of relapse or advanced stage autologous or allogeneic HSCTs seems to be a promising avenue similar to other types of lymphomas [4,5,19]. 7.2. Systemic type After making an accurate diagnosis based on EBVspecific serology, detection of EBV-infected cells, and monoclonality of proliferating cells, immunosuppressive and cytoreductive therapy such as prednisolone/cyclosporine A/etoposide are currently used for EBVAHS and CAEBV. More intensive combination chemotherapy should be applied for resistant cases and more advanced leukemia/lymphoma cases, and the final goal seems to eradicate EBV-infected T/NK cells (Table 6). However, since the complete eradication of EBVinfected T/NK cells by conventional chemotherapy is often very difficult at present the application of allogeneic HSCT should be considered for all patients when minimum residual disease is not disappeared. Autologous HSCT is also a feasible treatment. But without purging, contamination of EBV-infected T/NK-cells in the graft is always the risk of relapse. As mentioned before (Table 3), the clinical course and laboratory findings of our patient with CAEBV and HV are shown in Fig. 2. After starting chemotherapy the patient’s skin lesions gradually improved, and although EBV-DNA levels in plasma soon decreased under the detection level, EBV-DNA in the mononuclear cells did not disappear until administration of high-dose Ara C Table 6 Diagnosis and treatment for EBV-associated T/NK */cell LPD 1 EBV-specific serologic test (anti-VCAs, EAs and EBNAs) 2 Detection of EBV-related proteins and genome in proliferating cells. Subset of lymphocytes, cell sorting and PCR, immunostaining0 double staining, in situ hybridization 3 Determination of monoclonality, TCR/Ig gene rearrangements, EBV-terminal region, chromosomal abnormality 4 Immunosuppressive/cytoreductive therapy 5 Combination chemotherapy 6 Stem cell transplantation 7 Immunotherapy/cell therapy
255
(HDCA). After three courses of HDCA the patient received HSCT from an HLA-matched unrelated donor with preconditioning of TBI (12 Gy)/etoposide (900 mg/m2)/cyclophosphamide (120 mg/kg). Prophylaxis for graft-versus-host disease (GVHD) consisted of tacrolimus and a short course of methotrexate. Posttransplant clinical course was uneventful and EBVDNA in the peripheral blood mononuclear cells became undetectable. The patient is well in complete remission at the time of writing (UPN 252). Thus far, we have performed allogeneic HSCT for eight patients with EBV-associated T/NK-cell LPD as shown in Table 7. Age at diagnosis ranged from 3 to 28 years. Among six patients with CAEBV, two had hypersensitivity to mosquito allergy (UPN209, 250) and one had hydroa vacciniforme (UPN252). UPN185 had nasal NK-cell lymphoma with disseminated metastases, and UPN224 developed fulminant IM to lymphoma-associated hemophagocytic syndrome (LAHS) [28]. Three patients (UPN146, 209, 224) had EBVinfected T-cell LPD and four patients (UPN185, 247, 249, 251) had EBV-infected NK-cell LPD. In UPN184, EBV-infected T-cells and NK-cells were detected at different time during the patient’s clinical course. All studied cases (seven cases) showed monoclonal expansion of EBV-infected T/NK-cells. Three types of HSCT were performed: two with CD34 positive cell selection (HLA-haploidentical), two with HLA-matched related BMT, and four with unrelated BMT; three with HLA matching and one with HLA one locus mismatching. Except for UPN247 in which cyclophosphamide was replaced by melphalan due to cardiotoxicity, all other patients received a preconditioning regimen consisting of TBI, etoposide, and cyclophosphamide. As GVHD prophylaxis, tacrolimus was used for CD3 positive cell transplant, cyclosporin A was used for related BMT, and tacrolimus/short term MTX were used for unrelated BMT. Although UPN209 developed grade III GVHD, all other patients had less than grade II GVHD. Posttransplant clinical course of UPN185 was uneventful, but the patient died suddenly of undetermined causes and permission for autopsy was not obtained. At the time of transplant in UPN146 the disease state was progressive and UPN258 had organ failures. Both patients subsequently died, which suggests that disease status and the patient’s condition just prior to transplant influence the outcome. Five patients are alive and well with no EBV-infected T/NK-cells. Based on the above findings, we suggest that allogeneic HSCT is a feasible and promising method to cure EBV-associated T/NK-cell LPD. In addition, reports of successful autologous HSCT for the treatment of EBVassociated T/NK-cell LPD have also been published [19,20]. Since T-cell-based therapies (CTLs, cytotoxic Tcells) are being applied for the treatment of posttransplant B-cell LPD in which target EB viral antigens such
K. Kawa et al. / Critical Reviews in Oncology/Hematology 44 (2002) 251 /257
256
Fig. 2. Clinical course (M.S., UPN252). Pred, prednisolone; CyA, cyclosporin A; CHOP, (combination of vincristine, cyclophosphamide, doxorubicin, and prednisolone); HDCA, high dose Ara C; U-BMT, unrelated BMT; MNC, mononuclear cells; w, weak.
Table 7 SCT for EBV-associated T/NK-cell LPD Type of SCT
UPN Age/sex
Diagnosis
Pre SCT
Complication
Outcome
CD34
146 209 184 185 224 258 250 252
CAEBV CAEBV HMB CAEBV Nasal lymphoma IM0 LAHS CAEBV NK-LPD CAEBV HMB NK-LPD HV CAEBV
3 years/Progressive 4 years/PR 3 years/PR 7 ms/Stable disease 11 ms/CR 11 years/PR 4 years/Stable disease 8 years/CR
VOD relapse aGVHD(GIII) convulsion sepsis / Convulsion effusion cGVHD (limited) VOD infection renal failure aGVHD (GII) aGVHD (GI)
Dead (day 26) CR (28 msB ) CR (38 msB ) Dead (day 48) CR (23 msB ) Dead (day 14) CR (14 msB ) CR (14 msB )
RBMT URBMT
8 years/M 5 years/M 7 years/M 28 years/F 17 years/F 4 years/M 3 years/F 11 years/M
as EBV nuclear antigens (EBNAs) and latent membrane protein (LMP) are expressed, similar approach seems to be possible if specific CTLs against LMP which is expressed on the EBV-infected T/NK-cells are exploited [12,29]. Until more sophisticated approach become available, due to the poor outcome of this disorder, the early application of HSCT for the treatment of EBVassociated T/NK-cell LPD is recommended to avoid the development of a fatal clinical course.
Reviewers Thomas G. Gross, Division of Hematology/Oncology, Director, Blood Marrow Transplant Program, Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA. Raymond Liang, Department of Medicine, University of Hong Kong, K417, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong.
Tibor Kovacsovics, Hematology Division, Chuv (University Hospital), CH-1011 Lausanne, Switzerland.
References [1] Kato S, Yabe H, Yasui M, et al. Allogeneic hematopoietic transplantation of CD34/ selected cells from an HLA haploidentical related donor. A long-term follow-up of 135 patients and a comparison of stem cell source between the bone marrow and the peripheral blood. Bone Marrow Transplant 2000;26:1281 /90. [2] Filipovich AH, Blazar BR, Ramsay NKC, et al. Allogeneic bone marrow transplantation for X-linked lymphoproliferative syndrome. Transplantation 1986;42:222 /4. [3] Imashuku S, Hibi S, Todo S, et al. Allogeneic hematopoietic stem cell transplantation for patients with hemophagocytic syndrome (HPS) in Japan. Bone Marrow Transplant 1999;23:569 /72. [4] Teshima T, Miyaji R, Fukuda M, Ohshima K. Bone marrow transplantation for Epstein /Barr-virus-associated natural killer cell large granular lymphocytic leukemia. Lancet 1996;347:1124. [5] Okamura T, Hatsukawa Y, Arai H, Inoue M, Kawa K. Blood stem-cell transplantation for chronic active Epstein /Barr virus with lymphoproliferation. Lancet 2000;356:223 /4.
K. Kawa et al. / Critical Reviews in Oncology/Hematology 44 (2002) 251 /257 [6] Okano M. Epstein /Barr virus infection and its role in the expanding spectrum of human diseases. Acta Paediatr 1998;87:11 /8. [7] Coffey AJ, Brooksbank RA, Brandan O, et al. Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene. Nat Genet 1998;20:129 /35. [8] Sayos J, Wu C, Morra M, et al. The X-linked lymphoproliferative disease gene product SAP regulates signals induced through the co-receptor SLAM. Nature 1998;395:462 /9. [9] Nichols KE, Harkin DP, Levitz S, et al. Inactivating mutations in an SH2 domain-encoding gene in X-linked lymphoproliferative syndrome. Proc Natl Acad Sci USA 1998;95:13765 /70. [10] Gross TG, Filipovich AH, Conley ME, et al. Cure of X-linked lymphoproliferative disease (XLP) with allogeneic hematopoietic stem cell transplantation (HSCT): report from the XLP registry. Bone Marrow Transplant 1996;17:741 /4. [11] Risdall RJ, Mckenna RW, Nesbit ME, et al. Virus associated hemophagocytic syndrome: a benign histiocytic proliferation distinct from malignant histiocytosis. Cancer 1979;44:993 /1002. [12] Kawa K. Epstein /Barr virus-associated diseases in humans. Int J Hematol 2000;71:108 /17. [13] Kawa K, Ishihara S, Okamura T, Inoue M. Chronic active Epstein /Barr virus infection and lymphoproliferative diseases. In: Osato T, Takada K, Tokunaga M, editors. Epstein /Barr virus and human cancer: Gann monograph on cancer research no. 45. Tokyo: Japan Scientific Societies Press, 1998:139 /47. [14] Kawa-Ha K, Ishihara S, Ninomiya T, et al. CD3-negative lymphoproliferative disease of granular lymphocytes containing Epstein /Barr viral DNA. J Clin Invest 1989;84:52 /5. [15] Imai S, Sugiura M, Oikawa S, et al. Epstein /Barr virus (EBV)carrying and expressing T-cell lines established from severe chronic active EBV infection. Blood 1996;87:1446 /57. [16] Kimura H, Hoshino Y, Kanegane H, et al. Clinical and virologic characteristics of chronic active Epstein /Barr virus infection. Blood 2001;98:280 /6. [17] Jaffe ES. Classification of natural killer (NK) cell and NK-like Tcell malignancies. Blood 1996;87:1207 /10. [18] Nakamura S, Katoh E, Koshikawa T, et al. Clinicopathologic study of nasal T/NK-cell lymphoma among the Japanese. Pathol Int 1997;47:38 /53. [19] Liang R, Chen F, Lee CY, et al. Autologous bone marrow transplantation for primary nasal T/NK cell lymphoma. Bone Marrow Transplant 1997;19:91 /3. [20] Sasaki M, Matsue K, Takeuchi M, et al. Successful treatment of disseminated nasal NK/T-cell lymphoma using double autologous peripheral blood stem cell transplantation. Int J Hematol 2000;71:75 /8.
257
[21] Ishihara S, Ohshima K, Tokura Y, et al. Hypersensitivity to mosquito bites conceals clonal lymphoproliferation of Epstein / Barr viral DNA-positive natural killer cells. Jpn J Cancer Res 1997;88:82 /7. [22] Kawa K, Okamura T, Yagi K, Takeuchi M, Nakayama M, Inoue M. Mosquito allergy and Epstein /Barr virus-associated T/natural killer-cell lymphoproliferative disease. Blood 2001;98:3173 /4. [23] Iwatsuki K, Xu Z, Takata M, et al. The association of latent Epstein /Barr virus infection with hydroa vacciniforme. Br J Dermatol 1999;140:715 /21. [24] Zaia JA, Krishnan. Progenitor cell transplantation for AIDSrelated lymphoma: response in terms of lymphoma and HIV, In: Schechter GP, Broudy VC, Williams M, editors. Hematology 2001. pp. 470 /78. [25] Yamaguchi M, Kita K, Miwa H, et al. Frequent expression of Pglycoprotein/MDR1 by nasal T-cell lymphoma cells. Cancer 1995;76:2351 /6. [26] Egashira M, Kawamata N, Sugimoto K, et al. P-glycoprotein expression on normal and abnormally expanded natural killer cells and inhibition of P-glycoprotein function by cyclosporin A and its analogue. Blood 1999;93:599 /606. [27] Nagafuji K, Fujisaki T, Arima F, Ohshima K. L-asparaginase induced durable remission of relapsed nasal NK/T-cell lymphoma after autologous peripheral blood stem cell transplantation. Int J Hematol 2001;74:447 /50. [28] Yagita M, Iwakura H, Kishimoto T, et al. Successful allogeneic stem cell transplantation from an unrelated donor for aggressive Epstein /Barr virus-associated clonal T-cell proliferation with hemophagocytosis. Int J Hematol 2001;74:451 /4. [29] Rooney CM, Heslop HE, Brenner MK. EBV specific CTL: a model for immune therapy. Vox Sanguinis 1998;74:497 /8.
Biography In March 1970: Keisei Kawa graduated from Osaka University Medical School. Until June 1982: Pediatric clinical work at Osaka University Hospital and at affiliated hospitals. From July 1982 to June 1984: Terry Fox Research Fellowship at Hospital for Sick Children in Toronto. In October 1989: Assistant Professor at Osaka University Hospital. In July 1990: Associate Professor at Osaka University Hospital. From July 1991 to present: Director of Department of Pediatrics, Osaka Medical Center and Research Institute for Maternal and Child Health.