Hematopoietic stem cell transplantation for adults with EBV-positive T- or NK-cell lymphoproliferative disorders: efficacy and predictive markers

Arai, Ayako; Sakashita, Chizuko; Hirose, Christopher B.; Ki, Imadome; Yamamoto, Masahide; Jinta, Minako; Fujiwara, Shigeyoshi; Tomita, Makoto; Shimizu, Norio; Morio, Tomohiro; Miura, Osamu

doi:10.1038/bmt.2016.3

Cited by 24 publications

(44 citation statements)

References 11 publications

(7 reference statements)

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“…In our series, in contrast to the promising findings of planned HSCT ( n = 63; 3y-OS 87.3 ± 4.2%), most patients with advanced/uncontrollable disease ( n = 12), including 8 who managed to undergo emergent HSCT, were not rescued (3y-OS 16.7 ± 10.8%) ( 6 ). Our findings were consistent with those by Arai et al who reported that OS was 100% after HSCT for inactive disease, but was 0% after HSCT for active disease ( 24 ).…”

Section: Hsct For Caebv In Various Situationssupporting

confidence: 93%

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Hematopoietic Stem Cell Transplantation for the Treatment of Epstein-Barr Virus-Associated T- or NK-Cell Lymphoproliferative Diseases and Associated Disorders

Sawada

Inoue

2018

Front. Pediatr.

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Chronic active Epstein-Barr virus infection (CAEBV) is a prototype of EBV-associated T- and/or NK-cell (EBV+ T/NK-cell) lymphoproliferative disorders. Most subtypes of these are lethal. We established a unified treatment strategy composed of step 1 (immunochemotherapy: steroids, cyclosporine A, and etoposide), step 2 (multi-drug block chemotherapy), and step 3 (allogeneic hematopoietic stem cell transplantation; HSCT) for CAEBV and its related diseases. Allogeneic HSCT is the only cure for CAEBV with few exceptions. Primary-EBV infection-associated hemophagocytic lymphohistiocytosis (primary-EBV HLH) is also an EBV+ T/NK-cell lymphoproliferation. The nature of EBV+ T/NK cells in CAEBV and those in primary-EBV HLH differ. In primary-EBV HLH, most patients need step 1 only and some require step 2 for the successful induction of apoptosis in EBV-infected T cells; however, some exceptional patients require HSCT. We herein present our single institutional experience of CAEBV and primary-EBV HLH, together with that of post-transplant EBV+ T/NK-cell lymphoproliferative disease. We also discuss some practical points on HCST with a review of the literature.

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Section: Hsct For Caebv In Various Situationssupporting

confidence: 93%

“…Therefore, we concluded that our 3-step strategy is also applicable to adults. Arai et al reported similar findings (OS 61.5%) for adult-onset CAEBV ( 24 ).…”

Section: Hsct For Caebv In Various Situationssupporting

confidence: 55%

Hematopoietic Stem Cell Transplantation for the Treatment of Epstein-Barr Virus-Associated T- or NK-Cell Lymphoproliferative Diseases and Associated Disorders

Sawada

Inoue

2018

Front. Pediatr.

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“…The two characteristics of CAEBV are a T- or NK-cell lymphoproliferative disorder and an inflammatory disorder [ 7 , 8 ]. Although EBV-infected T or NK cells in CAEBV clonally proliferate, they usually do not form solid tumors [ 8 , 9 ]. Instead, they can be detected in the peripheral blood and can infiltrate into organs, leading to their dysfunction.…”

Section: Introductionmentioning

confidence: 99%

“…Unfortunately, the mechanism underlying the CAEBV development remains unclear. At present, no effective agent exists for CAEBV, and the only curative treatment strategy has been allogeneic hematopoietic stem cell transplantation (allo-HSCT) [ 9 , 11 ]. However, only a limited number of patients are suitable candidates for allo-HSCT.…”

Section: Introductionmentioning

confidence: 99%

STAT3 is constitutively activated in chronic active Epstein-Barr virus infection and can be a therapeutic target

et al. 2018

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Chronic active Epstein-Barr virus infection (CAEBV) is a lymphoproliferative disorder characterized by the clonal proliferation of EBV-infected T or NK cells and is related to severe systemic inflammation. This study aims to investigate STAT3 to elucidate the mechanism underlying the CAEBV development. We determined that STAT3 was constitutively activated in EBV-positive T- or NK-cell lines. We also determined that STAT3 was activated in the peripheral blood mononuclear cells (PBMCs) containing EBV-infected clonally proliferating T or NK cells in six of seven patients with CAEBV. We conducted direct sequencing of the STAT3 Src homology 2 (SH2) domain, which has previously been reported to be mutated in T- or NK-cell neoplasms. No mutation was detected in the STAT3 SH2 domain in patients with CAEBV. Next, we investigated the effects of ruxolitinib, an inhibitor of both JAK1 and JAK2, which phosphorylates and activates STAT3. Ruxolitinib suppressed the phosphorylation of STAT3 in EBV-positive T- or NK-cell lines. Ruxolitinib also decreased the viable cell number of EBV-positive T- or NK-cell lines and PBMCs from patients with CAEBV. Furthermore, ruxolitinib suppressed the production of inflammatory cytokines in the cell lines and CAEBV patient-derived cells. In conclusion, constitutively activated STAT3, which promotes survival and cytokine production, could be a therapeutic target for CAEBV.

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“…Two reports indicated poor outcomes of allo-HSCT in CAEBV patients with active disease [7,14]. Active disease is defined as condition accompanied by any of following: fever, liver dysfunction, progressive skin lesions, vasculitis or uveitis, accompanied by a significant increase in EBV-DNA copies.…”

Section: Current Problems Of Caebvmentioning

confidence: 99%

Chronic active Epstein–Barr virus infection: a bi-faceted disease with inflammatory and neoplastic elements

Arai

2018

Immunological Medicine

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Chronic active Epstein-Barr virus infection (CAEBV) is one of the Epstein-Barr virus (EBV)positive T-or NK-cell lymphoproliferative diseases. It is characterized by clonal proliferation of EBV-infected T or NK cells and their infiltration into systemic organs, leading to their failure. Inflammatory symptoms, fever, lymphadenopathy and liver dysfunction are main clinical findings of CAEBV. EBV itself contributes to the survival of the host cells via induction of CD40 and CD137 expression and constitutive activation of NF-jB. Accumulation of gene mutations in the infected cells may lead to the development of highly malignant lymphoma or leukemia. Furthermore, constitutive activation of STAT3 is detected in the infected cells, which not only promotes cell survival but also enhances production of inflammatory cytokines. Currently, allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only effective treatment strategy for eradication of EBV-infected T or NK cells. However, active disease at the time of allo-HSCT (defined as presence of fever, liver dysfunction, progressive skin lesions, vasculitis or uveitis) is a negative prognostic factor. Establishment of chemotherapy regimens for effective resolution of disease activity in patients with CAEBV is a key imperative. Based on the recently unraveled molecular mechanisms CAEBV development, pathways mediated by NF-jB or JAK/STAT are potential novel therapeutic targets.

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Hematopoietic stem cell transplantation for adults with EBV-positive T- or NK-cell lymphoproliferative disorders: efficacy and predictive markers

Cited by 24 publications

References 11 publications

Hematopoietic Stem Cell Transplantation for the Treatment of Epstein-Barr Virus-Associated T- or NK-Cell Lymphoproliferative Diseases and Associated Disorders

Hematopoietic Stem Cell Transplantation for the Treatment of Epstein-Barr Virus-Associated T- or NK-Cell Lymphoproliferative Diseases and Associated Disorders

STAT3 is constitutively activated in chronic active Epstein-Barr virus infection and can be a therapeutic target

Chronic active Epstein–Barr virus infection: a bi-faceted disease with inflammatory and neoplastic elements

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