Chronic active Epstein-Barr virus infection (CAEBV) is one of the Epstein-Barr virus (EBV)-positive T- or NK-lymphoproliferative diseases. It is considered rare and geographically limited to Japan and East Asia. However, CAEBV is drawing international attention, and the number of case reported worldwide is increasing, after its classification in the EBV-positive T- or NK-cell neoplasms, in the 2016 WHO classification. In this article, I review current advances in the study of CAEBV under the new definition and show future directions. In CAEBV, EBV-infected T or NK cells clonally proliferate and infiltrate multiple organs, leading to their failure. These characteristics define CAEBV as a lymphoid neoplasm. However, the main symptom of CAEBV is inflammation. Recently, the mechanisms underlying the development of CAEBV have gradually become clearer. EBV infection of T or NK cells can occur during the acute phase of primary infection with a high EBV load in the peripheral blood. In addition, it was reported that cytotoxic T cells decreased in numbers or showed dysfunction in CAEBV. These findings suggest that undetermined immunosuppressive disorders may underlie persistent infection of T or NK cells. Furthermore, EBV itself contributes to the survival of host cells. In vitro EBV infection of T cells induced intercellular survival-promoting pathways. Constitutive activation of NF-kB and STAT3 was observed in EBV-positive T or NK cells in CAEBV, promoting not only cell survival but also CAEBV development. During the disease course, CAEBV can lead to two lethal conditions: hemophagocytic lymphohistiocytosis and chemotherapy-resistant lymphoma. It is necessary to start treatment before these conditions develop. At present, the only effective treatment strategy for eradicating EBV-infected T or NK cells is allogeneic stem cell transplantation (allo-HSCT). However, patients with an active disease, in which the condition is accompanied by fever, liver dysfunction, progressive skin lesions, vasculitis, or uveitis, had worse outcomes after allo-HSCT, than patients with an inactive disease had. Unfortunately, current chemotherapies are insufficient to improve the activity of CAEBV. Based on the molecular mechanisms for the development of the disease, the NF-kB, or JAK/STAT mediating pathways are attractive candidate targets for new treatments.

Systemic chronic active Epstein-Barr virus infection (sCAEBV) was defined as a T- or NK-cell neoplasm in the 2017 World Health Organization (WHO) classification. To clarify the clinical features of sCAEBV under this classification and review the effects of chemotherapy, we performed a nationwide survey in Japan from 2016 through 2018 of patients with sCAEBV newly diagnosed from January 2003 through March 2016. One hundred cases were evaluated. The patients were aged 1 to 78 years (median, 21) and included 53 males and 47 females. Spontaneous regression was not observed in patients with active disease. In the childhood-onset group (age, <9 years), 78% of the patients were male. In contrast, 85% of the patients in the elderly-onset group (age, >45 years) were female. The prognosis of the childhood-onset group was better than those of the adolescent/adult- and elderly-onset groups. The main chemotherapies used were a combination of cyclosporine A, steroids, and etoposide (cooling therapy) in 52 cases and cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) in 45 cases. The rate of complete response (CR), defined as complete resolution of disease activity, was 17% for cooling therapy and 13% for CHOP. Virological CR was not observed. The 3-year overall survival rates in patients treated with chemotherapy only (n = 20), chemotherapy followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT; n = 47), and allo-HSCT only (n = 12) were 0%, 65%, and 82%, respectively. Distinct characteristics were observed between childhood- and elderly-onset sCAEBV, and they appeared to be different disorders. Chemotherapy is currently insufficient to resolve disease activity and eradicate infected cells. The development of an effective treatment is urgently needed.

The CrkL adaptor protein is involved in signaling from the receptor for erythropoietin (Epo) as well as interleukin (IL)-3 and activates ␤ 1 integrin-mediated hematopoietic cell adhesion through its interaction with C3G, a guanine nucleotide exchange factor for Rap1. We demonstrate here that Epo as well as IL-3 activates Rap1 in an IL-3-dependent hematopoietic cell line, 32D, expressing the Epo receptor. The cytokine-induced activation of Rap1 was augmented in cells that inducibly overexpress CrkL or C3G. The CrkL-mediated enhancement of cell adhesion was inhibited by expression of a dominant negative mutant of Rap1, Rap1A-17N, whereas an activated mutant of Rap1, Rap1A-63E, activated ␤ 1 integrin-dependent adhesion of hematopoietic cells. In 32D cells, Rap1 was also activated by phorbol 12-myristate 13-acetate and ionomycin, which also enhanced cell adhesion to fibronectin, whereas U73122, an inhibitor of phospholipase C, inhibited both cytokine-induced activation of Rap1 and cell adhesion. It was also demonstrated that Rap1 as well as CrkL is involved in signaling from the EpoR endogenously expressed in a human leukemic cell line, UT-7. These results suggest that Epo and IL-3 activate Rap1 at least partly through the CrkL-C3G complex as well as through additional pathways most likely involving phospholipase C␥ and strongly implicate Rap1 in regulation of ␤ 1 integrin-mediated hematopoietic cell adhesion.

Epstein-Barr virus (EBV) infection is usually asymptomatic and persists lifelong. Although EBV-infected B cells have the potential for unlimited proliferation, they are effectively removed by the virus-specific cytotoxic T cells, and EBV-associated lymphoproliferative disease develops only in immunocompromised hosts. Rarely, however, individuals without apparent immunodeficiency develop chronic EBV infection with persistent infectious mononucleosis-like symptoms. These patients have high EBV-DNA load in the peripheral blood and systemic clonal expansion of EBVinfected T cells or natural killer (NK) cells. Their prognosis is poor with life-threatening complications including hemophagocytic lymphohistiocytosis, organ failure, and malignant lymphomas. The term "chronic active EBV infection" (CAEBV) is now generally used for this disease. The geographical distribution of CAEBV is markedly uneven and most cases have been reported from Japan and other East Asian countries. Here we summarize the current understanding of CAEBV and describe the recent progress of CAEBV research in Japan.

A combination of PCR assay to detect gene rearrangement of IgH and cytokine profiling (IL-10 and IL-6) is extremely useful for the diagnosis of intraocular lymphoma.

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Large granular lymphocyte leukemia-associated pure red cell aplasia accounts for a significant portion of secondary pure red cell aplasia cases. However, because of its rarity, long-term responses and relapse rates after immunosuppressive therapy are largely unknown. We conducted a nationwide survey in Japan and collected 185 evaluable patients. Fourteen patients with large granular lymphocyte leukemia-associated pure red cell aplasia were evaluated. Cyclophosphamide, cyclosporine A and prednisolone produced remissions in 6/8, 1/4 and 0/2 patients respectively. Seven and 5 patients were maintained on cyclophosphamide or cyclosporine A respectively. Two patients relapsed after stopping cyclophosphamide, and 2 patients relapsed during maintenance therapy with cyclosporine A. The median relapse-free survival in the cyclophosphamide -and the cyclosporine A groups was 53 and 123 months respectively. Large granular lymphocyte leukemia-associated pure red cell aplasia showed a good response to either cyclophosphamide or cyclosporine A. Most patients continued to receive maintenance therapy and it remains uncertain whether cyclophosphamide or cyclosporine A can induce a maintenance-free hematologic response in large granular lymphocyte leukemia-associated pure red cell aplasia.

In order to prevent central nervous system (CNS) involvement and improve the prognosis of primary intraocular lymphoma (PIOL), we prospectively evaluated the efficacy of combined therapy using intravitreal methotrexate (MTX) and systemic high‐dose MTX on treatment‐naïve PIOL. Patients with newly diagnosed PIOL whose lymphoma was limited to the eyes were enrolled. The patients were treated with weekly intravitreal MTX until the ocular lesions were resolved, followed by five cycles of systemic high‐dose MTX (3.5 g/m2) every other week. Ten patients were enrolled in this study and completed the treatment. All patients achieved complete response for their ocular lesions with rapid decrease of intravitreal interleukin‐10 concentration. Adverse events of intravitreal and systemic high‐dose MTX were mild and tolerable. With a median follow‐up of 29.5 months, four patients (40%) experienced the CNS disease development and the mean CNS lymphoma‐free survival (CLFS) time was 51.1 months. Two‐year CLFS, which was the primary end‐point of the study, was 58.3% (95% confidence interval, 23.0–82.1%). In contrast, eight patients were treated with intravitreal MTX alone in our institute, and their 2‐year CLFS was 37.5% (95% confidence interval, 8.7–67.4%). In conclusion, systemic high‐dose MTX following intravitreal MTX is feasible and might be effective in preventing CNS involvement of PIOL. Further arrangements are worth considering in order to improve the effects. This study was registered with UMIN Clinical Trials Registry (UMIN000003921).