Metabolic reprogramming regulated by TRAF6 contributes to the leukemia progression.

TNF receptor associated factor 6 (TRAF6) is an E3 ubiquitin ligase that has been implicated in myeloid malignancies. Although altered TRAF6 expression is observed in human acute myeloid leukemia (AML), its role in the AML pathogenesis remains elusive. In this study, we showed that the loss of TRAF6 in AML cells significantly impairs leukemic function in vitro and in vivo, indicating its functional importance in AML subsets. Loss of TRAF6 induces metabolic alterations, such as changes in glycolysis, TCA cycle, and nucleic acid metabolism as well as impaired mitochondrial membrane potential and respiratory capacity. In leukemic cells, TRAF6 expression shows a positive correlation with the expression of O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT), which catalyzes the addition of O-GlcNAc to target proteins involved in metabolic regulation. The restoration of growth capacity and metabolic activity in leukemic cells with TRAF6 loss, achieved through either forced expression of OGT or pharmacological inhibition of O-GlcNAcase (OGA) that removes O-GlcNAc, indicates the significant role of O-GlcNAc modification in the TRAF6-related cellular and metabolic dynamics. Our findings highlight the oncogenic function of TRAF6 in leukemia and illuminate the novel TRAF6/OGT/O-GlcNAc axis as a potential regulator of metabolic reprogramming in leukemogenesis.

The pathogenetic significance of exhausted T cells in a mouse model of mature B cell neoplasms.

Dysfunctional anti-tumor immunity has been implicated in the pathogenesis of mature B cell neoplasms, such as multiple myeloma and B cell lymphoma; however, the impact of exhausted T cells on disease development remains unclear. Therefore, the present study investigated the features and pathogenetic significance of exhausted T cells using a mouse model of de novo mature B cell neoplasms, which is likely to show immune escape similar to human patients. The results revealed a significant increase in PD-1+ Tim-3- and PD-1+ Tim-3+ T cells in sick mice. Furthermore, PD-1+ Tim-3+ T cells exhibited direct cytotoxicity with a short lifespan, showing transcriptional similarities to terminally exhausted T cells. On the other hand, PD-1+ Tim-3- T cells not only exhibited immunological responsiveness but also retained stem-like transcriptional features, suggesting that they play a role in the long-term maintenance of anti-tumor immunity. In PD-1+ Tim-3- and PD-1+ Tim-3+ T cells, the transcription factors Tox and Nr4a2, which reportedly contribute to the progression of T cell exhaustion, were up-regulated in vivo. These transcription factors were down-regulated by IMiDs in our in vitro T cell exhaustion analyses. The prevention of excessive T cell exhaustion may maintain effective anti-tumor immunity to cure mature B cell neoplasms.

Prognostic factors for the development of lower respiratory tract infection after influenza virus infection in allogeneic hematopoietic stem cell transplantation recipients: A Kanto Study Group for Cell Therapy multicenter analysis.

OBJECTIVES: Influenza virus infection (IVI) occasionally causes lower respiratory tract infection (LRTI) in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Although the progression to LRTI entails a high mortality, the role of early antiviral therapy for its prevention has not been fully elucidated. METHODS: This was a multicenter retrospective study using an additional questionnaire. Allo-HSCT recipients who developed IVI between 2012 and 2020 were included. RESULTS: A total of 278 cases of IVI after allo-HSCT were identified from 15 institutions. The median patient age was 49 years, and the median time from allo-HSCT to IVI was 918 days. Neuraminidase inhibitors were administered within 48 hours of symptom onset (early neuraminidase inhibitor [NAI]) in 199 (76.9%) patients. Subsequently, 36 (12.3%) patients developed LRTI. On the multivariate analysis, age ≥50 years (hazard ratio [HR], 2.16; 95% confidence interval [CI], 1.02-4.58) and moderate to severe chronic graft-versus-host disease (HR, 2.28; 95% CI, 1.14-4.58) were significantly associated with progression to LRTI, whereas early NAI suppressed the progression (HR, 0.17; 95% CI, 0.06-0.46). The IVI-related mortality rate was 2.2%. CONCLUSION: To reduce the risk of LRTI development after IVI, early NAI therapy should be considered in allo-HSCT recipients, especially with older patients and those with chronic graft-versus-host disease.

Dose-finding trial of azacitidine as post-transplant maintenance for high-risk MDS: a KSGCT prospective study.

This 3+3 dose-escalation phase I multicenter study investigated the optimal dose of azacitidine (AZA) for post-hematopoietic stem cell transplantation (HSCT) maintenance, which remains unknown in Japan. Recipients of a first HSCT for high-risk myelodysplastic syndromes (MDS, n = 12) or acute myeloid leukemia (AML) with antecedent MDS (n = 3) received post-HSCT AZA maintenance in 2015-2019. The optimal AZA dose was defined as the dose at which 50-70% of patients can complete four cycles without dose-limiting toxicity (DLT). The initial dose level 1 was set as 30 mg/m2 for 5 days per 28-day cycle, and dose levels 0, 2, and 3 were set as 20, 40, and 50 mg/m2. DLT was defined as any grade 3 non-hematological or grade 4 hematological toxicity. The 15 evaluable patients were 55 (37-64) years old. The median observation of the post-HSCT survivors was 935 (493-1915) days. The median number of days post-HSCT to the start of AZA was 101 (59-176). In the first, second, and third cohorts, five of nine patients completed four cycles at dose level 1. In the final cohort, five of six additional patients completed at the same dose. In total, 10 (67%) patients tolerated AZA 30 mg/m2, which was determined as optimal. DLT occurred in five cases: grade 3 hepatotoxicity, pneumonia, enterocolitis, and grade 4 thrombocytopenia and neutropenia. The 2-year overall survival and disease-free survival rates post-HSCT were 77.0% and 73.3%. Post-HSCT AZA maintenance was well-tolerated and merits further evaluation for patients with MDS or AML with antecedent MDS. Trial registration: UMIN000018791.

Unraveling unique features of plasma cell clones in POEMS syndrome with single-cell analysis.

POEMS syndrome is a rare monoclonal plasma cell disorder, with unique symptoms distinct from those of other plasma cell neoplasms, including high serum VEGF levels. Because the prospective isolation of POEMS clones has not yet been successful, their real nature remains unclear. Herein, we performed single-cell RNA-Seq of BM plasma cells from patients with POEMS syndrome and identified POEMS clones that had Ig λ light chain (IGL) sequences (IGLV1-36, -40, -44, and -47) with amino acid changes specific to POEMS syndrome. The proportions of POEMS clones in plasma cells were markedly smaller than in patients with multiple myeloma (MM) and patients with monoclonal gammopathy of undetermined significance (MGUS). Single-cell transcriptomes revealed that POEMS clones were CD19+, CD138+, and MHC class IIlo, which allowed for their prospective isolation. POEMS clones expressed significantly lower levels of c-MYC and CCND1 than MM clones, accounting for their small size. VEGF mRNA was not upregulated in POEMS clones, directly indicating that VEGF is not produced by POEMS clones. These results reveal unique features of POEMS clones and enhance our understanding of the pathogenesis of POEMS syndrome.

Combined Therapy with Ixazomib, Lenalidomide, and Dexamethasone for Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal Gammopathy, and Skin Changes Syndrome.

Objective Immunomodulatory drugs and proteasome inhibitors are therapeutic options for polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome. This study aimed to evaluate the efficacy and safety of the combination of ixazomib, lenalidomide, and dexamethasone (IRd) for POEMS syndrome. Methods Six consecutive patients with POEMS syndrome who were treated with the IRd regimen at Chiba University Hospital between April 2018 and August 2021 were included. Serum M-protein and serum vascular endothelial growth factor (sVEGF) levels, overall neuropathy limitation scales (ONLS), clinical symptoms, and adverse events were assessed. Results Of the six patients, five had received prior treatments. Patients received a median of 5 cycles (range, 3-28 cycles) of IRd. Following treatment, serum M-protein disappeared in two patients, sVEGF levels returned to normal in two patients, two patients showed a reduction in the ONLS of 1, and clinical symptoms improved in four patients. The median level of sVEGF decreased from 2,395 pg/mL (range, 802-6,120 pg/mL) to 1,428 pg/mL (range, 183-3,680 pg/mL) in three months. Adverse events, including rash, neutropenia, sensory peripheral neuropathy, and nausea, were observed in three patients, which necessitated dose reduction or discontinuation of treatment. Conclusion IRd can be a therapeutic option for POEMS syndrome, albeit with careful monitoring of adverse events.

A high prevalence of myeloid malignancies in progeria with Werner syndrome is associated with p53 insufficiency.

Werner syndrome (WS) is a progeroid syndrome caused by mutations in the WRN gene, which encodes the RecQ type DNA helicase for the unwinding of unusual DNA structures and is implicated in DNA replication, DNA repair, and telomere maintenance. patients with WS are prone to develop malignant neoplasms, including hematological malignancies. However, the pathogenesis of WS-associated hematological malignancies remains uncharacterized. Here we investigated the somatic gene mutations in WS-associated myelodysplastic syndrome/acute myeloid leukemia (MDS/AML). Whole-exome sequencing (WES) of 4 patients with WS with MDS/AML revealed that all patients had somatic mutations in TP53 but no other recurrent mutations in MDS/AML. TP53 mutations were identified at low allele frequencies at more than one year before the MDS/AML stage. All 4 patients had complex chromosomal abnormalities including those that involved TP53. Targeted sequencing of nine patients with WS without apparent blood abnormalities did not detect recurrent mutations in MDS/AML except for a PPM1D mutation. These results suggest that patients with WS are apt to acquire TP53 mutations and/or chromosomal abnormalities involving TP53, rather than other MDS/AML-related mutations. TP53 mutations are frequently associated with prior exposure to chemotherapy; however, all four patients with WS with TP53 mutations/deletions had not received any prior chemotherapy, suggesting a pathogenic link between WRN mutations and p53 insufficiency. These results indicate that WS hematopoietic stem cells with WRN insufficiency acquire competitive fitness by inactivating p53, which may cause complex chromosomal abnormalities and the subsequent development of myeloid malignancies. These findings promote our understanding of the pathogenesis of myeloid malignancies associated with progeria.

Immunogenicity and safety of routine 13-valent pneumococcal conjugate vaccination outside recommended age range in patients with hematological malignancies and solid tumors.

Hematological malignancy and solid tumor are major risks for invasive pneumococcal disease. Thirteen-valent pneumococcal conjugate vaccine (PCV13) is recommended for immunocompromised patients aged 6 years and older and adults who had not received the vaccine previously. However, vaccination for these individuals is not publicly subsidized in Japan. We measured pneumococcal serotype-specific IgGs (Pn-IgGs) and opsonophagocytic activities (Pn-OPAs) against PCV13 serotypes (1, 3, 5, 6A, 7F, and 19A) in patients with hematological malignancies and solid tumors who were outside the recommended age range for routine vaccination at baseline and at 1 and 6 months after the first dose of PCV13. Pneumococcal serotype-specific memory B cells (Pn-MBCs) against serotype 3 were measured from a portion of the study samples. Thirty-seven patients (30 in the young patient group and 7 in the adult patient group) completed the study. Pn-IgGs were significantly elevated at 1 month post-vaccination and persisted in protection level for 6 months after the first vaccination against all six serotypes measured except serotype 3. Pn-OPAs were significantly elevated and persisted as well against all six serotypes. Pn-MBCs were measured in 10 patients, and 90% of them had at least one detectable Pn-MBC, and 70% of them showed an increased frequency of Pn-MBCs against serotype 3. No serious adverse events were observed up to 1 month after vaccination. PCV13 is thus safe and immunogenic, including against serotype 3, in patients with hematological malignancies and solid tumors outside the recommended age range for routine vaccination.

Lung Autotransplantation for Bulky Superior Sulcus Tumor With Hilar Involvement.

Lung autotransplantation with ex vivo bench surgery is a useful surgical technique for centrally located and locally advanced lung cancer to spare lung parenchyma by avoiding pneumonectomy. Here, we present a patient with a bulky superior sulcus tumor with hilar involvement for which lung-sparing complete resection was achieved with autotransplantation. After concurrent chemoradiotherapy, en bloc resection, consisting left pneumonectomy combined with apical chest wall resection (1-4 ribs), back-table extended double-sleeve resection after lung preservation, and reimplantation of basal segment was performed. The postoperative course was uneventful, and the patient is alive without tumor recurrence at 18 months after surgery.

Successful allogeneic bone marrow transplantation after massive gastrointestinal bleeding in a patient with myelodysplastic syndrome associated with intestinal Behçet-like disease.

A 45-year-old woman was diagnosed with myelodysplastic syndrome (MDS) with trisomy 8 and Behçet-like disease (BLD) with multiple colorectal ulcers. Nonspecific inflammatory cells were infiltrated in the intestinal mucosa, whereas fluorescence in situ hybridization (FISH) analysis revealed only sporadic trisomy 8-positive cells. She presented massive lower gastrointestinal bleeding early after bone marrow transplantation but achieved long-term remission of both MDS and BLD. This is the first report of massive gastrointestinal bleeding after transplantation for MDS with BLD. Based on FISH analysis, dysregulation of systemic inflammation may be involved in BLD rather than direct invasion by trisomy 8-positive MDS clones.

A Reference Laboratory Surveillance on Fungal Isolates from Patients with Haematological Malignancy in Japan.

Invasive fungal disease (IFD) in patients with haematological disorders is a fatal disease, making rapid identification and treatment crucial. However, the identification of the causative fungus is often difficult, sometimes even impossible. There have been few reports concerning the causative species of IFD. This study aimed to investigate the epidemiology and causative organism of IFD in patients with haematological diseases in Japan. We analyzed the IFD cases among the patients with haematological malignancies identified at the Medical Mycological Research Center, Chiba University, between 2013 and 2019. The most common underlying disease was acute myeloid leukaemia (34.3%). Forty-six point one percent of IFD patients received haematopoietic stem cell transplantation (HSCT). The major pathogens were Aspergillus, Candida, and Fusarium. Aspergillus fumigatus was the most common Aspergillus species, and Candida fermentati and Fusarium petroliphilum were the most common Candida and Fusarium species, respectively, in this analysis. Furthermore, various cryptic species and non-albicans Candida were identified. The drug susceptibility of such relatively rare strains suggests that analysis of the causative fungi should provide valuable information for therapeutic options. Therefore, our study indicated that it is clinically significant to identify the organism in as much detail as possible.

Pharmacokinetically guided, once-daily intravenous busulfan in combination with fludarabine for elderly AML/MDS patients as a conditioning regimen for allogeneic stem cell transplantation.

The efficacy of pharmacokinetically (PK) guided, once-daily administration of busulfan (BU) was evaluated in elderly patients with acute myeloid leukemia/myelodysplastic syndrome (AML/MDS). Twenty-one patients (median age 61) received 30 mg/m2 fludarabine for 6 days and BU for 4 days, starting from 3.2 mg/m2 and subsequently adjusted to the target area under the curve (AUC) of 6000 µmol-min/L. The median AUC of day 1 (AUC1), AUC4, and their average were 4871.3, 6021.0, and 5368.1 µmol-min/L, respectively. Veno-occlusive disease/sinusoidal obstructive syndrome (VOD/SOS) occurred in five patients (24%) but all recovered well. Four patients (20%) had non-infectious pulmonary complications (NIPCs). Patients with high AUC1 had frequent gastrointestinal adverse events, but similar incidence of VOD/SOS and NIPCs. Two-year overall survival (OS), non-relapse mortality (NRM), and relapse rates were 44.4%, 28.6%, and 29.1%, respectively. Patients with high AUC1 had significantly high NRM (57.1% vs. 14.3%, P = 0.04) and inferior OS (14.3% vs. 60.1%, P = 0.002), while patients with high AUC4 had a significantly low relapse rate (8.3% vs. 55.6%, P = 0.02). In conclusion, once-daily BU and a PK-guided dose intensification were beneficial for reducing relapse in elderly patients with AML/MDS. However, caution should be exercised as rapid BU dose elevation may contribute to NRM.

Identification of clonal immunoglobulin λ light-chain gene rearrangements in AL amyloidosis using next-generation sequencing.

Amyloid light-chain (AL) amyloidosis is caused by deposition of abnormally folded clonal immunoglobulin (Ig) light chains made by malignant plasma cells in the bone marrow (BM), leading to multiorgan dysfunction. However, little is known of the factors that regulate the organ tropism of amyloid deposition in this disease. We aimed to identify the clonal composition of Igλ light-chain variable region (IGLV) genes in BM cells in patients with AL amyloidosis using next-generation sequencing. Based on our definition of the clonal IGLV rearrangement (dominant clone >2.5%, dominant cluster >5%), we identified clonal IGLV in 33 of 38 patients with AL amyloidosis (86.8%), 6 of 9 with monoclonal gammopathy of undetermined significance (67%), and 7 of 7 with multiple myeloma (100%). The clones in AL amyloidosis were significantly smaller than those in multiple myeloma (p < 0.01) but comparable to those in monoclonal gammopathy of undetermined significance. Importantly, in patients with AL amyloidosis, the difference in involved and uninvolved free light chains was not correlated with the clonal size of BM plasma cells in our repertoire analysis using NGS. In summary, the clonal composition of IGLV genes in the BM was successfully identified in most patients with AL amyloidosis using NGS. The clonal size of plasma cells in the BM is small, and small malignant clones of plasma cells may secrete free light chi and cause light chain depositions in AL amyloidosis.

Genetic subtype classification using a simplified algorithm and mutational characteristics of diffuse large B-cell lymphoma in a Japanese cohort.

Recent large-scale genetic studies have proposed a new genetic classification of diffuse large B-cell lymphoma (DLBCL), which is clinically and biologically heterogeneous. However, the classification methods were complicated to be introduced into clinical practice. Here we retrospectively evaluated the mutational status and copy number changes of 144 genes in 177 Japanese patients with DLBCL, using targeted DNA sequencing. We developed a simplified algorithm for classifying four genetic subtypes-MYD88, NOTCH2, BCL2, and SGK1-by assessing alterations in 18 representative genes and BCL2 and BCL6 rearrangement status, integrating the significant genes from previous studies. In our cohort and another validation cohort from published data, the classification results in our algorithm showed close agreement with the other established algorithm. A differential prognosis among the four groups was observed. The NOTCH2 group showed a particularly poorer outcome than similar groups in previous reports. Furthermore, our study revealed unreported genetic features in the DLBCL subtypes that are mainly reported in Japanese patients, such as CD5-positive DLBCL and methotrexate-associated lymphoproliferative disorders. These results indicate the utility of our simplified method for DLBCL genetic subtype classification, which can facilitate the optimisation of treatment strategies. In addition, our study highlights the genetic features of Japanese patients with DLBCL.

Metastatic Orbital Tumor From Breast Ductal Carcinoma With Neuroendocrine Differentiation Initially Presenting as Ocular Symptoms: A Case Report and Literature Review.

Background: Orbital metastases from cancers of various organs can arise via the hematogenous route, and many originate from breast, prostate, and lung cancers. Such metastatic orbital tumors may be diagnosed before the primary tumor. We have encountered a case of breast ductal carcinoma with neuroendocrine differentiation that metastasized to the orbit and responded to chemotherapy, with improvement in visual function. Case Presentation: A woman in her fifties visited our ophthalmology department with a chief complaint of foreign body sensation and exophthalmos in her right eye. An elastic soft mass was palpated from the lateral orbit to the temporal region. A systemic examination revealed breast cancer and a metastatic orbital tumor. Excisional biopsy of the breast revealed a diagnosis of invasive ductal carcinoma with neuroendocrine differentiation, and immunohistochemical examination was negative for cytokeratin 7, making the case unusual. Chemotherapy was remarkably effective, and the tumor size decreased, resulting in improvement of visual function. Her general condition and quality of life are still good at present. We searched the PubMed English language literature focusing on metastatic orbital tumors from breast cancer in which ocular symptoms had been the initial presenting sign. No previous reports have documented neuroendocrine differentiation or cytokeratin 7 expression in isolated orbital metastases from breast cancer. Although it is not possible to be certain from this case alone, we speculated that some such cases might involve cytokeratin 7-negative invasive breast cancer with neuroendocrine differentiation. Conclusion: We have described our experience of a very rare case of cytokeratin 7 negative breast ductal carcinoma with neuroendocrine differentiation that metastasized to the orbit and formed a solitary giant tumor initially manifesting as ocular symptoms.

The combination of the tubulin binding small molecule PTC596 and proteasome inhibitors suppresses the growth of myeloma cells.

The novel small molecule PTC596 inhibits microtubule polymerization and its clinical development has been initiated for some solid cancers. We herein investigated the preclinical efficacy of PTC596 alone and in combination with proteasome inhibitors in the treatment of multiple myeloma (MM). PTC596 inhibited the proliferation of MM cell lines as well as primary MM samples in vitro, and this was confirmed with MM cell lines in vivo. PTC596 synergized with bortezomib or carfilzomib to inhibit the growth of MM cells in vitro. The combination treatment of PTC596 with bortezomib exerted synergistic effects in a xenograft model of human MM cell lines in immunodeficient mice and exhibited acceptable tolerability. Mechanistically, treatment with PTC596 induced cell cycle arrest at G2/M phase followed by apoptotic cell death, associated with the inhibition of microtubule polymerization. RNA sequence analysis also revealed that PTC596 and the combination with bortezomib affected the cell cycle and apoptosis in MM cells. Importantly, endoplasmic reticulum stress induced by bortezomib was enhanced by PTC596, providing an underlying mechanism of action of the combination therapy. Our results indicate that PTC596 alone and in combination with proteasome inhibition are potential novel therapeutic options to improve outcomes in patients with MM.

Myocyte-specific enhancer factor 2c triggers transdifferentiation of adipose tissue-derived stromal cells into spontaneously beating cardiomyocyte-like cells.

Cardiomyocyte regeneration is limited in adults. The adipose tissue-derived stromal vascular fraction (Ad-SVF) contains pluripotent stem cells that rarely transdifferentiate into spontaneously beating cardiomyocyte-like cells (beating CMs). However, the characteristics of beating CMs and the factors that regulate the differentiation of Ad-SVF toward the cardiac lineage are unknown. We developed a simple culture protocol under which the adult murine inguinal Ad-SVF reproducibly transdifferentiates into beating CMs without induction. The beating CMs showed the striated ventricular phenotype of cardiomyocytes and synchronised oscillation of the intracellular calcium concentration among cells on day 28 of Ad-SVF primary culture. We also identified beating CM-fated progenitors (CFPs) and performed single-cell transcriptome analysis of these CFPs. Among 491 transcription factors that were differentially expressed (≥ 1.75-fold) in CFPs and the beating CMs, myocyte-specific enhancer 2c (Mef2c) was key. Transduction of Ad-SVF cells with Mef2c using a lentiviral vector yielded CFPs and beating CMs with ~ tenfold higher cardiac troponin T expression, which was abolished by silencing of Mef2c. Thus, we identified the master gene required for transdifferentiation of Ad-SVF into beating CMs. These findings will facilitate the development of novel cardiac regeneration therapies based on gene-modified, cardiac lineage-directed Ad-SVF cells.

Pharmacokinetics of intravenous busulfan as condition for hematopoietic stem cell transplantation: comparison between combinations with cyclophosphamide and fludarabine.

Busulfan (Bu) has been used in combination with fludarabine (Flu; BuFlu) or cyclophosphamide (Cy; BuCy) as conditioning for allogeneic hematopoietic stem cell transplantation (HSCT). This multi-institutional prospective study compared pharmacokinetic (PK) parameters of Bu between BuFlu and BuCy. Plasma Bu concentrations were measured by high-performance liquid chromatography at the first dose of the first and fourth days of intravenous Bu administrations (total of 16 doses of 0.8 mg/kg). Thirty-seven patients were evaluable (BuFlu, N = 18; BuCy, N = 19). The median age was significantly higher in BuFlu. In BuFlu, the median area under the blood concentration-time curve of Bu on the fourth day was 1183 µmol min/L (range 808-1509), which was significantly higher than that on the first day [1095 µmol min/L (range 822-1453), P < 0.01]. In contrast, such differences were not observed in BuCy. Consistently, there was a significant decrease in the clearance of Bu on the fourth day as compared with the first day in BuFlu. These results suggest that the PK of Bu was altered during the co-administration of Flu, which was not the case with Cy. A large-scale study is required to evaluate the significance of the differences in the PK of Bu between the conditionings on HSCT outcomes.

Nationwide survey of systemic chronic active EBV infection in Japan in accordance with the new WHO classification.

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.