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CD5-positive diffuse large B-cell lymphoma (CD5+ DLBCL) is characterized by poor prognosis and a high frequency of central nervous system relapse after standard immunochemotherapy. We conducted a phase II study to investigate the efficacy and safety of dose-adjusted (DA)- EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) combined with high-dose methotrexate (HD-MTX) in newly diagnosed patients with CD5+ DLBCL. Previously untreated patients with stage II to IV CD5+ DLBCL according to the 2008 World Health Organization classification were eligible. Four cycles of DA-EPOCH-R followed by two cycles of HD-MTX and four additional cycles of DAEPOCH- R (DA-EPOCH-R/HD-MTX) were planned as the protocol treatment. The primary end point was 2-year progression-free survival (PFS). Between September 25, 2012, and November 11, 2015, we enrolled 47 evaluable patients. Forty-five (96%) patients completed the protocol treatment. There were no deviations or violations in the DA-EPOCH-R dose levels. The complete response rate was 91%, and the overall response rate was 94%. At a median follow up of 3.1 years (range, 2.0-4.9 years), the 2- year PFS was 79% [95% confidence interval (CI): 64-88]. The 2-year overall survival was 89% (95%CI: 76-95). Toxicity included grade 4 neutropenia in 46 (98%) patients, grade 4 thrombocytopenia 12 (26%) patients, and febrile neutropenia in 31 (66%) patients. No treatment-related death was noted during the study. DA-EPOCH-R/HD-MTX might be a first-line therapy option for stage II-IV CD5+ DLBCL and warrants further investigation. (Trial registered at: UMIN-CTR: UMIN000008507.)

Fusions of the Runt-related transcription factor 1 (RUNX1) with different partner genes have been associated with various hematological disorders. Interestingly, the C-terminally truncated form of RUNX1 and RUNX1 fusion proteins are similarly considered important contributors to leukemogenesis. Here, we describe a 59-year-old male patient who was initially diagnosed with acute myeloid leukemia, inv(16)(p13;q22)/CBFB-MYH11 (FAB classification M4Eo). He achieved complete remission and negative CBFB-MYH11 status with daunorubicin/cytarabine combination chemotherapy but relapsed 3 years later. Cytogenetic analysis of relapsed leukemia cells revealed CBFB-MYH11 negativity and complex chromosomal abnormalities without inv(16)(p13;q22). RNA-seq identified the glutamate receptor, ionotropic, kinase 2 (GRIK2) gene on 6q16 as a novel fusion partner for RUNX1 in this case. Specifically, the fusion of RUNX1 to the GRIK2 antisense strand (RUNX1-GRIK2as) generated multiple missplicing transcripts. Because extremely low levels of wild-type GRIK2 were detected in leukemia cells, RUNX1-GRIK2as was thought to drive the pathogenesis associated with the RUNX1-GRIK2 fusion. The truncated RUNX1 generated from RUNX1-GRIK2as induced the expression of the granulocyte colony-stimulating factor (G-CSF) receptor on 32D myeloid leukemia cells and enhanced proliferation in response to G-CSF. In summary, the RUNX1-GRIK2as fusion emphasizes the importance of aberrantly truncated RUNX1 in leukemogenesis.

Primary effusion-based lymphoma (EBL) presents as a malignant effusion in a body cavity. The clinicopathologic features and prognosis of primary human herpesvirus 8 (HHV8)–negative EBL remain unclear. We therefore conducted a retrospective study of 95 patients with EBL, regardless of HHV8 status, in Japan. Of 69 patients with EBL tested for HHV8, a total of 64 were negative. The median age of patients with primary HHV8-negative EBL at diagnosis was 77 years (range, 57-98 years); all 58 tested patients were negative for HIV. Primary HHV8-negative EBL was most commonly diagnosed in pleural effusion (77%). Expression of at least 1 pan B-cell antigen (CD19, CD20, or CD79a) was observed in all cases. According to the Hans algorithm, 30 of the 38 evaluated patients had nongerminal center B-cell (non-GCB) tumors. Epstein-Barr virus–encoded small RNA was positive in 6 of 45 patients. In 56 of 64 HHV8-negative patients, systemic therapy was initiated within 3 months after diagnosis. Cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) or CHOP-like regimens with or without rituximab (n = 48) were the most common primary treatments. The overall response and complete response rates were 95% and 73%, respectively. Three patients did not progress without systemic treatment for a median of 24 months. With a median 25-month follow-up, the 2-year overall survival and progression-free survival rates were 84.7% and 73.8%. Sixteen patients died; 12 were lymphoma-related deaths. Thus, most EBL cases in Japan are HHV8-negative and affect elderly patients. The non-GCB subtype is predominant. Overall, primary HHV8-negative EBL exhibits a favorable prognosis after anthracycline-based chemotherapy.

Introduction The prognosis of classic Hodgkin lymphoma (cHL) in young adults has improved following advances in current therapeutics. However, evidence of elderly patients with cHL has limited due to its rarer. To analyze clinical outcomes and risk factors in elderly patients with advanced-stage cHL who received a doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) regimen, we conducted a nationwide multi-center retrospective study in Japan (UMIN000033264). Methods The key eligibility criteria of the current study were as follows: 1) patients with histologically diagnosed cHL between 2007 and 2016 in each institution; 2) advanced-stage cHL (stage III, IV or IIB with bulky or extranodal lesion); 3) age at diagnosis > 60 years; and 4) had received at least one cycle of an ABVD regimen as initial treatment including a modified ABVD regimen (dacarbazine dose reduced to 250 mg/m 2 at first cycle). Patients with human immunodeficiency virus infection or methotrexate-associated cHL were excluded. The primary endpoint was 5-year overall survival (OS). Secondary endpoints included progression-free survival (PFS) and event-free survival (EFS), the latter defined as the time from a diagnosis of cHL to disease progression or relapse, subsequent systemic chemotherapy for cHL, or death due to any cause in this study. The average relative dose intensity (ARDI) of ABVD was calculated as the sum of the relative dose intensity of each drug divided by four. Results A total of 171 patients from 45 institutions were included in this study. The central pathological review could be performed in 140 cases (82%), in which histological subtypes of cHL were determined as follows: mixed cellularity, 89 (64%); nodular sclerosis, 33 (24%); lymphocyte-deleted, 4 (3%); lymphocyte-rich, 2 (1%); not otherwise specified, 12 (9%). The median age was 71 years (interquartile range [IQR] 65-76). The number of patients in each 10-year age group was 79 (46%) for 61-70 years, 78 (46%) for 71-80 years, and 14 (8%) for > 81 years. The numbers of patients with ECOG performance status (PS) ≥2 and B symptoms were 33 (19%) and 85 (50%), respectively. Bulky mediastinal diseases were found in four patients (2%). The risk factors used for the International Prognostic Score (IPS), including male sex, stage IV, hypoalbuminemia, anemia, leukocytosis, and lymphopenia, were not significantly different among these age groups. The median number of cycles of ABVD was 6 (IQR:5-7), and 66% of patients completed at least 6 cycles. The median ARDI was 77%. The median ARDI in each 10-year age group was 88% for 61-70 years, 71% for 71-80 years, and 54% for > 81 years. With a median follow-up time of 52 months (IQR:31-76), the estimated OS, PFS, and EFS at 5 years were 72%, 59%, and 54%, respectively. Among 131 patients whose Epstein-Barr virus (EBV) status was analyzed using EBV-encoded small RNA1 (EBER1) in situ hybridization, 61 (46%) were positive for EBER1. The OS was not significantly different between EBV-positive and EBV-negative patients (75% and 76% at 5 years, respectively). Univariate analysis for OS revealed that age, PS ≥ 2, hypoalbuminemia, anemia, lymphopenia, and the presence of B symptoms were significantly associated with short OS. In multivariate analysis, age (hazard ratio [HR] 1.568 per 10-year increase, 95% confidence interval [CI] 1.020-2.411) was only an independent risk factor for OS, whereas lymphopenia (HR 1.967, 95% CI 1.196-3.235) was an independent risk factor for EFS. Higher ARDI was significantly associated with improved OS and EFS. Bleomycin-induced lung toxicity (BLT), observed in 41 (24%) patients, was not associated with OS. In this study, we found that 55 patients died: 23 within two years after diagnosis mainly due to cHL progression (n = 10, 43%) and treatment-related toxicity (infection [n = 4, 17%] and BLT [n = 4, 17%]). The remaining 32 patients died more than two years after diagnosis mainly due to second primary malignancies (n = 14, 44%), including solid tumors (n = 6), other types of lymphoma (n = 4), and myelodysplastic syndrome/acute myeloid leukemias (n = 4). Conclusions The HORIZON study showed relatively good prognosis for elderly patients with advanced-stage cHL who received an ABVD regimen (estimated five-year OS rates was 72%). Age and lymphopenia were an independent risk factors for OS and EFS, respectively. The development of novel therapies is warranted to improve the outcomes of such patients. Disclosures Makita: SymBio: Honoraria; Novartis: Honoraria; Eisai: Honoraria; Daiichi-Sankyo: Consultancy; CSL Behring: Honoraria; Chugai: Honoraria; BMS: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Kusumoto: Kyowa Kirin: Honoraria; Chugai: Honoraria, Research Funding; Daiichi Sankyo: Research Funding. Tsujimura: Takeda: Honoraria; Chugai: Honoraria; Kyowa Kirin: Honoraria; Eisai: Honoraria; Janssen: Honoraria. Takayama: Chugai: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding. Kuroda: Otsuka Pharmaceutical: Honoraria, Research Funding; Astellas Pharma: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; MSD: Research Funding; Abbvie: Consultancy, Honoraria; Ono Pharmaceutical: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Sysmex: Research Funding; Pfizer: Honoraria, Research Funding; Nippon Shinyaku: Honoraria, Research Funding; Shionogi: Research Funding; Asahi Kasei: Research Funding; Taiho Pharmaceutical: Research Funding; Fujimoto Pharmaceutical: Current Employment, Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Dainippon Sumitomo Pharma: Honoraria, Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding; Bristol-MyersSquibb: Consultancy, Honoraria, Research Funding; Janssen Pharmaceutical K.K: Consultancy. Shimada: BMS: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Janssen: Honoraria; Chugai: Consultancy, Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; AstraZeneca: Honoraria; Otsuka: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; SymBio: Honoraria. Okamoto: Chugai: Research Funding; Kyowa Kirin: Research Funding; Ono: Research Funding; Taiho: Research Funding; Takeda: Research Funding. Asano: Takeda: Honoraria. Maruyama: Janssen: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Novartis: Research Funding; MSD: Honoraria, Research Funding; Otsuka: Research Funding; Ono: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Astellas Pharma,: Research Funding; Celgene: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Amgen: Research Funding; BMS: Honoraria, Research Funding; Mundipharma: Honoraria; Kyowa Kirin: Honoraria; Zenyaku: Honoraria; AstraZeneca: Honoraria; Nippon: Honoraria; SymBio: Honoraria. Yamaguchi: Chugai: Honoraria, Research Funding; Genmab: Research Funding; MSD: Honoraria; Kyowa Kirin: Honoraria, Research Funding; Takeda: Honoraria; Ono: Honoraria; Celgene: Honoraria; Otsuka: Honoraria; Sumitomo Dainippon: Honoraria; Eisai: Honoraria; AstraZeneca: Consultancy. Nagai: AbbVie: Research Funding; AstraZeneca: Honoraria, Research Funding; Bayer: Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Chordia Therapeutics: Honoraria; Chugai Pharmaceutical: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Kyowa Kirin: Research Funding; Mundipharma: Honoraria, Research Funding; Nippon Shinyaku: Research Funding; Novartis: Honoraria; Ono Pharmaceutical: Honoraria; Sanofi: Honoraria; Sumitomo Dainippon Pharma: Honoraria; SymBio Pharmaceuticals: Honoraria, Research Funding; Takeda Pharmaceutical: Honoraria, Research Funding; Zenyaku Kogyo: Research Funding.

Variant chromosomal translocations associated with t(8;21) are observed in 3-4% of acute myeloid leukemia (AML) cases with a RUNX1-RUNX1T1 fusion gene. However, the molecular events that occur in variants of t(8;21) are not well characterized. In the present study, we report genetic features of a variant three-way translocation of t(8;12;21)(q22;p11;q22) in a patient with AML. In this patient, leukemia cells lacked azurophilic granules, which does not correspond with the classic features of t(8;21). RNA-seq analysis revealed that TM7SF3 at 12p11 was fused to VPS13B at 8q22 and VPS13B to RUNX1, in addition to RUNX1-RUNX1T1. VPS13B was located near RUNX1T1 and both were localized at the same chromosomal bands. The reading frames of TM7SF3 and VPS13B did not match to those of VPS13B and RUNX1, respectively. Disruption of VPS13B causes Cohen syndrome, which presents intermittent neutropenia with a left-shifted granulopoiesis in the bone marrow. Disruption of VPS13B may thus cause the unusual features of RUNX1-RUNX1T1 leukemia. Our case indicates that rearrangement of VPS13B may be additional genetic events in variant t(8;21).

Summary Background Intravascular large B-cell lymphoma (IVLBCL) is a rare disease for which there is no available standard treatment. We aimed to ascertain the safety and activity of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) with high-dose methotrexate and intrathecal chemotherapy as CNS-oriented therapy for patients with previously untreated IVLBCL. Methods PRIMEUR-IVL is a multicentre, single-arm, phase 2 trial at 22 hospitals in Japan. Eligible patients had untreated histologically confirmed IVLBCL, were aged 20–79 years, had an Eastern Cooperative Group performance status of 0–3, and had no apparent CNS involvement at diagnosis. Patients received three cycles of R-CHOP (rituximab 375 mg/m2 intravenously on day 1 [except cycle one, which was on day 8]; cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1·4 mg/m2 [maximum 2·0 mg] intravenously on day 1 of cycle one and day 2 of cycles two and three; and prednisolone 100 mg/day orally on days 1–5 of cycle one and days 2–6 of cycles two and three) followed by two cycles of rituximab with high-dose methotrexate (3·5 g/m2 intravenously on day 2 of cycles four and five) every 2 weeks and three additional cycles of R-CHOP. Intrathecal chemotherapy (methotrexate 15 mg, cytarabine 40 mg, and prednisolone 10 mg) was administered four times during the R-CHOP phase. The primary endpoint was 2-year progression-free survival. Efficacy analyses were done in all enrolled patients; safety analyses were done in all enrolled and treated patients. The trial is registered in the UMIN Clinical Trials Registry (UMIN000005707) and the Japan Registry of Clinical Trials (jRCTs041180165); the trial is ongoing for long-term follow-up. Findings Between June 16, 2011, and July 21, 2016, 38 patients were enrolled, of whom 37 were eligible; one patient was excluded because of a history of testicular lymphoma. Median follow-up was 3·9 years (IQR 2·5–5·5). 2-year progression-free survival was 76% (95% CI 58–87). The most frequent adverse events of grade 3–4 were neutropenia and leucocytopenia, which were reported in all 38 (100%) patients. Serious adverse events were hypokalaemia, febrile neutropenia with hypotension, hypertension, and intracerebral haemorrhage (reported in one [3%] patient each). No treatment-related deaths occurred during protocol treatment. Interpretation R-CHOP combined with rituximab and high-dose methotrexate plus intrathecal chemotherapy is a safe and active treatment for patients with IVLBCL without apparent CNS involvement at diagnosis, and this regimen warrants future investigation. Funding The Japan Agency for Medical Research and Development, the Center for Supporting Hematology-Oncology Trials, and the National Cancer Center.

Background & Aims HBV reactivation is a risk in patients receiving anti-CD20 antibodies for the treatment of lymphoma. The purpose of this post hoc analysis was to evaluate the efficacy of an ultra-high sensitivity HBsAg assay to guide preemptive antiviral treatment in patients with lymphoma and resolved HBV infections using prospectively stored samples from an HBV DNA monitoring study. Methods HBV reactivation (defined as HBV DNA levels of ≥11 IU/ml) was confirmed in 22 of 252 patients. A conventional HBsAg assay (ARCHITECT, cut-off value: 0.05 IU/ml) and an ultra-high sensitivity HBsAg assay employing a semi-automated immune complex transfer chemiluminescence enzyme technique (ICT-CLEIA, cut-off value: 0.0005 IU/ml) were performed at baseline, at confirmed HBV reactivation and monitored after HBV reactivation. Results Baseline HBsAg was detected using ICT-CLEIA in 4 patients; in all of whom precore mutants with high replication capacity were reactivated. Of the 6 patients with HBV DNA detected below the level of quantification at baseline, 5 showed HBV reactivation and 3 of the 5 had precore mutations. Sensitivity for detection by ARCHITECT and ICT-CLEIA HBsAg assays at HBV reactivation or the next sampling after HBV reactivation was 18.2% (4 of 22) and 77.3% (17 of 22), respectively. Of the 5 patients undetectable by ICT-CLEIA, HBV reactivation resolved spontaneously in 2 patients. All 6 patients reactivated with precore mutations including preS deletion could be diagnosed by ICT-CLEIA HBsAg assay at an early stage of HBV reactivation. Multivariate analysis showed that an anti-HBs titer of less than 10 mIU/ml, HBV DNA detected but below the level of quantification, and HBsAg detected by ICT-CLEIA at baseline were independent risk factors for HBV reactivation (adjusted hazard ratios, 15.4, 31.2 and 8.7, respectively; p Conclusions A novel ICT-CLEIA HBsAg assay is an alternative method to diagnose HBV reactivation. Clinical trial number UMIN000001299. Lay summary Hepatitis B virus can be reactivated in lymphoma patients receiving anti-CD20 antibodies such as rituximab. Currently, reactivation requires the monitoring of HBV DNA, but monitoring of the surface antigen (HBsAg) could provide a relatively inexpensive, quick and easy alternative. We assessed the performance of an ultra-high sensitivity HBsAg assay and showed that it could be effective for the diagnosis and monitoring of HBV reactivation.

Control of serum uric acid (sUA) levels is very important during chemotherapy in patients with malignant tumors, as the risks of tumor lysis syndrome (TLS) and renal events are increased with increasing levels of sUA. We investigated the efficacy and safety of febuxostat, a potent non-purine xanthine oxidase inhibitor, compared with allopurinol for prevention of hyperuricemia in patients with malignant tumors, including solid tumors, receiving chemotherapy in Japan.An allopurinol-controlled multicenter, open-label, randomized, parallel-group comparative study was carried out. Patients with malignant tumors receiving chemotherapy, who had an intermediate risk of TLS or a high risk of TLS and were not scheduled to be treated with rasburicase, were enrolled and then randomized to febuxostat (60 mg/day) or allopurinol (300 or 200 mg/day). All patients started to take the study drug 24 h before chemotherapy. The primary objective was to confirm the non-inferiority of febuxostat to allopurinol based on the area under the curve (AUC) of sUA for a 6-day treatment period.Forty-nine and 51 patients took febuxostat and allopurinol, respectively. sUA decreased over time after initiation of study treatment. The least squares mean difference of the AUC of sUA between the treatment groups was -33.61 mg h/dL, and the 95 % confidence interval was -70.67 to 3.45, demonstrating the non-inferiority of febuxostat to allopurinol. No differences were noted in safety outcomes between the treatment groups.Febuxostat demonstrated an efficacy and safety similar to allopurinol in patients with malignant tumors receiving chemotherapy.http://www.clinicaltrials.jp ; Identifier: JapicCTI-132398.

Multicentric Castleman disease (MCD) describes a heterogeneous group of disorders involving systemic inflammation, characteristic lymph node histopathology, and multi-organ dysfunction because of pathologic hypercytokinemia. Whereas Human Herpes Virus-8 (HHV-8) drives the hypercytokinemia in a cohort of immunocompromised patients, the etiology of HHV-8-negative MCD is idiopathic (iMCD). Recently, a limited series of iMCD cases in Japan sharing a constellation of clinical features, including thrombocytopenia (T), anasarca (A), fever (F), reticulin fibrosis (R), and organomegaly (O) has been described as TAFRO syndrome. Herein, we report clinicopathological findings on 25 patients (14 males and 11 females; 23 Japanese-born and two US-born), the largest TAFRO syndrome case series, including the first report of cases from the USA. The median age of onset was 50 years old (range: 23-72). The frequency of each feature was as follows: thrombocytopenia (21/25), anasarca (24/25), fever (21/25), organomegaly (25/25), and reticulin fibrosis (13/16). These patients frequently demonstrated abdominal pain, elevated serum alkaline phosphatase levels, and acute kidney failure. Surprisingly, none of the cases demonstrated marked hypergammoglobulinemia, which is frequently reported in iMCD. Lymph node biopsies revealed atrophic germinal centers with enlarged nuclei of endothelial cells and proliferation of endothelial venules in interfollicular zone. 23 of 25 cases were treated initially with corticosteroids; 12 patients responded poorly and required further therapy. Three patients died during the observation period (median: 9 months) because of disease progression or infections. TAFRO syndrome is a unique subtype of iMCD that demonstrates characteristic clinicopathological findings. Further study to clarify prognosis, pathophysiology, and appropriate treatment is needed.

Elderly patients with Epstein-Barr virus (EBV) infection are at increased risk for developing B-cell lymphoproliferative disorder (B-LPD) due to immunosenescence. Here, we describe a case of a 75-year-old man who developed an EBV-positive (EBV+) mucocutaneous ulcer (EBVMCU) in the gingiva with spontaneous regression. Eighteen months after regression, he had a cervical lymph node enlargement that was diagnosed as EBV+ nodal polymorphous B-LPD, Ann Arbor stage IA. Clinicians decided to observe his clinical course without any treatment. Fourteen months later, the patient developed EBV-positive diffuse large B-cell lymphoma (DLBCL), Ann Arbor stage IIA, and received six courses of age-adjusted dose chemotherapy and achieved a complete remission. No evidence of a clonal relationship was found among these three lesions by standard polymerase chain reaction (PCR) analysis for immunoglobulin heavy chain. However, they all had expression of PD-L1 in the EBV+ large B-cells and Hodgkin Reed-Sternberg-like cells. This is the first case report of a PD-L1-positive (PD-L1+) EBVMCU and the development of multiple EBV-driven B-LPDs in the setting of immunosenescence within a 32-month period.

ETV6, which encodes an ETS family transcription factor, is frequently rearranged in human leukemias. We show here that a patient with acute myeloid leukemia with t(7;11)(p15;p15) gained, at the time of relapse, t(11;12)(q12.1;p13) with a split ETV6 FISH signal. Using 3'-RACE PCR analysis, we found that ETV6 was fused to LPXN at 11q12.1, which encodes leupaxin. ETV6-LPXN, an in-frame fusion between exon 4 of ETV6 and exon 2 of LPXN, did not transform the interleukin-3-dependent 32D myeloid cell line to cytokine independence; however, an enhanced proliferative response was observed when these cells were treated with G-CSF without inhibition of granulocytic differentiation. The 32D and human leukemia cell lines each transduced with ETV6-LPXN showed enhanced migration towards the chemokine CXCL12. We show here for the first time that LPXN is a fusion partner of ETV6 and present evidence indicating that ETV6-LPXN plays a crucial role in leukemia progression through enhancing the response to G-CSF and CXCL12.

It is still a matter of debate whether detection of Epstein–Barr virus (EBV) DNA in pretreatment serum has clinical implications for diffuse large B‐cell lymphoma. For this study, we measured EBV DNA load in pretreatment serum from 127 diffuse large B‐cell lymphoma patients without any underlying immunodeficiency to evaluate its effects on clinical manifestations and prognosis. Anthracycline‐based chemotherapy in combination with rituximab was given as initial therapy for 119 patients (94%). Epstein–Barr virus DNA was detected in 15 patients (12%), who were older (P = 0.005) and tended to be at a more advanced disease stage (P = 0.053). They showed significantly worse progression‐free survival (PFS) and overall survival (OS) than other patients (P < 0.001 each). This effect remained significant (P = 0.004 and P = 0.027, respectively) after adjustment for age, lactate dehydrogenase, performance status, stage, and extranodal sites. The status of EBV‐encoded small RNA in situ hybridization was known for 123 patients; 6 of 8 positive patients (75%) and 9 of 115 negative patients (8%) had detectable EBV DNA in pretreatment serum. While patients positive for EBV‐encoded small RNA had significantly worse PFS and OS than negative patients (P = 0.001 and P = 0.029, respectively), EBV DNA detection in pretreatment serum was associated with poorer PFS and OS even for the 115 patients negative for EBV‐encoded small RNA (P < 0.001 each). These findings suggest that EBV DNA detection in pretreatment serum may have an adverse prognostic impact for patients with diffuse large B‐cell lymphoma.

Epstein-Barr virus (EBV)-encoded small RNA in situ hybridization (EBER-ISH) is a widely accepted method to evaluate EBV involvement in diffuse large B-cell lymphoma (DLBCL), although little is known regarding associations between EBV DNA load and the EBER status and whether EBV DNA load data provide additional clinical information. In this study, we quantified EBV DNA load in diagnostic specimens from DLBCL patients diagnosed at our hospital to evaluate clinical implications of EBV DNA load in diagnostic specimens as contrasted with EBER-ISH. Among 140 DLBCL patients without underlying immunodeficiency, 51 were evaluable for both EBER and EBV DNA load, 83 for EBER only and one for EBV DNA load only. The median EBV DNA load was 708 copies/µg. Although EBV DNA load was significantly higher for EBER-positive patients than for EBER-negative patients (p

Mantle cell lymphoma (MCL) is essentially incurable with conventional chemotherapy. The MCL International Prognostic Index (MIPI) is a validated specific prognostic index, but was derived from patients with advanced-stage disease primarily in the pre-rituximab era. We analysed 501 MCL patients (median age, 67 years; range 22-90) treated with rituximab-containing chemotherapy, and evaluated the prognostic factors adjusted by the treatment. Five-year overall survival (OS) in the low, intermediate and high MIPI groups was 74%, 70% and 35%, respectively. Additional to MIPI risk factors, multivariate analysis revealed that low serum albumin and bone-marrow involvement were also significantly associated with a poor outcome. The revised-MIPI (R-MIPI) was constructed using six factors, namely age, performance status, white blood cell count, serum lactate dehydrogenase, bone-marrow involvement and serum albumin, which is divided into four prognostic groups. Five-year OS in low, low-intermediate (L-I), high-intermediate (H-I) and high R-MIPI groups was 92%, 75%, 61% and 19%, respectively. Hazard ratio for OS of L-I, H-I and high risk to low risk patients were 5·4, 8·3 and 33·0, respectively. R-MIPI, a new prognostic index with easy application to the general patient population, shows promise for identifying low- and high-risk MCL patients in the rituximab era.

BACKGROUND There is no standard management of reactivation of hepatitis B virus (HBV) infection in HBV-resolved patients without hepatitis B surface antigen (HBsAg), but with antibodies against hepatitis B core antigen and/or antibodies against HBsAg (anti-HBs). METHODS We conducted a prospective observational study to evaluate the occurrence of HBV reactivation by serial monthly monitoring of HBV DNA and to establish preemptive therapy guided by this monitoring in B-cell non-Hodgkin lymphoma (B-NHL) treated with rituximab plus corticosteroid-containing chemotherapy (R-steroid-chemo). The primary endpoint was the incidence of HBV reactivation defined as quantifiable HBV DNA levels of ≥ 11 IU/mL. RESULTS With a median HBV DNA follow-up of 562 days, HBV reactivation was observed in 21 of the 269 analyzed patients. The incidence of HBV reactivation at 1.5 years was 8.3% (95% confidence interval, 5.5-12.4). No hepatitis due to HBV reactivation was observed in patients who received antiviral treatment when HBV DNA levels were between 11 and 432 IU/mL. An anti-HBs titer of

DEK-NUP214 gene fusion in acute myeloid leukemia (AML) is associated with poor prognosis. It is most often a sole translocation and more rarely observed as complex chromosomal forms. We describe an AML case with complex karyotype abnormalities involving chromosome bands 6p23, 6q13, 7p22, and 9q34. RNA sequencing analysis revealed that exon 17 of NUP214 (9q34) was fused to exon 2 of RAC1 (7p22). We also detected that the 5′-end of intron 1 of RAC1 was fused with the antisense strand of intron 5 of COL12A1 (6q13). RT-PCR analysis confirmed the expression of DEK-NUP214, NUP214-RAC1, RAC1-COL12A1, NUP214, and RAC1. These results suggest that the 5′- and 3′-ends of NUP214 from the breakpoint in the same locus were fused to RAC1 and DEK, respectively, and the 5′-end of RAC1 was fused to COL12A1. The reading frame of NUP214 was not matched with RAC1; however, high expression of the RAC1 protein was detected by Western blotting. This study identifies the variant complex fusion genesNUP214-RAC1 and RAC1- COL12A1 in a case of AML.

Multicentric Castleman disease (MCD) is a heterogeneous lymphoproliferative disorder. It is characterized by inflammatory symptoms, and interleukin (IL)-6 contributes to the disease pathogenesis. Human herpesvirus 8 (HHV-8) often drives hypercytokinemia in MCD, although the etiology of HHV-8-negative MCD is idiopathic (iMCD). A distinct subtype of iMCD that shares a constellation of clinical features including thrombocytopenia (T), anasarca (A), fever (F), reticulin fibrosis (R), and organomegaly (O) has been reported as TAFRO-iMCD, however the differences in cytokine profiles between TAFRO-iMCD and iMCD have not been established. We retrospectively compared levels of serum interferon γ-induced protein 10 kDa (IP-10), platelet-derived growth factor (PDGF)-AA, interleukin (IL)-10, and other cytokines between 11 cases of TAFRO-iMCD, 6 cases of plasma cell type iMCD, and 21 healthy controls. During flare-ups, patients with TAFRO-iMCD had significantly higher serum IP-10 and tended to have lower PDGF-AA levels than the other 2 groups. In addition, serum IL-10, IL-23, and vascular endothelial growth factor-A were elevated in both TAFRO-iMCD and iMCD. Elevated serum IP-10 is associated with inflammatory diseases including infectious diseases. There was a strong correlation between high serum IP-10 and the presence of TAFRO-iMCD, suggesting that IP-10 might be involved in the pathogenesis of TAFRO-iMCD.

Varicella, characterized by a vesicular rash, occurs primarily in young children. Although older individuals can also be affected or vaccinated, outbreaks among adults are rare. We investigated a small outbreak of varicella in B-cell lymphoma patients for elucidation of risk factor of the disease. We experienced four cases of varicella after an index herpes zoster case. All varicella cases were confirmed varicella zoster virus (VZV) infection by PCR. All varicella cases occurred in diffuse large B-cell lymphoma patients receiving rituximab-containing chemotherapy. On the other hand, only three of the 18 non-varicella patients in the same room were receiving rituximab-containing chemotherapy (P = 0.005). All varicella patients had detectable serum anti-varicella zoster virus IgG antibodies before chemotherapy. Even in the presence of neutralizing antibodies to the virus, lymphoma patients treated with rituximab-containing chemotherapy can possibly become re-infected with varicella. These findings suggest that zoster patients should be strictly isolated in hematology and oncology ward, and prophylactic acyclovir should be considered for such patients when exposed to zoster/varicella.

The immunological status of patients with Epstein-Barr virus-positive diffuse large B-cell lymphoma (EBV+ DLBCL) without obvious immunodeficiency has not been elucidated. A multicenter prospective study was conducted to assess pretreatment T-cell responses to EBV, EBV-DNA load and anti-EBV antibody in these patients. The proliferative and interferon (IFN)-γ-producing capacity of T-cells in response to autologous B-lymphoblastoid cell lines was determined using carboxyfluorescein diacetate succinimidyl ester (CFSE)-based assay. Frequencies of EBV-specific CD4+ T-cells in patients with EBV+ DLBCL (n = 13) were significantly higher than in healthy controls (HCs) (n = 16) after both ex vivo and in vitro stimulation. Frequencies of EBV-specific CD8+ T-cells in patients with EBV+ DLBCL tended to be higher than in HCs after in vitro stimulation. Patients with EBV+ DLBCL also showed increased immunoglobulin G (IgG) responses to lytic EBV-encoded antigens. Pretreatment plasma EBV-DNA level was significantly higher in patients with EBV+ DLBCL than in patients with EBV- DLBCL or HCs. In conclusion, EBV-specific T-cells showed increased reactivity, accompanied by higher levels of plasma virus DNA in patients with EBV+ DLBCL.

Introduction: Intravascular large B-cell lymphoma (IVLBCL) is a rare disease entity characterized by selective growth of lymphoma cells in the lumina of small vessels. IVLBCL has been listed in the WHO classification, which improves recognition of the disease. However, no standard therapy has been established based on the results of prospective studies. We previously reported promising efficacy of rituximab (R)-containing chemotherapy for IVLBCL (JCO 2008) and a high incidence of central nervous system (CNS) recurrence (25% at 3 y) after R-chemotherapy (Lancet Oncol 2009, Cancer Sci 2010). To explore a more effective first-line treatment, we conducted a phase 2 trial of R-CHOP combined with CNS prophylaxis including R-high-dose methotrexate (R-HDMTX) and intrathecal chemotherapy with MTX, cytarabine (Ara-C), and prednisolone (PSL) (IT). Methods: Major inclusion criteria were untreated, histologically confirmed IVLBCL, age 20-79 y, ECOG PS 0-3, and no apparent CNS involvement at diagnosis. Patients received 3 cycles of R-CHOP followed by 2 cycles of R-HDMTX (3.5 g/m2; 2 g/m2 for ≥70 y) every 2 weeks, and 3 additional cycles of R-CHOP. IT (MTX 15 mg, Ara-C 40 mg, PSL 10 mg) was performed twice during the first 3 cycles of R-CHOP and twice during the final 3 cycles of R-CHOP (4 times in total). If patients achieved complete response (CR), they were observed without any therapy until relapse or disease progression. The primary endpoint was 2-y progression-free survival (PFS), and secondary endpoints included 2-y overall survival (OS), CR rate, cumulative incidence of CNS recurrence at 2 y, patterns of progression, and adverse events. The threshold 2-y PFS was estimated to be 35%, with expected 2-y PFS estimated to be 60%. With a statistical power of 90% and a one-sided, type I error of 5%, a projected sample size of 37 was calculated in anticipation of 10% ineligible patients. The trial was registered in the UMIN Clinical Trials Registry (UMIN000005707). Results: 38 IVLBCL patients were enrolled between June 2011 and July 2016. One patient was found to be ineligible after completion of the protocol treatment due to a past history of lymphoma. The protocol treatment was completed in 34 (89%) of 38 patients. The diagnosis of IVLBCL was histologically confirmed by central pathological review in all enrolled patients. The baseline characteristics of the 37 eligible patients were: male sex, 16 (43%); median age, 66 (range 38-78) y; ECOG PS >1, 15 (41%); stage IV, 37 (100%); serum LDH >ULN, 36 (97%); WBC Conclusion: This phase 2 trial met its primary endpoint and showed favorable outcomes with a low cumulative incidence of CNS recurrence and acceptable toxicity profiles. These results indicate that R-CHOP combined with CNS prophylaxis including R-HDMTX and IT could be a reasonable treatment option for untreated IVLBCL without apparent CNS involvement at diagnosis. Disclosures Shimada: Takeda Pharmaceutical: Honoraria; MSD: Research Funding; Otsuka Pharmaceutical: Research Funding; Janssen Pharmaceutical: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Eisai: Honoraria, Research Funding; Chugai Pharmaceutical: Consultancy, Honoraria; Kyowa Kirin: Honoraria, Research Funding; AstraZeneca: Honoraria. Yamaguchi:Ono Pharmaceutical: Research Funding; Teijin Pharma: Honoraria; MSD: Honoraria; Astrazeneca: Membership on an entity's Board of Directors or advisory committees; Sumitomo Dainippon Pharma: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Astellas Pharma: Research Funding; Sorrento: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Meiji Seika Kaisha: Honoraria; Kyowa Hakko Kirin: Honoraria, Research Funding; Eisai: Honoraria; Chugai: Honoraria, Research Funding. Atsuta:Chugai Pharmaceutical Co., Ltd.: Honoraria; Kyowa Kirin Co., Ltd: Honoraria; Mochida Pharmaceutical Co. Ltd: Honoraria; Janssen Paharmaceutical K.K.: Honoraria. Matsue:Celgene: Honoraria; Takeda Pharmaceutical Company Limited: Honoraria; Ono Pharmaceutical: Honoraria; Novartis Pharma K.K: Honoraria; Janssen Pharmaceutical K.K.: Honoraria. Kusumoto:Chugai Pharmaceutical Co., Ltd.: Consultancy, Honoraria, Research Funding; Kyowa Kirin Co., Ltd.: Honoraria, Research Funding. Nagai:Eisai: Honoraria, Research Funding; HUYA Bioscience International: Research Funding; AstraZeneca: Honoraria, Research Funding; Takeda Pharmaceutical: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen Pharmaceutical: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Zenyaku Kogyo: Honoraria, Research Funding; Sanofi: Honoraria; Otsuka Pharmaceutical: Research Funding; SymBio Pharmaceuticals Limited: Honoraria, Research Funding; Solasia Pharma K.K.: Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; IQVIA: Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding; MSD: Honoraria; Novartis Pharma: Honoraria; Mundi Pharma: Honoraria, Research Funding; Bayer Pharma: Honoraria, Research Funding; AbbVie: Research Funding. Fukuhara:Mundi: Honoraria; Celgene Corporation: Honoraria, Research Funding; Chugai Pharmaceutical Co., Ltd.: Honoraria; Eisai: Honoraria, Research Funding; Janssen Pharma: Honoraria; Kyowa-Hakko Kirin: Honoraria; Mochida: Honoraria; Nippon Shinkyaku: Honoraria; Ono Pharmaceutical Co., Ltd.: Honoraria; Takeda Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Zenyaku: Honoraria; AbbVie: Research Funding; Bayer: Research Funding; Gilead: Research Funding; Solasia Pharma: Research Funding. Miyazaki:Eisai: Honoraria; Chugai: Honoraria; Kyowa Hakko Kirin: Honoraria, Research Funding; Celgene: Honoraria; Ono Pharmaceutical: Research Funding; Astellas Pharma: Research Funding; Takeda: Honoraria; SymBio Pharmaceuticals: Honoraria; Nippon Shinyaku: Honoraria; Janssen Pharmaceutical: Honoraria. Okamoto:Kyowa Kirin Co., Ltd.: Other: Scholarship donation; Chugai Pharmaceutical Co., Ltd.: Other: Scholarship donation; Takeda Pharmaceutical Co., Ltd.: Other: Scholarship donation; Taiho Pharmaceutical Co., Ltd.: Other: Scholarship donation. Uchida:Eisai: Honoraria. Tsukasaki:Daiichi Sankyo: Consultancy; Kyowa Kirin: Honoraria; Huya: Consultancy, Honoraria, Research Funding; Byer: Research Funding; Mundi Pharma: Honoraria; Ono Pharmaceutical: Consultancy; Eisai: Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Masaki:Tanabe Mitsubishi: Research Funding; Taiho: Research Funding; Kyowa Kirin: Research Funding; Astellas Pharma: Research Funding; Chugai Pharmaceutical: Research Funding; Ono Pharmaceutical: Research Funding; Pfizer: Research Funding; Eisai: Research Funding; Taisho Toyama: Research Funding; Daiichi Sankyo: Research Funding; Teijin: Research Funding; Takeda Pharmaceutical: Research Funding. Kiyoi:Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Bristol-Myers Squibb: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Astellas Pharma Inc.: Honoraria, Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding; Zenyaku Kogyo Co., Ltd.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co.,Ltd.: Research Funding; FUJIFILM Corporation: Research Funding; Eisai Co., Ltd.: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Pfizer Japan Inc.: Honoraria; Perseus Proteomics Inc.: Research Funding; Daiichi Sankyo Co., Ltd: Research Funding. Suzuki:Chugai Pharmaceutical Co.,Ltd.: Honoraria; Meiji Seika: Honoraria; Merck Sharp & Dohme: Honoraria; Takeda Pharmaceutical Co., Ltd.: Honoraria; Bristol-Myers Squibb: Honoraria; Kyowa Hakko Kirin: Honoraria; Celgene: Honoraria; Eisai: Honoraria; ONO Pharmaceutical Co., Ltd.: Honoraria; Janssen: Honoraria; AbbVie: Honoraria; Novartis: Honoraria.

The beneficial effect of rituximab for first-line treatment of diffuse large B-cell lymphoma (DLBCL) has been demonstrated by several randomized controlled trials. To clarify whether results for selected patient populations also apply to unselected patients, we analyzed long-term outcomes for all the 277 consecutive adults diagnosed with de novo DLBCL in a single center between 1998 and 2008. The study population included 147 and 130 patients diagnosed before (Cohort A) and after the advent of rituximab (Cohort B). Progression-free survival (PFS) was significantly better for Cohort B than for Cohort A (P = 0.005). For patients age 60 or younger, PFS did not differ significantly between Cohort A and Cohort B (P = 0.329), but for patients over 60, Cohort B showed superior PFS (P = 0.002). Patients with high or high-intermediate risk according to the International Prognostic Index score showed less improvement in PFS than did those with low or low-intermediate risk primarily because of still unfavorable outcomes of patients with poor performance status. These results indicate that the advent of rituximab has significantly improved outcome for unselected patients with DLBCL, and that improvement was greater for older patients. Further investigations are warranted in the hope of improving outcomes for younger patients with DLBCL.

Aims Epstein–Barr virus (EBV)-positive diffuse large B-cell lymphoma (DLBCL) not otherwise specified is defined as monoclonal EBV+ B-cell proliferation affecting patients without any known immunosuppression. Non-neoplastic EBV+ cells proliferating in or adjacent to EBV− DLBCL were reported recently, but their clinical significance is unclear. Thus, the aim of this study was to investigate the prognostic impact of EBV+ cells in DLBCL. Methods and results We compared the clinicopathological characteristics of 30 EBV+ DLBCL patients and 29 and 604 EBV− DLBCL patients with and without EBV+ bystander cells (median age of onset 71, 67 and 62 years, respectively). Both EBV+ DLBCL patients and EBV− DLBCL patients with EBV+ bystander cells tended to have high and high–intermediate International Prognostic Index scores (60% and 59%, respectively), as compared with only 46% of EBV− DLBCL patients without EBV+ bystander cells. EBV− DLBCL patients with EBV+ bystander cells showed a significantly higher incidence of lung involvement than those without EBV+ bystander cells (10% versus 2%, P < 0.05). Furthermore, EBV+ DLBCL patients and EBV− DLBCL patients with EBV+ bystander cells had a poorer prognosis than patients without any detectable EBV+ cells [median overall survival (OS) of 100 months and 40 months versus not reached, P < 0.01]. Notably, EBV+ DLBCL patients and EBV− DLBCL patients with EBV+ bystander cells treated with rituximab showed overlapping survival curves (OS, P = 0.77; progression-free survival, P = 1.0). Conclusions EBV− DLBCL with bystander EBV+ cells has similar clinical characteristics to EBV+ DLBCL. DLBCL with EBV+ bystander cells may be related to both age-related and microenvironment-related immunological deterioration.

Objective: To assess the immunosuppressive effect of R-CHOP in patients with B-cell lymphoma at 2 years. Methods: Parameters of humoral and cell-mediated immunity were assessed in 89 patients with diffuse large B-cell lymphoma or follicular lymphoma before and after 6-8 cycles of R-CHOP-14 or R-CHOP-21 regimen. Results: Data on pre- and posttreatment serum IgG (sIgG) levels were available for all 89 patients, while the corresponding data on serum CD20+, CD3+, CD4+, and CD8+ lymphocyte counts were available in only 43. Median sIgG levels significantly decreased from 1,221 mg/dl (baseline) to 733 mg/dl (after chemotherapy) (p < 0.001). Although CD20+ and CD4+ cell counts decreased (p < 0.001), no significant effect of chemotherapy on CD3+ and CD8+ cell counts was observed. CD20+ cell counts were restored to baseline levels at the 12-month follow-up. sIgG levels and CD4+ cell counts were not completely restored at 24 months, indicating a sustained immunosuppressive effect of R-CHOP in these patients. The incidence of infections over the 2-year period was 16.3-23.6%. Conclusion: The immunosuppressive effect of R-CHOP in newly diagnosed cases of B-cell lymphoma tends to persist for >2 years, although sIgG levels were restored more quickly than CD4+ cell counts.

High dose chemotherapy followed by autologous stem cell transplantation (SCT) has been shown to be effective therapy for patients with relapsed lymphoma responsive to standard-dose salvage chemotherapy. Here we report a patient in second complete remission (CR) from relapsed follicular lymphoma (grade 3) who was successfully treated with peripheral blood stem cells (PBSC) that had been harvested in first CR 10 years before. One of six frozen bags was thawed and submitted for progenitor cell assays. Because the number of progenitors was considered to be sufficient for engraftment, autologous SCT was performed without further stem cell harvest. At infusion, the viability of all nucleated cells (ANC) of the 5 remaining bags was 61.4%. She was expected to receive 2.87

Peripheral T-cell lymphoma (PTCL) has a poorer prognosis than diffuse large B-cell lymphoma (DLBCL). We administered the CyclOBEAP regimen (cyclophosphamide, vincristine, bleomycin, etoposide, doxorubicin, prednisolone) to patients with DLBCL, and reported its safety and efficacy. Here, we report the results of a multicentre phase II study of the CyclOBEAP regimen in patients with PTCL. In addition, NME1 remained a prognostic factor for survival, as shown in patients who were treated with CyclOBEAP. There were 84 eligible patients and the median age was 54 years. The 5-year overall survival (OS) rate was 72% and progression-free survival (PFS) rate was 61%. The 5-year OS was 93% among the anaplastic large-cell lymphoma cases, 74% among the angioimmunoblastic T-cell lymphoma cases, and 63% among the cases of PTCL-not otherwise specified. When the patients were divided according to the International Prognostic Index or Prognostic Index for PTCL, the 5-year OS and PFS rates did not significantly differ among the risk groups. Positivity for NME1 was found to be a significant independent prognostic factor. Grade 4 neutropenia was observed in 80 patients and thrombocytopenia in nine patients. Our results suggest that the CyclOBEAP therapy is safe and effective for PTCLs. Furthermore, the NME1 protein may be an important prognostic factor in PTCL.

Bendamustine is an agent that contains a nitrogen mustard group and a purine-like benzimidazole ring, thus combining alkylating and antimetabolic properties. It is highly active against relapsed or...

In our previous study on nm23-H1 expression with diffuse large B-cell lymphoma (DLBCL), we found that patients with positive nm23-H1 had significantly poorer prognosis than patients with negative nm23-H1. We examined whether nm23-H1 is a prognostic factor of DLBCL in the rituximab era. The subjects were 101 DLBCL patients who underwent R-CyclOBEAP (rituximab, cyclophosphamide, vincristine, bleomycin, etoposide, doxorubicin, and prednisolone) therapy and in whom markers could be analyzed. We evaluated CD5, CD10, BCL2, BCL6, MUM1, and nm23-H1 expression by immunohistochemistry. Ninety-four DLBCL patients who underwent CyclOBEAP therapy were assumed as historical controls. Among DLBCL patients who underwent CyclOBEAP therapy, BCL2 positivity, MUM1 positivity, non-germinal center B-cell (non-GCB), and nm23-H1 positivity were associated with significantly shorter overall survival (OS) and progression-free survival (PFS). On the other hand, among DLBCL patients who underwent R-CyclOBEAP therapy, the 5-year OS rates of the nm23-H1-positive DLBCL (n = 32) and nm23-H1-negative DLBCL groups (n = 69) were 65% and 97%, respectively (p = 0.001), with 5-year PFS rates of 51% and 89%, respectively (p = 0.001). In the rituximab era, BCL2, MUM1, and non-GCB were not prognostic factors. We demonstrated that among patients with DLBCL who underwent R-CyclOBEAP therapy, patients with nm23-H1 expression had a significantly poorer prognosis than patients without nm23-H1 expression. These results suggest an important role for nm23-H1 in malignant progression and a potential therapeutic target for DLBCL.

Among methotrexate (MTX)-related lymphoproliferative disorders (MTX-LPD), diffuse large B-cell lymphoma (DLBCL) accounts for about half. We studied the clinicopathological characteristics and prognosis of patients with DLBCL in MTX-LPD. This study included 29 patients who developed DLBCL after receiving MTX for rheumatoid arthritis. MTX was discontinued in all patients. Their median age was 62 years. Elevated lactate dehydrogenase (LDH) level was observed in 97% of the patients, bone marrow involvement in 17%, and involvement of extranodal sites in 41%. As for the cellular immunophenotype, CD20 was positive in 93%, CD5 in 3%, CD10 in 31%, BCL2 in 21%, BCL6 in 69%, and Epstein-Barr virus (EBV)-encoded small non-polyadenylated RNA (EBER) in 24%. Chemotherapy was started within 2 months after MTX withdrawal in 23 patients, of whom 12 patients received combination with rituximab. Spontaneous remission occurred in the remaining six patients. The EEBV-positive rate was 67% (4/6), and the four EBV-positive patients achieved complete response. Among the 23 DLBCL patients treated with chemotherapy, 20 patients achieved complete response. The 5-year overall survival was 74% and the 5-year progression-free survival was 65%. After the development of DLBCL, withdrawal of MTX was the first choice of treatment. Germinal center B-cell type and EBER-positive patients tended to show spontaneous remission. The utility of rituximab should be examined in future studies.

Background: We carried out immunohistochemistry to examine the expression of nm23-H1 in Hodgkin and Reed–Sternberg cells in patients with classical Hodgkin’s lymphoma (CHL). Patients and methods: We evaluated 128 patients with CHL [87 patients with nodular sclerosis (NS) and 41 patients with mixed cellularity (MC)] for CD15, CD20, Ki-67, EBER, TIA-1, and nm23-H1 by immunohistochemistry. Results: CD15 was expressed in 79%, CD20 in 11%, Ki-67 in 93%, EBER in 34%, TIA-1 in 11%, and nm23-H1 in 60% of the CHL patients. NS patients showed a significantly higher rate of nm23-H1 expression than MC patients (P < 0.001). The serum nm23-H1 level was significantly higher in patients with positive nm23 expression. Univariate analysis showed that stage IV, poor performance status, low hemoglobin level, low serum albumin level, age of 45 years or older, TIA-1-positive status, and nm23-H1-positive status were associated with significantly shorter progression-free survival. Multivariate analysis with these factors showed TIA-1 and cytoplasmic nm23-H1 expression to be significant and independent prognostic factors. Conclusions: Our results indicate that nm23-H1 expression is a prognostic factor for CHL and that it is as important as serum nm23-H1, both of which are useful for planning the treatment strategy.

Background De novo CD5-positive diffuse large B-cell lymphoma (CD5+ DLBCL) is clinicopathologically and genetically distinct from CD5-negative (CD5−) DLBCL and mantle cell lymphoma. The aim of this retrospective study was to clarify the histopathological spectrum and obtain new information on the therapeutic implications of CD5+ DLBCL. Design and Method From 1984 to 2002, 120 patients with CD5+ DLBCL were selected from 13 collaborating institutes. We analyzed the relationship between their morphological features and long-term survival. The current series includes 101 patients described in our previous study. Results Four morphological variants were identified: common (monomorphic) (n=91), giant cell-rich (n=13), polymorphic (n=14), and immunoblastic (n=2). Intravascular or sinusoidal infiltration was seen in 38% of the cases. BCL2 protein expression in CD5+ DLBCL was more frequent than in CD5− DLBCL ( p =0.0003). Immunohistochemical analysis in 44 consecutive cases of CD5+ DLBCL revealed that 82% of these cases (36/44) were non-germinal center B-cell type DLBCL. The 5-year overall survival rate of the patients with CD5+ DLBCL was 38% after a median observation time of 81 months. Patients with the common variant showed a better prognosis than those with the other three variants ( p =0.011), and this was confirmed on multivariate analysis. Overall, 16 patients (13%) developed central nervous system recurrence. Conclusions Our study revealed the morphological spectrum of CD5+ DLBCL, found that the incidence of central nervous system recurrence in this form of lymphoma in high, confirmed that CD5+ DLBCL frequently expresses BCL2 protein and showed that it is mainly included in the non-germinal center B-cell type of DLBCL.

Purpose To evaluate the safety and efficacy of rituximab-containing chemotherapies for intravascular large B-cell lymphoma (IVLBCL). Patients and Methods We retrospectively analyzed 106 patients (59 men, 47 women) with IVLBCL who received chemotherapy either with rituximab (R-chemotherapy, n = 49) or without rituximab (chemotherapy, n = 57) between 1994 and 2007 in Japan. The median patient age was 67 years (range, 34 to 84 years). The International Prognostic Index was high-intermediate/high in 97% of patients. Results The complete response rate was higher for patients in the R-chemotherapy group (82%) than for those in the chemotherapy group (51%; P = .001). The median duration of follow-up for surviving patients was 18 months (range, 1 to 95 months). Progression-free survival (PFS) and overall survival (OS) rates at 2 years after diagnosis were significantly higher for patients in the R-chemotherapy group (PFS, 56%; OS, 66%) than for patients in the chemotherapy group (PFS, 27% with P = .001; OS, 46% with P = 0.01). Multivariate analysis revealed that the use of rituximab was favorably associated with PFS (hazard ratio [HR], 0.45; 95% CI, 0.25 to 0.80; P = .006) and OS (HR, 0.42; 95% CI, 0.21 to 0.85; P = .016). Treatment-related death was observed in three patients (6%) who received R-chemotherapy and in five patients (9%) who received chemotherapy. Conclusion Our data suggest improved clinical outcomes for patients with IVLBCL in the rituximab era. Future prospective studies of rituximab-containing chemotherapies are warranted.

Background: We studied the clinicopathological characteristics and prognoses of localized stage thyroid diffuse large B-cell lymphoma (DLBCL). Patients and methods: This study included 32 patients with stage I/IIE thyroid DLBCL. Their median age was 66 years, the male/female ratio was 10/22. Results: As to the cellular immunophenotype, CD20 was positive in 31/32, CD5 in 0/32, CD10 in 4/32, CD23 in 1/32, BCL2 in 14/30, and BCL6 in 24/32. Twelve cases showed abnormal karyotypes: two cases with t(8;14)(q24;q32), four cases with 3q27, two cases with 17p11, and four cases with other abnormal karyotypes. As for treatment, eight cases were treated with chemotherapy alone and 24 cases were treated with chemotherapy followed by radiotherapy. Complete response was achieved in 94%. The 5-year progression-free survival was 84% and the 5-year overall survival was 90% with a median follow-up period of 62 months. The germinal center B-cell (GCB) type had a significantly better prognosis than the non-GCB type. Conclusion: Localized stage thyroid DLBCL is a disease with a relatively good prognosis. It is, however, a heterogeneous disease with regard to histological type and pathological state. Localized stage thyroid DLBCL has a good prognosis and it is that there are more GCB-type DLBCL lymphomas.

Diffuse large B-cell lymphoma (DLBCL) with the 8q24 translocation is occasionally seen in the gastrointestinal tract, but has rarely been reported in the thyroid gland. We experienced two cases of primary thyroid DLBCL having t(8;14)(q24;q32). The immunophenotype and karyotype of Case 1 (66-year-old female) and Case 2 (70-year-old female) were: CD10-, CD20+, BCL-2+/add(13)(q34), t(8;14)(q24;q32) and CD10-, CD20-, CD79a+, BCL-2-/t(8;14)(q24;q32), respectively. Although long-term complete remission could be achieved in both of our patients by conventional chemotherapy with/without radiation therapy, accumulation of further such cases is necessary to develop a standard treatment protocol and also to elucidate the pathogenesis of t(8;14)(q24;q32)-positive primary thyroid DLBCL.

In adult T-cell lymphoma/leukemia (ATLL), the neoplastic lymphoid cells are usually medium-sized to large, often with pronounced nuclear pleomorphism compatible with the diagnosis of diffuse pleomorphic peripheral T-cell lymphoma. We describe here 11 patients with the rare morphologic variant of ATLL, angioimmunoblastic T-cell lymphoma (AILT)-like type. The examined lymph nodes showed proliferation of high endothelial venules and presence of various infiltrating inflammatory cells including plasma cells and eosinophils. The lymphoma cells were medium-to-large size with clear cytoplasm. These findings were suggestive of AILT. However, immunohistochemical features of AILT, namely, CD10 and CXCL13 expression in lymphoma cells and proliferation of CD21-positive follicular dendritic cells, were not detected. Two cases were CXCR3-positive, whereas 9 expressed CCR4, which are usually positive in ATLL. All patients were positive for antiadult T-cell leukemia/lymphoma-associated antigen, which is a specific antibody for human T-cell lymphotropic virus type-I. Southern blot analysis revealed proviral DNA integration in lymphoma cells in 9 patients. The latter was not evident in the first biopsy of 2 patients but in the second biopsy obtained within several months after the first biopsy revealed definite proviral integration. Almost all patients showed aggressive clinical course and poor survival (median survival: 5 mo). This is the first report of ATLL with AILT-like morphologic features.

The net benefits of induction therapy for older adults with acute myeloid leukemia (AML) remain controversial. Because AML in older adults is a heterogeneous disease, it is important to identify those who are unlikely to benefit from induction therapy based on information available at the initial assessment. We used next-generation sequencing to analyze TP53 mutation status in AML patients aged 60 years or older, and evaluated its effects on outcomes. TP53 mutations were detected in 12 of 77 patients (16 %), and there was a significant association between TP53 mutations and monosomal karyotype. Patients with TP53 mutations had significantly worse survival than those without (P = 0.009), and multivariate analysis identified TP53 mutation status as the most significant prognostic factor for survival. Neverthelsess, TP53-mutated patients had a 42 % chance of complete remission and a median survival of 8.0 months, which compares favorably with those who did not undergo induction therapy, even in the short term. These results suggest that screening for TP53 mutations at diagnosis is useful for identifying older adults with AML who are least likely to respond to chemotherapy, although the presence of this mutation alone does not seem to justify rejecting induction therapy.

DEK-NUP214 gene fusion in acute myeloid leukemia (AML) is associated with poor prognosis. It is most often a sole translocation and more rarely observed as complex chromosomal forms. We describe an AML case with complex karyotype abnormalities involving chromosome bands 6p23, 6q13, 7p22, and 9q34. RNA sequencing analysis revealed that exon 17 of NUP214 (9q34) was fused to exon 2 of RAC1 (7p22). We also detected that the 5'-end of intron 1 of RAC1 was fused with the antisense strand of intron 5 of COL12A1 (6q13). RT-PCR analysis confirmed the expression of DEK-NUP214, NUP214-RAC1, RAC1-COL12A1, NUP214, and RAC1. These results suggest that the 5'- and 3'-ends of NUP214 from the breakpoint in the same locus were fused to RAC1 and DEK, respectively, and the 5'-end of RAC1 was fused to COL12A1. The reading frame of NUP214 was not matched with RAC1; however, high expression of the RAC1 protein was detected by Western blotting. This study identifies the variant complex fusion genesNUP214-RAC1 and RAC1- COL12A1 in a case of AML.

Multicentric Castleman disease (MCD) describes a heterogeneous group of disorders involving systemic inflammation, characteristic lymph node histopathology, and multi-organ dysfunction because of pathologic hypercytokinemia. Whereas Human Herpes Virus-8 (HHV-8) drives the hypercytokinemia in a cohort of immunocompromised patients, the etiology of HHV-8-negative MCD is idiopathic (iMCD). Recently, a limited series of iMCD cases in Japan sharing a constellation of clinical features, including thrombocytopenia (T), anasarca (A), fever (F), reticulin fibrosis (R), and organomegaly (O) has been described as TAFRO syndrome. Herein, we report clinicopathological findings on 25 patients (14 males and 11 females; 23 Japanese-born and two US-born), the largest TAFRO syndrome case series, including the first report of cases from the USA. The median age of onset was 50 years old (range: 23-72). The frequency of each feature was as follows: thrombocytopenia (21/25), anasarca (24/25), fever (21/25), organomegaly (25/25), and reticulin fibrosis (13/16). These patients frequently demonstrated abdominal pain, elevated serum alkaline phosphatase levels, and acute kidney failure. Surprisingly, none of the cases demonstrated marked hypergammoglobulinemia, which is frequently reported in iMCD. Lymph node biopsies revealed atrophic germinal centers with enlarged nuclei of endothelial cells and proliferation of endothelial venules in interfollicular zone. 23 of 25 cases were treated initially with corticosteroids; 12 patients responded poorly and required further therapy. Three patients died during the observation period (median: 9 months) because of disease progression or infections. TAFRO syndrome is a unique subtype of iMCD that demonstrates characteristic clinicopathological findings. Further study to clarify prognosis, pathophysiology, and appropriate treatment is needed.