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INTRODUCTION Adult T-cell leukemia-lymphoma (ATL) is a mature T-cell lymphoproliferative neoplasm caused by human T-cell leukemia virus type-1infection. There is no standard treatment for relapsed or refractory (r/r) ATL and clinical outcomes are poor. This systematic review examined the survival outcomes for r/r ATL treated with various systemic therapies. METHODS EMBASE and PubMed were searched for studies on r/r ATL, published between January 2010 and January 2020. The main outcome of interest was overall survival (OS). Median OS and an exploratory 30% OS time were assessed based on published data and Kaplan-Meier curves. RESULTS There were 21 unique treatment subgroups (from 14 studies), that met the eligibility criteria. Nine subgroups were mogamulizumab treatment, two were mogamulizumab prior to allogenic hematopoietic stem cell transplantation (allo-HSCT), five were allo-HSCT and five were other chemotherapy. Respectively, the median OS and 30% OS varied considerably in range for mogamulizumab treatment (2.2-17.6 months and 8.7-27.1 months), allo-HSCT (3.8-6.2 months and 7.5-19.8 months), and other chemotherapy arms (4.1-20.3 months and 7.1-17.0 months). CONCLUSION Mogamulizumab was the most frequently studied treatment regimen and can potentially provide longer survival compared to chemotherapy alone. Future comparisons with synthetic or historical control arms may enable clearer insights into treatment efficacy.

We conducted a nationwide retrospective analysis of 116 hepatitis B virus (HBV) surface antigen (HBsAg)‐positive patients with diffuse large B‐cell lymphoma (DLBCL) and 278 HBsAg‐negative patients with DLBCL, as a control cohort, who received rituximab‐containing regimens as an induction chemotherapy at 30 Japanese medical centers between January 2004 and December 2014. Hepatitis was defined as an absolute serum alanine aminotransferase (ALT) level of ≥100 U/L. HBV reactivation‐related hepatitis was defined as hepatitis with an absolute serum HBV DNA level of ≥3.3 log IU/mL or an absolute increase of ≥2 log compared with the baseline value. HBsAg‐positive patients were divided into three groups based on anti–HBV prophylactic therapy: no nucleos(t)ide analogue (non–NA, n = 9), lamivudine (LAM, n = 20), and entecavir (ETV, n = 87). The 4‐year cumulative incidence (CI) of hepatitis in HBsAg‐positive and HBsAg‐negative patients was 21.1% and 14.6% (P = .081), respectively. The 4‐year CI of HBV reactivation‐related hepatitis was higher in HBsAg‐positive patients than in HBsAg‐negative patients (8.0% vs 0.4%; P, Prophylactic use of entecavir reduced HBV‐related hepatitis and mortality in HBsAg‐positive DLBCL treated with R‐chemotherapy. The 4‐year overall survival rate in HBsAg‐positive DLBCL patients receiving prophylactic entecavir was similar to that in HBsAg‐negative DLBCL.

Adult T‐cell leukemia/lymphoma (ATL) is a mature T‐cell neoplasm and is classified into four subtypes (acute, lymphoma, chronic, and smoldering) according to the Shimoyama classification, established in 1991 through several nationwide surveys based on the clinical diversity of patients diagnosed in 1983‐1987 in Japan. Thereafter, no such studies have been conducted. Recently, we conducted a nationwide hospital survey using the method of the 1980s studies, collected baseline data on 996 ATL patients diagnosed in 2010‐2011 from 126 hospitals, and reported their unique epidemiological characteristics. Here, we report the follow‐up results of registered ATL patients with the goal of evaluating current prognoses and treatment modalities as of 2016‐2017. Of 770 evaluable patients, 391 (50.8%) had acute‐type, 192 (24.9%) had lymphoma‐type, 106 (13.8%) had chronic‐type, and 81 (10.5%) had smoldering‐type ATL. The initial therapy regimens used for acute/lymphoma‐type ATL were vincristine, cyclophosphamide, doxorubicin and prednisone, followed by doxorubicin, ranimustine, and prednisone and then by vindesine, etoposide, carboplatin, and prednisone (VCAP‐AMP‐VECP)‐like in 38.5/41.7% and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)‐like in 14.6/13.7% of patients. Allogeneic hematopoietic stem cell transplantation was used to treat 15.9/10.4% of acute/lymphoma‐type ATL patients. The 4‐year survival rates (the median survival time, days) for acute‐, lymphoma‐, unfavorable chronic‐, favorable chronic‐, and smoldering‐type ATL were 16.8% (252), 19.6% (305), 26.6% (572), 62.1% (1937), and 59.8% (1851), respectively. The 4‐year survival rates for acute‐ and lymphoma‐type ATL improved compared with those reported in 1991, but those for chronic‐ and smoldering‐type ATL were not. Further efforts are warranted to develop more efficient therapeutic strategies to improve the prognosis of ATL in Japan., The survival curve shows that the prognoses of patients with acute and lymphoma‐type ATL in Japan have improved modestly, but those of patients with chronic and smoldering‐type ATL have not improved.

The efficiency of upfront consolidation with high‐dose chemotherapy/autologous stem‐cell transplantation (HDCT/ASCT) for newly diagnosed high‐risk diffuse large B‐cell lymphoma (DLBCL) may be influenced by induction chemotherapy. To select better induction chemotherapy regimens for HDCT/ASCT, a randomized phase II study was conducted in high‐risk DLBCL patients having an age‐adjusted International Prognostic Index (aaIPI) score of 2 or 3. As induction chemotherapy, 6 cycles of R‐CHOP‐14 (arm A) or 3 cycles of R‐CHOP‐14 followed by 3 cycles of CHASER (arm B) were planned, and patients who responded proceeded to HDCT with LEED and ASCT. The primary endpoint was 2‐y progression‐free survival (PFS), and the main secondary endpoints included overall survival, overall response rate, and adverse events (AEs). In total, 71 patients were enrolled. With a median follow‐up of 40.3 mo, 2‐y PFS in arms A and B were 68.6% (95% confidence interval [CI], 50.5%‐81.2%) and 66.7% (95% CI: 48.8%‐79.5%), respectively. Overall survival at 2 y in arms A and B was 74.3% (95% CI: 56.4%‐85.7%) and 83.3% (95% CI: 66.6%‐92.1%). Overall response rates were 82.9% in arm A and 69.4% in arm B. During induction chemotherapy, 45.7% and 75.0% of patients in arms A and B, respectively, had grade ≥ 3 non‐hematologic toxicities. One patient in arm A and 6 in arm B discontinued induction chemotherapy due to AEs. In conclusion, R‐CHOP‐14 showed higher 2‐y PFS and less toxicity compared with R‐CHOP‐14/CHASER in patients with high‐risk DLBCL, suggesting the former to be a more promising induction regimen for further investigations (UMIN‐CTR, UMIN000003823)., The efficiency of upfront consolidation with high‐dose chemotherapy/autologous stem‐cell transplantation (HDCT/ASCT) for newly diagnosed high‐risk diffuse large B‐cell lymphoma (DLBCL) may be influenced by induction chemotherapy. To select better induction chemotherapy regimens for HDCT/ASCT, a randomized phase II study was conducted in patients with high‐risk DLBCL who had an age‐adjusted International Prognostic Index (aaIPI) score of 2 or 3. R‐CHOP‐14 showed higher 2‐y PFS and less toxicity compared with R‐CHOP‐14/CHASER in patients with high‐risk DLBCL, suggesting the former to be a more promising induction regimen for further investigations.

Although the superiority of vancomycin dosing based on area under the concentration-time curve (AUC0-24) over that based on trough concentration has been reported, a dosing strategy to achieve the target AUC0-24 has yet to be developed. The objective of this study was to develop a convenient useable nomogram for vancomycin dosing to obtain the target AUC0-24 (400 μg h/mL). The nomogram was pharmacokinetically developed in a retrospective manner. The number of enrolled patients and concentrations was 166 and 309 for development of the nomogram, 99 and 181 for evaluation of the nomogram, respectively. The nomogram was developed as doses per personal body weight corresponding to each range of estimated glomerular filtration rate (eGFR), which was identified to be the covariate for vancomycin clearance by non-linear mixed effect modeling. The nomogram described the surrogate trough concentration for the target AUC0-24 was calculatedly different for each eGFR range (9.3–15.0 μg/mL). The rate of attainment of therapeutic range using surrogate trough concentration to obtain the target AUC0-24 was 63.8% in the evaluation period. We have developed and evaluated the first convenient useable nomogram of vancomycin dosing to obtain the target AUC0-24.

Adult T‐cell leukemia‐lymphoma (ATL) is a T‐cell malignancy that is endemic to Japan. In this latest nationwide study of ATL, we collected the data from 4 nationwide registries of patients diagnosed in 2012‐2013; the Hematology Blood Disease, the Skin Cancer Society, the Hospital‐Based Cancer Registries, and information from the hospitals that participated in the Japanese nationwide survey of ATL in 2010‐2011. In the present study, 2614 patients with ATL were diagnosed based on the registries, and 117 departments registered 1042 patients. Among these patients, 984 were eligible for analysis. The median age at diagnosis was 69 y. A larger proportion of patients with ATL older than 70 y was diagnosed with the lymphoma subtype, and more than half of the patients with ATL in the metropolitan areas were born in the human T‐cell leukemia virus type I (HTLV‐1)‐endemic areas of Kyushu/Okinawa, which are almost identical to the findings in our 2010‐2011 study. Additionally, we identified that patients with ATL migrated from the endemic areas for HTLV‐1 to the non‐endemic metropolitan areas. The present study was able to reduce the burden of searching each hospital and to update the clinico‐epidemiological characteristics of a large number of patients with ATL in Japan, suggesting the usefulness and feasibility of the novel data collection method. The establishment of a more sophisticated database management system for ATL is necessary for future continuous surveys., We identified that ATL patients shifted from areas endemic for HTLV‐1 to non‐endemic metropolitan areas. The median age at diagnosis was 69 y, which was significantly older than that in the 1980s and 1990s. We conducted a nationwide survey of ATL during 2012‐2013 by modifying data acquisition from 4 nationwide registries.

Tazemetostat is a selective, reversible, small‐molecule inhibitor of the histone methyltransferase enzyme, enhancer of zest homolog 2 (EZH2). In this multicenter, open‐label, phase II study, we assessed the efficacy and safety of tazemetostat in Japanese patients with relapsed or refractory (R/R) B‐cell non‐Hodgkin lymphoma harboring the EZH2 mutation. Tazemetostat (800 mg twice daily) was given orally (28‐day cycle) until disease progression or unacceptable toxicity. Among the 20 eligible patients, 17 were enrolled in cohort 1 (follicular lymphoma [FL]), and three were enrolled in cohort 2 (diffuse large B‐cell lymphoma). At data cut‐off, the objective response rate in cohort 1 was 76.5%, including six patients (35.3%) with complete response and seven patients (41.2%) with partial response (PR). All three patients in cohort 2 achieved PR. In cohort 1, median progression‐free survival (PFS) was not reached at the median follow‐up of 12.9 months. The estimated PFS rate at 12 and 15 months was 94.1% and 73.2%, respectively. The most common grade 3 treatment‐emergent adverse event (TEAE) was lymphopenia (n = 2). Grade 4 TEAEs included hypertriglyceridemia and pneumonia aspiration (n = 1 each), which were not related to tazemetostat. Treatment‐emergent adverse events leading to study drug discontinuation were reported in four of the 20 patients, indicating that the safety profile of tazemetostat was acceptable and manageable. Tazemetostat 800 mg twice daily showed encouraging efficacy in patients with R/R EZH2 mutation‐positive FL with a manageable safety profile in the overall population. Thus, tazemetostat could be a potential treatment for R/R EZH2 mutation‐positive FL., Percentage change from baseline in sum of the product of the perpendicular diameters of target lesions based on independent reviewer assessment.

Mogamulizumab (Mog) is effective against adult T-cell leukemia-lymphoma (ATL), but as we reported previously, Mog increases the incidence of severe acute GVHD when administered before allogeneic hematopoietic cell transplantation (allo-HCT). Here, we report the cases of two ATL patients who did not develop acute GVHD despite receiving Mog before allo-HCT. Case 1: a 63-year-old female who underwent allo-HCT from an HLA-matched donor 2 months after the last dose of Mog. Case 2: a 47-year-old male with ATL that relapsed 3 months after first allo-HCT. He received eight doses of Mog and underwent a second allo-HCT from a haploidentical donor 4 months after the last dose of Mog. Mog blood levels were measured and lymphocytes analyzed by mass cytometry. Mog blood levels measured before starting the conditioning regimens were low. A small proportion of regulatory T cells (Tregs) was detected before and shortly after allo-HCT. When using Mog before allo-HCT, it is important to consider the number of Mog doses and the interval from the last dose of Mog to allo-HCT. Analyzing Mog blood levels and Treg counts before and after allo-HCT should also be useful.

Monitoring of Immune Responses Following Mogamulizumab-Containing Treatment in Patients with Adult T-Cell Leukemia-Lymphoma (ATL) (MIMOGA) is a multicenter prospective observational study to establish the most effective and safe treatment strategy using mogamulizumab for ATL patients (UMIN000008696). Mogamulizumab-naive patients were enrolled (n = 102), of whom 101 received mogamulizumab-containing treatment (68 acute, 18 lymphoma, 12 chronic, and 3 smoldering subtypes). At enrollment, there was a significant inverse correlation between serum soluble interleukin-2 receptor (sIL-2R) levels and percentages of Tax-specific cytotoxic T lymphocytes (Tax-CTLs) in the entire lymphocyte population or in the CD8+ T cell subset, but there was not a correlation with cytomegalovirus pp65–specific cytotoxic T lymphocytes (CMV-CTLs). The overall response rate was 65%, and median progression-free survival and overall survival (OS) were 7.4 and 16.0 months, respectively. A higher percentage of Tax-CTLs, but not CMV-CTLs, within the entire lymphocyte population or in the CD8+ T cell subset was significantly associated with longer survival. Multivariate analysis identified the clinical subtype (acute or lymphoma type), a higher sIL-2R level, and a lower percentage of CD2−CD19+ B cells in peripheral blood mononuclear cells as significant independent unfavorable prognostic factors for OS. This indicates that a higher percentage of B cells might reflect some aspect of a favorable immune status leading to a good outcome with mogamulizumab treatment. In conclusion, the MIMOGA study has demonstrated that mogamulizumab exerts clinically meaningful antitumor activity in ATL. The patient’s immunological status before mogamulizumab was significantly associated with treatment outcome. Further time series immunological analyses, in addition to comprehensive genomic analyses, are warranted.

Vancomycin is often employed as an antibacterial agent against Gram-positive bacteria, although dose-dependent nephrotoxicity is a concern. Although the risk may be reduced by therapeutic drug monitoring (TDM) guided by area under the concentration–time curve (an attempt to target an AUC > 400 μg•h/mL by Bayesian prediction: AUC400-guided TDM), the clinical efficacy of AUC400-guided TDM compared with trough concentration-guided TDM within 15–20 μg/mL (Trough15–20-guided TDM) has yet to be determined. We aimed to retrospectively evaluate the difference in the incidence rate of acute kidney injury (AKI), classified according to the Acute Kidney Injury Network, between these TDM groups. Individual AUC in the AUC400-guided TDM group was calculated by Bayesian prediction using trough and peak concentrations (within 3 h after the end of infusion). The AKI incidence in the Trough15–20-guided TDM group was 28.8% (15/52 patients) compared with an AKI incidence in the AUC400-guided TDM group of 9.1% (2/22 patients). Application of AUC400-guided TDM was identified as an independent factor for avoiding the incidence of AKI by Cox hazard regression analysis [hazard ratio = 0.168, 95% confidence interval (CI) 0.034–0.839] and logistic regression analysis (odds ratio = 0.037, 95% CI 0.003–0.285). As the estimated glomerular filtration rate (eGFR) improved, the surrogate target trough concentration for an AUC > 400 μg•h/mL was lowered (intercept 15.0074, slope –0.0598). In conclusion, AUC400-guided TDM may be superior to Trough15–20-guided TDM for the reduction of nephrotoxicity during vancomycin therapy.

Bacteremia is often caused by gram-negative bacteria (represented by EKP; Escherichia coli, Klebsiella species, and Proteus mirabilis), and the excessive use of cefazolin, as the first-line antimicrobial in its treatment, has been a source of concern in the emergence of resistant strains. As an antimicrobial, cefotiam may be an alternative to cefazolin; however, little evidence is available for its use in the treatment of bacteremia. The purpose of this non-inferiority study was to retrospectively compare the therapeutic efficacy of cefotiam with some antimicrobials of narrow spectrum (cefazolin, cefmetazole, and flomoxef) in the treatment of EKP-induced bacteremia. The number of patients recruited was 32 in the cefotiam group and 29 in the control group. In the primary endpoint, the survival rate on day 28 for the cefotiam group and the control group was 93.5% and 89.3%, respectively (relative risk at day 28, 1.048; 95% confidence interval, 0.894-1.227). In the secondary end point, treatment success rate in the two groups was 71.9% and 69.0%, respectively (relative risk, 1.042; 95% confidence interval, 0.752-1.445). Intensive care unit admission, low body weight, hypoalbuminemia, and infections unassociated with the urinary tract were identified to be the risk factors responsible for treatment failure. We demonstrated cefotiam may be non-inferior to other antimicrobials of similar spectrum, in terms of survival rate, in EKP-induced bacteremia.

Summary Background Standard treatment for untreated advanced-stage follicular lymphoma is rituximab plus chemotherapy. The incidence of histological transformation of follicular lymphoma has been reported only in heterogeneously treated populations and rarely with long-term follow-up. Additionally, the incidence of secondary malignancies after treatment, without high-dose therapy for follicular lymphoma, is largely unknown. The aim of our study was to assess progression-free survival, overall survival, incidence of secondary malignancies, and incidence of histological transformation in a 10-year follow-up analysis of the JCOG0203 trial. Methods In the phase 2–3 randomised JCOG0203 trial, previously untreated patients with stage III or IV indolent B-cell lymphoma, including grades 1–3 follicular lymphoma, from 44 hospital centres in Japan, were randomly assigned (1:1) by use of a minimisation method to receive six cycles of R-CHOP (rituximab [375 mg/m2], given on day 1, plus cyclophosphamide [750 mg/m2], doxorubicin [50 mg/m2], vincristine [1·4 mg/m2, capped at 2·0 mg] given intravenously on day 3, and oral prednisone [100 mg once daily on days 3–7]) every 3 weeks (R-CHOP-21) or every 2 weeks (enabled by mandatory granulocyte-colony stimulating factor administration once daily for 6 days, starting on day 8; R-CHOP-14) without rituximab maintenance. Age, bulky disease (nodal or extranodal mass ≥10 cm in diameter on CT), and institution were used as adjustment factors. Investigators enrolled participants, and assignment to trial groups was done with a computer-assisted randomisation allocation sequence that took place centrally at the Japan Clinical Oncology Group Data Center, without the intervention of investigators. Interventions were not masked for patients or investigators. Data were collected 10 years after enrolment of the last patient. The primary endpoint of the phase 3 part of the study was progression-free survival, and the primary endpoint of the phase 2 part of the study was the proportion of patients who achieved a complete response. Accrual was 4·5 years, and follow-up was 3 years after registration was closed. Data were updated on the cutoff date of Feb 28, 2017. Intention-to-treat analyses (ie, progression-free survival, overall survival, and incidence of secondary malignancies) were predefined, to be done at 10 years after the last patient was enrolled. An additional analysis of the incidence of histological transformation was defined 15 years after the protocol, on May 8, 2017, in a supplementary analysis plan, and assessed at 10 years after the last patient was enrolled. Follow-up is ongoing. This trial is registered with ClinicalTrials.gov, number NCT00147121. Findings Between Sept 1, 2002, and Feb 28, 2007, 300 patients were enrolled, and 149 (50%) were assigned to the R-CHOP-21 group and 151 (50%) were assigned to the R-CHOP-14 group. After eligibility was assessed, one patient was excluded from the R-CHOP-21 group. 10-year progression-free survival was not different between groups (R-CHOP-21 33%, 95% CI 25–41; R-CHOP-14 39%, 31–47; hazard ratio 0·89, 95% CI 0·67–1·17). In 248 patients with grade 1–3a follicular lymphoma, progression-free survival was 39% (33–45) at 8 years and 36% (30–42) at 10 years. The cumulative incidence of histological transformation was 3·2% (95% CI 1·5–6·0) at 5 years, 8·5% (5·4–12·4) at 8 years, and 9·3% (6·1–13·4) at 10 years after enrolment. At 10 years, the cumulative incidence of secondary malignancies was 8·1% (5·1–12·0) and the cumulative incidence of haematological secondary malignancies was 2·9% (1·3–5·5). Interpretation R-CHOP is a viable option for first-line treatment in patients with newly diagnosed advanced follicular lymphoma. Clinicians choosing a first-line treatment for patients with follicular lymphoma should be cautious of secondary malignancies caused by immunochemotherapy and severe complications of infectious diseases in the long-term follow-up—both of which could lead to death. Funding National Cancer Center and Ministry of Health, Labour and Welfare of Japan.

Adult T-cell leukemia/lymphoma (ATL) is a heterogeneous group of peripheral T-cell malignancies characterized by human T-cell leukemia virus type-1 infection, whose genetic profile has recently been fully investigated. However, it is still poorly understood how these alterations affect clinical features and prognosis. We investigated the effects of genetic alterations commonly found in ATL on disease phenotypes and clinical outcomes, based on genotyping data obtained from 414 and 463 ATL patients using targeted-capture sequencing and single nucleotide polymorphism array karyotyping, respectively. Aggressive (acute/lymphoma) subtypes were associated with an increased burden of genetic and epigenetic alterations, higher frequencies of TP53 and IRF4 mutations, and many copy number alterations (CNAs), including PD-L1 amplifications and CDKN2A deletions, compared with indolent (chronic/smoldering) subtypes. By contrast, STAT3 mutations were more characteristic of indolent ATL. Higher numbers of somatic mutations and CNAs significantly correlated with worse survival. In a multivariate analysis incorporating both clinical factors and genetic alterations, the Japan Clinical Oncology Group prognostic index high-risk, older age, PRKCB mutations, and PD-L1 amplifications were independent poor prognostic factors in aggressive ATL. In indolent ATL, IRF4 mutations, PD-L1 amplifications, and CDKN2A deletions were significantly associated with shorter survival, although the chronic subtype with unfavorable clinical factors was only marginally significant. Thus, somatic alterations characterizing aggressive diseases predict worse prognosis in indolent ATL, among which PD-L1 amplifications are a strong genetic predictor in both aggressive and indolent ATL. ATL subtypes are further classified into molecularly distinct subsets with different prognosis. Genetic profiling might contribute to improved prognostication and management of ATL patients.

Background: Tazemetostat is a selective, reversible, small-molecule inhibitor of enhancer of zest homolog 2 (EZH2), a histone methyltransferase. EZH2 is the catalytic subunit of polycomb repressive complex 2, which methylates lysine 27 on histone 3 (H3K27). Recurrent gain-of-function alterations in EZH2 occur in approximately 30% of germinal center B-cell like diffuse large B-cell lymphoma (GCB-DLBCL) and 27% of follicular lymphoma (FL). The aim of this multicenter, open-label, Phase 2 study was to assess the efficacy and safety of tazemetostat in Japanese patients with relapsed or refractory B-cell Non-Hodgkin's Lymphoma (NHL) harboring the EZH2 mutation. Methods: Patients with histologically diagnosed FL (cohort 1) or DLBCL (cohort 2) were screened centrally for EZH2 mutation using the cobas EZH2 Mutation Test. Tazemetostat (800 mg BID) was administered orally for 28 days/cycle until disease progression, occurrence of unacceptable toxicity, or withdrawal of consent. The primary endpoint was the objective response rate (ORR) based on IWG-2007 by independent imaging review and safety was evaluated as the secondary endpoint. Results: Among the 20 eligible patients, 17 were enrolled in cohort 1, and 3 were enrolled in cohort 2. In cohort 1, the median number of prior chemotherapy was 2 (range 1-4) and the ORR was 76.5% , including 6 patients (35.3%) achieving a complete response and 7 patients (41.2%) achieving a partial response (PR) as of the data cutoff. The ORR in subjects who received prior treatment with bendamustine, rituximab, and CHOP was 87.5%, 76.9%, and 76.9%, respectively. All 3 patients in cohort 2 (100%) achieved PR. In cohort 1, 3 of the 17 subjects (17.6%) had progression-free survival (PFS) events. The median PFS was not reached. Estimated PFS rates at 12 and 15 months based on the Kaplan-Meier analysis were 94.1% and 73.2%, respectively. The median duration of response (DOR) was not reached, and the DOR rate at 9 and 12 months was 100% and 80.0%, respectively. The median time to response was 3.6 months. The most common grade-3 treatment emergent adverse event (TEAE) was lymphopenia (2 patients, 10.0%). Grade-4 TEAEs included hypertriglyceridemia and pneumonia aspiration (1 patient each, 5.0%). TEAEs leading to study drug discontinuation were reported by 4 of 20 (20.0%) patients, including fatigue (2 patients, 10.0%), atypical pneumonia, traumatic intracranial haemorrhage, non-small cell lung cancer, muscle spasticity, and dysgeusia (1 patient each, 5.0%), indicating that the safety profile was acceptable and manageable. Conclusion: Tazemetostat at a dose of 800 mg BID showed encouraging efficacy in patients with relapsed or refractory EZH2 mutation-positive FL with an acceptable safety profile in the overall population. Thus, tazemetostat may be a potential option for the treatment of relapsed or refractory EZH2 mutation-positive FL. Citation Format: Shinya Rai, Kiyoshi Ando, Akifumi Takaori-Kondo, Hirohiko Shibayama, Takanori Teshima, Junya Kuroda, Koji Kato, Yoshitaka Imaizumi, Kisato Nosaka, Rika Sakai, Tadashi Nakanishi, Seiichiro Hojo, Koji Izutsu. Phase 2 study of tazemetostat in Japanese patients with relapsed or refractory EZH2 mutation-positive B-cell Non-Hodgkin's Lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT176.

Adult T-cell leukemia-lymphoma (ATL) is a mature T-cell malignancy associated with human T-cell leukemia virus type 1 (HTLV-1) infection. Japan is the most endemic country for HTLV-1 and ATL in the world. Recent nationwide studies of Japanese blood donors reported that HTLV-1 carriers spread from endemic areas to non-endemic areas. Therefore, the latest information on nationwide epidemiological and clinical data for ATL is necessary to guide clinical practice. We undertook a multicenter, hospital-based survey of newly diagnosed ATL patients from 2010 to 2011. A total of 996 patients with ATL were registered from 126 hospitals across Japan. Of those, 922 (487 men and 435 women) were included in the analysis. The median age at diagnosis was 68 years (interquartile range, 60-75 years). Overall, 67.2% of ATL was diagnosed in the Kyushu-Okinawa area. The most common subtype was acute (49.5%), followed by lymphoma (25.7%), chronic (14.2%), and smoldering (10.6%). Lymphoma type was more prevalent in men (60%), whereas chronic was more prevalent in women (60%). Half of patients with lymphoma type were aged over 70 years, whereas one-third of patients with the chronic type were aged under 60 years. All of these characteristics were different from those of the previous nationwide surveys in the 1980s and 1990s. This survey clarified that half of current patients with ATL are aged over 68 years who were unable to receive intensive cytotoxic therapies. New less toxic agents for aged patients and further strategies to prevent the development of ATL from HTLV-1 carrier status are needed.

Adult T-cell leukemia/lymphoma (ATL) is an aggressive T-cell malignancy with a dismal prognosis, caused by HTLV-1. Although our previous study, mainly using whole-exome sequencing and SNP array karyotyping, discovered many driver mutations and copy number alterations (CNAs), the whole-genome landscape of ATL still remains elusive. To this end, we have performed high-depth whole-genome sequencing (WGS) of 155 ATL cases with a median sequencing depth of 96-fold for tumors. Among them, 75 cases were also analyzed by RNA sequencing (RNA-seq). In total, we detected 1,952,490 single nucleotide variants (SNVs) and 159,141 insertion-deletions (4.0 SNVs and 0.3 indels/Mb/case), 10,279 SVs (66.3 SVs/case), and 3,975 CN altered segments (25.7 segments/case). Using several driver discovery algorithms (dNdScv, MutSig2CV, and DriverPower), we identified 47 significantly mutated genes, 19 of which were mutated in more than 10% of cases. These included several novel mutations, such as those affecting XPO1 (7.1%), ZNF292 (6.5%), and ITGB1 (5.2%). Using GISTIC2.0, we identified 13 significant CNAs, such as IRF4 amplifications and CDKN2A deletions, consistent with previous SNP array data. To detect significantly recurrent SVs, we calculated SV breakpoint frequency and identified 13 genes affected by SVs, including the previously identified genes (such as CARD11, CD274, and TP73). In addition, we investigated recurrent mutations in non-coding elements by DriverPower and LARVA and discovered 12 recurrently mutated elements. Among them, the most frequent were splice site mutations, including those of HLA-A and HLA-B, most of which caused loss of function as revealed by RNA-seq. By contrast, we found recurrent mutations in TP73 splice site, which induced skipping of exons 2 and 3, generating a dominant-negative variant similar to their SVs. In addition, recurrent non-coding elements contained several novel regions, such as 3´-untranslated region (UTR) of NFKBIZ and 5´- UTR of TMSB4X. Altogether, a total of 56 genes were recurrently altered. The median number of driver alterations was eight per case, and at least one driver alteration was found in 149 cases (96.1%). Among 56 driver genes, 40 (71.4%) genes were affected by more than one alteration class. Some drivers, such as CDKN2A, IKZF2, and CD274, were affected almost exclusively by CNAs and/or SVs, while showing quite high alteration frequencies (11.6-29.0%). These observations suggest that WGS presented a substantially different overview of driver alterations from our previous study. The overall numbers of mutations and SVs were linked to these driver alterations, suggesting their etiology. In particular, inactivation of EP300 and immune-related molecules, such as HLA-A, HLA-B, and CD58, were associated with an increased number of mutations and SVs, especially deletions and tandem duplications. By contrast, cases with TP53-altered cases harbored more inversions and translocations. These results emphasize a pivotal role of immune evasion for acquiring genetic alterations to drive ATL progression. To define molecular subgroups in ATL, we integrated the 56 identified genetic drivers using non-negative matrix factorization clustering and identified two robust subgroups with discrete clinical and genetic characteristics. Group 1 was enriched with alterations affecting distal components of T-cell receptor (TCR)/NF-κB signaling (such as CARD11, PRKCB, and IRF4) and immune-related molecules (HLA-A, HLA-B, and CD58), whereas proximal regulators of TCR/NF-κB signaling (PLCG1, VAV1, and CD28) and a JAK/STAT signaling molecule (STAT3) were more frequently altered in group 2. In addition, group 1 cases had a larger number of mutations, SVs, and CNAs than group 2 cases. Clinically, most cases with lymphoma subtype were classified into group 1, whereas group 2 mainly consisted of cases with leukemic subtypes. Moreover, group1 cases showed a worse overall survival than group 2, independently of clinical subtype. These results suggest the biological and clinical relevance of the molecular classification of ATL. In summary, our WGS analysis not only identifies novel somatic alterations but also extends the overview of ATL genome. We also propose a new molecular classification of ATL, with its clinical relevance, which can lead to the future improvement of patient management. Disclosures Kogure: Takeda Pharmaceutical Company Limited.: Honoraria. Nosaka:Kyowa Kirin Co.Ltd: Honoraria; Chugai pharmaceutical Co. Ltd: Honoraria; Novartis international AG: Honoraria; Celgene K.K: Honoraria; Eisai Co., Ltd: Honoraria; Merck Sharp & Dohme K.K.: Honoraria; Bristol-Myer Squibb: Honoraria. Imaizumi:Kyowa Kirin Co. Ltd.: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Eisai: Honoraria. Utsunomiya:Kyowa Kirin: Honoraria; Celgene: Honoraria. Shah:Celgene: Research Funding; BMS: Research Funding; Physicians Education Resource: Honoraria. Janakiram:Takeda, Fate, Nektar: Research Funding. Ramos:NIH: Research Funding. Takaori-Kondo:Astellas Pharma: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; Ono Pharmaceutical: Research Funding; Thyas Co. Ltd.: Research Funding; Takeda: Research Funding; CHUGAI: Research Funding; Eisai: Research Funding; Nippon Shinyaku: Research Funding; Otsuka Pharmaceutical: Research Funding; Pfizer: Research Funding; OHARA Pharmaceutical: Research Funding; Sanofi: Research Funding; Novartis Pharma: Honoraria; MSD: Honoraria. Miyazaki:Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; Kyowa Kirin Co., Ltd.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Celgene: Honoraria; NIPPON SHINYAKU CO.,LTD.: Honoraria; Otsuka Pharmaceutical: Honoraria; Novartis Pharma KK: Honoraria; Astellas Pharma Inc.: Honoraria. Matsuoka:Chugai Pharmaceutical Co. Ltd: Research Funding; Bristol-Myers Squibb: Research Funding; Kyowa Kirin Co. Ltd.: Research Funding. Ishitsuka:Takeda: Other: Personal fees, Research Funding; mundiharma: Other: Personal fees; Taiho Pharmaceuticals: Other: Personal fees, Research Funding; Janssen Pharmaceuticals: Other: Personal fees; Novartis: Other: Personal fees; Pfizer: Other: Personal fees; Astellas Pharma: Other, Research Funding; Genzyme: Other; Sumitomo Dainippon Pharma: Other, Research Funding; Eisai: Other, Research Funding; Mochida: Other, Research Funding; Shire: Other; Otsuka Pharmaceutical: Other; Ono Pharmaceutical: Other, Research Funding; Teijin Pharma: Research Funding; MSD: Research Funding; Asahi kasei: Research Funding; Eli Lilly: Research Funding; Daiichi Sankyo: Other; Huya Japan: Other; Celgene: Other: Personal Fees; Kyowa Hakko Kirin: Other: Personal fees, Research Funding; BMS: Other: Personal fees; Chugai Pharmaceutical: Other: Personal fees, Research Funding. Ogawa:Asahi Genomics Co., Ltd.: Current equity holder in private company; Chordia Therapeutics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; KAN Research Institute, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Eisai Co., Ltd.: Research Funding. Shimoda:Takeda Pharmaceutical Company: Honoraria; Bristol-Myers Squibb: Honoraria; Shire plc: Honoraria; Celgene: Honoraria; Perseus Proteomics: Research Funding; PharmaEssentia Japan: Research Funding; AbbVie Inc.: Research Funding; Astellas Pharma: Research Funding; Merck & Co.: Research Funding; CHUGAI PHARMACEUTICAL CO., LTD.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; Pfizer Inc.: Research Funding; Otsuka Pharmaceutical: Research Funding; Asahi Kasei Medical: Research Funding; Japanese Society of Hematology: Research Funding; The Shinnihon Foundation of Advanced Medical Treatment Research: Research Funding; Novartis: Honoraria, Research Funding. Kataoka:CHUGAI PHARMACEUTICAL CO., LTD.: Research Funding; Takeda Pharmaceutical Company: Research Funding; Otsuka Pharmaceutical: Research Funding; Asahi Genomics: Current equity holder in private company.

TAFRO syndrome is a rare variant type of multicentric Castleman disease, which is characterized by thrombocytopenia, anasarca, reticulin fibrosis of bone marrow, renal dysfunction and organomegaly. Here, we report a case of TAFRO syndrome that was successfully treated with tocilizumab. A 50-year-old man, who presented with fever, epigastric pain, abdominal fullness, and massive edema of the extremities, was admitted to our hospital. Computed tomography revealed bilateral pleural effusions, ascites, and lymphadenopathy. Laboratory data showed renal dysfunction, anemia, and thrombocytopenia. Examination of bone marrow and cervical lymph nodes led to a diagnosis of hyaline vascular-type Castleman disease. The level of serum interleukin (IL)-6 was extremely high. TAFRO syndrome was finally diagnosed. The patient was treated weekly with tocilizumab, an anti-IL-6 receptor antibody and steroids. In 4 weeks, all symptoms disappeared and serum IL-6 level returned to normal. Activity of ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13), which was significantly decreased (9.9 %) prior to treatment, increased after treatment with tocilizumab. The present case suggests that tocilizumab is an effective therapeutic agent for TAFRO syndrome. We suggest that hypercytokinemia in TAFRO syndrome inhibits ADAMTS13 activity, thereby inducing thrombotic microangiopathy.

Summary Background Patients with adult T-cell leukaemia-lymphoma have few treatment options after relapse and poor survival outcomes with current therapies. We aimed to determine the maximum tolerated dose of lenalidomide, an oral immunomodulator, in Japanese patients with relapsed adult T-cell leukaemia-lymphoma and other peripheral T-cell lymphomas. Methods In this phase 1 study, we enrolled patients aged 20 years or older with Eastern Cooperative Oncology Group performance status 0–2, documented diagnosis of aggressive adult T-cell leukaemia-lymphoma or other peripheral T-cell lymphoma subtypes, and at least one previous antilymphoma therapy. Patients were sequentially assigned to lenalidomide 25 mg/day, days 1–21 of a 28-day cycle (cohort 1), 25 mg/day continuously (cohort 2), and 35 mg/day continuously (cohort 3) in a 3 + 3 design. The primary study endpoint was to identify the maximum tolerated dose of lenalidomide. Analyses were performed per protocol for efficacy and in the intent-to-treat patient population for safety. This completed trial is registered with ClinicalTrials.gov, number NCT01169298. Findings We enrolled 14 patients from six centres in Japan. Of 13 assessable patients (nine with adult T-cell leukaemia-lymphoma, four with other peripheral T-cell lymphomas) receiving lenalidomide, dose-limiting toxic effects were reported in three patients during cycle 1 (one grade 4 thrombocytopenia [cohort 2], one grade 3 QT prolongation on electrocardiogram [cohort 3], and one grade 3 fatigue and grade 4 thrombocytopenia [cohort 3]). The maximum tolerated dose was identified as lenalidomide 25 mg/day given continuously. The most common grade 3 or worse adverse events were neutropenia (eight [62%] patients), lymphopenia (seven [54%] patients), and thrombocytopenia (four [31%] patients); myelosuppression was similar in each cohort. Serious adverse events occurred in eight (62%) patients; thrombocytopenia, which occurred in three (23%) patients, was the only serious adverse event reported in more than one patient. Interpretation We were able to determine the dose and schedule for lenalidomide treatment in previously treated patients with aggressive, adult T-cell leukaemia-lymphoma. This dose will be used in a subsequent phase 2 study. Funding Celgene Corporation.

BACKGROUND: Initial results from the ongoing GALLIUM trial have shown that patients with follicular lymphoma have a longer progression-free survival after first-line immunochemotherapy with obinutuzumab than with rituximab. The aim of this secondary analysis was to evaluate the prognostic value of PET-CT responses after first-line immunochemotherapy in the GALLIUM study.METHODS: GALLIUM is an open-label, parallel-group randomised, phase 3 trial, which recruited previously untreated patients with CD20-positive follicular lymphoma (grades 1-3a; disease stage III/IV, or stage II with largest tumour diameter ≥7 cm) who were aged 18 years or older and met the criteria for needing treatment. Eligible patients were randomly assigned in a 1:1 ratio to receive intravenous administration of obinutuzumab (1000 mg on days 1, 8, and 15 of cycle 1, then day 1 of subsequent cycles) or rituximab (375 mg/m2 on day 1 of each cycle), in six 21-day cycles with cyclophosphamide, doxorubicin, vincristine, and prednisone (known as CHOP; oral administration) followed by two 21-day cycles of antibody alone, or eight 21-day cycles cyclophosphamide, vincristine, and prednisone (known as CVP; oral administration), or six 28-day cycles with bendamustine, followed by maintenance antibody every 2 months for up to 2 years. The primary endpoint of the trial, investigator-assessed progression-free survival, has been reported previously. This secondary analysis reports PET and CT-based responses at end-of-induction therapy and explains their relation with progression-free and overall survival outcomes in patients with available scans. As per protocol, during the trial, PET scans (mandatory in the first 170 patients enrolled at sites with available PET facilities, and optional thereafter), acquired at baseline and end of induction (PET population), were assessed prospectively by investigators and an independent review committee (IRC) applying International Harmonisation Project (IHP) 2007 response criteria, and retrospectively by the IRC only applying current Lugano 2014 response criteria. IRC members (but not study investigators) were masked to treatment and clinical outcome when assessing response. The landmark analyses excluded patients who died or progressed (contrast enhanced CT-based assessment of progressive disease, or started next anti-lymphoma treatment) before or at end of induction. GALLIUM is registered at ClinicalTrials.gov, number NCT01332968.FINDINGS: 1202 patients were enrolled in GALLIUM between July 6, 2011, and Feb 4, 2014, of whom 595 were included in the PET population; 533 (IHP 2007; prospective analysis), and 508 (Lugano 2014; retrospective analysis) were analysed for progression-free survival (landmark analysis). At end of induction, 390 of 595 patients (65·5% [95% CI 61·6-69·4]) achieved PET complete response according to IHP 2007 criteria, and 450 (75·6% [95% CI 72·0-79·0]) obtained PET complete metabolic response according to Lugano 2014 criteria. With a median of 43·3 months of observation (IQR 36·2-51·8), 2·5-year progression-free survival from end of induction was 87·8% (95% CI 83·9-90·8) in PET complete responders and 72·0% (63·1-79·0) in non-complete responders according to IRC-assessed IHP 2007 criteria (hazard ratio [HR] 0·4, 95% CI 0·3-0·6, pINTERPRETATION: Our results suggest that PET is a better imaging modality than contrast-enhanced CT for response assessment after first-line immunochemotherapy in patients with follicular lymphoma. PET assessment according to Lugano 2014 response criteria provides a platform for investigation of response-adapted therapeutic approaches. Additional supportive data are welcomed.FUNDING: F Hoffmann-La Roche.

This multicentre, randomized, phase II study was conducted to examine whether the addition of mogamulizumab, a humanized anti‐CC chemokine receptor 4 antibody, to mLSG15, a dose‐intensified chemotherapy, further increases efficacy without compromising safety of patients with newly diagnosed aggressive adult T‐cell leukaemia‐lymphoma (ATL). Patients were assigned 1:1 to receive mLSG15 plus mogamulizumab or mLSG15 alone. The primary endpoint was the complete response rate (%CR); secondary endpoints included the overall response rate (ORR) and safety. The %CR and ORR in the mLSG15‐plus‐mogamulizumab arm (n = 29) were 52% [95% confidence interval (CI), 33–71%] and 86%, respectively; the corresponding values in the mLSG15 arm (n = 24) were 33% (95% CI, 16–55%) and 75%, respectively. Grade ≥ 3 treatment‐emergent adverse events, including anaemia, thrombocytopenia, lymphopenia, leucopenia and decreased appetite, were observed more frequently (≥10% difference) in the mLSG15‐plus‐mogamulizumab arm. Several adverse events, including skin disorders, cytomegalovirus infection, pyrexia, hyperglycaemia and interstitial lung disease, were observed only in the mLSG15‐plus‐mogamulizumab arm. Although the combination strategy showed a potentially less favourable safety profile, a higher %CR was achieved, providing the basis for further investigation of this novel treatment for newly diagnosed aggressive ATL. This study was registered at ClinicalTrials.gov, identifier: {"type":"clinical-trial","attrs":{"text":"NCT01173887","term_id":"NCT01173887"}}NCT01173887.

Amyloid light-chain amyloidosis (ALA) is a rare disease with poor prognosis and is often associated with monoclonal gammopathy of undetermined significance, multiple myeloma, or Waldenström macroglobulinemia. Only high-dose melphalan with auto-peripheral blood stem cell transplantation (PBSCT) has shown high long-term hematological response rates, but combinations with novel agents, including bortezomib or lenalidomide, have recently shown high hematological response rates for AL amyloidosis patients. In the present study, we treated eight Japanese patients with AL amyloidosis using bortezomib, cyclophosphamide, and dexamethasone (CyBorD). Overall response rate was 100 %; four patients (50 %) had complete remissions (CR), two (25 %) had very good partial responses, and two (25 %) had partial responses. Five of six patients (83 %) had organ responses in the heart and/or kidney. A relapsed patient repeatedly achieved CR with the CyBorD treatment. One patient died of sudden cardiac arrest a month after normalization of his serum free light chain level, which may be attributable to his spending the previous 6 months undergoing PBSCT collection and high-dose melphalan with auto-PBSCT. Altogether, the CyBorD regimen achieved high levels of hematological responses relatively quickly (within 2-3 months). The CyBorD regimen, rather than high-dose melphalan treatment, could serve as a first-line therapy for Japanese patients with ALA.

Mucosa-associated lymphoid tissue (MALT) lymphoma is a subtype of non-Hodgkin’s lymphoma and classified as marginal-zone B cell lymphoma. Although its most common organ is the stomach, it rarely arises in the rectum. Treatment for gastric MALT lymphoma has been established. However, primary rectal MALT lymphoma is so rare that standard therapy has not been established. We report the case of a 75-year-old man who was diagnosed rectal MALT lymphoma. Elevated lesions of the lower rectum were detected in a screening colonoscopy at a local clinic. The biopsy of the lesions revealed the lesions to be MALT lymphoma, and he was diagnosed with stage I E MALT lymphoma by Ann Arbor classification. Bacteria elimination was performed as initial treatment, but the lesion did not regress. Radiation therapy was chosen as second line therapy. A dose of 30 Gy to the small pelvic field in 15 fractions, followed by 10 Gy to the whole rectum in 5 fractions as boost was irradiated. Endoscopy at 20 Gy revealed a remarkable tumor reduction, and the lesions disappeared at the end of radiation therapy. Grade 1 urinary frequency and grade 1 diarrhea occurred during treatment, but the treatment was completed without cessation. The present case suggests that radiation therapy is one of the promising and safe options for rectal MALT lymphoma.

Purpose Few treatment options exist for adult T-cell leukemia/lymphoma (ATL), and the prognosis for this disease is poor. A phase I study of lenalidomide demonstrated preliminary antitumor activity in patients with relapsed ATL. The current phase II study evaluated the efficacy and safety of lenalidomide monotherapy in patients with relapsed or recurrent ATL. Patients and Methods Patients 20 years of age or older with acute, lymphoma, or unfavorable chronic subtype ATL, who had received one or more prior anti-ATL systemic chemotherapy and achieved stable disease or better on their last anti-ATL therapy with subsequent relapse or recurrence, were eligible. Patients received oral lenalidomide 25 mg/d continuously until disease progression or unacceptable toxicity. The primary end point was overall response rate; secondary end points included safety, tumor control rate (stable disease or better), time to response, duration of response, time to progression, progression-free survival, and overall survival. Results Objective responses were noted in 11 of 26 patients (overall response rate, 42%; 95% CI, 23% to 63%), including four complete responses and one unconfirmed complete response. The tumor control rate was 73%. The median time to response and duration of response were 1.9 months and not estimable, respectively, and the median time to progression was 3.8 months. The median progression-free survival and overall survival were 3.8 and 20.3 months, respectively. The most frequent grade ≥ 3 adverse events were neutropenia (65%), leukopenia (38%), lymphopenia (38%), and thrombocytopenia (23%), which were all manageable and reversible. Conclusion Lenalidomide demonstrated clinically meaningful antitumor activity and an acceptable toxicity profile in patients with relapsed or recurrent aggressive ATL, hinting at its potential to become a treatment option. Further investigations of lenalidomide in ATL and other mature T-cell neoplasms are warranted.

Purpose Adult T-cell leukemia-lymphoma (ATL) is usually resistant to conventional chemotherapies, and there are few other treatment options. Because CC chemokine receptor 4 (CCR4) is expressed on tumor cells from most patients with ATL, KW-0761, a humanized anti-CCR4 monoclonal antibody, which markedly enhances antibody-dependent cellular cytotoxicity, was evaluated in the treatment of patients with relapsed ATL. Patients and Methods A multicenter phase II study of KW-0761 for patients with relapsed, aggressive CCR4-positive ATL was conducted to evaluate efficacy, pharmacokinetic profile, and safety. The primary end point was overall response rate, and secondary end points included progression-free and overall survival from the first dose of KW-0761. Patients received intravenous infusions of KW-0761 once per week for 8 weeks at a dose of 1.0 mg/kg. Results Of 28 patients enrolled onto the study, 27 received at least one infusion of KW-0761. Objective responses were noted in 13 of 26 evaluable patients, including eight complete responses, with an overall response rate of 50% (95% CI, 30% to 70%). Median progression-free and overall survival were 5.2 and 13.7 months, respectively. The mean half-life period after the eighth infusion was 422 ± 147 hours (± standard deviation). The most common adverse events were infusion reactions (89%) and skin rashes (63%), which were manageable and reversible in all cases. Conclusion KW-0761 demonstrated clinically meaningful antitumor activity in patients with relapsed ATL, with an acceptable toxicity profile. Further investigation of KW-0761 for treatment of ATL and other T-cell neoplasms is warranted.

Hepatitis B virus (HBV) surface antigen (HBsAg)-positive patients treated with anti-B-cell lymphoma therapy are at high risk of HBV reactivation; indeed, the incidence is as high as 60-80% without antiviral prophylaxis. Hepatitis caused by HBV reactivation usually leads to discontinuation of chemotherapy, which in itself may be fatal. Therefore, several guidelines recommend antiviral prophylaxis for HBsAg-positive patients treated with chemotherapy. However, there is limited evidence regarding the clinical impact of antiviral prophylaxis on HBV reactivation and subsequent hepatitis and long-term outcome, particularly in patients treated with rituximab (R)-containing regimens. To answer these questions, we conducted a nationwide multicenter retrospective analysis for HBsAg-positive patients with diffuse large B-cell lymphoma (DLBCL) treated with R-chemotherapy. Data were collected from HBsAg-positive patients with DLBCL who received R-CHOP or R-THP-COP regimens as an initial chemotherapy (regardless of steroid use) at 29 participating institutions between January 2004 and December 2014. Key exclusion criteria were as follows: seropositive for HCV or HIV; alanine transaminase (ALT) levels ≥ 100 U/L at the time of diagnosis; and a history of decompensated cirrhosis or hepatocellular carcinoma. Medical data were also obtained for HBsAg-negative DLBCL patients (controls), regardless of anti-HBc or anti-HBs seropositivity; these patients were diagnosed within 2 month (before and after 1 month) of the diagnosis date of each HBsAg-positive patient. Hepatitis was defined as an absolute serum ALT level of ≥ 100 U/L. HBV reactivation-related hepatitis was defined as hepatitis accompanied by an absolute serum HBV DNA level of ≥ 3.3 Log IU/mL or an absolute increase of ≥ 2 Log compared with the baseline value. Statistical analysis was performed at the Japanese Data Center for Hematopoietic Cell Transplantation using Stata software Version 13.1 and EZR 1.35. The study was registered at UMIN (ID: 000025574). A total of 394 patients were eligible: 116 (29.4%) were HBsAg-positive and 278 (70.6%) were HBsAg-negative. The baseline characteristics of the two cohorts were similar; exceptions was HBV status (Table). R-CHOP was the most common regimen (n=337, 85.5%), followed by R-THP-COP (n=57, 14.5%). For HBsAg-positive patients with detectable and quantifiable HBV DNA (n=65, 56.0%), the median baseline HBV DNA level was 2.9 Log IU/mL (interquartile range, 2.0-3.7). HBsAg-positive patients were divided into three groups based on prophylactic nucleoside analogue (NA) therapy: no prophylactic therapy (non-NA, n=9), prophylactic therapy with lamivudine (LAM, n=20), and prophylactic therapy with entecavir (ETV, n=87). Of the HBsAg-negative patients, 64 (23.0%) were seropositive for anti-HBc or anti-HBs. The median follow-up time for HBsAg-positive and HBsAg-negative patients was 4.3 years and 4.5 years, respectively. The 4-year cumulative incidence of hepatitis in HBsAg-positive and HBsAg-negative patients was 21.1% (95% confidence interval (CI): 14.1-28.9%) and 14.6% (95% CI: 10.7-19.2%), respectively (p=0.081). Importantly, the 4-year cumulative incidence of HBV reactivation-related hepatitis was higher in HBsAg-positive patients than in HBsAg-negative patients (8.0% (95% CI: 3.9-14.0%) vs. 0.4% (95% CI: 0.0-2.0%, respectively; p Prophylactic use of entecavir reduced the incidence of HBV reactivation-related hepatitis and reduced mortality associated with HBV reactivation-related hepatitis in HBsAg-positive patients with DLBCL treated with R-chemotherapy. Disclosures Maruyama: Abbvie: Research Funding; Nippon Boehringer Ingelheim: Research Funding; Pfizer: Research Funding; Amgen Astellas BioPharma: Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Fujifilm: Honoraria, Research Funding; MSD: Honoraria, Research Funding; Novartis: Research Funding; GlaxoSmithKline: Research Funding; Chugai Pharma: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Biomedis International: Honoraria, Research Funding; Solasia Pharma: Research Funding; AstraZeneca: Research Funding; Asahi Kasei Pharma: Honoraria; Dai-Nippon-Sumitomo: Honoraria; Zenyaku Kogyo: Honoraria, Research Funding; Mundipharma International: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Astellas Pharma: Research Funding; Otsuka: Research Funding; Dai-ichi-Sankyo: Honoraria. Yamamoto:Bristol-Myers Squibb: Honoraria. Igarashi:Eisai Co Ltd.: Research Funding; Celltrion Inc.: Research Funding; Zenyaku-Kogyo Co.Ltd.: Research Funding; Sanofi K.K.: Research Funding. Izutsu:Takeda: Honoraria, Research Funding; Zenyaku: Research Funding; Amgen: Research Funding; Gilead Sciences: Honoraria; Solasia: Research Funding; Sanofi: Research Funding; Otsuka: Honoraria; Mundhi: Honoraria; Kyowa Hakko Kirin: Honoraria; Abbvie: Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Symbio: Research Funding; Celltrion: Research Funding; Chugai: Honoraria, Research Funding; Nihon Medi-Physics: Honoraria; MSD: Honoraria; Celgene: Consultancy, Research Funding; Bristol- Myers Squibb: Honoraria; Daiichi Sankyo: Honoraria, Research Funding; Astellas: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; HUYA Bioscience International: Research Funding; Eisai: Honoraria, Research Funding; Novartis: Honoraria; Ono: Honoraria, Research Funding; Meiji Seika: Honoraria; Shionogi: Honoraria; Asahi Kasei: Honoraria. Uchida:Nippon Shinyaku: Honoraria; Pfizer: Honoraria; Bristol-Myers Squibb: Honoraria; Meiji Seika Pharma: Honoraria; Mundipharma: Honoraria; Celgene: Honoraria; Teijin: Honoraria; Novartis: Honoraria; Janssen Pharma: Honoraria; Takeda Pharmaceutical: Honoraria; Otsuka Pharmaceutical: Honoraria; Eisai: Honoraria; Kyowa Hakko Kirin: Honoraria; Chugai Pharmaceutical: Honoraria. Tsukamoto:Chugai: Research Funding; Eisai: Research Funding; Pfizer: Research Funding; Kyowa-Kirin: Research Funding. Nosaka:Celgene Co. LTD.,: Honoraria; Chugai Pharmaceutical Co.LTD.,: Honoraria; Kyowa Kirin Pharmaceutical Development, Inc.,: Honoraria; Eisai Co. Ltd.,: Honoraria; Ono Pharmaceutical Co.LTD.: Honoraria; Bristol-Myers Squibb: Honoraria. Ueda:Rikaken Co. Ltd.: Research Funding; Medical and Biological laboratories Co. Ltd.: Research Funding; Chugai Pharmaceutical Co. Ltd.: Research Funding; Kyowa Hakko Kirin Co. Ltd.: Honoraria, Research Funding; Terumo Co.: Consultancy; Ono Pharmaceutical Co.: Consultancy, Honoraria, Research Funding; Mundipharma K.K.: Consultancy. Mizokami:Sysmex Corporation: Honoraria; Gilead Sciences: Honoraria. Kusumoto:Bristol-Myers Squibb: Honoraria, Research Funding; Chugai Pharmaceutical Co. Ltd: Honoraria, Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding.

Background: CHOP plus rituximab (R-CHOP) is the standard of care for previously untreated DLBCL. R-CHOP comprises CHOP and one-dose rituximab in each 21-day cycle; however, the schedule of rituximab administration has not been fully optimized. Dose-dense rituximab was expected to increase its peak concentration to enhance the synergistic effect with chemotherapy at early phase of treatment. To compare weekly administration of rituximab combined with CHOP (RW-CHOP) with standard R-CHOP in patients with previously untreated DLBCL, we conducted a multicenter, randomized phase II/III study (JCOG0601, UMIN000000929). Methods: Previously untreated patients with CD20+ DLBCL were eligible. Other major inclusion criteria were as follows: aged 20-79 years; ECOG performance status 0-2, at least 1 measurable lesion and preserved organ functions. At the beginning of the study, patients with advanced stage disease and the low or low-intermediate risk group by the International Prognostic Index (IPI) were eligible. These criteria were amended in September 2010 to allow enrollment of the patients with any IPI risk and any clinical stage because of slow accrual. Patients were randomly assigned to standard R-CHOP (rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 1.4 mg/m2 [max 2 mg], all IV on day 1, and prednisone 100 mg/day PO [40mg/m2 for aged >65] on days 1-5, every 3 weeks) or RW-CHOP (standard CHOP with eight doses of weekly rituximab [375mg/m2 IV on days1, 8, 15, 22, 29, 36, 43 and 50]). Six cycles of CHOP were given in stage I non-bulky patients, 8 cycles were given in stage I bulky and II-IV patients, and rituximab was given 8 times regardless of cycles of CHOP. Randomization was stratified by institution, presence or absence of bulky mass and patient age. The primary endpoint of phase III part was progression-free survival (PFS). Secondary endpoints included overall survival (OS) and adverse events (AE). Assuming 3-year PFS in the R-CHOP arm to be 77% and expecting a 7% increase in 3-year PFS of the RW-CHOP arm, required sample size was 211 per arm with a one-sided alpha of 5%, power of 80%, an accrual period of 7 years, and a follow-up period of 3 years. Results: Between December 2007 and December 2014, a total of 422 patients were randomized to study treatments but primary analysis was performed in 421 patients: 213 to the R-CHOP arm and 208 to the RW-CHOP arm, because of one consent withdrawal. Baseline characteristics of 421 eligible patients were as follows (R-CHOP vs. RW-CHOP): median age, 61 vs. 62 years; male sex, 54.5% vs. 55.8%; Ann Arbor stage I/II/III/IV, 14.6/32.9/26.8/25.8% vs. 16.3/42.8/20.2/20.7%; and IPI score ≤2, 77.0% vs. 87.5%. With a median follow-up of 63.4 months (range: 3.2-119.2) among all patients, there was no significant difference in PFS between the arms (hazard ratio [HR], 0.95; 90.6% confidence interval [CI], 0.68 to 1.31; one-sided log-rank P = 0.39). The 3-year PFS and OS were 79.2% and 88.7% with the R-CHOP arm and 80.3% and 90.4% with the RW-CHOP arm, respectively. The complete response rate and overall response rate were 77.0% and 93.0% in the R-CHOP arm and 82.2% and 91.8% in the RW-CHOP arm, respectively. Major AEs were hematological toxicities and infections. Grade (G) 3/4 neutropenia and G 3/4 thrombocytopenia were observed in 97.7% and 8.0% in the R-CHOP arm and 97.1% and 5.3% in the RW-CHOP arm, respectively. G3 febrile neutropenia was occurred in 33.8% in the R-CHOP arm and in 22.1% in the RW-CHOP arm. The frequency of severe AE was 2.3% in the R-CHOP arm and 3.8% in the RW-CHOP arm. Safety profile was comparable. No unexpected AEs were experienced. Conclusion: In combination of standard CHOP and rituximab, dose-dense weekly rituximab at early phase of treatment did not improve the PFS in patients with untreated DLBCL. Figure. Figure. Disclosures Ohmachi: Celgene: Honoraria; Takeda Pharmaceutical Co., Ltd,: Honoraria; Pfizer: Honoraria; Chugai Pharma: Honoraria; Kyowa Hakko Kirin: Honoraria; Eisai: Honoraria; Janssen: Honoraria; Meiji Pharma: Honoraria. Kinoshita:Takeda: Honoraria; Takeda: Research Funding; Ono: Research Funding; MSD: Research Funding; Solasia: Research Funding; Janssen: Honoraria; Ono: Honoraria; Zenyaku: Research Funding; Eisai: Research Funding; Gilead: Research Funding. Tobinai:Kyowa Hakko Kirin: Honoraria, Research Funding; Zenyaku Kogyo: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; GlaxoSmithKline: Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Chugai Pharma: Honoraria, Research Funding; HUYA Bioscience International: Consultancy, Honoraria; SERVIER: Research Funding; Abbvie: Research Funding. Fukuhara:Sumitomo Dainippon: Research Funding; Solasia: Research Funding; Symbio: Research Funding; Sanofi: Research Funding; Pfizer: Research Funding; Otsuka Pharmaceutical: Research Funding; Ono: Honoraria, Research Funding; Novartis pharma: Research Funding; Nippon-shinyaku: Research Funding; MSD: Research Funding; Mundipharma: Honoraria, Research Funding; Mitsubishi Tanabe: Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding; Japan Blood Products Organization: Research Funding; Janssen: Honoraria, Research Funding; GlaxoSmithKline: Research Funding; Eisai: Honoraria, Research Funding; Boehringer Ingelheim: Research Funding; Daiichi-Sankyo: Research Funding; Chugai: Research Funding; Celgene: Research Funding; Baxalta: Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Bayer Yakuhin: Research Funding; Alexionpharma: Research Funding; AbbVie: Research Funding; Astellas: Research Funding; Nihon Ultmarc: Research Funding; Taiho: Research Funding; Teijin Pharma: Research Funding; Zenyaku Kogyo: Honoraria, Research Funding; Takeda: Honoraria. Uchida:Takeda Pharmaceutical: Honoraria; Chugai Pharmaceutical: Honoraria; Kyowa Hakko Kirin: Honoraria; Meiji Seika Pharma: Honoraria; Bristol-Myers Squibb: Honoraria; Pfizer: Honoraria; Nippon Shinyaku: Honoraria; Novartis: Honoraria; Teijin: Honoraria; Celgene: Honoraria; Mundipharma: Honoraria; Janssen Pharma: Honoraria; Otsuka Pharmaceutical: Honoraria; Eisai: Honoraria. Yamamoto:Solasia Pharma: Research Funding; Bristol-Myers Squibb: Honoraria; Novartis: Honoraria, Research Funding; ARIAD Pharmaceuticals: Research Funding; Bayer: Research Funding; Celgene: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Ono: Consultancy, Honoraria, Research Funding; AbbVie: Research Funding; Boehringer Ingelheim: Consultancy; Chugai: Consultancy, Honoraria, Research Funding; Meiji Seika Pharma: Consultancy; MSD: Research Funding; Takeda: Honoraria, Research Funding; Zenyaku: Research Funding; Kyowa Hakko Kirin: Honoraria; Otsuka: Honoraria; Pfizer: Honoraria; Sumitomo Dainippon: Honoraria; Mundipharma: Consultancy, Honoraria; HUYA: Honoraria; SymBio: Research Funding; Gilead Sciences: Research Funding. Miyazaki:Kyowa Hakko Kirin,: Honoraria, Research Funding; Celgene: Honoraria; Chugai Pharma,: Honoraria, Research Funding; Sumitomo Group: Research Funding; Nippon Shinyaku: Research Funding; Takeda: Research Funding; Astellas Pharma: Research Funding; Shionogi Pharmaceutical: Research Funding; Daiichi Sankyo: Research Funding; Eisai: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Teijin Pharma: Research Funding; Ono Pharmaceutical: Research Funding; Toyama Chemical Co: Research Funding; Mochida Pharmaceutical Co. Ltd.: Research Funding; Novo Nordisk: Research Funding. Tsukamoto:Kyowa-Kirin: Research Funding; Pfizer: Research Funding; Chugai: Research Funding; Eisai: Research Funding. Iida:Teijin Pharma: Research Funding; Toyama Chemical: Research Funding; Ono: Consultancy, Honoraria, Research Funding; Kyowa-Hakko Kirin: Research Funding; Chugai: Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Astellas: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Gilead: Research Funding; MSD: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Sanofi: Consultancy. Yoshida:Taiho Pharma: Honoraria; Takeda Pharma: Honoraria; Celegene: Honoraria; Chugai Pharma: Honoraria, Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding. Masaki:Ono: Research Funding; Kyowa Hakko Kirin: Research Funding; Phizer: Research Funding; Astellas: Research Funding; Eisai: Research Funding. Yakushijin:Mundipharma Co.,: Research Funding; Chugai Co.,: Research Funding; Kyowa-kirin Co.,: Research Funding; Merch Sharp & Dohme Corp.,,: Research Funding; Daiichi-Sankyo Inc.,: Research Funding; Eisai Co.: Research Funding. Suehiro:Kyowa Hakko Kirin: Research Funding; Ono Pharmaceutical: Research Funding; Chugai Pharmaceutical: Research Funding; Takeda Pharmaceutical: Research Funding. Nosaka:Bristol-Myers Squibb: Honoraria; Ono Pharmaceutical Co.LTD.: Honoraria; Eisai Co. Ltd.,: Honoraria; Kyowa Kirin Pharmaceutical Development, Inc.,: Honoraria; Chugai Pharmaceutical Co.LTD.,: Honoraria; Celgene Co. LTD.,: Honoraria. Dobashi:Celgene Co.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Eisai Co., Ltd.: Research Funding; Zenyaku Kogyo Co., Ltd.: Research Funding; Kyowa Hakko Kirin Co. Ltd.: Research Funding; Astellas Pharma Inc.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Pfizer Inc.: Research Funding; Sysmex Co.: Research Funding. Kuroda:Chugai Pharma: Honoraria, Research Funding. Takamatsu:Taisho Toyama Pharmaceutical: Research Funding; TAIHO Pharmaceutical: Research Funding; Pfizer: Research Funding; Bristol-Myers Squibb: Research Funding; Ono Pharmaceutical: Research Funding; Astellas Pharma: Research Funding; Kyowa Hakko Kirin: Research Funding; Chugai Pharma: Research Funding; Takeda Pharmaceutical: Research Funding; Celgene: Honoraria. Maruyama:Ono Pharmaceutical: Honoraria, Research Funding; Fujifilm: Honoraria, Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding; Asahi Kasei Pharma: Honoraria; AstraZeneca: Research Funding; Solasia Pharma: Research Funding; Pfizer: Research Funding; Nippon Boehringer Ingelheim: Research Funding; Dai-Nippon-Sumitomo: Honoraria; Dai-ichi-Sankyo: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Biomedis International: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Chugai Pharma: Honoraria, Research Funding; MSD: Honoraria, Research Funding; Novartis: Research Funding; Otsuka: Research Funding; Amgen Astellas BioPharma: Research Funding; Zenyaku Kogyo: Honoraria, Research Funding; GlaxoSmithKline: Research Funding; Abbvie: Research Funding; Astellas Pharma: Research Funding; Mundipharma International: Honoraria, Research Funding. Ando:Eisai: Research Funding; Meiji Seika Pharma: Research Funding; Takeda Pharmaceutical: Research Funding; Kyowa Hakko Kirin: Research Funding; Japan Blood Products Organization: Research Funding. Ishizawa:Eisai: Honoraria; Janssen: Honoraria; Chugai: Honoraria; Celgene: Honoraria; Otsuka: Research Funding; Sanofi: Research Funding; Phizer: Research Funding. Ogura:Celltrion: Consultancy, Research Funding; Mundi Pharma: Consultancy; SymBio: Research Funding; Takeda: Honoraria; Cellgene: Honoraria; MeijiSeika Pharma: Consultancy. Hotta:SymBio: Consultancy; CellSeed Inc.: Membership on an entity's Board of Directors or advisory committees. Tsukasaki:Celgene: Honoraria; Eisai: Research Funding; Chugai Pharma: Honoraria, Research Funding; HUYA: Consultancy, Research Funding; Ono Pharma: Consultancy; Daiich-Sankyo: Consultancy; Mundy Pharma: Honoraria; Kyowa-hakko/Kirin: Honoraria; Seattle Genetics: Research Funding. Nagai:HUYA Bioscience International: Research Funding; Chugai Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Ono Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Gilead Sciences Inc.: Honoraria, Research Funding; Bayer Yakuhin Ltd.: Research Funding; Sanofi K. K.: Honoraria; Zenyaku Kogyo Co., Ltd.: Honoraria, Research Funding; Solasia Pharma K.K.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Roche Ltd.: Honoraria; Esai Co., Ltd.: Honoraria, Research Funding; Takeda Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; SymBio Pharmaceuticals Limited: Research Funding; Janssen Pharmaceutical K.K.: Honoraria, Research Funding; Kyowa Hakko Kirin Co., Ltd.: Honoraria, Research Funding; Mundipharma K.K.: Honoraria, Research Funding; AstraZeneca plc.: Research Funding; Abbvie G. K.: Research Funding.

A 60-year-old male patient suffered from mild exertional dyspnea, wheezing, and systemic blisters. He was diagnosed with paraneoplastic pemphigus (PNP) with follicular lymphoma in the pancreas head and pelvic cavity. He was first treated with eight cycles of rituximab; his blisters and erosions gradually improved and highly elevated levels of auto-antibodies related to PNP gradually decreased to normal levels. However, obstructive and restrictive respiratory failure still progressed. Computed tomography of the inspiratory and expiratory phases revealed obstructive pulmonary disorder, leading to a diagnosis of bronchiolitis obliterans (BO). The patient underwent plasma exchange and was repeatedly treated with rituximab monotherapy and rituximab-containing chemotherapies, but died 7 months after the diagnosis of BO. Early introduction of rituximab-containing regimens may be necessary to prevent the development of BO accompanying PNP. However, when a diagnosis of PNP-related BO is made, lung transplantation may also be considered for patients in whom rituximab-containing regimens are effective for PNP.

Hypercalcemia is one of the most frequent and serious complications in patients with adult T-cell leukemia (ATL) and is due to marked bone resorption by accumulation of osteoclasts (OCLs). Although several cytokines such as interleukin 1 and parathyroid hormone–related protein are thought to be involved in the development of high serum Ca++ levels, its precise underlying mechanism remains unknown. This study analyzed the expression of various genes that are thought to regulate serum Ca++ levels in ATL and showed that the overexpression of the receptor activator of nuclear factor κB (RANK) ligand gene correlated with hypercalcemia. ATL cells from patients with hypercalcemia, which highly expressed the transcripts of the RANK ligand (RANKL) gene, induced the differentiation of human hematopoietic precursor cells (HPCs) into OCLs in vitro in the presence of macrophage colony-stimulating factor (M-CSF). In contrast, ATL cells from patients without hypercalcemia did not induce such differentiation, suggesting that the induction of the differentiation correlated with the expression of the RANKL gene in ATL cells. Cell differentiation was suppressed by osteoprotegerin/Fc, an inhibitor of RANKL, indicating that such differentiation occurred through the RANK-RANKL pathway. In addition, direct contact between ATL cells and HPCs was essential for the differentiation, suggesting that not the soluble form but membrane-bound RANKL played a role in this process. These results strongly suggested that ATL cells induce the differentiation of HPCs to OCLs through RANKL expressed on their surface, in cooperation with M-CSF, and ultimately cause hypercalcemia.

This study evaluated the clinical features of 276 patients with aggressive adult T-cell leukaemia-lymphoma (ATL) in 3 Japan Clinical Oncology Group (JCOG) trials. We assessed the long-term survivors who survived >5 years and constructed a prognostic index (PI), named the JCOG-PI, based on covariates obtained by Cox regression analysis. The median survival time (MST) of the entire cohort was 11 months. In 37 patients who survived >5 years, no disease-related deaths in 10 patients with lymphoma-type were observed in contrast to the 10 ATL-related deaths in other types. In multivariate analysis of 193 patients, the JCOG-PI based on corrected calcium levels and performance status identified moderate and high risk groups with an MST of 14 and 8 months respectively (hazard ratio, 1·926). The JCOG-PI was reproducible in an external validation. Patients with lymphoma-type who survived >5 years might have been cured. The JCOG-PI is valuable for identifying patients with extremely poor prognosis and will be useful for the design of future trials combining new drugs or investigational treatment strategies.

Background: Adult T-cell leukemia-lymphoma (ATL) is a rare and refractory malignancy of regulatory T /TH2 cell associated with human T-lymphotropic virus type I (HTLV-1). In recent years, the introduction of intensive chemotherapy, allogeneic hematopoietic stem cell transplantation (Allo-HSCT), and mogamulizumab (anti-CCR4 antibody, which was approved in Japan in May 2012 for relapsed/refractory ATL, and in Dec. 2014 for newly diagnosed ATL) are expected to improve the prognosis of ATL. Meanwhile, the aging tendency of the ATL patient population has been recognized recently in Japan. Therefore, for the development of future treatment strategies for ATL, it is important to assess the therapeutic utilization and prognosis in patients with ATL not only in clinical trials but also in clinical practices. Aim: To report the current clinical features and outcomes of patients with ATL who were newly diagnosed during 2010-2011 from 114 hospitals in Japan. Methods: A questionnaire for each of 996 patients was sent to the hospitals, requesting information on treatment options and outcomes in detail. Statistical analysis was undertaken using Chi-squared tests to identify significant differences in the proportion, and using Kaplan-Meier curves to estimate the probability of overall survival (OS) with the log-rank test to identify significant differences in the probability, according to age, subtypes, and initial treatment. Results: We received 94.7% response rate from hospitals. Among 800 patients registered in this prognosis survey, 45 patients were not assessable for outcomes because of insufficient data, therefore, 755 (male 397, female 355, unknown 3) were included in the outcome analysis. The median age at diagnosis was 68 years old for all and the median follow-up time was 49 months for survivors. The distributions of ATL subtypes according to Shimoyama criteria were 382 (51%) for acute, 192 (25%) for lymphoma, 86 (11%) for chronic, and 95 (13%) for smoldering types, respectively. The median survival time and 2-year survival rate were: acute (n=377) (264 days, 24%), lymphoma (n=212) (293 days, 26%), chronic (n=71) (1,094 days, 56%), and smoldering (n=99) (1,900 days, 80%), respectively. Overall, the initial therapy-regimens used for aggressive ATL (acute and lymphoma subtypes) were VCAP-AMP-VECP-like regimen in 49%, CHOP-like regimen in 42%, and others in 9%. However, the utilization percentage of each option varied with age, VCAP-AMP-VECP-like regimen was used 68% of those aged 65 or younger but 32% of those over 65, respectively. CHOP-like regimen was used 29% for those aged 65 or younger but 52% for those over 65, respectively. Allo-HSCT for aggressive ATL was performed about 50% for those aged 55 or younger, 30% for those aged 56-65, but only 1% for those aged over 66, respectively. A total of 75 (10%) patients were treated with mogamulizumab. Fifty-six of them were treated with mogamulizumab after May 2012, when mogamulizumab was approved and generally adopted in Japan. When comparing the OS by pre- or post- general adoption of mogamulizumab, the 2-year OS was significantly worse in those treated after general adoption (18%) than those before (61%). When the response to initial chemotherapies was poor, the prognosis was worse regardless of treatment options, i.e., chemotherapy, allo-HSCT, and mogamulizumab. Response rate to initial chemotherapy differed by age, i.e., the older the age, the worse the response rate. Conclusion: This work highlights the difference in the treatment and the prognosis by age in patients with ATL in the current clinical practice in Japan. Intensive chemotherapy and allo-HSCT are not fully applicable for the elderly patients, who account for more than half of the ATL patients. Better strategies are required to improve clinical outcomes of the primary treatment, especially of the elderly ATL patients. Funding : This work was supported by Health and Labor Science Research Grant, Grant Number H26-ganseisaku-ippan-006. Disclosures Utsunomiya: Daiichi Sankyo Co., Ltd.: Speakers Bureau. Tobinai:Kyowa Hakko Kirin: Research Funding; Eisai: Honoraria, Research Funding; Abbvie: Research Funding; Chugai Pharma: Research Funding; Janssen Pharmaceuticals: Honoraria, Research Funding; Zenyaku Kogyo: Honoraria; Celgene: Research Funding; GlaxoSmithKline: Research Funding; Ono Pharmaceutical: Research Funding; SERVIER: Research Funding; HUYA Bioscience: Honoraria; Mundipharma KK: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Daiichi Sankyo Co., Ltd.: Consultancy. Tsukasaki:Daiichi Sankyo Co., Ltd.: Consultancy; Takeda: Research Funding.

Aggressive natural killer cell leukemia (ANKL) is a rare malignant disease of NK cells that has a median survival of less than 2 months and a strong association with the Epstein-Barr virus. Herein, we report three Japanese cases of the disease. A 21-year male patient, a 31-year female patient, and a 76-year female patient presented with high fever, lymphadenopathy, hepatosplenomegaly, and severe liver damage. All three cases had granular lymphocytes in both peripheral blood and bone marrow. The phenotype of these cells was CD2(+)CD3(-)CD56(+)HLA-DR(+). All cases had a high copy number of serum Epstein-Barr virus DNA in the peripheral blood and were diagnosed with ANKL. Case 1 and Case 2 were treated with chemotherapy, but suffered from gross intestinal bleeding or massive bleeding in the cerebellum, resulting in death. Although not treated with chemotherapy, Case 3 also suffered gross bleeding from an atypical duodenal ulcer and died from hemorrhagic shock 15 days after admission. There have been no previous reports of such acute lethal hemorrhagic complications with ANKL. The present cases suggest that patients with ANKL need a sufficient supply of coagulation factors, and that chemotherapy for this disease should be carefully designed with promising agents. [J Clin Exp Hematopathol 52(2) : 101-106, 2012].

Hairy cell leukemia (HCL) is occasionally misdiagnosed as aplastic anemia when only a few leukemic cells are present in the circulation. Here, we describe a patient with HCL who initially presented with pancytopenia and received a diagnosis of aplastic anemia. The patient was treated with immunosuppressive therapy including cyclosporine A and anti-thymocyte globulin (ATG). No blood cell transfusion was required for approximately 3 years after ATG therapy. She was referred to our hospital because of an abdominal mass and requiring periodic blood transfusions. A bone marrow biopsy at this time revealed proliferation of lymphocytes with a fried egg appearance and an increase in reticulin fibers that are typical findings of HCL. It is notable that our patient with a presumably long history of HCL and an increase in marrow reticulin fibers showed good recovery of hematopoiesis after cladribine therapy. Some HCL patients may receive an initial diagnosis of aplastic anemia and may show a good response to ATG masking the underlying HCL.

[Graphic][1] Introduction: Adult T-cell leukemia-lymphoma (ATL), a distinct subtype of peripheral T-cell lymphoma (PTCL), is caused by human T-lymphotropic virus type-I (HTLV-1). Although rare in the rest of the world, ATL accounts for 25% of PTCL cases diagnosed in Japan, where ATL cases are clustered in areas endemic for HTLV-1 infection. Studies of lenalidomide, an oral immunomodulatory agent that has antiproliferative and direct antineoplastic activity in cutaneous T-cell lymphoma and PTCL, have reported encouraging clinical activity. On the basis of the results from the ATLL-001 dose-finding study of lenalidomide (Uike et al. ASH 2012. Abstract 2737), this multicenter phase II study (ATLL-002) was designed to investigate the efficacy and safety of single-agent lenalidomide in Japanese patients with relapsed ATL. Methods: Patients with relapsed acute, lymphoma, or the unfavorable chronic subtype of ATL who were at least 20 years of age, had ECOG performance status 0-2, no prior allogeneic stem cell transplant, and who had failed at least 1 chemotherapy were included in the study. Patients refractory to their last prior therapy were excluded. Treatment consisted of oral lenalidomide 25 mg/day administered continuously until disease progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR). The secondary endpoints were progression-free survival (PFS), duration of response (DOR), overall survival (OS), and safety. Response was assessed by central review using the criteria proposed by Tsukasaki et al in their international consensus report (J Clin Oncol. 2009;27:453-459.); safety was assessed per NCI CTCAE v4.0 criteria. The estimated number of patients required was 25, for 90% power to detect a lower limit of the 95% confidence interval (CI) exceeding the 5% threshold of ORR, based on the assumptions that the minimum required ORR to a new drug for relapsed or recurrent ATL is 5% and the expected ORR to lenalidomide is 25%. Results: Twenty-six patients were enrolled and received lenalidomide. The median age was 68.5 years (range, 53-81), with 15 (58%) acute, 7 (27%) lymphoma, and 4 (15%) unfavorable chronic type ATL patients. Patients had received a median of 2 (range, 1-4) prior chemotherapeutic or antibody agents for ATL, 11 (42%) of whom received prior mogamulizumab (anti-CCR4 antibody). At a median 3.8-month follow-up, lenalidomide met the primary endpoint by exhibiting an ORR of 42% (11/26; 95% CI, 23-63) (acute 33% [5/15], lymphoma 57% [4/7], unfavorable chronic 50% [2/4]), including 5 (19%) complete responses (CR)/CR unconfirmed (95% CI, 7 to 39; Table 1). Stable disease was 31%, and progressive disease was 27%. The median time to response was 1.9 months (95% CI, 1.8 to 3.7). Although the data were immature at the time of analysis, median DOR for all responders was not reached (NR) (95% CI, 0.5 months to NR), median PFS was 3.8 months (95% CI, 1.9 months to NR), and median OS was 20.3 months (95% CI, 9.1 months to NR). At the time of the data cut-off, 5 (19%) patients remained on lenalidomide treatment. The most common grade 3/4 adverse events (AEs), accounting for at least 10% of all cases, were neutropenia (65%), leukopenia (39%), lymphopenia (39%), thrombocytopenia (23%), anemia (19%), and hypokalemia (12%). Serious AEs were reported in 9 (35%) patients; only thrombocytopenia (2 patients [8%]) was observed in >1 patient. AEs led to dose reduction/interruption in 17 (65%) patients and study discontinuation in 6 (23%). Seven deaths occurred during the study, 6 due to disease progression and 1 due to pneumonia unrelated to lenalidomide treatment. Conclusions: In this multicenter, open-label, phase II study, lenalidomide monotherapy demonstrated a 42% ORR and acceptable tolerability profile. These results support the potential for lenalidomide monotherapy becoming a treatment option for patients with relapsed ATL. | ATL type | All patients (N = 26) | Acute (n = 15) | Lymphoma (n = 7) | Unfavorable chronic (n = 4) | | ------------- | ------------------------------ | ----------------------- | ------------------------- | --------------------------- | | ORR, n (%) | 11 (42) | 5 (33) | 4 (57) | 2 (50) | | CR/CRu, n (%) | 5 (19) | 3 (20) | 2 (29) | | | PR, n (%) | 6 (23) | 2 (13) | 2 (29) | 2 (50) | | SD, n (%) | 8 (31) | 6 (40) | | 2 (50) | | PD, n (%) | 7 (27) | 4 (27) | 3 (43) | | * CR, complete response; CRu, CR unconfirmed; ORR, overall response rate; PD, progressive disease; PR, partial response; SD, stable disease. Table. Best response to lenalidomide in relapsed ATL Disclosures Fujiwara: Celgene: Honoraria, Other: Research funding to my institution; travel, accommodations, expenses. Off Label Use: Lenalidomide to treat ATL. Ishida: Celgene K.K.: Other: Research Funding to my institution; Bayer Pharma AG: Other: Research Funding to my institution; Kyowa Hakko Kirin Co., LTD: Honoraria, Other: Research Funding to my institution. Moriuchi: Celgene: Other: Research Funding to my institution; travel, accommodations, expenses, Speakers Bureau. Jo: Celgene: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Kyowa Kirin: Honoraria; Nippon Shinyaku: Honoraria. Ishizawa: Kyowa Kirin: Research Funding; Celgin: Research Funding; Janssen: Research Funding; Takeda: Research Funding; GSK: Research Funding; Takeda: Speakers Bureau; Kyowa Kirin: Speakers Bureau; Pfizer: Speakers Bureau; Celgin: Speakers Bureau. Tobinai: Gilead Sciences: Research Funding. Tsukasaki: Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Chugai: Consultancy, Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Mundipharma: Research Funding; Kyowa Kirin Hakkou: Research Funding. Ogura: Mundipharma: Consultancy, Research Funding; MeijiSeika Pharma: Consultancy; Zenyaku: Research Funding; Eisai: Research Funding; Pfizer: Research Funding; Janssen: Research Funding; Celgene: Research Funding; Solaisia: Research Funding. Midorikawa: Celgene K.K.: Employment; Celgene Corporation: Equity Ownership. Ruiz: Celgene K.K.: Employment. Ohtsu: Celgene: Employment, Equity Ownership, Other: travel, accommodations, expenses. [1]: /embed/inline-graphic-2.gif

Introduction: Adult T-cell leukemia-lymphoma (ATL) is a distinct peripheral T-cell lymphomacaused by human T-lymphotropic virus type I (HTLV-1), which is endemic in Japan. Only a small percentage of HTLV-1 carriers infected through breast-feeding develop the disease. Previous nationwide surveys during 1980s-2000s in Japan provided a comprehensive view on the clinio-epidemiological profiles of ATL, including the establishment of the subtype-classification (i.e., the Shimoyama criteria: acute, lymphoma, chronic, and smoldering type) based on the diversity of the clinical features and prognosis. Treatment strategies have been developed by the subtype-classification; watchful waiting for indolent ATL, intensive chemotherapy followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT) for aggressive ATL. The aim of this 11th survey is to characterize the current clinio-epidemiological features of ATL in Japan in the light of previous surveys. Methods: In 2013-14, we conducted an anonymous, cross-sectional, hospital-based survey of patients with ATL who were newly diagnosed during 2010-2011 across Japan. First, we asked 2500 hospitals with departments of hematology and dermatology to participate in this survey, and then we sent questionnaires to 128 participating hospitals to accumulate data of ATL. Skilled five hematologists reviewed the data of each questionnaire sheet, and the agreements of ATL diagnosis including the subtypes between the central review and participating hospitals were evaluated using Kappa statistics. Most of the collected data were analyzed by descriptive statistics. Results: A total of 996 ATL patients were registered; of these, 41 were eliminated because of the insufficient information for the diagnosis of ATL. Overall diagnostic agreement on subtype of ATL was substantial, with a kappa value 0.71 (standard error, 0.021); most of the disagreement was within aggressive/indolent category, acute vs. lymphoma types or acute vs. unfavorable chronic types. Among the 955 evaluable patients (M/F ratio, 1.12), 70% were diagnosed in the southwest region of Japan (Kyusyu/Okinawa) where HTLV-1 is endemic, which was consistent with the past surveys. The mean age at diagnosis was 68.3 years (median 68.8, range 24.7-100.3), which was significantly higher than 60.3 years in 1994-1995 and 57.7 years in 1986-1987. The proportion of ATL patients aged over 65 years was 79 % in this survey (whereas, 48% in the 1990-1991 survey), which indicates that the allo-HSCT is not applicable to the majority of current ATL patients in Japan. The proportion of acute, lymphoma, chronic, and smoldering types was 48, 28, 10 and 13%, respectively. The proportion of smoldering and chronic types tended to be greater than previous surveys (7% and 10% in the 1988-1997 surveys combined). The proportion of subtype by age group in this survey showed that the older in age at diagnosis are, the higher proportion of lymphoma subtype (10% in those aged younger than 40 years, 20% in those 50-59, and 31% in those 70 years or older. Discussion: This 11th survey revealed several clinio-epidemiological features of current ATL in Japan different from those in past two decades. First, a considerably increasing proportion of elderly ATL patients were diagnosed, which may be expected from a recent distribution of nationwide HTLV-1 carriers in Japan (Satake, et al, 2011). Second, there is an increasing tendency in the proportion of indolent types of ATL. This may be partly influenced by participation of the dermatology departments for the first time, because early phase of ATL localized in skin were frequently diagnosed in the dermatology department. Third, the proportion of lymphoma subtype was increased with age, which suggests that aging-related unknown mechanisms may affect the subtype distribution. More detailed analysis and subsequent surveys are planned to further evaluate clinical features and the efficacy of modern therapies on prognosis of ATL. Disclosures Ishizawa: Kyowa Kirin: Speakers Bureau; GSK: Research Funding; Takeda: Research Funding; Celgin: Speakers Bureau; Kyowa Kirin: Research Funding; Celgin: Research Funding; Janssen: Research Funding; Takeda: Speakers Bureau; Pfizer: Speakers Bureau. Ishida:Bristol-Myers Squibb: Honoraria. Ishida:Kyowa Hakko Kirin Co., LTD: Honoraria, Other: Research Funding to my institution; Bayer Pharma AG: Other: Research Funding to my institution; Celgene K.K.: Other: Research Funding to my institution. Tobinai:Gilead Sciences: Research Funding. Watanabe:Daiichi Sankyo Co., Ltd.: Research Funding.

8565 Background: Although HDAC-containing CTX with rituximab (R) followed by high-dose CTX (HDC) with autologous stem cell transplantation (ASCT) has been recommended in younger untreated MCL patie...

Introduction: The spinal cord is an extremely rare site for primary central nervous system lymphoma. Here, we present two cases of B cell lymphoma of cauda equina. Case1: A 80 year-old woman was admitted to our hospital with progressive pain and muscle weakness of both lower extremities. Magnetic resonance imaging (MRI) uncovered a tumor in cauda equina. A diagnosis of B cell lymphoma was made with cytological examination of cerebrospinal fluid. The patient received one cycle of high-dose methotrexate therapy, but it was not effective. Case2: A 62 year-old man was referred to our hospital because of a progressive pain and paralysis of lower extremities. MRI revealed a significant large tumor in the cauda equina. Diagnosis of diffuse large B cell lymphoma was made with biopsy of the tumor. The patient received three cycles of chemotherapy with high-dose methotrexate and high-dose cytarabine with 40 Gy of irradiation, leading to partial remission. Conclusion: We presented two cases of B cell lymphoma of cauda equina. Neither of the two cases achieved complete remission with high-dose methotrexate chemotherapy. Treatment of primary B cell lymphoma of spinal cord is very difficult because most cases are refractory to standard chemotherapy, including high-dose methotrexate. More effective therapeutic regimens with novel agents are urgently needed for treating primary B cell lymphoma of spinal cord.

We have reported that S-phase kinase-associated protein 2 (Skp2) expression in tumor cells is an unfavorable prognostic factor in diffuse large B cell lymphoma (DLBCL) with CHOP-R. Therapeutic strategies other than CHOP-R should be needed for DLBCL patients exhibiting a high Skp2 expression at the time of diagnosis. High dose chemotherapy followed by autologous peripheral blood stem cell transplantation (APBSCT) is mainly adapted for DLBCL patients in high and high intermediate risk groups in IPI. However, the definite beneficial evidence for APBSCT in DLBCL remains unclear. In the present study, we investigated the clinical significance of Skp2 expression in the patients with DLBCL treated with CHOP-R plus high-dose chemotherapy followed by APBSCT. We retrospectively analyzed the outcomes of 93 patients (age range: 14-65). The patients were newly diagnosed as having DLBCL from 2002 to 2012, and were treated with either CHOP-R plus upfront APBSCT (n=31) or CHOP-R (n=62) in the19 hospitals in Kyushu, Japan. All patients had high and high intermediate risk in IPI. All biopsy specimens were immunohistopathologically reconfirmed by one pathologist with expertise before entering into this study. The median follow-up time was 2.3 y. Survival analyses were performed using the Kaplan-Meier method and the Cox proportional Hazard model with inverse probability of treatment weight (IPTW). In background of the patients, age was younger in transplant group (mean age 52) than in non-transplant group (mean age 59). CR rate was higher in non-transplant (30.7%) than in transplant (12.9%). Sex, stage, PS, LDH extranodal lesion and IPI showed no difference in both group. Overall survival (OS) for 3 years were 77.0% and 59% in transplant group and in non-transplant group (P=0.077), respectively. Progression-free survival (PFS) for 3 years, 65.7% and 53.2% in transplant and non-transplant group (P=0.233), respectively. In Skp2 high expression (positive rate >40%) group (n=37), 3y-OS was 44.9% and 16.4% in transplant (n=13) and non-transplant (n=24) group (P=0.065), respectively. 3y-PFS was 40.3% and 7.5% in transplant and non-transplant (P=0.032), respectively (Fig A). However, in low Skp2 expression group (n=56), OS was 100% and 92.7% (P=0.254), PFS was 83.6% and 82.6% (P=0.945)(Fig B)in transplant (n=18) and non-transplant (n=38) group, respectively. In propensity score analysis using center effect, age, extranodal lesion, IPI and CR rate as logistic regression model, transplant group showed the excellent benefit in OS ( OR= 0.469, 95%CI =0.266-0.825, P=0.009) and PFS (OR=0.456, 95%CI=0.255-0.815, P=0.008) in Skp2 high expression group (n=37).P value for transplant x Skp2 interaction was P=0.643 in OS and P=0.020 in PFS. In conclusion, Skp2 was a good biomarker for indication of ABSCT for high risk DLBCL patients. In low expression of Skp2, patients should not be treated with high dose chemotherapy followed by APBSCT, even though in patients with high risk in IPI. However, ABSCT have some advantage in DLBCL patients with high expression of Skp2. Disclosures: No relevant conflicts of interest to declare.

8506 Background: Mogamulizumab (Moga), a defucosylated humanized anti-CCR4 antibody, was approved for the treatment of relapsed/refractory ATL in Japan in 2012. This multicenter, randomized, phase II trial was conducted to examine the efficacy of the combination of Moga with standard chemotherapy for untreated aggressive ATL. Methods: Previously untreated patients (pts) with CCR4-positive ATL were randomly assigned to receive mLSG15 plus Moga (arm A) or mLSG15 alone (arm B). The primary endpoint was CR rate (%CR), and secondary endpoints included ORR, PFS, OS and safety. Pts received 4 courses of mLSG15 regimen, with or without a total of 8 doses of Moga (1.0 mg/kg) once every 2 weeks. The planned sample size, 22 pts per arm, provided a probability of 80% that %CR in arm A would have larger %CR when true %CR for arm A is 15% better than that for arm B. Results: Of 54 pts randomized, 53 were treated (arm A: 29; arm B: 24). Male/female ratio was 53/47%, median age was 63 (37-81), and subtype was acute/lymphoma/unfavorable chronic, 70/25/6%. %CR and ORR in arms A and B was 52% (95%CI [CI]; 33, 71) vs. 33% (CI; 16, 55) and 86% (CI; 63, 96) vs. 75% (CI; 53, 90), respectively. The results in arm B were similar to the previously reported %CR of 40% and ORR of 72% with mLSG15 (Tsukasaki et al, JCO 2007). ORR according to the disease subtype, in arms A and B, was 55% vs. 29% for acute, 50% vs. 43% for lymphoma and 33% vs. 0% for unfavorable chronic. Median PFS was 259 days (CI; 197, -) for arm A and 192 days (CI; 147, -) for arm B. Median OS was not reached in both arms. The most common treatment-related AEs in each arm were neutropenia (100%, 96%), thrombocytopenia (100%, 96%), leukopenia (100%, 92%), lymphocytopenia (97%, 96%), anemia (97%, 92%) and febrile neutropenia (90%, 88%). In arm A, skin disorders were more frequent but manageable, and no serious skin disorder like Stevens-Johnson syndrome was observed. There was one treatment-related death, which was not related to Moga. Conclusions: The combination of Moga with mLSG15 was well tolerated and the study met its primary endpoint. These results suggest that Moga with mLSG15 is a rational treatment option for newly diagnosed aggressive ATL. Clinical trial information: NCT01173887.

Abstract 2641 INTRODUCTION: Since the introduction of the anti-CD20 monoclonal antibody rituximab, the outcomes of B-cell non-Hodgkin lymphoma (B-NHL) have improved markedly. However, fulminant hepatitis due to reactivation of hepatitis B virus (HBV) infection has emerged as a serious problem. Recently, rituximab plus corticosteroid containing chemotherapy (R-chemo) has been identified as a risk factor for HBV reactivation in hepatitis B surface antigen (HBsAg)-negative B-NHL patients. Currently, there is no standard management to prevent HBV reactivation in HBV-resolved patients without HBsAg, but with antibodies against hepatitis B core antigen (anti-HBc) and/or HBsAg (anti-HBs). PATIENTS AND METHODS: We conducted a multicenter prospective observational study to estimate the incidence of HBV reactivation by serial monthly monitoring of HBV DNA in HBV-resolved patients with B-NHL during and just after R-chemo, and to establish preemptive antiviral therapy guided by this monitoring. The major eligibility criteria included previously untreated CD20-positive B-NHL with prior HBV-resolved infection, and planned treatment with 6 to 8 cycles of R-chemo defined by protocol. The baseline HBV status was evaluated on enrollment at each institute, comprising HBsAg, anti-HBc, and anti-HBs serology. Patients were excluded if they were seropositive for hepatitis C virus or human immunodeficiency virus. Plasma HBV DNA levels were measured independently at a central laboratory, using an automated real-time TaqMan polymerase chain reaction assay after enrollment. The primary end point was the incidence of HBV reactivation defined as HBV DNA levels of 1.8 log copies per mL or more. If HBV DNA levels of less than 1.8 log copies per mL were confirmed at baseline, the serial monitoring of HBV DNA (without prophylaxis of antiviral drugs) was performed with assessments every 4 weeks after enrollment for 1.5 years. Prompt antiviral treatment with an anti-HBV nucleoside analogue (entecavir, 0.5 mg per day) was highly recommended in patients with confirmed HBV reactivation. An ancillary study was conducted to identify risk factors for HBV reactivation using the preserved specimens. The protocol was approved by the Institutional Review Board of each participating institution. All patients gave written informed consent. The planned interim analysis was performed after the enrollment of 200 patients, using data available up to June 30, 2011. RESULTS: Between Sept. 2008 and Sept. 2010, a total of 187 patients (50.8% male) with a median age of 63 years (range, 26 to 79) from 45 institutes were analyzed. Histologic subtypes of B-NHL were diffuse large B-cell lymphoma (n=121, 64.7%), follicular lymphoma (n=57, 30.5%), MALT lymphoma (n=5, 2.7%) and other types (n=4, 2.0%). The number (%) of patients positive for both anti-HBc and anti-HBs was 132 (70.6%), 35 (18.7%) were positive for anti-HBc but negative for anti-HBs, and 19 (10.2%) were negative for anti-HBc but positive for anti-HBs. One patient was positive for anti-HBc but lacked anti-HBs measurement. 168 (89.8%) patients received 6 to 8 cycles of R-CHOP (n=151) or other R-chemo (n=17). With a median follow-up of 549 days (range, 35 to 939), HBV reactivation was observed in 16 out of 187 analyzed patients. The incidence of HBV reactivation at 1 year was 7.7% (95% confidence interval [CI], 4.7 to 12.7). HBV reactivation was diagnosed at a median time of 158 days (range, 33 to 490) after enrollment. No hepatitis due to HBV reactivation was observed in patients who received antiviral treatment when HBV DNA levels were 1.8 to 3.1 log copies per mL. Multivariate analysis of the ancillary study showed that an anti-HBs baseline titer less than 10 mIU per mL was an independent risk factor for HBV reactivation, compared to a titer of 100 mIU per mL or more (adjusted hazard ratio, 5.3; 95% CI, 1.3 to 21.8; p=0.02). HBV mutations of precore (G1896A) or basal core promoter (A1762T/G1764A) that enhanced HBV replication were identified in 4 patients, two of whom had both mutations. Our strategy could inhibit such highly replicative clones and prevent hepatitis. CONCLUSIONS: Monthly monitoring of HBV DNA is highly effective for preventing hepatitis due to HBV reactivation in HBV-resolved B-NHL patients treated with R-chemo. (UMIN-CTR 000001299) (This study was supported by the Ministry of Health, Labour and Welfare of Japan.) Disclosures: Kusumoto: Bristol-Myers Squibb: Honoraria; Zenyaku Kogyo: Honoraria; Chugai Pharmaceutical Co., LTD.: Honoraria, Research Funding; Abbott: Honoraria. Tanaka:Chugai Pharmaceutical Co., LTD.: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Zenyaku Kogyo: Honoraria; Abbott: Honoraria. Tanaka:Chugai Pharmaceutical Co., LTD.: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Kinoshita:Chugai Pharmaceutical Co., LTD.: Honoraria, Research Funding; Zenyaku Kogyo: Honoraria. Ogura:Chugai Pharmaceutical Co., LTD.: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Zenyaku Kogyo: Honoraria, Research Funding. Mizokami:Chugai Pharmaceutical Co., LTD.: Honoraria; Abbott laboratories: Honoraria. Ueda:Chugai Pharmaceutical Co., LTD.: Research Funding.

Abstract 2737 Introduction: ATL is prevalent in Japan and has the worst prognosis among T-cell malignancies. PTCL also has a poor prognosis with currently available chemotherapeutic regimens, and both would benefit from better treatment modality. Lenalidomide is an immunomodulatory agent with direct tumoricidal and antiproliferative activity, and is approved for multiple myeloma (MM) in combination with dexamethasone after at least 1 prior therapy and for transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes associated with 5q deletion. We conducted a phase 1 study of lenalidomide in patients with relapsed ATL or PTCL to establish the recommended dose and schedule for a subsequent phase 2 study. Patients and Methods: This multicenter, phase 1, dose-escalation study assessed the safety, maximum tolerated dose (MTD), pharmacokinetics, and efficacy in patients with relapsed advanced ATL or PTCL. Dose-escalation was conducted according to the standard 3+3 design. Up to one PTCL patient was allowed to be included in each cohort of 3 patients. Patients in Cohort 1 received oral lenalidomide 25 mg daily on Days 1–21 of a 28-day cycle. Patients in Cohorts 2 and 3 received 25 and 35 mg/day, respectively, on each day of the 28-day cycle. Dose-limiting toxicity (DLT) was defined as febrile neutropenia lasting 5 or more days; thrombocytopenia (platelets Results: From July 2010–June 2012, 13 Japanese patients (9 ATL and 4 PTCL; age 32–74 years [median, 64]; 1–11 prior therapies [median, 1]) were enrolled: 3 in Cohort 1, 6 in Cohort 2, and 4 in Cohort 3. The 3 patients in Cohort 1 received lenalidomide for 21, 103, and 637 days, respectively, until PD with no instances of DLT. In Cohort 2, 1 patient experienced DLT (thrombocytopenia, platelets 75% reduction in lymph nodes, which lasted for 282 days. PK profiles of patients in the study were generally consistent with that observed in Japanese MM patients. Plasma exposure of lenalidomide increased with increasing dose with a mean Cmax on Day 1 for 25 mg and 35 mg of 493 ng/mL and 628 ng/mL, respectively, and a mean AUC24 of 2774 ng/mL and 3062 ng/mL, respectively. There was no evidence of accumulation following multiple dosing for 8 days. Conclusions: This phase 1 study identified lenalidomide 25 mg daily per 28-day cycle as the dose and schedule for a subsequent phase 2 study in patients with ATL or PTCL. Based on the preliminary evidence of antitumor activity in ATL and PTCL patients, a phase 2 study in patients with relapsed ATL in Japan is planned. Disclosures: Off Label Use: Lenalidomide (CC-5013) is an investigational agent in Japan; this abstract assesses its use in adult ATL patients. Tobinai:Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Zenyaku: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Symbio: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Eli Lilly: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa-Kirin: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biomedics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Solasia Pharma: Clinical trials, Clinical trials Other, Research Funding; Novartis: Research Funding; Johnson & Johnson: Research Funding; Pfizer: Research Funding; GSK: Research Funding; Chugai/Roche: Research Funding; Takeda: Clinical trials, Clinical trials Other, Research Funding.

Abstract 285 Background: KW-0761 is a defucosylated, humanized, monoclonal antibody with enhanced antibody-dependent cellular cytotoxicity (ADCC; Potelligent®) that binds to CC chemokine receptor 4 (CCR4). CCR4 is expressed on the surfaces of cells comprising several T-cell malignancies such as ATL, peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL). A phase I study of KW-0761 in patients with CCR4-positive ATL and PTCL demonstrated that 4 weekly intravenous infusions of KW-0761 were well tolerated up to 1.0 mg/kg and it showed encouraging clinical activity with an overall response rate (ORR) of 31.3% (4 of 13 ATL and 1 of 3 PTCL) in 16 patients (J Clin Oncol 2010;28:1591-8). Methods: A multicenter phase II study of KW-0761 has been conducted for relapsed patients with CCR4-positive ATL to evaluate its efficacy, pharmacokinetics (PK), safety and immunogenicity. Patients were planned to receive 8 weekly intravenous infusions of KW-0761 at 1.0 mg/kg. The primary endpoint was ORR. Objective responses were assessed after the 4th and 8th infusions of KW-0761 according to the response criteria for ATL (J Clin Oncol 2009;27:453-9) by each investigator and the independent efficacy assessment committee. The number of patients required was estimated to be 25, for 90% power to detect a lower limit of the 95% confidence interval (CI) exceeding the 5% threshold of ORR, based on the assumptions that the minimum required response ORR to a new drug for relapsed ATL is 5% and the expected ORR to KW-0761 is 30%. Results: Twenty-seven patients (12 males and 15 females) were enrolled and received KW-0761. The median age was 64 years (range: 49–83). The disease subtypes of ATL consisted of 14 acute-, 6 lymphoma-, and 7 chronic-types with unfavorable prognostic factors. Among the 27 patients enrolled, 14 patients (52%) completed the protocol treatment of 8 infusions. Eleven patients (41%) discontinued the protocol treatment because of progressive disease, and the remaining 2 discontinued because of skin rash or the concurrent colon tumor. The treatment-related grade (G) 2 or greater adverse events (AEs) were lymphopenia (96%), leukopenia (56%), skin rash (52%), neutropenia (33%), thrombocytopenia (26%), AST increase (26%), ALT increase (22%), hypoxemia (19%), anemia (15%), pruritus (15%), g-GTP increase (15%) and hypophosphatemia (15%). G2 or greater Infusion-related toxicities were observed in 22 of 27 patients (81%) including 1 G3, but immediately recovered after treatment with systemic steroids. Treatment-related severe AEs (SAEs) were observed in 5 patients, including a Stevens-Johnson syndrome (G3) and 4 skin rashes (each G3). All these AEs also improved by steroids. PK analysis demonstrated that Cmax and trough (C168h) after the 8th infusion was 38,853 ± 11,267 and 25,934 ± 10,193 ng/mL, respectively, and T1/2 after the 8th infusion were 457 ± 144 h. No anti-KW-0761 antibody has been detected. Among the 26 patients evaluable for efficacy, KW-0761 exhibited an ORR of 54% (14/26; 95% CI, 33 to 73) (acute: 6/14 patients, lymphoma: 3/6 patients, chronic: 5/6 patients) including 7 complete responses (CRs) (27%; 95% CI, 12 to 48) and 7 partial responses (PRs). These are remarkable results, considering that the ORR of relapsed or refractory patients with ATL to a single-agent chemotherapy has been reported to be low (7 to 39%). Response rates according to the affected disease lesion were 100% (13 patients, all CR), 71% (5 of 7 patients), and 38% (5 of 13 patients), respectively, for peripheral blood, skin, and lymph node disease. Conclusions: KW-0761 is a highly effective agent with acceptable toxicity profiles in relapsed patients with CCR4-positive ATL who have no standard therapies. A multicenter, randomized study for untreated ATL patients to compare mLSG15 (a dose-intensified multi-agent regimen, J Clin Oncol 2007;25:5458-64) + KW-0761 with mLSG15 alone has been initiated. Disclosures: Ogura: Kyowa Hakko Kirin Co Ltd: Consultancy. Akinaga:Kyowa Hakko Kirin Co Ltd: Employment.

Abstract 2920 Poster Board II-896 [Background] Epstein-Barr virus (EBV) is currently recognized as a pathogen of several known human diseases ranging from transient infection, chronic lymphoproliferative disorder (LPD) to EBV-positive malignant lymphomas. Chronic active EBV infection (CAEBV) is typically an indolent but long-lasting EBV-LPD of childhood. Another well documented EBV-associated LPD is the post-transplant EBV-LPD, which also occurs in adults. Fulminant proliferation of EBV after primary infection or in the setting of CAEBV is an aggressive type of disease, which has recently been included in the 4th version of WHO classification as “systemic EBV-positive T-cell LPD of childhood”. Here, we present a previously unrecognized type of EBV-associated LPD mainly developed in adults who experienced progressive clinical course. [Patients] A total of 13 adult patients with progressive EBV-LPD was identified from patient files of collaborative institutions. The patient clinical records and data were investigated retrospectively. [Results] There were six males and seven females with an age ranging from 16 to 85 years (median: 27 years). All patients were previously healthy without history of opportunistic infections or administration of immunosuppressants. Patients presented with persistent fever, hepatosplenomegaly and cytopenia, and all showed increasing number of EBV-DNA copies in peripheral blood. Proliferation of T- or NK-cells was recognized. Four patients showed elevated VCA-IgM antibody, and fell in the category of fulminant EBV-positive T-cell LPD after primary EBV infection. However, the other nine showed EBV-antibodies of previous infection. The bone marrow, liver, and lymph nodes were common sites of involvement. Morphological atypia of lymphocytes were faint in peripheral blood or biopsied specimens. Therefore, pathological diagnosis of malignant condition was difficult at the initial presentation. Because of the deteriorating clinical conditions, chemotherapy was administered to 12 patients, but the disease was resistant in 10 patients. Four patients underwent allogeneic hematopoietic stem cell transplantation. In total, 3 patients are alive and 10 patients were dead. The causes of death were primary disease in 5 patients, bleeding in 2, infection in 2, but unknown in one. All but one patient without allogeneic transplantation died within a year. The median survival time was eight months. [Discussion] In contrast to CAEBV in childhood, these 13 adult patients pursued obviously different, more aggressive clinical courses. However, early diagnosis had been difficult because of the little morphological abnormalities and disease recognition. Prompt administration of cytotoxic chemotherapy and/or stem cell transplantation is possibly needed to conquer this aggressive disease. Therefore, for this purpose, we here propose a novel nomenclature of progressive adult-onset EBV-LPD (PAEBV). PAEBV is (1) the disease with increasing number of EBV-DNA in T or NK cells, (2) the malignant disease without or mild atypia in its early stage, and (3) associated with a poor prognosis. For adolescence or young adults, both classical CAEBV and PAEBV can be recognized. Further investigations for differential diagnosis are required, as well as those for appropriate therapeutic approaches against this rare and intractable disease. Disclosures: No relevant conflicts of interest to declare.

Background. ATL is an HTLV-I-associated hematological malignancy. The majority of ATL patients are not curable using current chemotherapy with median survival time of 13 months. Recently, patients undergoing allo-SCT with conventional conditioning regimen were reported to have a 3-year overall survival (OS) rate of 45%, however, with high transplant-related mortality (TRM) rate as much as 40% (Fukushima T. Leukemia19:829, 2005). Since most ATL patients are over 50 years old with various complications, limited numbers of patients are eligible for conventional transplant. We have already conducted a phase I multi-center trial testing the feasibility of RIST in ATL patients, where 2-year OS was 33% and some differences in the outcome were suggested among participating institutes. Hence, we investigated the efficacy of RIST performed exclusively in our single institute (NCCH, Japan). Patients and Methods. Between Oct 2000 and Jun 2005, 16 ATL patients underwent RIST from a related donor. Since 3 have been enrolled into an on-going multi-center trial, 13 patients were analyzed in this retrospective study, including 3 who were enrolled into the above-mentioned multi-center trial (Okamura J. Blood105;4143, 2005). Median age was 51 years old (range, 44–61), 8 males and 5 females, and 8 were of acute type and 5 of lymphoma. The disease status at transplant was 3 CR, 7 PR and 3 primary refractory. Three donors were HTLV-I healthy carriers. Eleven were HLA 6/6, 2 were 5/6, 12 were PBSCT and 1 was BMT. Conditioning regimen was fludarabine 30 mg/m2 x6, busulfan 4 mg/kg x2 with (n=5) or without (n=8) rabbit ATG 2.5 mg/kg x2. Prophylaxis of GVHD was CSP alone. Results. Engraftment was rapid (median, 11 days) in all cases, and there was no TRM. Acute GVHD of grade II–IV developed in 7, and chronic extensive GVHD in 5. Eleven patients achieved CR after RIST, and 6 relapsed or progressed, among whom 2 achieved CR after cessation of CSP, donor lymphocyte infusion and local irradiation, and have been disease-free for more than 1 year. Ten patients are alive, 9 without disease, with median follow-up time of 26 mos (range, 4–45 mos). HTLV-I proviral titers determined using real time PCR decreased after RIST and became undetectable in 8 out of 13 patients. In 3, including one transplanted from an HTLV-I carrier donor, anti-HTLV-1 antibody transiently decreased and became nearly undetectable. Conclusions. RIST is feasible and safe in ATL patients, and it has not only an anti-ATL but also an anti-HTLV-I activity. This is the first report documenting the efficacy of RIST for ATL in terms of survival and remission durability. Figure Figure

Background and Methods: Donor-derived CTL that respond to tumor antigens emerge after SCT, particularly in association with the status of immune recovery and disease remission. To analyze the frequency of CTL against WT1, PR1 and PRAME after SCT, tetramer-based analysis was performed in 69 samples taken from 34 patients with the HLA-A02 phenotype, including 2 with RCC (10 MDS, 8 AML, 6 NHL, 4 ALL, 2 CML, 2 RCC, 1 ATL, 1 PCL). Peripheral blood samples were stained with WT1 126, PR1 169, and PRAME 300 tetramers, and CMV pp65 tetramer was used as a positive control. Antigen -specific CTL was defined as CD3+, CD13−, CD19−, CD4−, CD8+, and tetramer + cells present in the lymphocyte gate, and the cut-off level was defined as 0.02% per CD8+ lymphocytes. Results: All samples from CMV-seropositive patients were positive for CMV-CTL with high titers (average 2.3%). Regarding PR1, only 1 sample showed the presence of tetramer-positive cells (0.04%). Similarly in PRAME, only 3 samples from 3 different patients were sporadically positive with low titers ( Case monitoring: Based on these results, we performed serial analyses of WT1-CTL during the clinical course in 2 patients with RCC who underwent reduced-intensity stem cell transplantation (RIST). Before RIST, both RCC patients had undergone resection of the primary disease, but had developed multiple lung metastases, which were progressive despite interferon therapy. WT1-CTL in one of the RCC patients was detected at day 40 post-SCT after the development of skin GVHD, and the peak formation of WT1-CTL occurred on day 128 when oral chronic GVHD was noted. WT1-CTL became undetectable after day 268, but the disease has not progressed up to day 359. The other patient became positive for WT1-CTL on day 90, one week after the onset of liver acute GVHD. Cyclosporine was started at a dose of 400 mg/body and WT1-CTL disappeared. However, when cyclosporine was tapered to 100 mg/body, WT1-CTL became detectable again on day 146 following the development of skin GVHD. While the number of WT1-CTL was correlated with the presence of allo-reaction and cyclosporine treatment, the total lymphocyte count and CMV-CTL counts did not change significantly. This patient is currently showing stable disease beyond day 200. This is the first report of the precise monitoring of WT1-CTL after SCT in patients with RCC, and of the correlation of WT1-CTL with the clinical response. Further studies will be needed to evaluate the correlation between WT1-CTL and disease control. Figure Figure