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Ethnic and regional differences in the epidemiology and pathological aspects of Hodgkin’s lymphoma (HL) between Western and Asian patients may be associated with differences in clinical features and prognosis. We retrospectively analyzed the clinical and histopathological characteristics, therapeutic outcomes, and prognostic factors of 539 HL patients treated at 16 centers in Korea. We found that the incidence of histological subtypes of HL in Korea was similar to that in Western and other Asian countries. However, the incidence peaked between 16 and 30 years of age, unlike the bimodal age distribution seen in Western countries. In patients with stage I–IIA non-bulky disease, the complete response (CR) rate was similar between combined modality therapy and chemotherapy alone (93% vs. 84%, P = 0.44), and there was no difference in relapse-free survival (RFS) and overall survival (OS). Patients with stage I–II disease plus unfavorable factors and those with advanced-stage disease treated with combination chemotherapy regimens had an overall CR rate of 77%, with no difference between doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and non-ABVD regimens (77.2% vs. 76.8%, P = 0.95). Among those patients who achieved final CR, there was no significant difference in RFS or OS between those who achieved interim CR and PR. Only the presence of B symptoms was independently predictive of a shorter RFS. Age > 45 years, Eastern Cooperative Oncology Group 2–4, and B symptoms were independent risk factors for death. Although the incidence of HL was lower in Korea than in Western countries, the distribution of morphological subtypes, treatment outcomes, and patient prognosis were similar.

There are few treatment options for patients with non-Hodgkin lymphoma (NHL) who experienced progression after high-dose chemotherapy (HDC) with autologous stem cell transplantation (auto-SCT). The role of allogeneic stem cell transplantation (allo-SCT) in these patients has not been clarified yet. In this study, we report clinical outcomes of allo-SCT in patients with NHL who experienced progression after HDC with auto-SCT. Patients were enrolled from seven hospitals in Korea. A total of 38 patients were included: 18 patients (47.4%) underwent myeloablative conditioning and 20 patients (52.6%) reduced intensity conditioning. Overall response rate was 73.3%. Median event-free survival was 6.3 months. Median overall survival (OS) was 19.0 months. Estimated 5-year survival rate was 35.0%. Acute graft-versus-host disease developed in 13 patients (34.2%). Transplant-related mortality (TRM) was 21.1% (eight patients). Ann Arbor stage (p = 0.022), performance status (p

The current retrospective study investigated the incidence of lymphocytosis following second-line dasatinib therapy in chronic myeloid leukemia (CML) and analyzed the clinical factors predictive of the development of lymphocytosis, as well as association with treatment outcomes. Fifty CML patients who failed imatinib treatment and received dasatinib were included from nine centers in the Republic of Korea. The cumulative incidence of lymphocytosis was assessed, and cytogenetic and molecular response, treatment failure, loss of response, progression to advanced disease, and survival were evaluated and analyzed according to the development of lymphocytosis. After a median of 17 months of dasatinib therapy, 23 patients (46%) developed lymphocytosis (median onset 4 months). No clinical predictive factor for the development of lymphocytosis was found. The group presenting lymphocytosis showed a higher complete cytogenetic response (CCyR; 78.3 vs. 29.6%, P = 0.001) and major molecular response (MMR; 52.2 vs. 14.8%, P = 0.005), in comparison to the group without presenting lymphocytosis. The development of lymphocytosis after dasatinib was identified as a favorable independent marker for predicting a CCyR (P = 0.002) or MMR (P = 0.003). Further study is necessary to identify which subset of lymphocytes was expanded and to reveal the exact mechanism by which dasatinib induces lymphocyte expansion.

Nitric oxide (NO) synthesis is strongly induced during interleukin (IL)-2 treatment of mice and humans. Although this free radical can act as a cytotoxic effector molecule against cancer cells, immunosuppressive effects have also been suggested. We evaluated the effects of curcumin on IL-2-induced NO synthesis and IL-2-induced antitumor responses in a mouse ascites tumor model. Curcumin inhibited inducible nitric oxide synthase (iNOS) expression and NO production, and thereby enhanced the proliferation and cytotoxic activity of cocultured lymphocytes and macrophages during IL-2 stimulation which we earlier established as an in vitro model of IL-2-induced NO synthesis. Curcumin also decreased apoptosis of cocultured lymphocytes and macrophages during IL-2 stimulation. In contrast, the curcumin-induced changes in proliferation and apoptosis were not observed in cultures of lymphocytes alone, macrophages alone, and cocultured lymphocytes/iNOS-knock out macrophages, all of which produced little nitrite during IL-2 stimulation. In conjunction with IL-2 treatment, oral curcumin administration significantly inhibited IL-2 therapy-induced urinary nitrite/nitrate excretion and iNOS expression of tumor tissues, and further increased the IL-2 therapy-induced prolongation of survival in a murine Meth-A ascites tumor model. Curcumin may be useful as an adjunct to increase the antitumor activity of IL-2 therapy.

The prognostic relevance of tumor human papillomavirus (HPV) status in anal squamous cell carcinoma (SCC) had not been previously investigated, although its relevance to cervical, head and neck SCC is known. We retrospectively evaluated outcomes in 47 patients with anal SCC treated with combined chemoradiotherapy (CCRT) and determined tumor HPV status by HPV DNA chip method and p16 expression by immunohistochemistry (IHC) from paraffin-embedded tumor tissues. The median age was 65 years (range, 44-90 years). Sixteen (34%) patients were diagnosed with T stage 3 to 4, and 18 (38%) patients had regional nodal disease (N-positive). Thirty-five (75%) patients were HPV positive, and 31 (66%) patients were genotype 16 (HPV16-positive). Thirty-nine (83.0%) patients were positive for p16. After median follow-up of 51.7 months (range, 5.1-136.0 months), HPV16-positive group had significantly better 4-year progression-free survival (PFS, 63.1% vs. 15.6%, p < 0.001) and overall survival (84.6% vs. 39.8%, p = 0.008) than HPV genotype 16 negative (HPV16-negative) group. Patients with p16-positive tumor also had a better 4-year PFS (52.5% vs. 25.0%, p = 0.014) than those with p16-negative tumor. In multivariate analysis for PFS, N-positive and HPV16-negative were independent prognostic factors for shorter PFS. Comparing patterns of failure, time to loco-regional failure was statistically superior in HPV16-positive over HPV16-negative groups (p = 0.006), but time to systemic failure was not different (p = 0.098). Tumor HPV genotype 16 status is a prognostic and predictive factor in anal SCC treated with CCRT, and p16 expression determined by IHC might be advocated as a surrogate biomarker of HPV integration in anal SCC. Further studies are warranted.

The aim of this retrospective cohort study was to analyze the impact of surgery on the outcomes and qualities of life (QOL) in patients with intestinal diffuse large B-cell lymphoma (DLBCL). We assessed 345 patients with either localized or disseminated intestinal DLBCL and compared them according to treatment: surgical resection followed by chemotherapy versus chemotherapy alone. In patients with localized disease (Lugano stage I/II), surgery plus chemotherapy yielded a lower relapse rate (15.3%) than did chemotherapy alone (36.8%, P < .001). The 3-year overall survival rate was 91% in the surgery plus chemotherapy group and 62% in the chemotherapy-alone group (P < .001). The predominant pattern in the chemotherapy group was local relapse (27.6%). When rituximab was used with cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP), there was no improvement of the outcomes in patients treated with primary surgical resection. The QOL of patients who underwent surgery and chemotherapy was lower than chemotherapy alone, but its difference was acceptable. Multivariate analysis showed that surgical resection plus chemotherapy was an independent prognostic factor for overall survival. Surgical resection followed by chemotherapy might be an effective treatment strategy with acceptable QOL deterioration for localized intestinal DLBCL. This study was registered at www.clinicaltrials.gov as #NCT01043302.

Background Interim 18F-fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) scan may predict outcomes in patients with diffuse large B-cell lymphoma (DLBCL). However, overall accuracy in predicting treatment outcomes on adopting 5-point Deauville score (DS) was considerably low in DLBCL because of mainly low positive predictive value of interim PET-CT scans. This suggested that additional tool might be needed to more accurately predict treatment outcomes. International prognostic index (IPI) was greatly associated with outcomes for DLBCL and considered to reflect biologic aggressiveness of DLBCL. Thus, we hypothesized that combined assessments using DS on interim PET-CT scan and baseline IPI might improve the prediction of treatment outcomes in DLBCL patients. In this study, we aimed to establish the risk predicting model integrating DS on interim PET-CT as an estimate of early metabolic response and baseline IPI as a predictor of biologic aggressiveness in patients with newly diagnosed DLBCL. Methods In this retrospective cohort study, we consecutively enrolled patients with newly diagnosed DLBCL. Patients were eligible if they were histologically confirmed with DLBCL from Jan 2007 to June 2016, received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), and had PET-CT scan data at baseline and at interim after 3 cycles of R-CHOP. Primary CNS or transformed DLBCLs were excluded. Interim PET-CT was assessed using 5-point DS and four point or higher was regarded as positive. All PET-CT scans were assessed by 2 experienced nuclear medicine physicians, who were masked to treatment outcomes of the patients. Discrepant interpretations between 2 nuclear medicine physicians were resolved by consensus through mutual discussion. Results A total of 316 patients were screened for eligibility. Ninety-six patients were excluded from the analysis due to following reasons: unavailable baseline (n=9) or interim PET-CT scans (n=48), early death before interim PET-CT (n=16), Primary CNS or transformed DLBCLs (n=15), and insufficient medical records (n=8). Thus, 220 patients were analyzed. Median age was 64 years (range, 19-87) and 132 (60%) were male. Based on the IPI risk, patients were classified as the low or low-intermediate (LI; N=126, 57%), and high-intermediate (HI) or high (N=94, 43%) groups. Interim DS was determined as 1 (n=67, 30.5%), 2 (n=65, 29.5%), 3 (n=39, 17.7%), 4 (n=36, 16.4%), and 5 (n=13, 5.9%). With a median follow-up of 56.6 months (IQR 36.0-71.8), 5-year progression-free survival (PFS) rate was 65.2% (95% CI, 58.1-72.3) and overall survival (OS) rate was 69.9% (95% CI, 63.2-76.6). Interim DS (1-3 vs 4-5) and the IPI (low-LI vs HI-high) were independently associated with PFS (for interim DS of 4-5, hazard ratio [HR], 2.96 [95% CI, 1.83-4.78], P < 0.001; for HI-high IPI, HR, 4.84 [2.84-8.24], P < 0.001) and OS (for interim DS of 4-5, HR, 2.98 [1.79-4.98], P < 0.001; for HI-high IPI, HR, 5.75 [3.14-10.51], P < 0.001) in the multivariate analysis. We stratified patients into 3 groups based on the risk of progression: Low (low-LI IPI and interim DS 1-3), Intermediate (low-LI IPI with interim DS 4-5, or HI-high IPI with interim DS 1-3), and High (HI-high IPI and interim DS 4-5) risk groups. The risk stratification model showed a significant association with PFS (for low risk vs intermediate risk, HR 3.98 [95% CI, 2.10-7.54], P Conclusion Combining interim DS with baseline IPI can improve risk stratification in patients with newly diagnosed DLBCL. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

Introduction: We successfully identified a subset of CD11b+ monocytes expressing CX3CR1, the only receptor of fractalkine (Fkn; CX3CL1), in G-CSF mobilized peripheral blood stem cell collection (PBSC). We found that Fkn-treated CD11b+CX3CR1+ monocytes express pigment epithelium-derived factor (PEDF) once Fkn activates Fkn/CX3CR1 signaling. PEDF is a glycoprotein, which belongs to the serpin family and involves various physiologic processes such as angiogenesis, cell proliferation, and survival. In this study, we investigate the role of PEDF and its mechanism of action in promoting angiogenesis. Materials andmethods: To mobilize mononuclear cells (MNCs) including CD11b+CX3CR1+ monocytes into peripheral blood (PB), heathy donors were subcutaneously injected with G-CSF (10μg/kg) for 5 days. Apheresis MNCs were collected from donor PB using a COBE spectra cell separator (COBE, Lakewood, CO) 5 days after daily G-CSF injection. Then, CD11b+CX3CR1+ cells were isolated with a MoFlo™ XDP Cell Sorter (Beckman Coulter, Brea, CA). Human umbilical vein endothelial cells (HUVECs) were isolated from human cords and cultured at 37 °C in 5% CO2 on top of collagen in four different settings: (1) untreated (HUVECs alone) (2) VEGF (1ng/mL) treated HUVECs; (3) PEDF (3,30 and 300 ng/mL) treated HUVECs; (4) VEGF (1ng/mL)+PEDF (3,30 and 300 ng/mL) treated HUVECs. To assess dose-dependency, PEDF was administered at different dosages (0, 3, 30 and 300 ng/mL) for 7 days in either the presence or absence of VEGF (1ng/mL). HUVEC growth areas were measured by image J. Results: CD11b+CX3CR1+ monocytes were found at 19.6±3.58% of total MNCs in human G-CSF mobilized PBSC. Fractalkine treatment (50ng/mL for 30 minutes) of these monocytes promoted endothelial cell proliferation of HUVECs and increased PEDF expression according to the angiogenic protein array results. Administration of PEDF inhibitor significantly decreased HUVEC proliferation and vascular structure formation compared to the control group (p Disclosures No relevant conflicts of interest to declare.

Background: In RERISE phase 3 study, radotinib demonstrated significantly higher and faster rates of major molecular response (MMR) than imatinib in patients with newly diagnosed CML-CP. By 36 months follow up, MMR (BCR-ABL1IS ≤ 0.1%) and MR4.5 (BCR-ABL1IS ≤ 0.0032%) in radotinib 300 mg twice daily (bid) were higher than imatinib group. Also, early molecular response (EMR) at 3 months could predict better long term outcomes in both radotinib and imatinib groups. Here, authors updated 48 months long-term benefits and risks of 300mg bid and imatinib 400mg qd from RERISE phase 3 study (NCT01511289). Methods: RERISE study was randomized trial of radotinib 300 mg bid (n=79), radotinib 400 mg bid (n=81), or imatinib 400 mg once daily (qd) (n=81) in patients with newly diagnosed CML-CP. We evaluated long-term MMR and MR4.5, overall survival (OS), and progression-free survival (PFS) including safety data by 48 months. Results: At the study completion, 53% of patients with radotinib and 44% of patients with imatinib treated were remained. MMR and MR4.5 continued to be higher in patients receiving radotinib 300 mg bid compared with imatinib 400mg qd (Table). Especially, MMR rate by 48 months was significantly higher for radotinib compared to imatinib (76% vs 56%; P=0.0070, Figure). Also, early molecular response (EMR) at 3 months were observed in 86% of patients in the radotinib 300 mg bid group and 68% in the imatinib group (P = 0.0179). More patients treated with radotinib 300mg bid who had EMR at 3 months achieved MMR and MR4.5 by 48 months: 84% and 53% in the radotinib 300 mg bid group and 71% and 44% in the imatinib group, respectively. 48 months estimated OS and PFS rate were not significantly different in two groups (99% vs 94%; P=0.3224, 97% vs 94%; P=0.4328). Treatment failure was lower in radotinib group compared with imatinib group (Table). The safety profiles were consistent with those previously reported and most of adverse events (AEs) developed within 12 months. No new or unexpected safety events were reported in both arms by 48 months and no serious CVE related with radotinib reported. Conclusions: With a minimum 48 months follow-up, radotinib continued to demonstrate higher rates of MMR and MR4.5 than imatinib in newly diagnosed CML-CP. Also, these responses with radotinib were earlier and deeper compared with imatinib. Up to 48 months, no new and serious safety events related with radotinib reported. These results demonstrate that radotinib may have higher possibility of treatment- free remission (TFR) on frontline therapy as well as it can be one of the standards of care in newly diagnosed CML-CP. Figure. Figure. Disclosures Bunworasate: IL-YANG: Research Funding. Comia:IL-YANG: Research Funding. Mun:IL-YANG: Research Funding. Caguioa:IL-YANG: Research Funding. Kim:Pfizer: Research Funding; Novartis: Research Funding; BMS: Research Funding; Ilyang: Research Funding.

Fas and Fas ligand (FasL) polymorphisms in the promoter regions influence transcriptional activities. The interaction of these two genes plays a crucial role in apoptotic cell death regulation. They have been associated with esophageal, lung, uterine cervical, and urinary bladder cancers in human. We performed a case-control study to investigate the association between Fas and FasL polymorphisms and acute myeloid leukemia (AML) risk. Fas−1377G>A (rs2234767), −670T>C (rs1800682), and FasL−844T>C (rs763110) polymorphisms in 592 AML patients and 858 healthy controls were genotyped and tested for associations between polymorphisms and AML risk. There were no significant differences in genotypic and haplotypic distributions and gene-gene interaction between patients and controls in the overall analysis (p > 0.05). These results suggested that polymorphisms of Fas and FasL genes were not associated with AML risk in the Korean population.

According to a previous review, multiple mucosa-associated lymphoid tissue (MALT)-organs involving marginal zone B cell lymphomas (MZLs) are present in 10-30% of patients. However, the clinical features and specific relationships among involved organs are yet to be clearly identified. In this study, we conducted retrospective analyses of multiple MALT organs involving MZLs (MM-MZLs) to identify their clinical features, treatment, prognosis, and specific relationships among involved organs. For analysis, between June 1987 and June 2009, a total of 55 patients from 17 different institutions in Korea, all of whom were histologically diagnosed with MM-MZL, were included in this study. MM-MZL was defined as MZL involving more than 2 different MALT organs. Multiple involvements within one MALT organ (e.g. both side ocular lesions, multiple lung nodules, and multiple stomach lesions, etc.) were excluded from this study. The male/female ratio of the 55 patients was 41/14. The median age of our subjects was 59 years (range 30-82 years). MM-MZL without lymph node (LN) was detected only in 9 patients (36.2%). Bone marrow (BM) involvement was observed in 17 patients (30.9%). The most common site of involvement was the gastrointestinal (GI) tract (25 patients, 45.5%) followed by the lung (40%), Waldeyer's ring (WR) (27.3%), and ocular area (25.5%). Ocular MZLs were commonly accompanied with WR- or lung-MZLs. GI-MZLs were WR or GI-MZLs. Lung-MZLs were frequently observed with ocular and GI-MZLs. WR-MZLs were ocular or GI-MZLs. A total of 53 patients were treated, and 2 on watchful wait. As much as 48 patients received chemotherapy-based treatment. Among them, CR or PR was achieved in 38 patients (79.2%, 95% CI 67-91%). Median time to progression (TTP) was 2.3 years (95% CI 1.4-3.2 years). Cause-specific overall survival (OS) did not reach the median value. The 5-year OS rate was 84.9%. MM-MZLs tend to be an indolent disease, characterized by prolonged survival with frequent relapses. The majority of cases could be controlled effectively via chemotherapy-based treatment, and prolonged survival was achieved in those patients. The GI, lung, WR, and ocular area were commonly presented with other MALT site MZLs, and an organ-specific relationship appears to be relevant to MM-MZLs.

Aim: The Korean Multiple Myeloma Working Party performed a nationwide registration of multiple myeloma patients via a web-based data bank system. Methods: We retrospectively analyzed registered data from 3,209 patients since 1999. Results: The median overall survival (OS) was 50.13 months (95% confidence interval: 46.20–54.06 months). Patients ≤40 years demonstrated a longer OS than patients >65 years of age (median OS 71.13 vs. 36.73 months, p < 0.001). Patients who received novel agents at any time during their treatments showed a longer OS than patients who did not (median OS 42.23 vs. 55.50 months, p < 0.001). Response to treatment was associated with OS, with tandem autologous stem cell transplantation (SCT) producing longer OS than single autologous SCT. Conclusions: We demonstrated associations between survival outcomes and treatment modalities as well as baseline disease characteristics in a registry of multiple myeloma patients using a web-based data analysis.

Prospective isolation of hematopoietic stem and progenitor cell subsets depends upon the premise that expression of combinations of surface antigens reflects developmental potential. During the process of differentiation, however, the loss of antigens associated with stem cells and the concomitant gain of those associated with progenitor cells often occurs as a continuum rather than by discrete binary steps. Coupled with the fact that assay conditions can profoundly influence the developmental fates of prospectively isolated cells, gradients of antigen expression during differentiation have led to a variety of interpretations of lineage commitment in hematopoiesis.

Mesenchymal stem cells (MSCs) have been shown to down-regulate T-cell responses. However, the mechanisms underlying remain unknown. In this study, we report that BALB/c bone marrow-derived MSCs inhibit the proliferation of allogeneic T-cells in mixed lymphocyte reactions (MLR), This inhibition is dependent on cell–cell contact, and do not induce apoptosis. Furthermore, cell-cycle analyses reveal that T-cells, in the presence of MSCs, are arrested in the G0/G1 phase through. The blockage of phosphorylation of retinoblastoma protein (Rb), mediated by the p16 INK4A -cyclin D1/cdk4 complex and p21 waf1 , p27 kip1 -cyclin E/cdk2 complex pathway. Our results suggest that MSCs may perform a crucial function in the maintenance of immune homeostasis, via direct regulation of the clonal expansion of activated T-cells. The novel T-cell regulatory mechanism exhibited by MSCs may prove useful in a variety of therapeutic applications.

The aim of this study was to investigate the changes in health-related profiles including quality-of-life (HRQoL) in the chronic myeloid leukemia (CML) patients who discontinued imatinib (IM). An HRQoL survey composed of 43 parameters about IM-related adverse events (AEs), physical health-related and mental health-related was provided at baseline and 6 months post-discontinuation. A total of 55 patients with a sustained UMRD over 6 months were analyzed. Although the majority of IM-related AEs were significantly improved, unexpectedly pruritus and musculoskeletal pain worsen or newly develop in 29.1% and 21.8% of patients, respectively. The improvements in physical and mental health condition were variable in individual patients. In addition, rapid restorations of the hematological and biochemical parameters were observed. The results showed the changes of HRQoL and laboratory tests in treatment-off patients and the necessity of continuing physical and mental support for some patients in tyrosine kinase inhibitor (TKI)-off studies.

The present study sought to elucidate the role of induction and consolidation therapy in elderly patients. We retrospectively collected data of 477 patients who were aged over 60 years at the time of acute myeloid leukemia (AML) diagnosis. The median overall survival (OS) was 339 days in the induction group (n = 266) and 86 days in the best supportive care group (n = 211) (P0.001). In the induction group, the complete remission (CR) rate was 58.3 %, and treatment-related death was 15.4 %. Successful induction was related to good performance [Eastern Cooperative Oncology Group (ECOG2)] [hazard ratio (HR) 3.215; P = 0.002]. Mortality correlated with failure to achieve CR (HR 4.059; P0.001) and poor performance status (ECOG2) (HR 2.731; P = 0.035). In CR patients, poor karyotype and absence of consolidation (HR 2.313; P = 0.003) correlated with mortality. More than one cycle of consolidation was associated with better OS (P0.001). Lack of salvage therapy was associated with mortality in patients who did not achieve CR (HR 3.223; P = 0.005). Intensive induction in patients with good performance and1 cycle of consolidation after CR may be the best strategy for improving OS in elderly AML patients.

To investigate telomere changes in patients with aplastic anaemia (AA) and clinical factors influencing the telomere dynamics, telomere length (TL) was measured in peripheral blood mononuclear cells using Southern blot analysis of 42 patients with AA and 39 healthy normal controls. Nineteen patients received supportive treatment only, while the remaining 23 patients received immunosuppressive therapy with anti-thymocyte globulin or anti-lymphocyte globulin +/- cyclosporin A. In AA patients, TL was on average 1.41 kb shorter than that of age-matched normal controls (P < 0.001). In patients treated with immunosuppression, the mean TL of non-responders was significantly shorter than that of age-matched normal controls (P < 0.001), while no difference in TL was detected in responders compared with controls. Positive correlation was observed between the extent of telomere shortening, the severity of neutropenia (P = 0.05) and the degree of mean corpuscular volume elevation (P = 0.005) at the time of the study. However, there was no correlation with time elapsed since diagnosis (P = 0.214). These findings suggest that haematopoietic stem cells in patients with AA rapidly lose TL at the onset of the disease. The TL shortening may reflect the severity of impairment of haematopoiesis.

Background: Radotinib is a BCR-ABL tyrosine kinase inhibitor (TKI) approved for the treatment of chronic myeloid leukemia in chronic phase (CP-CML). It is typically administered as a fixed dose; however, a subanalysis of the Phase 2 study (Leuk Lymphoma. DOI 10.3109/10428194.2015.1113278) demonstrated that as the dose adjusted for body weight (Dose/BW) increased the risk of dose-limiting toxicity (DLT) significantly. Aims: To assess the impact of Dose/BW of radotinib on the occurrence of DLT as well as on the achievement of major molecular response (MMR) using the clinical data obtained from the Phase 3 study Methods: The Phase 3 study involved 160 CP-CML patients who were randomly assigned to a fixed dose of radotinib 300 mg BID or 400 mg BID regardless of BW. The authors performed a logistic regression analysis to evaluate the relationship between daily Dose/BW and the probability of achieving MMR at 12 months as well as experiencing DLT by 12 months. Chi-square test and Kaplan-Meier analysis (log-rank test) were utilized to compare the incidence of MMR and DLT, respectively, according to specific Dose/BW cut-offs. Results: Efficacy. Dose/BW of radotinib was negatively associated with the rate of MMR when controlled for gender (p = 0.033). That is, increasing Dose/BW rather decreased the likelihood of achieving MMR. More specifically, patients who received ≥13 mg/kg/d showed a significantly lower rate of MMR at 12 months (35%) than those who received Conclusion: Dose adjustment of radotinib based on BW is warranted so as not to exceed 13 mg/kg/d. Therefore, a two-tier weight-based dosing regimen was developed: radotinib 300 mg BID for patients who weigh 60 kg or less, and 400 mg BID for patients who weigh more than 60 kg. A prospective clinical trial would be needed to confirm the efficacy and safety of this new dosing regimen. Disclosures Noh: Il-Yang Pharmaceutical: Research Funding. Jung:Il-Yang Pharmaceutical: Research Funding. Park:Il-Yang Pharmaceutical: Employment. Jo:Il-Yang Pharmaceutical: Employment. Shin:Il-Yang Pharmaceutical: Employment. Kim:BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; ILYANG: Consultancy, Honoraria, Research Funding. Lee:Il-Yang Pharmaceutical: Research Funding.

Background High dose chemotherapy followed by autologous stem cell transplantation (ASCT) has become the standard approach for relapsed or high risk non-Hodgkin's lymphoma (NHL). Several different high dose therapy (HDT) conditioning regimens have been used for NHL, such as BEAM(carustine, etoposide, cytosine arabinoside, melphalan), BEAC( carmustine, etoposide, cytosine arabinoside, cyclophosphamide), and CBV(cyclophosphamide, carmustine etoposide). Carmustine is an active drug in the HDT of NHL but the supply of carmustine is limited in some countries. Intravenous busulfan containing regimens as conditioning regimen have been used for both allogeneic and autologous stem cell transplantation in patients with hematologic and non-hematologic malignancies. We and CISL have previously studied that conditioning regimen of i.v. busulfan/melphalan/etoposide was well tolerated and effective in patients with relapsed or high risk NHL. And busulfan/cyclophosphamide/etoposide conditioning regimen has been extensively utilized in ASCT for NHL. Therefore, based on the encouraging results, we conducted a randomized phase II multicenter trial of busulfan/etoposide/cyclophosphamide (BCT) versus busulfan/etoposide/ melphalan/ (BMT) as conditioning therapy for ASCT in patients with NHL. Methods Patients with chemosensitive high risk NHL or relapsed or primary refractory NHL underwent high dose chemotherapy at 16 centers in Korea. Patients were randomly assigned to receive BCT conditioning chemotherapy or BMT conditioning chemotherapy. BCT regimen consisted of iv busulfan 3.2 mg/kg/day i.v. on days -8,-7, and -6, etoposide 400mg/m2 day i.v. on days -5 and -4 and cyclophosphamide 50mg/kg/day i.v. on days -3 and -2 and BMT regimen were iv busulfan 3.2 mg/kg/day i.v. on days -8,-7, and -6, etoposide 400mg/m2 day i.v. on days -5 and -4 and melphalan 50mg/m2/day i.v. on days -3 and -2. The primary efficacy end points were 2 year progression free survival. Results Seventy five patients were enrolled onto the study. Patients randomly assigned to the BCT group (39 patients) or the BMT group (36 patients). Main subgroups were DLBCL (n=42, 56%) and T cell lymphoma (n=27, 36%). Thirteen patients (33.3%) in the BCT group and 11 patients (30.5%) in the BMT group had disease progression or died. 2 year progression free survival rate was 62.5% in the BCT group and 63.1% in the BMT group (p=0.924) (Fig 1). There was no treatment related mortality. Conclusions No significant differences were observed in progression free survival between BCT group and BMT group. Accordingly, busulfan based conditioning regimen may be regarded as an important treatment option to substitute for BEAM regimen. Further, considering R-CHOP or CHOP regimes are standard induction regimens, BMT conditioning will be good alternative to patients who can't be used cyclophosphamide. Figure PFS after autologous stem cell transplantation. Survival rates among all patient who underwent randomiazation Figure. PFS after autologous stem cell transplantation. Survival rates among all patient who underwent randomiazation Disclosures Kim: Celltrion, Inc.: Consultancy, Honoraria.

Backgroud: Recent reports showing that imatinib (IM) discontinuation can be employed in patients who had enough IM therapy and undetectable molecular residual disease (UMRD) durations prior to IM discontinuation result in treatment-free remission (TFR) as a new therapeutic goal in chronic phase chronic myeloid leukemia (CP CML). Although 50-70% of patients experienced molecular relapse by several TFR studies, the most of patients resumed molecular responses (MR) following restart of IM. Through the Korean multicenter prospective study (Korean Imatinib Discontinuation Study; KID Study), we have identified predictors for sustained UMRD and explored molecular kinetics after the first IM discontinuation. In patients regaining durable UMRD with IM resumption, we tried second IM discontinuation and compared molecular kinetics between the first IM stop and second IM stop. Methods: CP CML patients who were treated with IM for more than 3 years and had undetectable levels of BCR-ABL1 transcripts determined by quantitative reverse transcriptase polymerase chain reaction (PCR) for at least 2 years were eligible for KID study and in cases of MMR loss after 2 consecutive assessments, IM treatment was re-introduced. After IM resumption for MMR loss, the molecular response was evaluated every month until MMR was re-achieved and every 3 months thereafter. The second stop was permitted in the patients who were in second UMRD for at least 2 years. Results: By the data cut-off date of 31 July 2015, among 90 non-transplant UMRD patients with at least 12 months of follow-up, 37 patients lost MMR in 2 consecutive analyses and resumed IM. Among them, 9 patients (5 men and 4 women) with a median age of 54 years (range, 35-59 years) entered into a second IM discontinuation after maintaining UMRD at least 2 years. Prior to first discontinuation, the median duration of IM therapy was 76.8 months (range, 38.5-129.0 months) and the duration of sustained UMRD was 30.1 months (range, 24.4-64.5 months). After first attempt of IM discontinuation, they relapsed after a median duration of 3.7 months (range, 1.9-20.8 months) and re-achieved UMRD at a median of 5.5 months (range, 1.8-9.4 months) after IM resumption. After sustaining a second UMRD for a median of 25.7 months, IM therapy discontinued for a second time. After a median follow-up of 37.4 months (range, 19.7-58.5 months) after second IM discontinuation, 7/9 patients (78%) and 4/9 patients (44%) lost UMRD and MMR, respectively. Among three patients who lost UMRD but not MMR, one patient showed fluctuation of BCR-ABL1 transcript under the level of 0.1% on IS for 19.5 months and two patients has not yet been followed up after a first detection of UMRD loss. Four patients who experienced second relapse (MMR loss) after a median 2.9 months (range, 2.7-3.9 months), which was similar to those of the first IM discontinuation [median 3.75 (range, 1.9-3.9 months)]. The patients who lost MMR were retreated with IM for a median of 13.6 months (range, 0.8-18.6 months); three patients re-achieved MMR at 3.5, 5.5, and 11.5 months, respectively and one re-achieved UMRD at 7.2 months. Conclusion: Our data demonstrated that a second attempt might be possible and the median time to MMR loss after second discontinuation was similar to those of the first discontinuation. But the molecular kinetics after second IM resumption needs longer follow-up with more patients. Further studies on the predictors to select patients for a trial of second TFR and novel strategies such as intermittent therapy will be warranted. Disclosures No relevant conflicts of interest to declare.

Background It has been well known that peripheral T cell lymphoma (PTCL) has undergone poor prognosis compared with other non-Hodgkin lymphomas (NHL). Although the National Comprehensive Cancer Network-International Prognostic Index (NCCN-IPI) has been proposed to determining prognosis for patients with diffuse large B-cell lymphoma (DLBCL) at 2014, there is no study examines whether NCCN-IPI could apply to the T-cell NHLs. In addition, a few studies suggest prognostic utility of interim PET/CT in PTCL, but the role of interim PET/CT is not clear. Purpose We evaluate the predictive efficacy of the NCCN-IPI and interim PET/CT based on visual assessment in patients with newly diagnosed PTCLs. Methods This study included 153 patients with de novo peripheral PTCLs, diagnosed from January 2010 to August 2015. The NCCN-IPI was calculated as following the original references. Survival outcomes were compared with a matched result of IPI and/or Prognostic Index for peripheral T cell lymphoma, unspecified (PIT). Visual assessment of interim PET/CT based on Deauville five point scales was performed at the time of diagnosis, mid-treatment and completion of CHOP/CHOP-like or other non-anthracycline chemotherapy. Results The subtypes of PTCLs included PTCL, not otherwise specified (PTCL-NOS) (26%), angioimmunoblastic T cell lymphoma (20%), anaplastic large cell lymphoma (13%), extranodal NK/T cell lymphoma, nasal type (35%), and the others (6%). The NCCN-IPI showed better risk-based prognostic discrimination than IPI and PIT, especially between high-intermediate and high risk subgroups (3-year overall survival 40% vs. 27% vs. 26% among the high-intermediate risk group, respectively; 3-year overall survival 15% vs. 33% vs. 32% among the high risk group, respectively) with a median follow-up of 25.1 months (Figure 1). The absolute difference of survival rates between the low and high risk groups was 75% based on the NCCN-IPI stratification compared with 45% on the IPI stratification or 54% on the PIT stratification, respectively. When divided into two histologic subgroups (nodal vs. extra-nodal type), the NCCN-IPI showed considerable discriminatory capacity in both histologic groups. However, the IPI or PIT classification could not have discrimination in extra-nodal PTCLs. The interim PET-CT was significantly predicting for progression free survival in all PTCL patients, however, it also showed no predictive value in the patients with extranodal PTCLs, especially NK/T cell lymphoma. Conclusions The NCCN-IPI is a powerful prognostic model in PTCLs predicting overall survival among high-intermediate and high risk patients. Also, interim PET/CT response based on visual assessment could be a valuable prediction tool in nodal PTCLs, however, it should be carefully interpreted in the treatment of extranodal subtypes. Disclosures No relevant conflicts of interest to declare.

Introduction : Myelo-monocytic cells expressing CD11b are involved in angiogenesis, but their specific roles and underlying mechanisms are unclear. CX3CR1 is the only known receptor for fractalkine (Fkn). CD11b+CX3CR1+ cells isolated from ischemic muscles expressed F4/80, which is a common marker for mouse macrophages (Tissue (T)-CD11b+CX3CR1+ macrophages). T-CD11b+CX3CR1+ macrophages exert pro-angiogenic effect by platelet factor-4 (PF-4) production. PF-4 did not promote angiogenesis by itself but magnified the angiogenic activity of VEGF. Although T-CD11b+CX3CR1+ macrophages show definite pro-angiogenic effects, their clinical implementation is limited because they require muscle excision for cell harvesting. Therefore, we focused on angiogenic potential of more accessible bone marrow (BM)-CD11b+CX3CR1+ monocytes, because the CD11b+CX3CR1+monocytes migrate from BM into ischemic muscles via Fkn-mediated chemotaxis and differentiate into macrophages upon tissue damage. Materials and methods: CD11b+CX3CR1+cells were isolated by MoFlo™ XDP Cell Sorter (Beckman Coulter, Brea, CA). Isolated CD11b+CX3CR1+ cells were fixed and stained with anti-PF-4 Ab with PE-conjugated IgG for immunofluorescence staining. For aortic tissue sprouting assay, thoracic aortas were embedded in Collagen Type-1. Aortic segments were incubated with CD11b+CX3CR1+ monocytes in the presence or absence of Fkn, and their conditioned medium (CM) at 37℃ in a humidified 5% CO2 atmosphere with triweekly media replacement. For Fkn treatment, CD11b+CX3CR1+monocytes were incubated with Fkn (50ng/mL) for 30 minutes. Morphometric analysis of sprouting was performed using Image J software (National Institute Health, Bethesda, MD, USA). Results: T-CD11b+CX3CR1+ macrophages greatly increased sprouting from mouse aortic tissue segments, while T-CD11b+CX3CR1- macrophages showed only modest effects (p Conclusion; Fkn triggers angiogenic potential of CD11b+CX3CR1+ monocytes by Fkn/CX3CR1 signaling. Thus, Fkn-treated CD11b+CX3CR1+monocytes may be of potential therapeutic use to accelerate recovery of blood perfusion in ischemic diseases. Disclosures Broxmeyer: CordUse: Other: SAB Member .

This study was conducted to verify whether the response to high-dose intravenous immune globulin (IVIG) was related to the effect of splenectomy in chronic idiopathic thrombocytopenic purpura (ITP) patients. A total of 79 patients over 16 years of age were enrolled in this study. The response to the treatment was classified on the basis of the platelet count as no response (NR, 150 x 10(9)/l). The response was evaluated after the infusion of high-dose IVIG, within 2 weeks after splenectomy (immediate response), and during a follow-up period of more than 6 months after splenectomy (sustained response), respectively. 58 patients (73.4%) showed responses (CR or IR) to high-dose IVIG. After splenectomy, immediate responses were observed in 73 patients (92%). The response to high-dose IVIG had no relationship with the immediate response to splenectomy (P = 0.333). A follow-up evaluation was possible with 58 patients; 6 patients with NR in immediate responses did not show any response during the follow-up period, and 17 patients relapsed within 6 months after immediate responses, so 35 patients (60.3%) had sustained responses. Responders to IVIG had significantly higher sustained response rates to splenectomy than non-responders (62% vs. 38%, P = 0.001). These results indicate that the response to high-dose IVIG could be a valuable factor predicting the sustained response to splenectomy in chronic ITP patients.

Linear IgA bullous dermatosis following autologous PBSC transplantation in a patient with non-Hodgkin's lymphoma

IL-2-activated killer lymphocytes (LAK cells) secrete inflammatory cytokines such as interferon-gamma (IFN-gamma) and tumor necrosis factor alpha (TNFalpha) that can induce nitric oxide (NO) synthesis. We evaluated whether LAK cells could activate NO synthesis in human cancer cells. LAK cells and their culture supernatants induced NO synthesis in DLD-1 colon cancer cells in a dose-dependent manner. NO synthesis was inhibited completely by blocking antibodies to IFN-gamma, demonstrating a key role for this LAK cell cytokine in regulating NO synthesis. The addition of TNFalpha antibodies resulted in partial inhibition. Induction of iNOS mRNA and protein expression in DLD-1 cells was detected. Endogenous NO production inhibited DLD-1 cell proliferation and induced apoptosis, processes that were inhibitable by the NO synthase inhibitor N(G)-monomethyl-l-arginine. Our study has identified a novel, non-contact-dependent LAK cell cytotoxic mechanism: induction of growth inhibition and programmed cell death due to endogenous NO synthesis in susceptible human cancer cells.

We assessed the success rate of empirical antifungal therapy with itraconazole and evaluated risk factors for predicting the failure of empirical antifungal therapy. A multicenter, prospective, observational study was performed in patients with hematological malignancies who had neutropenic fever and received empirical antifungal therapy with itraconazole at 22 centers. A total of 391 patients who had abnormal findings on chest imaging tests (31.0%) or a positive result of enzyme immunoassay for serum galactomannan (17.6%) showed a 56.5% overall success rate. Positive galactomannan tests before the initiation of the empirical antifungal therapy (P=0.026, hazard ratio [HR], 2.28; 95% confidence interval [CI], 1.10-4.69) and abnormal findings on the chest imaging tests before initiation of the empirical antifungal therapy (P=0.022, HR, 2.03; 95% CI, 1.11-3.71) were significantly associated with poor outcomes for the empirical antifungal therapy. Eight patients (2.0%) had premature discontinuation of itraconazole therapy due to toxicity. It is suggested that positive galactomannan tests and abnormal findings on the chest imaging tests at the time of initiation of the empirical antifungal therapy are risk factors for predicting the failure of the empirical antifungal therapy with itraconazole. (Clinical Trial Registration on National Cancer Institute website, NCT01060462).

We retrospectively investigated the incidence, risk factors, and outcomes of SOS (sinusoidal obstruction syndrome; previously veno-occlusive disease [VOD]) after allogeneic hematopoietic stem cell transplantation (alloHSCT) in aplastic anemia. Two hundred and sixty patients were included in the analysis. SOS developed in 7.3% (n=19/260) of patients. Classical Cy (200 mg/m(2))-ATG was the most common conditioning regimen (84.2%) in the SOS group. The SOS mortality rate was 4/19 (21.1%). Univariate analyses revealed that Cy 200 mg/m(2) conditioning (p=0.035), classical Cy-ATG conditioning (p=0.007), and horse ATG conditioning (p0.001) were significant risk factors for developing SOS. Multivariate analysis revealed that only horse ATG conditioning was a poor prognostic factor (HR=3.484; 95% CI 1.226-9.904; p=0.002). Rabbit ATG (HR 12.719; 95% CI 2.332-69.373; p=0.003) and weight gain10% (HR 35.655; 95% CI 2.208-575.805; p=0.012) were risk factors in the overall SOS group. Both rabbit ATG conditioning and weight gain of more than 10% were associated with poor overall survival with a median of 1.2 months (5Y survival rate, any risk factor vs. none: 74.6% vs. 0.0%; p0.001; Fig. 2) in the SOS group. In conclusion, SOS is a relatively rare (7.3%) but highly fatal (21.1%) acute complication of alloHSCT in AA, and the horse ATG conditioning regimen was a significant risk factor for developing SOS.

Despite current immunosuppressive therapies, acute graft-versus-host disease (aGVHD) is a major cause of morbidity and mortality in allogeneic hematopoietic stem cell transplantation (HSCT). In the present study, therapeutic effects of intraperitoneal glutamine (Gln) administration (1g/kg/day) in a mouse aGVHD model were evaluated. Gln administration significantly inhibited the GVHD-induced inflammation and tissue injury in the intestine, liver, skin and spleen. Gln therapy improved the score of clinical evidence of aGVHD and prolonged the median survival of aGVHD mice. Gln administration in aGVHD mice increased the fraction of Foxp3+/CD4+/CD25+ cells in the blood measured on day 7, and decreased the serum levels of tumor necrosis factor-α measured on days 7, 14 and 21 after aGVHD induction. These results demonstrated that Gln administration may be useful in protecting the host from aGVHD.

OBJECTIVES To evaluate if L-arginine: NO pathway is activated in tumor tissues during IL-2 therapy and to evaluate whether IL-2 induced NO synthesis represents an antitumor effector mechanism or an inhibitory factor against therapeutic effects of IL-2. METHODS Four groups [untreated control, NG-monomethyl-L-arginine (MLA) therapy only, IL-2 therapy only, IL-2/MLA therapy groups] of BALB/c mice were injected intraperitoneally with 2 x 10(8) Meth A tumor cells on day 0. MLA was administered subcutaneously with Alzet continuous infusion pumps on day 2. IL-2 therapy (180,000 IU s.c. every 12h for 5 days) was started on day 3. NO production within ascites tumors was assessed by measuring nitrite concentrations in cultures of ascites cells harvested on day 8. Survival and the rate of body weight increment of the mice were measured to evaluate therapeutic responses. Daily urinary nitrate excretion was monitored to demonstrate the effectiveness of MLA in inhibiting NO synthesis. RESULTS Nitrite production in supernatants of Meth A ascites cell cultures was 63 +/- 14 microM in IL-2 treated mice and 3.2 +/- 1.5 microM in untreated controls (p < 0.001). MLA prevented the IL-2 therapy induced increase in nitrite production. IL-2 therapy did not decrease the rate of body weight increment and marginally prolonged mean survival to 18.2 days, compared to 16.6 days in control mice (p = 0.255). MLA administration decreased the rate of body weight increment and prolonged mean survival of IL-2 treated mice (21.8 days, p = 0.001 versus IL-2 alone). Interestingly, the MLA treatment increased the rate of body weight increment and diminished the survival of control mice to 11.6 days (p = 0.003). MLA administration via Alzet continuous infusion pumps achieved approximately 60% suppression of urinary nitrate excretion by control mice. Subcutaneous IL-2 treatment strongly induced nitric oxide synthesis (up to 3.5 mumoles of urinary nitrate/ mouse/day). MLA also effectively suppressed IL-2 induced NO production. CONCLUSION L-arginine: NO pathway can be activated in malignant ascites by IL-2 therapy and NO synthesis functions as an inhibitory mechanism against IL-2 induced anti-tumor effects.

The aims of this study were to investigate the outcomes of second salvage auto-SCT and to identify the impacts of a second auto-SCT compared with systemic chemotherapy alone on disease outcome. Data from 48 patients who underwent second auto-SCT were matched to 144 patients (1:3) who received systemic chemotherapy alone from the Korean Myeloma Registry. Groups were matched for nine potential prognostic factors and compared for treatment outcomes. The median age of matching-pairs at relapse was 55.5 years. A total of 156 patients (81%) received vincristine, doxorubicin and dexamethasone induction therapy before the first auto-SCT. Thirty-five patients (73%) in the second auto-SCT group received novel agent-based therapies before the second auto-SCT, and similar proportion in both groups received novel therapies after relapse of front-line auto-SCT. With a median follow-up of 55.3 months, patients who underwent a second auto-SCT had significantly better median OS (55.5 vs 25.4 months, P=0.035). In multivariate analysis for OS

The effectiveness of high-dose chemotherapy (HDT) followed by autologous stem cell transplantation (ASCT) as a frontline treatment in peripheral T cell lymphomas (PTCLs) is still unclear. We retrospectively investigated the clinical outcomes of HDT/ASCT as an intensifying frontline treatment in 31 patients with newly diagnosed PTCLs. The conditioning regimen of HDT/ASCT consisted of busulfan, cyclophosphamide, and etoposide (BuCyE). At diagnosis, five (16.1 %) patients were classified as high risk according to the prognostic index for PTCL (PIT). The disease status of the patients before HDT/ASCT consisted of 23 patients (74.2 %) with complete response (CR) and eight patients (25.8 %) with partial response (PR). Six (75 %) out of eight patients with PR at pretransplantation were improved in terms of the response to CR after HDT/ASCT. At a median follow-up of 32.4 months, the 3-year probability of overall survival (OS) and progression-free survival (PFS) was 64.5 ± 8.6 %. Transplant-related mortality occurred in three patients (9.7 %), due to septic shock, hemorrhage, and delayed pneumonia, respectively. Bone marrow involvement of PTCL at diagnosis was a poor prognostic factor for OS. In conclusion, frontline HDT/ASCT with a conditioning regimen of BuCyE may be an effective and tolerable intensifying therapeutic option to improve outcomes in patients with PTCLs.

The effect of rosiglitazone, an agonist of peroxisome proliferator-activated receptor-γ (PPARγ), was investigated in a mouse parent-to-F1 GVHD model. Rosiglitazone inhibited mixed lymphocyte reactions, inducing enhanced apoptosis in CD4+, CD8+, and B220+ cells, but not in NK1.1+, Mac-1+, CD4+/CD25+ and CD3+/NK1.1+ cells. Rosiglitazone administration prevented GVHD in the liver, skin, spleen and intestine. Rosiglitazone inhibited GVHD-induced increases in serum levels of tumor necrosis factor-alpha, interferon-gamma, interleukin (IL)-6, and IL-12, and the GVHD-induced decreases in transforming growth factor-beta and IL-10. Immunophenotyping of splenic leukocytes demonstrated that while rosiglitazone treatment increased the population percentages of both donor and host CD4+/CD25+ and CD3+/NK1.1+ cells, the treatment resulted in lower fractions of both donor and host CD8+ cells. Rosiglitazone inhibited the GVHD-induced decreases in the expression of phosphatase and tensin homologue deleted on chromosome 10 (PTEN), as well as the GVHD-induced increase in the splenic p-Akt and nuclear factor-kappa B expression. These results indicate that rosiglitazone and PPARγ activation may be useful in protecting the host from GVHD.

This retrospective study concerns non-bacterial infections in Asian patients receiving alemtuzumab. The clinical data of 182 patients treated with alemtuzumab alone or alemtuzumab-containing chemotherapy between the years 2003 and 2009 was collected from six Asian countries. Alemtuzumab was used in the setting of frontline (n =48) or salvage (n =90) treatment, and as a part of the conditioning regimen for allogeneic stem cell transplant (n =44). Reactivation of cytomegalovirus (66/182) and varicella zoster virus (25/182), and fungal infection (31/182) including invasive pulmonary aspergillosis, were the most common infectious complications in this retrospective analysis. Thus, we recommend routine prophylaxis with valganciclovir and itraconazole, especially when alemtuzumab is used in the conditioning regimen for allogeneic stem cell transplant. Pneumocystis jirovecii pneumonia (PJP) was found in four patients (3%, 4/122) receiving alemtuzumab as conditioning for stem cell transplant or salvage treatment. Three cases of hepatitis B virus reactivation were found in antigen-negative patients, and 16 cases of tuberculosis were observed. Infection is the major complication of alemtuzumab therapy, and these infectious complications are potentially severe and life-threatening. Based on our retrospective analysis, we have constructed a guideline for antimicrobial prophylaxis in Asian patients receiving alemtuzumab therapy.

Background We previously have shown that concurrent chemoradiotherapy (CCRT) followed by chemotherapy such as VIPD (etoposide, ifosfamide, cisplatin and dexamethasone) or VIDL (etoposide, ifosfamide, dexamethasone and L-asparaginase) is an effective treatment for the management of localized extranodal NK/T-cell lymphoma (ENKTL), nasal type. To further improve efficacy, we designed a new treatment protocol, MIDLE (methotrexate, ifosfamide, dexamethasone, L-asparaginase and etoposide), which incorporates tri-weekly administration of L-asparaginase during CCRT to reduce the probability of systemic progression and high dose methotrexate to intensify chemotherapy based on previous excellent outcomes of methotrexate-containing regimens such as SMILE (dexamethasone, methotrexate, ifosfamide, L-asparaginase, etoposide) and MLD (methotrexate, L-asparaginase, dexamethasone). Methods The treatment scheme of CCRT consisted of radiation 36-45 Gy and weekly administration of cisplatin 30 mg/m2 (total: 4 doses). During the CCRT, tri-weekly 4,000 IU of Escherichia coli L-asparaginase was administered intravenously (IV). The chemotherapy, MIDLE (methotrexate 3 g/m2 on day 1, etoposide 100 mg/m2, Ifosfamide 1000 mg/m2 on day 2-3, dexamethasone 40mg on day 1-4, and L-asparaginase 6000 IU/m2 IV on day 4, 6, 8, 10) was repeated every 28 days for two cycles. All patients provided informed written consents and this trial was registered at www.ClinicalTrials.gov(NCT01238159). Results Twenty-eight patients with stage IE/IIE ENKTL were enrolled, and the median age was 51 years (range, 30-77 years). Twenty four patients were male while only four patients were female. Twenty-two patients had stage IE and six IIE disease. Twenty four were classified as low risk group and the other four intermediate group according to PINK-E (Kim SJ et al., EHA 2015 S110). All but two patients completed CCRT, which resulted in 85.7% of overall response rate including 16 complete responses (57.1%) and 8 partial responses (28.6%). One showed stable disease (SD) and the other one showed progressive disease (PD) with development of new distant lymph node involvement after CCRT. Grade 3 or 4 hematologic toxicity was not common. Only two patients experienced G3 neutropenia during or after CCRT. However, grade 3 non-hematologic toxicities were noted including bilirubin elevation (n = 3), mucositis (n = 1), anorexia (n=5) and nausea/vomiting (n = 11) Two could not complete CCRT according to the protocol due to G3 allergic reaction to L-asparaginase (n=1) and prolonged G3 mucositis (n=1). After the completion of CCRT, 23 out of 28 patients entered the MIDLE chemotherapy as five patients including one disease progression and four withdrawal during (n=2) or after (n=2) CCRT due to toxicities. All those who completed the planned two cycles of MIDLE chemotherapy achieved complete response after chemotherapy including those with PR (n=6) and SD (n=1) after CCRT. Three patients dropped out during or after their first cycle of MIDLE due to non-hematologic toxicities (recurrent G3 bilirubinemia (n=1), G3 increased creatinine (n=1), G5 infection (n=1)). The final complete response rate was 82% (23/28). It was associated with a significant rate of grade 3/4 neutropenia (n=21) and febrile neutropenia (n=10). Two patients experienced acute kidney injury (AKI) during the first cycle of MIDLE and one of them died of pneumonia complicated by sepsis. With a median follow-up of 46 months (95% confidence interval: 39 - 47 months), four patients progressed and five patients died with the estimated 3-year progression-free survival rate of 74.1% and overall survival rate of 81.5%. PINK-E could successfully stratify both time-to-progression (p=003) and overall survival (p=0.006) in this study. Conclusion L-asparaginase plus concurrent chemoradiotherapy followed by MIDLE chemotherapy may be an effective treatment strategy for stage I/II extranodal NK/T-Cell lymphoma, nasal type. However, higher numbers of patients were withdrawn during or after CCRT due to toxicity or poor tolerance than previous study. MIDLE chemotherapy was associated with high rate of G3 or 4 hematologic toxicities. Thus, this approach should be reserved for selected patients such as young fit but high risk of relapse. PINK-E can be a useful prognostic index for stage I/II extranodal NK/T-Cell lymphoma, nasal type. Disclosures No relevant conflicts of interest to declare.

[Graphic][1] Background Radotinib is a second generation BCR-ABL1 tyrosine kinase inhibitor (TKI) developed by IL-YANG Pharm. Co., Ltd (Seoul, South Korea) and approved by the Korea FDA for the treatment of chronic phase chronic myeloid leukemia (CML-CP) patients who have failed prior TKIs. We conducted the randomized, open-label, phase 3 study to assess the efficacy and safety of radotinib, as compared with imatinib, for the first-line treatment of newly diagnosed CML-CP. Methods Based on baseline demographics and Sokal risk score, 241 patients were randomized 1:1:1 to radotinib 300 mg twice daily (bid) (n=79), radotinib 400 mg bid (n=81), or imatinib 400 mg once daily (qd) (n=81). The primary endpoint was the rate of major molecular response (MMR) by 12 months and molecular response was assessed by RQ-PCR at baseline and every 3 months. Secondary endpoints were the rate of complete cytogenetic response (CCyR), MR4.5 by 12 months, and the rate of progression to accelerate phase or blast crisis. Results All three study groups were well balanced with baseline age, gender, race and Sokal risk score. With minimum follow-up of 12 months, the proportions of patients receiving a study drug were 86.3% (69/79) in radotinib 300 mg bid group, 71.6% (58/81) in radotinib 400 mg bid group, and 81.5% (66/81) in imatinib 400 mg qd group. By 12 months, rates of MMR were significantly higher in patients receiving radotinib 300 mg bid (51.9%, P = .0044) and radotinib 400 mg bid (45.7%, P = .0342) compared with imatinib (29.6%). The median time to MMR among responders were shorter on radotinib 300 mg bid (5.7 months) and radotinib 400 mg bid (5.6 months) than imatinib group (8.2 months). The MR4.5 rates by 12 months were also higher for both radotinib 300 mg bid (15.2%) and 400 mg bid (13.6%) compared to imatinib (8.6%). The CCyR rates by 12 months were also higher for radotinib 300 mg bid (91.1%, P = .0120) compared with imatinib (76.5%). There was no progression to accelerated phase or blast crisis in all groups by 12 months. Discontinuation due to adverse events (AEs) or laboratory abnormalities occurred in 7 (8.8%), 16 (19.8%), and 5 (6.2%) patients for radotinib 300 mg bid, radotinib 400 mg bid and imatinib, respectively. Grade 3/4 thrombocytopenia occurred in 16.5% of patients receiving radotinib 300 mg bid, in 13.6% for radotinib 400 mg bid, and in 19.8% receiving imatinib. And grade 3/4 neutropenia occurred in 19.0%, 23.5%, and 29.6% for radotinib 300 mg bid, 400 mg bid and imatinib, respectively. The most common any grade non-laboratory AEs were skin rash (35.4% and 33.3%), nausea/vomiting (22.8% and 23.5%), headache (19.0% and 30.9%), and pruritus (19.0% and 30.0%) in radotinib 300 mg bid and radotinib 400 mg bid, respectively; AEs in the imatinib group were edema (34.6%), myalgia (28.4%), nausea/vomiting (27.2%), and skin rash (22.2%). Overall, grade 3/4 non-laboratory AEs were uncommon in all groups. Conclusions With minimum 12 months follow-up, radotinib demonstrated significantly higher and faster rates of CCyR and MMR than imatinib in patients with newly diagnosed CML-CP. The safety profiles of the radotinib and imatinib were different, and most AEs were manageable with optimal dose reduction. The results of this trial support that radotinib can be one of the standard of care in newly diagnosed CML-CP. | | Radotinib 300mg BID | Radotinib 400mg BID | Imatinib 400mg QD | | --------------------------------------------- | --------------------------- | --------------------------- | ------------------------- | | | (N=79) | (N=81) | (N=81) | | Age, median (range), years | 45 (20-75) | 43 (18-84) | 45 (18-83) | | Gender, n (%) | | | | | Male | 52 (65.8) | 47 (58.0) | 52 (64.2) | | Female | 27 (34.2) | 34 (42.0) | 29 (35.8) | | Sokal risk, n (%) | | | | | Low | 21 (26.6) | 22 (27.2) | 22 (27.2) | | Intermediate | 38 (48.1) | 38 (46.9) | 39 (48.2) | | High | 20 (25.3) | 21 (25.9) | 20 (24.7) | | MMR by 12 months, % | 51.9 | 45.7 | 29.6 | | | P = .0044 | P = .0342 | | | Cumulative Incidence of MMR by 12 months¢O, % | 57.0 | 58.0 | 35.0 | | | P = .0040 | P = .0037 | | | MR4.5 by 12 months, % | 15.2 | 13.6 | 8.6 | | CCyR by 12 months, % | 91.1 | 81.5 | 76.5 | * ¢O Kaplan-Meier estimates of MMR Table. Baseline Characteristics, Molecular and Cytogenetic Response Rates Disclosures Kim: IL-YANG Pharm. Co. Ltd: Research Funding. Kim: Alexion Pharmaceuticals: Research Funding. Chung: Alexion Pharmaceuticals: Research Funding. Choi: Alexion Pharmaceuticals: Research Funding. [1]: /embed/inline-graphic-2.gif

Background: Recent studies have demonstrated that early molecular milestones were able to identify high-risk chronic myeloid leukemia patients treated with frontline imatinib (IM) and second generation tyrosine kinase inhibitors (2G TKIs) such as nilotinib and dasatinib. However, whether a single measurement of BCR-ABL1 transcripts level after 3 months of treatment is sufficient to define failure necessitating a change of treatment is not confirmed. Radotinib (RAD) is a 2G TKI for BCR-ABL1 tyrosine kinase, which was approved by the Korea FDA for the second-line therapy, and the phase 3 study comparing the efficacy and safety of RAD 300 and 400 mg twice daily and IM 400 mg once daily in patients with newly diagnosed CP CML was performed. The aim of this study was to identify the predictive value of 3-month molecular milestone for an achievement of major molecular response (MMR) by 12 months to RAD therapy. Additionally, in the same population, predictive factors for achieving MMR by 12 months were analyzed. Methods: Among 241 patients who were enrolled in the randomized, open-label, phase 3 study of RAD, 236 patients with available 3-month qRT-PCR on study therapy [RAD 300 mg twice (n = 79), RAD 400 mg twice (n = 79), IM 400 mg once (n = 78)] were evaluated. Molecular responses were monitored using a qRT-PCR assay in 3-month intervals by 12 months. All qRT-PCR were tested with at least 4.5-log sensitivity in the central laboratory (Cancer Research Institute, The Catholic University of Korea, Seoul, Korea) and MMR was defined as a BCR-ABL1 transcript level of 0.1% or lower on the international scale (IS). Results: 236 patients (including 149 men and 87 women) with available 3-month qRT-PCR on study therapy were evaluated. With a median age of 45 years (range, 18-84 years), the distribution of low, intermediate and high Sokal risk scores were 27%, 47% and 26%, respectively. At 3 months, BCR-ABL1 ≤10% [RAD 300 mg twice (n = 68), RAD 400 mg twice (n = 69), IM 400 mg once (n = 55)] and >10% [RAD 300 mg twice (n = 11), RAD 400 mg twice (n = 10), IM 400 mg once (n = 23)] were observed. In the IM 400 mg once group, patients with BCR-ABL1 ≤10% at 3 months showed a significant higher rate of MMR by 12 months compared with that of patients with BCR-ABL1 >10% (38.2% vs 13.0%, P = 0.028). In the RAD 300 and 400 mg twice group, an achievement of 3-month EMR was associated with a higher rate of MMR by 12 months [57.4% vs 18.2%, P = 0.016 (RAD 300 mg twice) and 50.7% vs 10.0%, P = 0.018 (RAD 400 mg twice)]. After adjusting for factors affecting achievement of MMR by 12 months on univariate analyses, multivariate analyses showed that b2a2 transcript type (RR of 0.46, P = 0.023), large spleen size (RR of 0.91, P = 0.001), and no achievement of 3-month EMR (RR of 0.24, P = 0.004) were predictor for not achieving MMR by 12 months. Significance of 3-month EMR for achieving MMR by 12 months was observed in the separated treatment groups: RR of 0.24, P = 0.037 in the IM 400 mg once group, RR of 0.17 P = 0.028 in the RAD 300 mg twice group, and RR of 0.11, P = 0.040 in the RAD 400 mg twice group. Conclusions: Our results suggest that 3-month EMR can play key roles for 12-month MMR achievement in CP CML patients treated with IM and RAD. In addition, some factors for achieving 12-month MMR were detected. To evaluate the long-term prognostic value of 3-month EMR, further clinical investigations in a larger patient population with longer follow-up are needed. Disclosures Kim: IL-YANG Pharm.Co.Ltd: Research Funding. Chung:Alexion Pharmaceuticals: Research Funding.

The clinical efficacy and safety of yttrium-90 ((90)Y)-ibritumomab tiuxetan consolidation treatment following rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) chemotherapy was investigated in patients with limited-stage and bulky diffuse large B-cell lymphoma (DLBCL). This prospective, multi-center, pilot trial included 21 patients who were newly diagnosed with stage I/II, bulky DLBCL and achieved a complete or partial response after six cycles of R-CHOP. The median size of bulky disease was 10.0 × 7.0 cm. After a median follow-up of 28.8 months, the overall response rate after (90)Y-ibritumomab tiuxetan consolidation treatment was 80.9%, including 4.8% partial response. However, six patients (28.6%) experienced a progression or relapse. The 3-year overall and progression-free survival rates were 85.0 ± 8.0% and 75.0 ± 9.7%, respectively. Grade 3-4 adverse events were mainly hematologic toxicities, such as thrombocytopenia (35%) and neutropenia (60%). One patient experienced grade 3 Pneumocystis carinii pneumonitis. Thus, (90)Y-ibritumomab tiuxetan consolidation following six cycles of R-CHOP resulted in an acceptable response with tolerable toxicity in patients with limited-stage and bulky DLBCL.

The aims were to investigate the feasibility of imatinib mesylate (IM) discontinuation in chronic myeloid leukemia patients who were initially treated with IM and achieved complete molecular response (CMR). Fourteen patients were included. Ten were relapsed within 9.5 months after discontinuation of IM. All 7 patients with high Sokal risk were relapsed. The probability of CMR persistence at 1-year was 28.6%. All relapsed patients were still responsive to IM. A high Sokal risk and delayed acquisition of CMR were associated with relapse. IM discontinuation in patients achieved CMR after treatment with front-line IM might be feasible. Further studies are warranted.

Background Primary intestinal non-Hodgkin lymphoma (NHL) is a heterogeneous disease with regard to anatomic and histologic distribution. Thus, analyses focusing on primary intestinal NHL with large number of patients are warranted. Methods We retrospectively analyzed 581 patients from 16 hospitals in Korea for primary intestinal NHL in this retrospective analysis. We compared clinical features and treatment outcomes according to the anatomic site of involvement and histologic subtypes. Results B-cell lymphoma (n = 504, 86.7%) was more frequent than T-cell lymphoma (n = 77, 13.3%). Diffuse large B-cell lymphoma (DLBCL) was the most common subtype (n = 386, 66.4%), and extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) was the second most common subtype (n = 61, 10.5%). B-cell lymphoma mainly presented as localized disease (Lugano stage I/II) while T-cell lymphomas involved multiple intestinal sites. Thus, T-cell lymphoma had more unfavourable characteristics such as advanced stage at diagnosis, and the 5-year overall survival (OS) rate was significantly lower than B-cell lymphoma (28% versus 71%, P < 0.001). B symptoms were relatively uncommon (20.7%), and bone marrow invasion was a rare event (7.4%). The ileocecal region was the most commonly involved site (39.8%), followed by the small (27.9%) and large intestines (21.5%). Patients underwent surgery showed better OS than patients did not (5-year OS rate 77% versus 57%, P < 0.001). However, this beneficial effect of surgery was only statistically significant in patients with B-cell lymphomas (P < 0.001) not in T-cell lymphomas (P = 0.460). The comparison of survival based on the anatomic site of involvement showed that ileocecal regions had a better 5-year overall survival rate (72%) than other sites in consistent with that ileocecal region had higher proportion of patients with DLBCL who underwent surgery. Age > 60 years, performance status ≥ 2, elevated serum lactate dehydrogenase, Lugano stage IV, presence of B symptoms, and T-cell phenotype were independent prognostic factors for survival. Conclusions The survival of patients with ileocecal region involvement was better than that of patients with involvement at other sites, which might be related to histologic distribution, the proportion of tumor stage, and need for surgical resection.

Cancer therapy often produces anemia, which is treated with erthropoietin (EPO) to stimulate erythrocyte production. However, concerns have recently arisen that EPO treatment may promote later tumor metastasis and mortality. The mechanisms underlying such effects are unknown, but it is clear that EPO has pleiotropic effects in cell types other than hematopoietic cells. In this study, we investigated how EPO affects lymphangiogenesis and lymph node tumor metastasis in mouse models of breast cancer and melanoma. In these models, EPO increased lymph node lymphangiogenesis and lymph node tumor metastasis in a manner associated with increased migration, capillary-like tube formation, and dose- and time-dependent proliferation of human lymphatic endothelial cells. EPO increased sprouting of these cells in a thoracic duct lymphatic ring assay. These effects were abrogated by cotreatment with specific inhibitors of phosphoinositide 3-kinase or mitogen-activated protein kinase, under conditions in which EPO increased Akt and extracellular signal–regulated kinase 1/2 phosphorylation. Intraperitoneal administration of EPO stimulated peritoneal lymphangiogenesis, and systemic treatment of EPO increased infiltration of CD11b+ macrophages in tumor-draining lymph nodes. Finally, EPO increased VEGF-C expression in lymph node–derived CD11b+ macrophages as well as in bone marrow–derived macrophages in a dose- and time-dependent manner. Our results establish that EPO exerts a powerful lymphangiogenic function and can drive both lymph node lymphangiogenesis and nodal metastasis in tumor-bearing animals. Cancer Res; 71(13); 4506–17. ©2011 AACR.

Stage IV marginal zone B-cell lymphomas (MZL) are detected in more than 25% of lymphoma patients. In this study, we conducted retrospective analyses of specific cases of stage IV MZL in order to assess their clinical features, as well as the treatments and prognoses of these cases. A total of 94 patients with histological diagnosis of stage IV-MZL from 17 different institutions in Korea were included. Multiple-mucosa-associated lymphoid tissue (MALT)-organs-involved MZL (M-MZL) was detected in 34 patients (36.2%). Bone-marrow-involved stage IV MZL (BM-MZL) was detected in 33 patients (35.1%). Median time to progression (TTP) was 2.4years (95% CI, 1.9-2.9). Five- and 10-year overall survival rates were 84.5% and 79.8%, respectively. Patients with lymph node involvement in stage IV MZL appeared to have worse prognoses in TTP (P=0.015). Thirty-one patients were treated with a regimen including rituximab (CTx-R[+]), and 31 with a regimen that did not include rituximab (CTx-R[-]). The CTx-R(+) group showed better responses than the CTx-R(-) group (83.9%versus 54.8%, P=0.026). However, no differences in TTP duration were detected (P=0.113). Stage IV MZL tend to follow an indolent disease course. Therefore, lymph node involvement is a more valuable prognostic factor for TTP. Rituximab appears to contribute to better responses, but not in cases of TTP.

Background The breast is a rare extranodal site of non-Hodgkin lymphoma, and primary breast lymphoma (PBL) has been arbitrarily defined as disease localized to one or both breasts with or without regional lymph nodes involvement. The aim of this study was to evaluate the clinical outcomes in patients with diffuse large B cell lymphoma (DLBCL) and breast involvement, and to find the criteria of PBL reflecting the outcome and prognosis. Methods We retrospectively analyzed data from 68 patients, newly diagnosed with DLBCL and breast involvement at 16 Korean institutions between January 1994 and June 2009. Results Median age at diagnosis was 48 years (range, 20-83 years). Forty-three (63.2%) patients were PBL according to previous arbitrary criteria, sixteen (23.5%) patients were high-intermediate to high risk of international prognostic index. The patients with one extranodal disease in the breast (OED) with or without nodal disease were 49 (72.1%), and those with multiple extranodal disease (MED) were 19 (27.9%). During median follow-up of 41.5 months (range, 2.4-186.0 months), estimated 5-year progression-free survival (PFS) was 53.7 ± 7.6%, and overall survival (OS) was 60.3 ± 7.2%. The 5-year PFS and OS was significantly higher for patients with the OED group than those with the MED group (5-year PFS, 64.9 ± 8.9% vs. 27.5 ± 11.4%, p = 0.001; 5-year OS, 74.3 ± 7.6% vs. 24.5 ± 13.0%, p < 0.001). In multivariate analysis, MED (hazard ratio [HR], 3.61; 95% confidence interval [CI], 1.07-12.2) and fewer than four cycles of systemic chemotherapy with or without local treatments (HR, 4.47; 95% CI, 1.54-12.96) were independent prognostic factors for worse OS. Twenty-five (36.8%) patients experienced progression, and the cumulative incidence of progression in multiple extranodal sites or other than breasts and central nervous system was significantly different between the OED group and the MED group (5-year cumulative incidence, 9.7 ± 5.4% vs. 49.0 ± 15.1%, p = 0.001). Conclusions Our results show that the patients included in OED group, reflecting different treatment outcome, prognosis and pattern of progression, should be considered as PBL in the future trial. Further studies are warranted to validate our suggested criteria.

Klinefelter syndrome (KS) is the most commonly diagnosed X chromosome aneuploid syndrome among males. The association between hematologic malignancies such as non-Hodgkin lymphoma and leukemia and KS has been established recently on the basis of numerous case reports and a large cohort study. The risk of chronic myeloproliferative disease (MPD) as a hematologic malignancy in KS, however, has not been evaluated to date. Moreover, to our knowledge, there is only one case report that observed MPD in a patient with KS. Even though the Janus kinase 2 (JAK2) mutation was considered the primary cause in the pathogenesis of MPD, the mutation status was not described in that report. We found JAK2 V617F mutation-positive essential thromobocythemia (ET) in a patient with KS. To the best of our knowledge, this case represents the first case report of JAK2 V617F mutation in a patient with KS. Furthermore, we also suggest the hypothesis that X chromosome aneuploidy as a "pre-JAK2" cytogenetic change may be associated with the development of clonal hematopoiesis and carcinogenesis, because of the finding of higher oncogenic potential of extra X chromosome. In this study, we present the first report of JAK2 V617F-positive ET in a patient with KS, as well as a review of the relevant literature.

Abstract 4999 Introduction Ovary can be involved as a primary ovarian lymphoma or secondarily involved by disseminated disease of non-Hodgkin's lymphoma. However, ovarian involvement is an extremely rare event in non-Hodgkin's lymphoma. Thus, it clinical features and prognostic relevance has rarely been addressed, and most publications refer to a single or a few cases. Thus, we retrospectively analyzed patients with ovarian involvement Patients and methods 32 patients with ovarian involvement were assembled from 8 hospitals affiliated with the CISL (Consortium for Improving Survival of Lymphoma), a Korean lymphoma study group. Primary ovarian involvement was defined as a lymphoma confined to ovary with or without involvement of adjacent lymph nodes and contiguous organs. Secondary ovarian lymphoma was defined as a secondary involvement of ovary in disseminated disease of lymphoma at initial diagnosis. Results Twelve patients had primary ovarian lymphoma (37.5%) while twenty patients (62.5%) had secondary ovarian involvement by systemic disease. The clinical manifestations of ovarian involvement were similar to that of other ovarian tumors, namely an abdominal pain (31%), abdominal distension (19%) or lower abdominal palpable mass (16%). Pathological review according to the WHO classification showed that the most common histological subtype was diffuse large B-cell lymphoma (DLBCL, 75.0%, 24/32), and the frequency of other subtypes was as follows: Burkitt lymphoma (BL, 12.5%, 4/32), lymphoblastic lymphoma (6.3%, 2/32), marginal zone B-cell lymphoma (MZL, 3.1%, 1/32), peripheral T-cell lymphoma, unspecified (PTCL-U, 3.1%, 1/32). The median age (43 years, range 18-80) was younger than that of previously reported other organs such as uterus or prostate. The presence of B symptoms was only observed in 31.3%, and the performance status was good (84.4% of patients had less than grade II of ECOG performance status). The cases involving two or more than two extranodal sites were 68.8% while cases with elevated level of serum LDH were 59.4%. Thus, 59.4% of patients had the low or low-intermediate score of IPI score. Bilateral ovarian involvement was found in 12/32 (38%) while unilateral involvement was 20/32 (63%, 9 right and 11 left side. Three patients showed the involvement of central nervous system (CNS) at diagnosis (3/32, 9.4%). These three patients had DLBCL histology and unfavorable parameters including stage IV, high IPI score and bone marrow BM involvement. Thus, the initial CNS involvement might be associated with advanced stage of lymphoma not with ovarian involvement itself. Surgical removal of involved ovary was performed in 20 patients (62%), and then they were treated with systemic chemotherapy. Twelve patients (38%) were treated with chemotherapy alone. The comparison of outcomes according to the treatment modalities showed the outcomes of chemotherapy-based treatment versus surgery-based treatment were not significantly different (2 year overall survival; 66% vs. 68%). With a median follow-up of 25 months (range 3-185), 13 patients (40.6%) relapsed. Two patients were relapsed in single lesion and 11 were relapsed in multiple lesions. The majority relapsed at various extranodal sites (11/13, 84.6%) and only 2 cases relapsed at nodal sites. Most common relapse site was CNS (4 cases among 13 cases of relapse, 31%). All CNS relapsed patients had DLBCL histology. Ovarian relapse observed in one case that had been involved both ovary at the time of diagnosis. The 2 year overall survivals (OS) were 67% (95% CI: 50 to 83%) and the 2 year progression free survivals (PFS) were 61% (95% CI: 44 to 78%). In univariate analysis, high IPI score, 2 or more extranodal sites involvement and elevated LDH level were statistically significant parameters for lower PFS; moreover, 2 or more extranodal sites involvement and elevated LDH level associated with poor OS. Conclusion Ovarian involvement of non-Hodgkin's lymphoma showed a dismal prognosis despite active treatment. Therefore, more optimal treatment strategy should be warranted. Disclosures No relevant conflicts of interest to declare.

High-dose chemotherapy followed by autologous stem cell transplantation (HDT/ASCT) offers a rescue option for T cell lymphoma patients with poor prognosis. However, the effectiveness of HDT/ASCT in patients with various peripheral T cell subtypes, optimal transplant timing, and the prognostic factors that predict better outcomes, have not been identified. We retrospectively investigated the clinical outcomes and prognostic factors for HDT/ASCT in 64 Korean patients with peripheral T cell lymphoma, unspecified (PTCL-U) between March 1995 and February 2007. The median age at transplantation was 44 years (range: 15-63 years). According to the age-adjusted International Prognostic Index (a-IPI) and the prognostic index of PTCL (PIT), 8 patients (12.5%) were in the high-risk group and 16 (26.6%) had the 2-3 PIT factors, respectively. After a median follow-up of 29.7 months, the 3-year overall survival (OS) and progression-free survival (PFS) rates were 53.0% ± 7.5% and 44.3% ± 7.0%, respectively. Univariate analysis showed that poor performance status, high lactate dehydrogenase (LDH) levels, high a-IPI score, high PIT classes, failure to achieve complete response (CR) at transplantation, and nonfrontline transplantation were associated with poor OS. Multivariate analysis showed that failure to achieve CR at transplantation (hazard ratio [HR] 2.23; 95% confidence interval [CI] 1.78-7.93) and 2-3 PIT factors (HR 3.76; 95% CI 1.02-5.42) were independent prognostic factors for OS. Failure to achieve CR at transplantation and high PIT are negative predictable factors for survival following HDT/ASCT in patients with PTCL-U.

Sirtuin1 (SIRT1) is a nicotinamide adenine dinucleotide-dependent deacetylase. Recently, it is suggested that SIRT1 may be involved in the development of malignant tumors including mouse lymphoma. Therefore, we investigated the prevalence and the prognostic impact of SIRT1 expression in diffuse large B-cell lymphoma (DLBCL). Immunohistochemical expression of SIRT1, p53, bcl2, CD10, bcl6, and multiple myeloma-1 (MUM1) were evaluated by using a 2 mm core from 104 DLBCL patients for tissue microarray. Positive expression of SIRT1 was seen in 74% (77/104) of patients. In total DLBCL patients, SIRT1 and p53 expression were significantly associated with shorter overall survival (OS) by univariate analysis (P=0.001 and P=0.011, respectively). SIRT1 was also an independent prognostic factor by multivariate analysis (P=0.01). According to the expression patterns of CD10, bcl6, and MUM1, germinal center B cell (GCB) types were represented in 38 cases (37%) and non-GCB types were represented in 66 cases (63%). In the GCB type, only p53 expression was associated with a significantly shorter OS (P=0.032). In the non-GCB type, expression of SIRT1 correlated with shorter OS by univariate analyses (P=0.005) and multivariate analyses (P=0.049). In conclusion, we showed that SIRT1 expression is a clinically significant prognostic indicator for DLBCL patients.