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T lymphocytes are critical players in graft-versus-host disease (GVHD); however, their specific roles and mechanisms in GVHD have not been clearly defined. Co-inhibitory receptors including PD1, TIM3, TIGIT, and LAG3 play a key role in regulating T cell responses and maintaining immune homeostasis. TIM3 expression on lymphocytes was identified to induce immune tolerance in a mouse GVHD model; in addition, PD1 +TIM3 + double-positive T cells displayed more potent immunosuppression compared to PD1 + T cells. However, despite the strong immunosuppression exerted by PD1 +TIM3 + double-positive T cells, their clinical potential is greatly limited by their low cell number in peripheral blood. In this study, we introduce a novel method to isolate CD3 + cells from G-CSF mobilized peripheral blood stem cells (G-PBSCs), and culture CD3 +PD1 +TIM3 + lymphocytes to treat GVHD. Methods. The donors were subcutaneously injected with G-CSF (10μg/kg) for five days. G-PBSCs were collected from the donors using a COBE spectra cell separator. Then, the highly purified CD3 + cells were isolated by positive selection with magnetic-activated cell sorting (MACS) from G-PBSCs using CD3 Dynabeads™. Isolated CD3 + cells were cultured with a low concentration of IL-2 (50U/mL), and PD1, TIM3, LAG3, and TIGIT expressions were assessed using flow cytometry (FACS). CD3 +PD1 +TIM3 +, CD3 +PD1 +TIM3 +LAG3 +TIGIT - and CD3 +PD1 +TIM3 +LAG3 +TIGIT +cells are sorted and cultured with irradiated allo-MNCs for 4 days (Mixed Lymphocyte Reaction; MLR). We used 5,6-carboxyfluorescein diacetate succinimidyl ester (CFSE) as an intracellular fluorescent dye in MLR (CFSE-MLR) to measure of T cells proliferation. Results. In normal, untreated G-PBSCs, very low percentages of cells are CD3 +PD1 +TIM3 +, CD3 +PD1 +LAG3 + and CD3 +PD1 +TIGIT + (0.6±0.4, 0.3±0.2 and 1.3±0.5% in G-PBSC, respectively). However, after treating G-PBSC cells with a low concentration of IL-2 (50 U/mL), we discovered the percentages of CD3 +PD1 +TIM3 +, CD3 +PD1 +LAG3 +, and CD3 +PD1 +TIGT + lymphocytes in G-PBSCs markedly increased by 19.6±5.9, 18.5±4.3, 17.7±6.5%, respectively. Of note, there was a very small change (~1.2 fold increase) in the total number of CD3 + lymphocytes, which indicates that the low dose IL-2 therapy alters subpopulations of T lymphocytes, rather than increasing the proliferation rate. Next, we tested the immunosuppressive capacity of the cultured CD3 +PD1 +TIM3 +cells. To do this, we used CSFE-MLR to measure T cell proliferation. CD3 +PD1 +TIM3 + lymphocytes were depleted in CD3 + G-PBSCs by flow cytometry-based cell sorting. Then we cultured the CD3 + G-PBSCs with allo-MNCs and discovered that the CD3 + G-PBSCs that lacked CD3 +PD1 +TIM3 + lymphocytes demonstrated a significantly increased level of T-cell proliferation compared to CD3 + G-PBSCs, and thereby confirming the immunosuppressive function of CD3 +PD1 +TIM3 + lymphocytes in inhibiting T cell proliferation (% of unstimulated T cells in CD3 + G-PBSCs vs. in CD3 +PD1 +TIM3 + depleted G-PBSC CD3 + cells; 33.5±7.5% vs. 6.3±4.2%). After confirming the immunosuppressive function of the IL-2 treated CD3 +PD1 +TIM3 + lymphocytes, we investigated expressions of other co-inhibitory surface markers such as LAG3 and TIGIT. Amongst the cultured CD3 +PD1 +TIM3 + lymphocytes, 96.2±3.3% of the CD3 +PD1 +TIM3 + lymphocytes were LAG3 +, 28.9±5.4% of the CD3 +PD1 +TIM3 + lymphocytes were TIGIT +, and 63.7±7.8% of the cells were TIGIT -. Interestingly, CD3 +PD1 +TIM3 +LAG3 +TIGIT - lymphocytes demonstrated significantly enhanced levels of immunosuppression compared to CD3 +PD1 +TIM3 +LAG3 +TIGIT + lymphocytes (% of unstimulated T cells in CD3 +PD1 +TIM3 +LAG3 +TIGIT - lymphocytes vs. in CD3 +PD1 +TIM3 +LAG3 +TIGIT + lymphocytes, 53.8±5.5% vs. 23.2±7.4%). Conclusion. We demonstrate that treating CD3 + G-PBSCs with low-dose IL-2 markedly increases the percentage of CD3 +PD1 +TIM3 + lymphocytes, which is known to exert strong immunosuppression. Also, we suggest that CD3 +PD1 +TIM3 +LAG3 +TIGIT - lymphocytes are the subpopulation within CD3 +PD1 +TIM3 + cells that demonstrate the most potent immunosuppression compared to other subpopulations of CD3 +PD1 +TIM3 + lymphocytes. Taken together, such findings suggest that the low-dose IL-2 therapy has therapeutic potential to treat patients with GVHD. Disclosures No relevant conflicts of interest to declare.

Backgroud: Although multiple trials have shown that stopping tyrosine kinase inhibitor (TKI) treatment can be employed in CP CML patients with sustained deep molecular response (DMR) after enough TKI therapy, they emphasized the need for close monitoring because about 50-70% of patients experienced molecular relapse. However, most patients with molecular recurrence regain their initial molecular level after restarting TKI therapy. Aims: In this study, we analyzed second imatinib (IM) discontinuation outcomes in patients regaining durable DMR in the Korean multicenter prospective study (Korean Imatinib Discontinuation Study; KID Study) Methods: CP CML patients who were treated with IM for more than 3 years and maintained DMR for at least 2 years were eligible for the Korean multicenter prospective study and in cases of MMR loss on 2 consecutive assessments, IM treatment was re-introduced. After IM resumption, the molecular response was evaluated every month until re-achievement of MMR and every 3 months thereafter. The second stop was permitted in the patients who were in second DMR for at least 2 years. Results: Among the patients who maintained a second DMR for at least 2 years after IM resumption, 23 patients entered into a second IM stop. Prior to first discontinuation, the median duration of IM therapy was 73.2 months (range, 38.4-133.2 months) and the duration of sustained UMRD was 38.4 months (range, 24-102 months). After first attempt of IM discontinuation, they relapsed after a median duration of 3.7 months (range, 1.8-20.8 months) and re-achieved UMRD at a median of 5.8 months (range, 1.7-12.1 months) after IM resumption. After sustaining a second DMR for a median of 26.3 months, IM therapy discontinued for a second time. With a median follow-up of 29.5 months (range, 9-63 months) since second IM stop, 15/23 patients (65%) lost MMR after a median 2.9 months (range, 1.8-30.7 months), which was similar to those of the first IM discontinuation [median 3.7 (range, 1.8-20.8 months)]. The patients who lost MMR were retreated with IM for a median of 24.5 months (range, 1.2-49.7 months); 14 patients re-achieved MMR and one patient was in therapy for 1.2 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. Further studies on the predictors to select patients for a trial of second TFR and novel strategies will be warranted. Disclosures Kim: Takeda: Research Funding; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; ILYANG: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sun Pharma.: Research Funding.

Background: Peripheral T-Cell Lymphoma (PTCL) is an aggressive malignancy which lacks effective treatment. Emerging data suggests that the JAK-STAT pathway may play an important role in mediating pathogenesis of PTCL. DZD4205 (AZD4205) is an orally available, potent and highly selective JAK1 inhibitor. In T-cell lymphoma cell lines, DZD4205 modulates pSTAT3 pathway and suppresses cell proliferation, and in tumor xenograft models, DZD4205 exhibits dose-dependent anti-tumor activities, with good correlation with drug exposure and modulations of pSTAT3 in tumor tissues. A phase I/II study (JACKPOT8) was initiated to assess the safety, tolerability, pharmacokinetics and anti-tumor efficacy of DZD4205 in patients with refractory/relapsed (r/r) PTCL. Methods: The JACKPOT8 study (ClinicalTrials.gov Identifier: NCT04105010) included two parts: Part A, dose escalation and Part B, dose expansion. In Part A, patients with r/r PTCL who have progressed on or were refractory to systemic therapy will be enrolled and treated with DZD4205 at two different dose levels, 150 mg or 250 mg once daily. In Part B, patients will receive DZD4205 treatment at a defined dose. The primary objective is to assess the safety and tolerability of DZD4205, and the secondary objectives include anti-tumor efficacy and pharmacokinetics. Evaluation of safety/tolerability and tumor response will be based on the CTCAE version 5.0 and 2014 Lugano classification, respectively. Patients will be treated until disease progression, intolerance to adverse events, or withdrawal of consent. Results: As of June 30, 2020, a total of 23 patients with r/r PTCL were enrolled and received DZD4205 at 150 mg (n = 19) or 250 mg (n = 4) once daily. Patient characteristics: median age (range): 65.0 years (34-79); median prior systemic therapies (range): 2 lines (1-8). Four patients had undergone prior hematopoietic stem cell transplantation (HSCT). Six patients had bone marrow involvement at the study entry. Histological subtypes included peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) (n = 10, 43.5%), angioimmunoblastic T-cell lymphoma (AITL) (n = 10, 43.5%), ALK-negative anaplastic large cell lymphoma (ALCL ALK-) (n = 2, 8.7%) and extra-nodal nasal NK/T-cell lymphoma (NKTCL) (n = 1, 4.3%) . Preliminary data showed that 20 patients experienced treatment emergent adverse events (TEAEs), among whom 13 (56.5%) had ≥ grade 3 TEAEs. Based on local investigators' assessment, eight patients (34.8%) had ≥ grade 3 TEAEs which were considered to be related to DZD4205. The most common (> 5% incidence) DZD4205-related TEAEs (any grade) included thrombocytopenia (n = 6, 26.1%), neutropenia (n = 4, 17.3%), decreased appetite (n = 3, 13.0%), nausea (n = 2, 8.7%), interstitial lung disease (n = 2, 8.7%) and pneumonia (n = 2, 8.7%). Most TEAEs were manageable with dose interruption and reduction. Preliminary PK data is available in 20 patients (n = 19 at 150 mg, n = 1 at 250 mg). Exposure at 250 mg is higher than 150 mg following a single and multiple dose. As expected from long t1/2 of DZD4205, accumulation of about 3 folds in AUC was observed. DZD4205 had flat PK profile with small difference between Css,max and Css,min after 22 days of once daily dosing, which is an optimal PK profile to maintain DZD4205 concentrations above effective levels throughout the dosing interval. As of June 30, 2020, 22 patients (n = 19 at 150 mg, n = 3 at 250 mg) had at least one post-treatment Lugano assessment. In 150 mg cohort, 8 out of 19 patients showed tumor response, with objective response rate (ORR) of 42%, among whom 4 (21%) had complete response (CR) and another 4 (21%) partial response (PR). In 250 mg cohort, 1 out of 3 patients showed tumor response, with ORR of 33%. Tumor response was observed in subtypes including AITL, PTCL-NOS, ALCL (ALK-) and NKTCL. At the data cut-off date, the longest duration on treatment was > 8 months. Patient enrolment is ongoing. Updated clinical data will be shared at the meeting. Conclusion: DZD4205 shows good tolerability, pharmacokinetic profiles and promising anti-tumor efficacy in patients with r/r PTCL, indicating its potential as a therapeutic option for this unmet medical need. Disclosures Kim: Donga: Research Funding; Kyowa-Kirin: Research Funding; Roche: Research Funding; Johnson&Johnson: Research Funding; Celltrion: Research Funding; Mundipharma: Research Funding. Yoon:Celltrion: Honoraria; Samyang: Research Funding; Amgen, Chongkundang, Celgene, Astrazeneca: Consultancy. Wang:Dizal Pharmaceuticals: Current Employment. Li:Dizal Pharmaceuticals: Current Employment. Huang:Dizal Pharmaceuticals: Current Employment. Deng:Dizal Pharmaceuticals: Current Employment. Chen:Dizal Pharmaceuticals: Current Employment. Yang:Dizal Pharmaceuticals: Current Employment.

Introduction T-cell lymphoma is a group of heterogeneous diseases with various clinical behaviors and treatment outcomes, representing 10-15% of non-Hodgkin lymphomas. Owing to its rarity and heterogeneity, the standard treatment approach for T-cell lymphoma is still not established. Accordingly, conventional chemotherapy regimens adapted from B-cell lymphoma treatment has been used for T-cell lymphoma. However, their outcome is still not satisfactory, and there are limited data representing the real-world situation in terms of clinical features and treatment outcomes. Given the incidence of T-cell lymphoma is relatively higher in Asian than Western countries; a comprehensive registry study focusing on Asian patients with T-cell lymphoma could be helpful for better understanding of T-cell lymphoma as well as the development of more effective treatment strategy. Methods We performed a multi-national, multi-center, prospective registry study for patients with T-cell lymphoma and enrolled patients between 01-March-2016 and 31-January-2019. All patients received chemotherapy with curative intent after diagnosis, and were pathologically diagnosed with T-cell lymphoma according to the 2008 World Health Organization classification of lymphoid neoplasms. Patients belonged to any one of following clinical situations could be enrolled: (1) newly diagnosed, treatment-naïve patients; (2) patients who started treatment or completed treatment; (3) relapsed or refractory patients. After we enrolled the planned number of patients (n = 500), we analyzed clinical features and treatment outcomes. Results Out of 500 patients enrolled from nine Asian countries (Korea, China, Taiwan, Singapore, Indonesia, Bangladeshi, Vietnam, Malaysia, and Philippines), 490 patients were analyzed because 10 patients with insufficient information were excluded. The median age was 59 years (range, 20-85), male patients (59%) were predominant compared to female patients (41%). Extranodal NK/T-cell lymphoma (ENKTL) was the most common (28%) and angioimmunoblastic T-cell lymphoma (AITL) was the second common (24%). Peripheral T-cell lymphoma, not-otherwise specified (PTCL-NOS, 20%) and ALK+/- anaplastic large cell lymphoma (ALCL, 16%) were also major subtypes of T-cell lymphoma. The proportion of stage IV was 40%, however, the distribution of stage was different between ENKTL and nodal T-cell lymphomas such as PTCL-NOS. The CHOP (Cyclophosphamide, doxorubicin, vincristine, and prednisone) or CHOP-like regimens accounted for the mainstay of primary treatment for nodal T-cell lymphoma whereas non-anthracycline-based chemotherapy regimens such as SMILE (steroid, methotrexate, ifosfamide, L-asparaginase, and etoposide) and GemOx-L (gemcitabine, oxaliplatin, and L-asparagainase) were mainly used for ENKTL. The overall survival of ENKTL was not significantly different from that of PTCL-NOS, AITL and ALK+/- ALCL. Conclusions Our study showed the distribution of T-cell lymphoma subtypes and tumor burdens at the time of diagnosis in Asian countries. Although clinical features of ENKTL are different from that of nodal T-cell lymphomas consisting of PTCL-NOS, AITL and ALK+/- ALCL, and the different types of treatment were used, survival outcome of patients were not significantly different. This finding might be associated with improved treatment outcomes of ENKTL compared to the past. However, considering a substantial number of patients experienced treatment failure in patients with PTCL-NOS as well as ENKTL, more effective treatment strategy should be warranted. Figure Disclosures Kim: F. Hoffmann-La Roche Ltd: Research Funding; Celltrion: Research Funding; Novartis: Research Funding; Donga: Research Funding; Kyowa-Kirin: Research Funding; Novartis: Research Funding; J + J: Research Funding.

Background The recent discontinuation clinical trials have demonstrated that IM discontinuation can be employed based on clinical study in patients who had enough IM therapy and undetectable molecular residual disease (UMRD) durations prior to IM discontinuation. Moreover, treatment rechallenge in patients with molecular recurrence lead a second deep molecular response, suggesting that IM discontinuation is safe. However, the issues on the definition of molecular relapse requiring treatment resumption and the occurrence of late relapse with a long-term follow-up after IM discontinuation are important. Therefore, here we analyzed the long-term follow-up results of the patients who lost UMRD after IM discontinuation 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 Between October 2010 and June 2015, a total of 126 patients (70 females, 56 males) were enrolled on KID Study, with a median age of 47 years (range, 18-82), the percentages of patients with low, intermediate and high Sokal risk scores were 33%, 25% and 15%, respectively with unknown Sokal risk scores in 27%. And the median time on IM therapy and the median duration of sustained UMRD prior to discontinuation were 83 months (range, 32-141) and 41 months (range, 22-131), respectively. After a median follow-up of 62.6 months (range, 4.9-100.8 months) after IM discontinuation, 83 patients (65.9%) lost UMRD. Among them, 56 (67.5%) patients lost MMR in 2 consecutive analyses. The other 27 (32.5%) patients who lost UMRD but not MMR exhibited different patterns of BCR-ABL1 kinetics: 8 patients spontaneously re-achieved UMRD after a median time of 2.8 months (range, 0.9-3.0 months), and 19 patient showed fluctuation of BCR-ABL1 transcript under the level of 0.1% on IS for a median 19 months (range, 3-34), and then spontaneously returned and maintained UMRD for a median 31 months (range, 2-64). Of 73 patients who lost MR4.0, the rate of MMR loss was 76.7%. Out of 56 patients with molecular relapse, 54 patients (except two patients who restart radotinib) were re-treated with IM, all patients (except one patient lost follow-up) re-achieved MMR at a median of 1.9 months (range, 0.0 - 5.4 months) after resuming treatment. Among them, two patients who re-achieving of MMR after resuming IM therapy lost MMR again; One patient who relapsed at 53.2 months after IM discontinuation, despite re-achieving MMR 1.4 later after IM restarting, suddenly progressed to blast crisis at 6 months after restarting IM and in spite of switching to dasatinib and ponatinib, she died. Another patient lost MMR at 7.4 months after IM discontinuation and re-achieved MMR 1.7 later after IM restarting, but progressed to AP on the assessment 32 months later. The patient switched to dasatinib and lost follow-up. Among the patients who maintained a second UMRD for at least 2 years after IM resumption, 23 patients entered into a second IM stop. With a median follow-up of 29.5 months (range, 9-63 months) since second IM stop, 15/23 patients (65%) lost MMR after a median 2.9 months (range, 1.8-30.7 months), which was similar to those of the first IM discontinuation [median 3.7 (range, 1.8-20.8 months)]. The patients who lost MMR were retreated with IM for a median of 24.5 months (range, 1.2-49.7 months); 14 patients re-achieved MMR and one patient was in therapy for 1.2 months. Conclusions Our results showed that 67.5% and 76.7% of patients who lost UMRD and MR4.0, respectively resulted in MMR loss, and the other patients were below MMR without re-treatment, suggesting loss of MMR can be chosen for treatment re-challenge. Overall, IM discontinuation could be applied with approximately 55% of probability of sustained MMR in the long term. In addition, we demonstrated that a second attempt might be possible. Further studies on the predictors to select patients for a trial of second stop are warranted. Disclosures Kim: Il-Yang co.: Research Funding; Pfizer: Research Funding; Takeda: Research Funding; BMS: Research Funding; Novartis: Research Funding.

Background: Primary breast diffuse large B-cell lymphoma (DLBCL) has poor outcomes with frequent extranodal failures, particularly in the central nervous system (CNS). To prevent CNS recurrence, we designed this phase II trial that addressed feasibility and activity of conventional immunochemotherapy and CNS prophylaxis. Methods: This prospective, multicenter, single-arm phase II study was conducted to evaluate efficacy and safety of 6 cycles of conventional rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone every 21 days (R-CHOP) with the addition of 4 doses of intrathecal methotrexate (IT MTX; 12mg) during the first 4 cycles of R-CHOP in patients with primary breast DLBCL. Primary breast lymphoma was defined as lymphoma involving one or both breasts as a sole extranodal site regardless of specific nodal involvement status. The primary end-point was 2-year progression-free survival (PFS). Secondary end-points included cumulative incidence of CNS recurrence, overall survival (OS), and safety. All patients provided written informed consents and the study was registered at www.clinicaltrials.gov as #NCT01448096. Results: Thirty-three patients with primary breast DLBCL were enrolled between Jan 2012 and Jul 2017 in the Consortium for Improving Survival of Lymphoma (CISL) member institutions. The median age was 50 years at diagnosis (range, 29-75) and all were female. Right breast involvement was more common than left (18 [55%] vs 14 [42%]) and bilateral breast involvement was found in one patient (3%). Nodal involvement was present in 16 patients (49%), primarily in regional nodes (14 patients). Thus, the Ann Arbor stage was IE in 17 (52%), IIE in 13 (39%), IIIE in 2 (6.1%), and IV in 1 (3.0%). ECOG performance status was ≥2 in 1 patient (3%) and serum LDH level was elevated in 9 (27%). Therefore, the IPI and the CNS-IPI risk were mainly low (28 patients, 85%; respectively). No patients had CNS involvement at diagnosis. 32 (97%) of the 33 patients completed R-CHOP as planned, and the remaining patient withdraw a consent after four cycles of R-CHOP because of poor tolerance. CNS prophylaxis using IT MTX was completed as planned in 31 patients (94%), but it was discontinued in 2 patients because of patient's refusal. These 2 patients received two and three IT MTX doses, respectively. 32 patients (97%) were evaluable for treatment response and all these patients achieved a complete response. At the cutoff date of this analysis (10 Jul 2019), all patients who entered a follow-up phase had at least 24.0 months of follow-up. With a median follow-up duration of 46.1 months (IQR 31.1-66.8), 6 patients had experienced treatment failure and 3 of these died. The 2-year PFS and OS were 81.3% (95% CI, 67.7-94.8) and 93.5% (95% CI, 84.9-100.0), respectively (fig 1A and B). Of the 6 patients with treatment failure, diseases involved CNS with or without lymph nodes in 4 patients and breasts in 2 patients (1 ipsilateral and 1 contralateral breast recurrence). 3 of the four patients with CNS recurrence had isolated CNS recurrences (2 brain parenchymal and 1 meningeal disease) and one had a concurrent meningeal and lymph nodal recurrence. All 4 patients with CNS recurrence had received prophylactic IT MTX as planned by protocol. The 2-year cumulative incidence of CNS recurrence, taking into account the competing risk of death, was 12.5% (95% CI, 0.3-23.2, fig 1C). Although the number of patients with intermediate CNS-IPI risk was small (5 patients, 15%), the cumulative incidence of CNS recurrence did not differ significantly according to the CNS-IPI risk group. All CNS recurrences occurred within the first 2 years after enrolment. Toxicities were generally manageable during the R-CHOP and IT MTX treatment. No deaths as a result of toxicity occurred during treatment. Conclusion: Our study shows that conventional R-CHOP with prophylactic IT MTX is feasible in patients with primary breast DLBCL. However, given a substantially high rate of CNS recurrence, further studies to properly define the best strategy for CNS prophylaxis should be needed in patients with primary breast DLBCL. Figure 1 Disclosures Yoon: F. Hoffmann-La Roche Ltd: Research Funding. Kim:Celltrion: Research Funding; Novartis: Research Funding; Donga: Research Funding; Kyowa-Kirin: Research Funding; Novartis: Research Funding; J + J: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding.

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.

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 .

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.

There are growing evidences that myelo-monocytic cells play a key role in mediating tissue repair and stimulating angiogenesis in response to ischemia. However, the subpopulations of myelo-monocytic cells participating in vascularization and their underlying mechanisms have not been well identified. We previously demonstrated that CD11b+CX3CR1+ cells, a type of proangiogenic myelo-monocytic cells, promotes angiogenesis in a C57BL/6 hind-limb ischemic mouse model. We now provide insight into mechanisms of CD11b+CX3CR1+ cells during recovery of blood perfusion after ischemia. Ischemic injuries were induced by dissecting the femoral artery of C57BL/6 mice. Single-cell suspensions were made from ischemic muscles, and ischemic muscle-derived CD11b+CX3CR1+ cells were isolated with a FACS Sorter. Extracted proteins (50ug) from the cells were loaded on nitrocellulose membranes, containing 53 different capture antibodies in proteome profiler mouse angiogenesis Kits (R&D systems, ARY105). For aortic ring sprouting assay, thoracic aortas were embedded in Matrigel. Proangiogenic effects of CD11b+CX3CR1+ cells were confirmed by enhanced blood perfusion upon injection of additional CD11b+CX3CR1+ cells into ischemic tissues after femoral artery dissection in C57BL/6 mice. Sprouting effects were specifically confirmed through purified CD11b+CX3CR1+ cells co-cultured with aortic ring sprouting assay. Also, medium conditioned by CD11b+CX3CR1+ cells was as efficient as CD11b+CX3CR1+ cells in supporting sprouting, suggesting that vascular endothelial cells (ECs) are likely activated by the proteins secreted by CD11b+CX3CR1+ cells in a paracrine fashion. To investigate whether muscle-derived CD11b+CX3CR1+ cells could secrete angiogenic proteins, we examined the angiogenic proteins in CD11b+CX3CR1+ cells isolated from ischemic muscles after 4 days of surgery. Contrary to our expectations, VEGF proteins were not detected from CD11b+CX3CR1+ cells. However, MCP-1, MIP-1α, platelet factor-4 (PF-4) and MMP-9 were expressed at a higher level in CD11b+CX3CR1+ cells than those of CD11b+CX3CR1- and CD11b-CX3CR1- cells. MCP-1, MIP-1α and MMP-9 have been reported to promote angiogenesis, while PF-4 is recognized as an angiostatic factor. However, it has recently been reported that PF-4 combined with VEGF is essential for the initial separation of ECs from vessels prior to angiogenic sprouting. It is postulated that, after ischemia, collaboration of VEGF with PF-4 secreted from CD11b+CX3CR1+ cells dissociates the ECs from vessels and promotes vascular branching processes. In summary, CD11b+CX3CR1+ cells are a newly identified myelo-monocytic subset for vessel formation, capable of vascular sprouting via secreting PF-4. Disclosures Broxmeyer: CordUse: Membership on an entity's Board of Directors or advisory committees.

Background: Second-generation BCR-ABL tyrosine kinase inhibitors (2nd generation TKIs) including nilotinib (NIL) and radotinib (RAD) are approved for the treatment of newly diagnosed and other TKI failed chronic myeloid leukemia (CML). Uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene promoter polymorphism, distinct number of TA repeats in promoter, has been reported for an association with hyperbilirubinemia on nilotinib therapy (Singer et al. Leukemia (2007) 21, 2311–2315). However, the distribution of UGT1A1 (TA)7 repeat polymorphism differs greatly between Caucasians and Japanese, namely, the frequency of UGT1A1(TA)7 repeat polymorphism is high in Caucasians, whereas it is low in Asians (Beutler et al. Proc. Natl. Acad. Sci. USA 95 (1998) 95, 8170–8174 ). Aims: The aim of this study was to investigate the association between UGT1A1 gene promoter polymorphism and hyperbilirubinemia in Korean CML patients treated with NIL and RAD as a frontline therapy. Methods: A total of 88 newly diagnosed chronic phase CML patients who treated with frontline NIL (n=39) and RAD (n=49) was screened for UGT1A1 promoter polymorphism genotype analysis. We used the High Pure PCR Template Preparation Kit (Roche, Germany) to prepare genomic DNA from whole blood and genotyped by direct sequencing of the 253- to 255-bp fragments produced by PCR. Results: The (TA)6/(TA)6 homozygote and (TA)6/(TA)7 heterozygote were seen in all genotyped population and frequency of (TA)6/(TA)6 homozygote was 79.5% (70/88) in our patients. (TA)6/(TA)6 homozygote predominated with 81.6% of the alleles in the RAD group and 76.9% in the NIL group. Relative riskfor each genotype presented in Table 1, with hyperbilirubinemia defined as CTCAE grade 2 or greater observed at any post-baseline point. The relative risks for 6/6 genotype versus 6/7 genotype was 3.5 with 95% CIs of (0.6, 18.9) in the RAD group compared with 8.1 (1.5, 43.8) in the NIL group and NIL group showed significantly high association with UGT1A1 gene promoter polymorphism (P Conclusions: This finding suggests that UGT1A1 gene promoter polymorphism may be an important determinant of hyperbilirubinemia in CML patients with NIL therapy, but not in RAD. However other mechanisms should be explored in patients who have significant hyperbilirubinemia with RAD therapy. Updated data with longer follow-up duration will be presented in the meeting. Table 1. Relative risk calculations for prevalence of hyperbilirubinemia Radotinib Nilotinib Max grade=,,=2 Total Max grade=,,=2 Total (TA)6/(TA)6 20 20 40 (TA)6/(TA)6 26 4 30 50.00% 50.00% 65.00% 10.00% (TA)6/(TA)7 2 7 9 (TA)6/(TA)7 4 5 9 22.22% 77.78% 44.44% 55.56% Total 22 27 49 Total 30 9 39 Relative risk=3.5, 95% CI of (0.6, 18.9) Relative risk=8.1, 95% CI of (1.5, 43.8) Abbreviation: CI, confidence interval. Disclosures No relevant conflicts of interest to declare.

Introduction Extranodal NK/T cell lymphoma (ENKTL) is a rare and aggressive lymphoma subtype, but standard front-line therapy has not been established. The clinical outcome of patients (pts) with ENKTL after the treatment of conventional chemotherapy, especially pts with advanced stage, was generally poor. Therefore, high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) as a consolidation could be one of promising strategies to improve the outcome of ENKTL. However, there have been few studies reporting the survival outcome or prognostic significances of front-line ASCT in pts with ENKTL. Thus, the aim of this study was to investigate the outcome of pts with ENKTL who had undergone front-line ASCT. Patients and methods We consecutively enrolled pts with ENKTL who achieved CR or PR after primary chemotherapy ± radiotherapy and underwent front-line ASCT from 8 institutions from Jan 2005 to Dec 2013. Pts who were performed ASCT for salvage setting after relapse were excluded. Pts were classified as limited or advanced diseases according to Ann Arbor stage, and NK/T cell prognostic index (NKPI), which included the presence of B symptom, stage III or IV, elevated serum lactate dehydrogenase (LDH) level, and regional lymph node involvement, were determined for prognosis. Treatment response was assessed according to the International Working Group response criteria. The progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan-Meier method. Results A total of 56 pts (39 male, 17 female) with median age of 47 years (range, 18-64) was included in this analysis. Twenty-seven pts (52%) were advanced disease and 18 (32%) had B symptoms at diagnosis. ECOG performance was ≥ 2 in 7 (13%) and serum LDH level was elevated in 25 (45%). Thus, 36 pts (64%) were classified as high risk (≥ 2 factors) by the NKPI. Pts with advanced disease were associated with worse performance status, higher risk of NKPI, and more frequent extra-upper aerodigestive (EUA) origin than those with limited disease. All pts received systemic chemotherapy including non-anthracycline-based (n=45, 80%) or CHOP/CHOP-like regimens (n=11, 20%). Involved field radiotherapy or chemoradiotherapy was given to 24 (83%) of pts with limited disease. The median time from diagnosis to ASCT was 6.7 months (range, 3.2-10.3), and pretransplant disease status consisted of 37 pts (66%) with complete response (CR) and 19 pts (34%) with partial response (PR). Only one treatment-related death (2%, fungal pneumonia) occurred following ASCT. With a median follow-up of 46.5 months (range, 3.7-109.5), 4-year PFS and OS were 50.5% (95% CI, 43.1-57.9) and 54.6% (95% CI, 46.6-62.6), respectively. Pts with advanced disease had inferior 4-year PFS (39.4% vs 63.2%, P=0.006) and OS (24.3% vs 69.9%, P=0.009), compared to pts with limited disease. CR achievement at transplantation was significantly associated with better PFS (4-year, 65.2% vs 21.1%, P=0.001) and OS (4-year, 67.1% vs 32.7%, P=0.006) than those with PR. This result was consistently important in pts with advanced disease (4-year PFS, 66.7% vs 8.3%, P=0.007). Multivariable analyses were performed separately in 2 steps. In the first step, analysis included all pts (N=56) and demonstrated that high risk of NKPI (HR, 3.10; 95% CI, 1.16-8.26), poor ECOG performance (HR, 3.84; 1.31-11.29), and PR at transplantation (HR, 4.22; 1.89-9.43) were independent predictors for worse PFS. In the second step, pts were stratified by stage. In the pts group with advanced stage (N=27), PR at transplantation (HR, 3.27; 1.07-10.04) and CHOP/CHOP-like primary chemotherapy (HR, 8.26; 1.59-43.05) were associated with higher risk of progression in multivariable analysis. In the pts group with limited stage (N=29), multivariable models revealed high risk of NKPI (HR, 4.22; 1.10-16.19) and EUA origin of anatomic subtype (HR, 10.02; 2.07-48.41) were independently associated with shortened PFS. Conclusion This is the largest study that specifically focused on the outcomes of front-line ASCT in pts with ENKTL. Our study represents that non-anthracycline-based chemotherapy followed by ASCT would be feasible and active treatment option for ENKTL. NKPI and pretransplant CR achievement were important factors for predicting clinical outcomes, particularly NKPI in limited disease and pretransplant response in advanced disease. Disclosures No relevant conflicts of interest to declare.

Background Approximately 50% of CP CML patients achieve undetectable molecular residual disease (UMRD) at 6-7 years of first-line imatinib (IM) therapy. Although imatinib therapy is effective in chronic myeloid leukemia (CML) patients and a substantial portion of patients achieve UMRD with prolonged IM therapy, up to 10^7 leukemic cells can still be present in the absence of detectable BCR-ABL1 in RQ-PCR assay due to the sensitivity limit of current RQ-PCR technology. The recent several reports to assess whether IM can be discontinued in CML patients have shown that IM discontinuation can be employed based on clinical study in patients who had enough IM therapy and UMRD durations prior to IM discontinuation. In our previous report, the 12-month probability of sustained UMRD of 48 patients was 80.8% (78.4% in 37 patients with at least 12 months follow-up), a higher rate than that reported by the ‘STIM’ (Stop Imatinib) trial. To identify predictors for safer, successful IM discontinuation and to explore additional contributing factors for sustained molecular responses (MRs), this multicenter prospective Korean Imatinib Discontinuation Study (KIDS) is on-going. Methods Patients who were treated with IM for more than 3 years and whose BCR-ABL1 was undetectable in RQ-PCR for at least 2 years were enrolled in this study. After discontinuation, molecular response was monitored using RQ-PCR assay every month up to 6 month follow-up, every 2 months up to 12 month follow-up, and every 3 months thereafter. In case of relapse, defined as loss of MMR on 2 consecutive assessments, IM therapy was re-introduced and molecular response after resumption was observed every month using RQ-PCR. Our primary objectives were to evaluate the probability of persistent UMRD at 12 month follow-up after discontinuation, and to measure the duration of persistent UMRD after discontinuation. The secondary objective was to evaluate the probability of major molecular response (MMR) loss and the time taken to lose MMR after discontinuation. Results Of the 148 patients who were screened for KIDS, 30 patients have failed because of positive result of RQ-PCR tested in the central laboratory (N= 21, 70%), failure to meet inclusion criteria (N=7, 23%) and informed consents withdrawal (N=2, 7%). As of data cut-off date of 2 July 2014, a total of 115 patients (66 females, 49 males) who were diagnosed between 20 Mar 1996 and 12 Jul 2012 were enrolled on KIDS, with a median age of 44 years (range, 19 – 77), the percentages of patients with low, intermediate and high Sokal risk scores were 35%, 25% and 17%, respectively with unknown Sokal risk scores in 23%. And the median time on IM therapy and the median duration of sustained UMRD prior to discontinuation were 84 months (range, 32 – 149) and 44 months (range, 22 – 131), respectively. With a median follow-up of 15 months (range, 0.2 – 45.4), 28 patients loss MMR and the probability of sustained MMR was 73.5 ± 4.3%. The 12-month probability of sustained MMR was 67.0 ± 5.2%. Among 21 patients who lost UMRD without confirmed MMR loss, 10 spontaneously re-achieved UMRD, 2 fluctuated BCR-ABL1 transcript under MMR and 9 continuously increase BCR-ABL1 transcript. All of 28 patients who confirmed MMR loss were re-treated with IM for a median of 9.9 months (range, 0.7 – 34.2 months), 22 patients re-achieved MMR at a median of 4.1 months (range, 0.5 - 6.5 months) after resuming IM therapy and 14 of these patients re-achieved UMRD at a median of 6.7 months (range, 3.3 - 13.3 months). One patient, who lost MMR at 7.6 months after KIDS enrollment, resuming IM for 26.7 months and sustained UMRD for 23.9 months, currently discontinues IM therapy (KIDS2) with the follow up of 6.5 months. Univariate analysis showed that IM duration and UMRD duration before treatment discontinuation had a higher 12-month probability of sustained MMR. Conclusions Based on results, IM discontinuation with resuming after MMR loss can be applied safely. In particular, the rate of screening failure due to positive result of RQ-PCR tested in the central laboratory implied that a strict PCR sensitivity criterion is important for safer, successful IM discontinuation. Overall, both UMRD and IM duration on treatment were the most important predictors for successful IM-off. Further studies on underlying mechanisms about immunological control, minimal residual leukemia and stem cell biology during TKI-off study should be conducted. Disclosures No relevant conflicts of interest to declare.

Introduction Although several previous studies addressed the role of radiation in treating localized diffuse large B-cell lymphoma (DLBCL), chemotherapy alone has shown promising efficacy with the emergence of Rituximab. Thus, we evaluated the clinical efficacy outcomes and failure patterns of patients with localized DLBCL according to two different treatment strategies, either 6 or more cycles of R-CHOP chemotherapy alone or 3 or 4 cycles of R-CHOP followed by involved field radiotherapy (IFRT). Methods A prospectively collected database from 21 tertiary centers participating the Consortium for Improving Survival of Lymphoma (CISL), built up for PROCESS study (NCT01202448) for secondary central nervous system involvement in DLBCL, was recruited for current study in addition to the Asan Medical Center (AMC) Lymphoma Registry. CISL database and AMC lymphoma registry consisted of data from patients with newly diagnosed DLBCL between August 2010 and August 2012, and between February 2004 and February 2012, respectively. Inclusion criteria were localized (stage I or II), non-bulky ( Results A total of 357 patients (CISL prospective cohort: 161 patients, AMC registry: 196 patients) were eligible for the analyses. Two hundred ninety nine patients (83.5%) received 6 or more cycles of R-CHOP chemotherapy alone, and 58 patients (16.2%) underwent 3 or 4 cycles of R-CHOP followed by IFRT. Median age was 54 years (range, 16-87). During the median follow-up of 24 months (range, 4-116 months), 35 patients (9.8%) experienced relapse, and 22 patients (6.1%) died. Two-year OS and EFS rate was 94.7% and 89.9%, respectively, and 345 out of 357 patients (96.6%) achieved CR. Comparing R-CHOP alone to R-CHOP plus RT group, there was no significant difference in clinicopathologic parameters. R-CHOP alone could achieve significantly higher CR rate of 97.7 % than 91.4% of R-CHOP plus RT group (p = 0.030). Two-year OS and EFS were significantly longer in R-CHOP alone group than R-CHOP plus RT group (96.1 vs 89.9 %, p = 0.029 and 91.7% vs 81.8%, p= 0.028) (Figure 1). Relapse rate was significantly lower in R-CHOP alone group compared with R-CHOP plus RT group than group (7.4% vs 22.4%, p=0.001), and distant relapses were also significantly lower (15.5% vs 2.7%, p Conclusion In our cohort, R-CHOP alone for six to eight cycles without IFRT could achieve significantly higher 2-year OS and EFS rate as well as CR compared with R-CHOP plus RT group. In addition, the rate of relapse and systemic failure were significantly lower in R-CHOP alone group, which altogether warrant further validation in prospective trial. Table 1. Explorative comparison of overall clinical outcomes and patterns of relapse between two subgroups: patients who underwent six or more cycles of R-CHOP chemotherapy alone and who underwent 3 or 4 cycles of R-CHOP followed by IFRT Total (%) R-CHOP alone group (%) R-CHOP plus RT group (%) P -value Number of patients 357 (100) 299 (83.5) 58 (16.2) Treatment response Complete response 345 (96.6) 292 (97.7) 53 (91.4) 0.030 Overall response 351 (98.3) 294 (98.3) 57 (98.3) 1.000 Rate of relapse 35 (9.8%) 14 (7.4) 11 (22.4) < 0.001 Median time to relapse (95% CI) 11 (7-15) 11 (8-14) 10 (5-14) 0.346 Pattern of relapse < 0.001 (0.062) Locoregional 14 (4.7) (63.6) 4 (6.9) (30.8) Distant 8 (2.7) (36.4) 9 (15.5) (69.2) Figure 1. Comparison of overall survival and event-free survival in two subgroups: patients who underwent six or more cycles of R-CHOP chemotherapy alone and who underwent 3 or 4 cycles of R-CHOP followed by IFRT Figure 1. Comparison of overall survival and event-free survival in two subgroups: patients who underwent six or more cycles of R-CHOP chemotherapy alone and who underwent 3 or 4 cycles of R-CHOP followed by IFRT Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

Introduction Imatinib (IM) is an effective treatment in patients with chronic phase chronic myeloid leukemia (CML-CP). In the previous report (Leukemia research, 2012;36:689-693), we demonstrated that IM could be discontinued in CML patients achieved undetectable minimal residual disease (UMRD) after the treatment of front-line IM therapy. These observations were confirmed by prospective STIM1 and TWISTER studies. However, in both studies, approximately half of patients were treated with front-line interferon therapy, which might be a confounding factor when considering the impact of prior interferon on treatment free remission (TFR) in the previous IM discontinuation studies. Thus, the aim of this study was to investigate the long-term outcomes of IM discontinuation in patients with CML-CP, who have treated with front-line IM therapy and achieved UMRD. Patients and methods We consecutively enrolled patients with CML-CP, discontinued IM therapy after achieving UMRD for at least 12 months in 2 Korean institutions from June 2009 to Jan 2013. Patients with a prior history of any other treatment (>1 months) for CML before IM administration were excluded. UMRD was defined by undetectable levels of BCR-ABL transcript by RQ-PCR with sensitivity of at least 0.0046%IS. After discontinuation, BCR-ABL/ABL ratio was monitored by RQ-PCR monthly during the first 6 months and every 3 months thereafter, and molecular relapse was defined by detectable levels of BCR-ABL transcript in two successive assays. Results Nineteen patients (8 male, 11 female) with a median age of 52 years (range, 29-78) were included. The reasons for discontinuing IM were shared decision between physicians and patients with long undetectable BCR-ABL transcript (n=9), chronic adverse events of IM (n=6), patient’s request (n=3), and wish for pregnancy (n=1). At initial diagnosis, the Sokal score was low to intermediate in 11 patients and high in 8 patients. All patients started IM at a dose of 400mg/day and median interval between IM initiation and UMRD was 21.5 months (range, 7.0-61.9). IM therapy was then maintained during a median of 34.8 months (range, 12.1-72.4). With a median follow-up of 52.1 months (range, 17.5-60.5), the overall probability of UMRD persistence at 4-year was 22.1% (95% CI, 11.6-32.6). Fourteen patients (73%) lost UMRD after a median of 4.0 months (range, 1.1-22.8). 12 patients relapsed within first 9 months and 2 late relapse were identified at 20.5 and 22.8 months, respectively. No patients included in this analysis were progressed to advanced stage CML or died. IM therapy was resumed in all patients with molecular relapse, but 2 patients were switched to dasatinib owing to chronic adverse events of IM. At the time of this analysis, all patients were still sensitive to IM and dasatinib therapy. 12 patients re-achieved UMRD and 2 patients maintained stable major molecular response. In univariate analysis for molecular relapse, high risk of Sokal score (P Conclusion This study represents that IM discontinuation in patients who have received front-line IM therapy and achieved UMRD would be feasible, as approximately one-fourth of these patients could enjoy long-term TFR. Moreover, no molecular relapse was observed after 2 year of IM discontinuation. Although the Sokal score, time to deep molecular response, and duration of IM therapy were suggested as clinical factors for predicting molecular relapse in this analysis, further studies would be necessary to confirm the results in this population. Disclosures No relevant conflicts of interest to declare.

Purpose Poor outcome of patients with elderly diffuse large B-cell lymphoma (DLBCL) has been linked to their decreased ability to receive full course of R-CHOP, dose-reduction of chemotherapy due to toxicities and their concomitant disease to interrupt the treatment. Recently, several studies suggested that attenuated R-CHOP regimen or reduced cycles of R-CHOP showed the survival benefit along with good tolerability and safety for very elderly patients. The study is aimed to determine objective response, toxicitiy and clinical outcome of weekly four times rituximab augmentation after reduced cycles of R-CHOP in extremely elderly patients with DLBCL. Patients and Methods Prospective, multi-institutional phase II trial was conducted for patients with previously untreated CD20+ diffuse large B cell lymphoma who aged more than 70 years and achieved complete or partial response after 4th R-CHOP chemotherapy (NCT01181999). R-CHOP was infused every 21 days, with initial dose-intensity of CHOP regimen was modulated according to Charlson Comorbidity Index (CCI). If patients were with CCI Results 51 DLBCL patients were enrolled from 14 institutes between June 2010 and April 2013. Median age was 76 years (range: 70-89) and 35.3% patients had more than 2 concomitant chronic disease. 36 out of 51 patients could be proceeded toward weekly four times rituximab consolidation. High treatment-related mortality (13.7%) during R-CHOP was huddle to proceeding to consolidation treatment. 35 patients (68.6%) presented with high-intermediate or high risk based on IPI and 12 patients (23.5%) were classified with a score of 2 by Glasgow prognostic score (GPS). After a median follow-up of 18.6 months, overall response rate was 70.6% with 66.7% of complete response and 3.9% of partial response. 31 patients (60.8%) were started with decreased dose of CHOP with median 75% reduction of CHOP (range; 50-100%). 2-year probability of progression-free survival (PFS) was 71.5 ±7.9% with 10 relapses. GPS based on systemic inflammatory indicators was a useful prognostic indicator for PFS compared to IPI. The adverse events were mainly related with hematologic toxicities and neutropenic infections during R-CHOP. However, no toxicities were reported associated with rituximab weekly infusion and no adverse events related with delayed infection after rituximab consolidation. Conclusions Rituximab consolidation after reduced cycles of R-CHOP resulted in a favorable response with high tolerability. Debulking R-CHOP and followed by weekly rituximab consolidation could be a good compromise between efficacy and tolerability for extremely elderly DLBCL Disclosures: No relevant conflicts of interest to declare.

Introduction Interim positron emission tomography (PET) scan has shown to be useful for evaluating response in Hodgkin lymphoma. And, there has been increasing interests in using interim PET for predicting outcomes in diffuse large B-cell lymphoma. However, few data are available regarding prognostic value of interim PET in patients with peripheral T cell lymphoma (PTCL). Recently, in an attempt to standardize reporting criteria for interim PET, Deauville five-point scale (5-PS), which visually assess the uptake of lesions in comparison with background mediastinal and liver uptakes, were proposed, but this was not investigated in PTCL. Therefore, the aim of this study was to determine the prognostic role of interim PET, assessed by Deauville 5-PS, in patients with PTCL treated with systemic chemotherapy. Patients and Methods We consecutively enrolled newly diagnosed PTCL patients, treated with systemic chemotherapy (CHOP/CHOP-like or non-anthracycline-based) and had the baseline PET data with ³1 evaluable hypermetabolic lesion between 2006 and 2012 in two Korean institutions. Patients treated with upfront chemoradiotherapy before interim PET scan were excluded. Interim PET scan was performed after 3 cycles of chemotherapy, before 1 week of the next cycle. Interim PET response was visually assessed by 5-PS and four point or higher was regarded as positive. All PET assessment was performed by 2 nuclear medicine specialists at each institution, and the discrepancy of assessment was resolved by the agreement through discussion. Results A total of 35 patients was included in this analysis. The median age was 60 years (range, 31-79) and 26 (74%) were male. Histologic subtypes included were PTCL, not otherwise specified in 10 (29%), extranodal NK/T cell lymphoma in 8 (23%), angioimmunoblastic T cell lymphoma in 7 (20%), anaplastic large cell lymphoma, ALK negative in 4 (11%), and others in 6 (18%). 22 patients (63%) were presented as advanced stage disease and 9 (26%) had B symptoms. ECOG performance status was ≥ 2 in 7 (20%), serum LDH level was elevated in 16 (46%), and bone marrow was involved in 5 (14%). Thus, 14 patients (40%) were classified as high risk (≥ 2 factors) by the prognostic index for PTCL (PIT). 31 patients (89%) completed planned systemic chemotherapy ± involved-field radiotherapy and 25 (71%) achieved complete response by systemic chemotherapy. 10 patients (29%) underwent consolidative autologous stem cell transplantation (ASCT). Using 5-PS, interim PET scan was visually scored as follows; 1 point in 10 patients (29%), 2 in 6 (17%), 3 in 8 (23%), 4 in 7 (20%), and 5 in 4 (11%). Among these, 11 patients (31%) had 4 point or above were considered positive for interim PET scan. With a median follow-up of 43.4 (range, 4.3-89.8) months, progression-free survival (PFS; median, 5.2 vs 38.0 months, respectively; P=0.001) and overall survival (median, 12.6 months vs not reached, respectively; P=0.004) was significantly worse in patients with positive interim PET than those with negative results. In multivariate analysis for PFS, high risk of PIT (HR, 3.67; 95% CI, 1.13-11.99) and positive interim PET (HR, 4.02; 95% CI, 1.32-12.23) were independently associated with faster disease progression, whereas consolidation with ASCT was independent prognostic factor for better PFS (HR, 0.23; 95% CI, 0.06-0.84). Conclusion Visual assessment of interim PET scan using Deauville 5-PS appears to predict early outcomes of patients with PTCL. Patients with positive interim PET shows highly predictive of extremely poor outcomes. Therefore, our findings suggest further studies regarding early stratification based on interim PET results as a response-adapted treatment strategies in patients with PTCL are needed to improve outcomes. Disclosures: No relevant conflicts of interest to declare.

There is solid evidence that myelo-monocytic cells actively contribute to angiogeneic processes. However, the specific subpopulations of myelo-monocytic cells participating in vascularization and their precise underlying mechanisms have not been well identified. Recently it has been reported that CX3CR1, a receptor for fractalkine (CX3CL1; Fkn), is highly induced at injury sites and CX3CR1 positive cells have an active role for angiogenesis in a mouse wound healing model. Therefore, we evaluated neovascularization activities of CD11b+CX3CR1+ cells during recovery of blood perfusion in a hind-limb ischemic injury mouse model and also identified their activities during the process of angiogenic sprouting in the retina of early postnatal Sprague-Dawley (SD) rat. Ischemic injuries were induced in C57BL/6 mice by femoral artery dissections. Single-cell suspensions were made from ischemic muscles using collagenase and dispase digestion. Isolated CD11b+CX3CR1+ cells and CD11b-CX3CR1- cells from ischemic muscle (5x105 cells/mouse) were injected into ischemic muscles 2 days after femoral artery dissections. Laser Doppler Perfusion (LDP) indexes were assessed as an indicator for blood perfusion. In order to block the functions of CX3CR1 and Fkn, either anti-CX3CR1 or anti-Fkn neutralizing antibody (Ab) were injected into ischemic muscles. To determine whether CX3CR1 has a role in actively growing retinal vessels, intravitreal microinjections were done with anti-CX3CR1 Ab at postnatal 2 days (P2) SD rat. P5 retinas treated with neutralizing anti-CX3CR1 Ab at P2 were used. CD11b+CX3CR1+ cells were positive for CD45 and F4/80, monocyte/macrophage marker. CD11b+CX3CR1+ cells accumulated at the injured muscles in C57BL/6 mice. We tested for contribution of CD11b+CX3CR1+ cells to neovascularization in the injury sites by injecting ischemic muscle-derived CD11b+CX3CR1+ cells or CD11b-CX3CR1- cells into the adductor muscles of C57BL/6 mice. CD11b+CX3CR1+ cells enhanced blood perfusion when compared to CD11b-CX3CR1- cells (78.0±3.2% vs 39.0±0.3% of LDP indexes at day 28, p In summary, CD11b+CX3CR1+ cells are a newly identified subset of myelomonocytic cells for vessel formation, capable of regulating vascular formation. CD11b+CX3CR1+ cells may be an attractive clinical tool to accelerate tissue vasculature development in various ischemic diseases. Disclosures: No relevant conflicts of interest to declare.

Background VMP regimen for newly diagnosed myeloma patients is well-documented treatment. However patients in real practice generally have worse performance status and less attention than those in clinical trials. Thus we conducted observational study to evaluate the efficacy and toxicity of VMP treatment in newly diagnosed Korean myeloma patients. Patients and Methods Data were prospectively collected from 39 hospitals. One hundred seventy three patients who started VMP as first line from 2011 May to 2012 April were included for analysis. Results Median age was 71 and 22.5% were more than 75 years old. Fifty-seven per cent were male sex. IgG type was most common (61.9%) and IgA 24.9%. ISS stage I was 13.8% and III was 51.5%. Patients with high risk FISH (Del17p, t(4;14), and t(4;16)) were 4.1%, 4.1%, and 2.3% respectively. Dose and schedule was followed original VISTA trial except for use of prednisolone instead of prednisone. Median 5cycles (range 1-9) were given and 105 patients stopped in the course of treatment. Most common cause were adverse event (28.8%) followed by disease progression or no response (19.6%). Twenty-five mortality cases were reported and 22 were in the course of treatment. The most common cause of mortality was infection (61%) followed by disease progression (13%). Overall response rate was 72.3% and response more than VGPR was 37.6%. Median progression free survival is 455 days and median OS was 504 days. One year PFS was 80.9 % and one year OS was 83.4%. Most common toxicity was cytopenia, peripheral neuropathy, and gastrointestinal toxicities such as nausea and diarrhea. Peripheral neuropathy of all grade and grade 3 or more was 58.6% and 6.36%, respectively Discussions Even though patients with higher proportion of ISS stage, efficacy of VMP regimen was considerable in Korean patients. With relatively high mortality due to infection in the course of treatment prophylactic measures for infection need to be developed. To reduce the incidence of peripheral neuropathy, close observation and intervention are needed to prevent aggravation of neuropathy. Disclosures: Off Label Use: lenalidomide in newly diagnosed myeloma. Kwak:celgene: Research Funding.

Introduction Older MM patients continue to have poor outcomes. Lenalidomide (L) and low dose dexamethasone (D) was found to result in better overall survival than L and high dose D in ND MM (Rajkumar et al. Lancet Oncol 2010). In an attempt to decrease toxicity from therapy in this vulnerable patient population, we have initiated two phase II clinical trials evaluating a response adapted therapy using single agent L with sequential addition of corticosteroids. The trials had similar design and were conducted in one site in the United States (US) and multiple sites in South Korea (SK). Methods Eligible patients had symptomatic standard risk MM (b2microglobulin (b2m)≤5.5, absence of t(4;14), t(14;16), 17p deletion, aneuploidy or 13q by metaphase cytogenetics) and were not eligible or not willing to undergo high-dose melphalan. Patients received L on D1-21 every 28 days for 2 cycles based on renal function. If patients had a minimal response (MR) or better (25% reduction in serum M spike) after 2 cycles, they continued on single agent L until progressive disease. If patients had stable disease (SD) after 2 cycles, prednisone 100 mg PO D1-5 (P) was added to their L. In the event of progressive disease on single agent L or on LP, therapy was changed to L (at the tolerated dose) with dexamethasone 40 mg PO weekly (D). Thromboprophylaxis was with aspirin, warfarin or low molecular weight heparin. Responses were per IMWG and the primary end point was the 1 year progression free survival (PFS)of LD. Results Between 2/2010 and 6/2013, 61 patients were enrolled (34 in SK and 27 in the US). The median age was 73 (range 48-85) and 58% were males. Compared to US, patients in SK had a younger age, lower weight and body surface area and a higher proportion of ISS 2. There were no differences in baseline performance status, hematologic parameters, creatinine clearance or baseline b2m. The overall response rate (≥PR) to single agent L was 48% (59% & 38% for US and SK) and the clinical benefit rate (≥MR) 64% (74% & 56% for the US and SK respectively). After a median follow up of 13.2 months, P was added for 16 patients (26%) and 7 (44%) had ≥PR. D was added for 14 patients (23%) and 10 patients (71%) had ≥PR. The 1 year dexamethasone free survival was 75% (84% & 67% in the US and SK respectively). To date, 3 patients progressed after the addition of D and the 1 year LD PFS was 90% (95% CI 78-96%). There were no statistical differences in grade 3/4 hematologic adverse events (table). Lenalidomide dose reduction was more frequent in the US (59% vs. 26%) however discontinuation from therapy for causes other than progressive disease or death was more frequent in SK (41% vs. 18%). Conclusion In This elderly patient population, response adapted (sequential) therapy results in outcomes comparable to LD in younger patients with MM with 78% of patients not requiring the addition of D. Social and ethnic causes of differential tolerance to therapy should be studied further. Disclosures: Baz: Celgene: Research Funding; Millenium: Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding. Off Label Use: lenalidomide in newly diagnosed myeloma. Alsina:Celgene: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Shain:Onyx: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity’s Board of Directors or advisory committees. Kwak:celgene: Research Funding.

Background The treatment of localized extranodal NK/T-cell lymphoma (ENKTL), nasal type has shifted to non-anthracycline-based intensive chemotherapy with radiotherapy since the poor response of ENKTL to anthracycline due to the expression of a multidrug-resistant (MDR) p-glycoprotein was proven. We previously proposed concurrent chemoradiotherapy (CCRT) followed by chemotherapy which is not affected by MDR and reported a significant improvement of outcomes of localized ENKTL. Based on our accumulated data, we designed a new treatment protocol. First, we added tri-weekly administration of L-asparaginase to reduce the probability of systemic progression during CCRT. Second, we designed MIDLE (methotrexate, ifosfamide, etoposide, dexamethasone, and L-asparaginase) according to 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 40 Gy and weekly administration of cisplatin 30 mg/m2 (total: 4 doses). During the CCRT, tri-weekly intravenous (IV) administration of 4,000 IU of Escherichia coli L-asparaginase was done. The chemotherapy, MIDLE (methotrexate 3g/m2 on day 1, etoposide 100mg/m2, Ifosfamide 1000mg/m2 on day 2-3, dexamethasone 40mg on day 1-4, and L-asparaginase 6000IU/m2 IV on day 4, 6, 8, 10) was repeated every 28 days up to 2 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). 24 patients were male while only four patients were female. Twenty-two patients were stage IE and six were IIE. All patients completed CCRT, which resulted in 92.9% of overall response rate including 20 complete responses and 6 partial responses. One patient showed stable disease after CCRT whereas the other patient progressed. No grade 3 or 4 hematologic toxicity was found during CCRT. However, grade 3 non-hematologic toxicities included bilirubin elevation (n = 4), mucositis (n = 1), and nausea/vomiting (n = 6). After the completion of CCRT, 23 patients entered the MIDLE chemotherapy as five patients including one disease progression and four cases of withdrawal could not receive MIDLE. All patients achieved complete response after they completed the planned two cycles of MIDLE chemotherapy whereas two patients dropped out after their first cycle due to non-hematologic toxicity. The final complete response rate of patients enrolled was 92.9% (26/28). The major toxicity of MIDLE was grade 3/4 leucopenia, and the non-hematologic toxicity included mucositis and nausea/vomiting. The hepatic toxicity-associated with L-asparaginase was frequent. However, the majority of the hepatic toxicities were grade 1 or 2. With the median potential follow-up of 25 months (95% confidence interval: 19 – 31 months), four patients relapsed. Conclusion L-asparaginase plus concurrent chemoradiotherapy followed by MIDLE chemotherapy can be an effective treatment strategy with acceptable toxicity in stage I/II extranodal NK/T-Cell lymphoma, nasal type. Disclosures: Kwak: celgene: Research Funding.

Background Approximately 50% of CP CML patients achieve undetectable molecular residual disease (UMRD) at 6-7 years of first-line imatinib (IM) therapy. Although imatinib therapy is effective in chronic myeloid leukemia (CML) patients and a substantial portion of patients achieve UMRD with prolonged IM therapy, up to 10^7 leukemic cells can still be present in the absence of detectable BCR-ABL1 in RQ-PCR assay due to the sensitivity limit of current RQ-PCR technology. The recent several reports to assess whether IM can be discontinued in CML patients have shown that IM discontinuation can be employed based on clinical study in patients who had enough IM therapy and UMRD durations prior to IM discontinuation. In our previous report, the 12-month probability of sustained UMRD of 48 patients was 80.8% (78.4% in 37 patients with at least 12 months follow-up), a higher rate than that reported by the ‘STIM’ (Stop Imatinib) trial. To identify predictors for safer, successful IM discontinuation and to explore additional contributing factors for sustained molecular responses (MRs), this multicenter prospective Korean Imatinib Discontinuation Study (KIDS) is on-going. Methods Patients who were treated with IM for more than 3 years and whose BCR-ABL1 was undetectable in RQ-PCR for at least 2 years were enrolled in this study. After discontinuation, molecular response was monitored using RQ-PCR assay every month up to 6 month follow-up, every 2 months up to 12 month follow-up, and every 3 months thereafter. In case of relapse, defined as loss of MMR on 2 consecutive assessments, IM therapy was re-introduced and molecular response after resumption was observed every month using RQ-PCR. Our primary objectives were to evaluate the probability of persistent UMRD at 12 month follow-up after discontinuation, and to measure the duration of persistent UMRD after discontinuation. The secondary objective was to evaluate the probability of major molecular response (MMR) loss and the time taken to lose MMR after discontinuation. Results Of the 100 patients who were screened for KIDS, 22 patients have failed because of positive result of RQ-PCR tested in the central laboratory (N= 15, 69%), failure to meet inclusion criteria (N=4, 18%) and informed consents withdrawal (N=3, 13%).As of data cut-off date of 10 July 2013, a total of 78 patients (42 females, 36 males) who were diagnosed between 26 Feb 1998 and 11 Dec 2009 were enrolled on KIDS, with a median age of 45 years (range, 19 – 82), the percentages of patients with low, intermediate and high Sokal risk scores were 37%, 29% and 13%, respectively with unknown Sokal risk scores in 18%. And the median time on IM therapy and the median duration of sustained UMRD were 85 months (range, 38 – 141) and 44 months (range, 23 – 114), respectively, prior to discontinuation. With a median follow-up of 14 months (range, 0.3 – 33.5), the 12-month probability of sustained MMR and UMRD were 78.5% ± 5.3% and 78.5% ± 5.1%, respectively. All patients with MMR loss were in non-transplant group, whereas none of the 21 patients in the transplant group experienced MMR loss. The probability of sustained MMR and UMRD in non-transplant group were 67.3% ± 7.7% and 68.5% ± 7.0%, respectively. Nine of 13 patients who lost MMR were resumed IM with a median time of 15 months (range, 0.1 - 22.3 months). All 9 patients, who resumed IM, re-achieved MMR at a median of 3 months (range, 1.4 - 4.7 months) after resuming IM therapy and re-achieved UMRD at a median of 7.5 months (range, 3.3 - 13.3 months). Univariate analysis of factors affecting loss of MMR showed that IM therapy duration and UMRD duration before treatment discontinuation had a higher 12-month probability of sustained MMR. Conclusions Our updated data shows lower relapse rate after discontinuation compared to previous discontinuation studies. In particular, the rate of screening failure due to positive result of RQ-PCR tested in the central laboratory implied that strict PCR sensitivity criteria is important for safer, successful IM discontinuation. Disclosures: No relevant conflicts of interest to declare.

Abstract 695 Background Radotinib is a novel, selective Bcr-Abl tyrosine kinase inhibitor (TKI) developed by IL-YANG Pharm, South Korea. Radotinib showed a good efficacy and safety profile to chronic myeloid leukemia (CML) in preclinical and phase 1 clinical studies. To investigate the clinical efficacy and safety of radotinib 400 mg twice daily, data from CML patients treated during phase 2 clinical trial are reported. Methods Philadelphia chromosome (Ph+)-positive chronic phase CML (CP-CML) patients who failed or were intolerable to TKIs (imatinib and/or dasatinib and/or nilotinib) were enrolled between July 2009 and November 2011. Patients were treated with radotinib 400 mg twice daily for 12 cycles (1 cycle=4 weeks). The primary end point was an achievement of major cytogenetic response (MCyR, Ph+£35%) by 12 months. Safety parameters were also analyzed. Results A total of 77 CP CML patients (18 years of age or over) were enrolled from 12 sites in Korea, India, and Thailand. This analysis includes data from last enrolled patient who received at least 3 months of radotinib therapy. The median age of patients was 47 (range; 24–76) years, and 65 (84.4%) were imatinib-resistant and 12 (15.6%) were imatinib-intolerant. Four patients also had intolerance to dasatinib. With a median follow-up of 10.6 months, treatment with radotinib is ongoing in 46 patients (59.7%) and 31 patients (40.3%) discontinued the treatment including two deaths (2.6%). However, there were no CML-related deaths. Median duration of radotinib exposure was 296 (8–798) days. Overall MCyR rate was 63.6%, including 35 patients (45.4%) complete cytogenetic response and 14 patients (18.2%) partial cytogenetic response. The median time to MCyR was 2.8 months (85 days) and the median duration of MCyR was 315 (range; 5–726) days. Of patients achieving complete cytogenetic response, 37% (13/35) achieved major molecular response. Within follow-up durations, 44 patients (57.1%) required dose interruption and 41 patients (53.3%) had dose reduction. Most common grade 3/4 hematologic and laboratory adverse events (AEs) were thrombocytopenia (27.3%), neutropenia (10.4%), anemia (6.5%), and hyperbilirubinemia (31.2%). Common non-hematologic AEs were rash (29.8%), fatigue (14.3%), nausea/vomiting (14.3%), headache (13.0%), and pruritus (11.7%). The majority of AEs were easily manageable with temporal dose interruption and/or reductions. In all patients with CP-CML treated with second-line radotinib, estimated progression-free survival and overall survival rate at 12months was 84.9% (95% CI, 72.7–92.0%) and 97.4% (95% CI, 89.9–99.3% ), respectively. Conclusion Radotinib phase 2 trial confirmed the efficacy and safety of radotinib 400 mg twice daily in patients with CP-CML after failure to TKIs. Most of the AEs occurred in the early treatment period, were tolerable, and were easily controlled by dose interruption or reduction. Disclosures: Off Label Use: Radotinib, new BCR/ABL tyrosine kinase inhibitor, treatment for CML. Lee:IL-YANG Pharm.: Employment. Park:IL-YANG Pharm.: Employment. Woo:IL-YANG Pharm.: Employment. Kim:IL-YANG Pharm.: Employment. Lee:IL-YANG Pharm.: Employment. Cho:IL-YANG Pharm.: Employment. Shin:IL-YANG Pharm.: Employment. Kim:IL-YANG Pharm.: Employment. Kim:IL-YANG Pharm.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Abstract 2247 Introduction Patients (pts) with cancer have been associated with increased risk of recurrent venous thromboembolism (VTE). However, few data are available regarding the recurrent VTE in Asian pts with advanced solid cancers. Thus, the aim of the study is to investigate the incidence and risk factors for recurrent VTE in pts with advanced solid cancers receiving anticoagulation therapy after index VTE. And, we also evaluate the prognostic impact of recurrent VTE on overall survival (OS) in this population. Methods This study was conducted using data from the web-based registry of the Korean Thrombosis Working Party (http://kdvt.chamc.co.kr), which is an ongoing, multicenter database for recruiting consecutive pts presenting with VTE. Pts were included in the study cohort if they had been diagnosed with recurrent/metastatic solid cancers between May 2004 and Dec 2011 and initiated anticoagulation therapy. Pts were excluded if they had received a diagnosis of hematologic malignancies, if solid cancers were not recurrent or metastatic disease, if index VTE was intra-abdominal venous thrombosis or vascular access-induced thrombosis, or if anticoagulation therapy was not instituted. Pts were also excluded if they were lost to follow-up within 1 week after initiating anticoagulation therapy. Maximal duration of anticoagulation therapy was 12 months and pts in whom anticoagulation therapy was stopped within 12 months were censored at the time of discontinuation. Results A total of 456 pts were included in this analysis. The median age was 65 (range, 27–91) years and 249 pts (55%) were male. Eastern Cooperative Oncology Group (ECOG) performance status (PS) was 0 or 1 in 185 pts (41%). The primary sites of tumor were breast in 22 (5%), genito-urinary tracts in 38 (8%), esophago-gastric in 76 (17%), colo-rectum in 81 (18%), hepato-biliary tracts in 37 (8%), pancreas in 66 (15%), and lung in 136 (30%). Palliative chemotherapy was administered in 328 pts (72%). The location of index VTE was isolated pulmonary embolism (PE) in 196 (43%), isolated lower-extremity deep venous thrombosis (DVT) in 169 (37%), and concomitant PE and DVT in 91 (20%). For initial anticoagulation therapy, low molecular weight heparin was administered in 362 pts (79%), and for long-term therapy, 306 pts (75%) received warfarin. The median duration of anticoagulation therapy after index VTE was 2.4 (range, 0.1–58.3) months. The 6-months and 12-month cumulative incidences of recurrent VTE were 22.4% (95% CI, 19.4–25.4) and 28.7% (95% CI, 24.0–33.4), respectively. In the multivariate analysis for identifying the risk factors associated with the development of recurrent VTE, pancreas (HR, 6.12; 95% CI, 2.00–18.73) and lung (HR, 2.98; 95% CI, 1.03–8.58) as the primary tumor site, poor ECOG PS (HR, 1.74; 95% CI, 1.14–2.67) and VTE initially presented with PE (HR, 2.29; 95% CI, 1.17–4.47) were independent risk factors for increased risk of recurrent VTE. With a median follow-up of 29.1 (range, 1.0–91.2) months, median OS was 11.9 (95% CI, 10.2–13.6) months. Pts with recurrent VTE had a significantly shorter OS than those without recurrent VTE (median, 8.4 vs. 13.0 months, P Conclusion Although Asian populations are thought to have lower risk for developing recurrent VTE, our study demonstrates that the incidence of recurrent VTE in pts with advanced solid cancers is comparable to that of Western populations. Lung or pancreas as a primary tumor site, poor PS, and initial presentation with PE are independent risk factors for recurrent VTE. Additionally, survival is adversely affected by recurrent VTE. Further studies are needed to validate the results of our study and to optimize the treatment strategies for improving treatment outcomes in advanced cancer pts. Disclosures: No relevant conflicts of interest to declare.

Abstract 3690 Introduction Positron emission tomography (PET) has been identified as a useful tool for initial staging and end-of-therapy response assessment in patients with diffuse large B-cell lymphoma (DLBCL). However, the role of an interim PET to predict outcome is still controversial. This may be related that reliable criteria to interpret interim PET has not been established. Recently, Deauville five-point scale (5-PS) and standardized uptake value (SUV)-based analysis were proposed for the interpretation of interim PET. However, Deauville 5-PS might still be related to false positive results in some patients and SUV-based analysis not be suitable for patients with low baseline or high interim SUVmax. Therefore, the aim of this study was to investigate the prognostic implication of interim PET interpretation combining visual and SUV-based quantitative assessments in patients with DLBCL treated with R-CHOP chemotherapy. Patients and methods We consecutively enrolled newly diagnosed DLBCL patients, treated with R-CHOP chemotherapy and had the baseline PET data with 31 evaluable hypermetabolic lesion between 2006 and 2011 in two Korean institutions. Interim PET scan was performed after 3 or 4 cycles of R-CHOP, before 1 week of the next cycle. All PET assessment was performed by 2 nuclear medicine specialists at each institution, and the discrepancy of assessment was resolved by the agreement through discussion. Interim PET response was assessed by visual analysis using Deauville 5-PS and quantitative method based on SUVmax reduction rate. After using the receiver operating characteristics analysis, SUVmax reduction Results One hundred thirty-two patients were included in this study. The median age was 62 years (range, 15–88) and 85 (64%) were male. Sixty-four patients (49%) were presented as advanced stage disease and 30 (23%) had B symptoms. ECOG performance status was 0 or 1 in 100 (76%) and serum LDH level was elevated in 76 (58%). Thus, 44 (33%) were classified as high-intermediate to high risk of International Prognostic Index (IPI). One hundred twenty-three patients (93%) completed planned R-CHOP ± involved-field radiotherapy. Using visual analysis based on Deauville 5-PS and quantitative analysis by SUVmax reduction, 28 (21%) and 26 patients (20%) were positive on interim PET scan, respectively. 18 patients (14%) showed positive PET in agreement between visual and quantitative assessments. However, 10 (8%) of the 28 PET positive patients on visual analysis showed negative PET based on quantitative assessment. Similarly, 8 (6%) among 26 positive patients on quantitative analysis were negative on visual assessment. Thus, 18 patients showed discordant interim PET results between visual and quantitative assessments. With a median follow-up of 25.3 (range, 5.6–75.5) months, 2-year progression-free survival (PFS) was significantly worse in patients with positive interim PET according to visual (27.4% vs. 88.2%, P Conclusion Interim PET appears to predict early outcomes of patients with DLBCL treated with R-CHOP. A positive interim PET in both analyses shows highly predictive of extremely poor outcome. Therefore, combined analysis of visual and SUV-based quantitative assessments makes it possible to more clearly differentiate the clinical outcomes in patients with DLBCL. Further studies are needed to validate our results. Disclosures: No relevant conflicts of interest to declare.

Abstract 3106 Background: Induction therapy followed by ASCT is the standard therapy for the newly diagnosed younger patients with MM. Recently, new drugs such as lenalidomide or bortezomib have shown the promising results as an induction treatment. However, these drugs are not available in many countries as a front line treatment and many different type of induction treatment regimens including old regimens are used. We evaluate the efficacy and safety of the brief course of high dose dexamethasone (HD) and the response adapted PAD (Bortezomib, Adriamycin, Dexamethasone) or VAD (Vincristine, Adriamycin, Dexamethasone) induction chemotherapy in the newly diagnosed younger patients with MM. Methods: One hundred fifty five newly diagnosed patients with MM from 23 institutions received 2 cycles of HD followed by PAD or VAD chemotherapy according to the response to the HD. PAD 4 cycles were given to nonresponsders and VAD 2 cycles were given to who achieved more than PR to HD. The primary endpoint was CR + nCR rate after ASCT. Among 155 patents enrolled this study from November 2009, 29 patients (19%) have been dropped out. This trial will be continued until total 210 patients will be enrolled. The trial is registered on National Cancer Institute website, number NCT01255514. Results: One hundred fifty five patients (88 male, 69 female) were enrolled (median age; 57). 34 (22%) patients had ISS stage I, 64 (41%) stage II and 55 (35%) stage III. Thirty six (26%) patients had abnormal cytogenetics. In FISH analysis, there were 25% del13, 9% del17, 21% t (4; 14), 13% t (14; 16) and 26% t (11; 14). Among the 115 evaluable patients, CR + PR rate was 53% (61/115) after 2 cycles of HD. 61 patients (53%) received subsequent VAD chemotherapy and 54 patients (47%) received PAD chemotherapy. Among the evaluable patients, CR + PR rate after induction therapy was 83% (79%, 48/61 in VAD group vs. 89%, 48/54 in PAD group). 95 patients finished ASCT. CR + nCR rate after ASCT were 74% (74% in VAD group vs 73% in PAD group). Mortality rate of this trial was 15% (17/115). The cause of death was disease progression (n=5), bleeding (n=1) and infections (n=11). Among 115 patients in whom VAD or PAD chemotherapy was actually performed, 1 year OS was 88.1%. (VAD arm 90.7% versus PAD arm 86.1% (P=0.105): median follow-up; 16.6 months). Conclusion: Risk adapted approach using initial HD response showed good response results after ASCT compared with previous trial (CR + nCR rate of IFM 2005-01 trial-Bortezomib+dexa induction & ASCT was 35%, J Clin Oncol. 2010;28:4621–9) The MM patients who showed poor response to HD also showed similar good response rate after ASCT compared with the patients who had good response to HD in this trial. PAD re-induction therapy after failure of initial steroid induction treatment might overcome the inferior results in the high risk MM patients. Our data shows that almost half of the patients who responded to HD can be saved of novel agents during induction treatment, and PAD can successfully rescue the other half who are not sensitive to HD. Therefore, initial steroid response adapted strategy might be the more cost-effective approach in the newly diagnosed ASCT eligible MM patients. Disclosures: No relevant conflicts of interest to declare.

Abstract 3738 Background BCR/ABL tyrosine kinase inhibitors (TKI) is now a standard initial treatment for chronic myeloid leukemia (CML). Several cases reported that hepatitis B virus (HBV) reactivation were related to imatinib therapy. However, it is still unclear whether imatinib or other TKIs induce HBV reactivation in hepatitis B surface antigen (HBsAg)-positive patients. The aim of this study is to investigate the incidence of HBV reactivation and analyze risk factors associated with HBV reactivation in CML patients who are treated with various TKIs. Methods We retrospectively reviewed the medical records from 8 centers in South Korea. HBsAg-positive CML patients under imatinib or other TKIs treatment were analyzed. Results 702 patients were diagnosed CML from participating centers. HBsAg-positive rate was 6.1% (43/702) at diagnosis. In the 43 HBsAg-positive patients, nine patients received prophylactic therapy and HBV reactivation rate was 34.9% (15/43) (95% CI: 21.0–50.9%). Patients who received prophylaxis did not develop HBV reactivation. The median age and the male to female ratio of the HBV reactivated patients were 47.0 years (range; 22–63) and 4:1, respectively. HBV reactivation according to each TKI treatments were: 12 cases under imatinib, 2 cases under dasatinib, and 1 case under nilotinib. Median time to HBV reactivation was 9.3 months (range; 2.3–68.8 months) (95% CI: 5.9 – 28.5 months). None of the patients died due to HBV reactivation, but one patient received liver transplantation due to hepatic failure. Prophylactic therapy and HBV DNA level at diagnosis were the factors associated with HBV reactivation (P=0.011 and P=0.036, respectively). Conclusion This is first report that has analyzed HBV reactivation in HBsAg-positive CML patients during TKIs treatment. Prophylaxis should be considered to prevent HBV reactivation during TKI treatment. Also, we recommend that HBsAg-positive patients with CML receiving TKI treatment be closely monitored. Disclosures: No relevant conflicts of interest to declare.

Abstract 2683 Background Secondary central nervous system (CNS) involvement in diffuse large B-cell lymphoma (DLBCL) includes CNS relapse or CNS involvement with systemic disease progression. Although many publications have provided information regarding the incidence and risk factors for CNS involvement in DLBCL, its incidence reported across those studies varies widely. It might be related with that the majority of data were from retrospective analyses. Furthermore, the role of CNS prophylaxis for DLBCL has been challenged, especially in the era of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). As a result, this rare but fatal clinical problem still remains a therapeutic dilemma in the management of DLBCL. In this study, we prospectively explored the risk factors of CNS involvement and the clinical impact of screening evaluation for CNS involvement. Methods We analyzed the incidence of secondary CNS involvement in pathologically confirmed DLBCL patients enrolled in the Prospective Cohort Study with Risk-adapted Central Nervous System Evaluation in Diffuse Large B-cell Lymphoma (PROCESS study, NCT01202448). Patients should be treated with at least one cycle of R-CHOP, and provide written informed consents. We assessed the risk of CNS involvement based on previously reported risk factors: serum LDH elevation, the number of extranodal involvements, serum albumin, bone marrow invasion, HIV positivity, the involvement of testis, breast, paranasal sinus, bone, retroperitoneal lymph nodes, orbit, and epidural space. If patients had any of these risk factors, they underwent CSF study to screen the CNS involvement at diagnosis. If the results were abnormal, additional studies including brain MRI could be done depending on physicians' decision. CNS prophylaxis was done with intrathecal chemotherapy with methotrexate for patients who had positive findings of screening evaluation or were determined to have a risk of CNS involvement based on physicians' decision. Results 564 patients were enrolled between 2010 and 2012 from 26 institutions belonged to the Consortium for Improving Survival of Lymphoma (CISL). They were prospectively monitored with the median follow-up duration of 10.5 months. The median age was 59.5 years old (range 20–89 years), and approximately a half of patients had Ann Arbor stage III/IV (n = 276, 48.9%) and 193 patients involved two or more than two extranodal sites (34.2%). Based on the International Prognostic Index (IPI) risk, 192 patients belonged to high or high-intermediate risk (34%). Among patients (n = 368) who had at least one of risk factors for CNS involvement, 243 patients underwent CNS evaluation, and the evidence of CNS involvement was found in16 patients including positive cytology (n = 11), and brain parenchyma lesion (n = 5). The other 78 patients showed equivocal results of CSF analysis including the presence of atypical cells (n = 17). Intrathecal prophylaxis was done for 51 patients whereas high dose methotrexate chemotherapy was combined with R-CHOP for patients with brain lesion. During follow-up, 14 cases of additional CNS involvement including brain parenchyma (n = 8), leptomeningeal (n = 5), and ocular invasion (n = 1) were observed. The median time to CNS event in these 14 patients was 7.5 months (range 1.2 – 15.9 months). Thus, 30 cases of secondary CNS involvement were documented in our study population at the time of analysis (5.3%) including 16 cases at diagnosis and 14 cases during follow-up. The univariate analysis for evaluation of risk factors demonstrated serum LDH, the number of extranodal involvements, bone marrow invasion, and the involvement of retroperitoneal lymph nodes, breast, paranasal sinus and orbit were significantly associated with CNS involvement. The high/high-intermediate risk of IPI was also predictive of CNS involvement (P < 0.05). However, in the multivariate analysis, bone marrow invasion and the involvement of breast, paranasal sinus and orbit were independently predictive for CNS involvement. Conclusions The incidence of secondary CNS involvement in DLBCL patients treated with R-CHOP was around 5%, and a half of cases had the evidence of CNS involvement at diagnosis. Considering a particular risk of CNS involvement of disease-related factors, risk-adapted active screening against CNS involvement may help to improve treatment outcome of patients with DLBCL. Disclosures: No relevant conflicts of interest to declare.

Abstract 3355 Introduction: Cancer patients (pts) with venous thromboembolism (VTE) have an increased risk of VTE recurrence. However, few data are available regarding the incidence, impact of malignancy characteristics on VTE recurrence in pts with recurrent/metastatic solid cancer. Reliable information on the factors determining the risk of VTE recurrence may facilitate tailored anticoagulation therapy by discriminating cancer-associated VTE pts according to the risk of recurrence. Therefore, the aims of this study are to investigate the incidence of VTE recurrence, its association with malignancy characteristics, and prognostic factors for VTE recurrence in pts with recurrent/metastatic solid cancer receiving anticoagulation therapy after prior index VTE. Methods: The data source in this study is a web-based registry of Korean VTE Working Party (http://kdvt.chamc.co.kr), which is an ongoing, multicenter database system recruiting consecutive patients with VTE confirmed by objective tests. The pts were eligible to enter the study cohort if they had received a diagnosis of recurrent/metastatic solid cancer between May 2005 and Dec 2010 and initiated anticoagulation therapy after the diagnosis of index VTE. Pts were excluded from the study cohort if they had received a diagnosis of hematologic malignancies, if solid cancers were not recurrent or metastatic disease, if index VTE was intra-abdominal venous thrombosis (IVT) or vascular access-induced thrombosis, or if anticoagulation therapy was not instituted. The period of follow-up considered for the analysis was the duration of anticoagulation therapy with a maximum of 6 months and pts in whom anticoagulation therapy was stopped within 6 months were censored at the time of treatment cessation. Results: The data of 363 recurrent/metastatic solid cancer pts with anticoagulation therapy following the diagnosis of index VTE were analyzed. The median age was 65 (range, 27–91) years and 201 pts (55%) were male. Eastern Cooperative Oncology Group (ECOG) performance status (PS) was 0 or 1 in 164 pts (55%). The primary sites of cancer were breast in 17 pts, genito-urinary tract in 36, stomach-esophagus in 74, colo-rectum in 81, hepato-biliary tract in 28, pancreas in 34, and lung in 93. Two hundred sixty (72%) pts received active systemic chemotherapy. The location of index VTE was isolated pulmonary embolism (PE) in 151 (42%), isolated deep venous thrombosis (DVT) in 136 (37%), and combined PE and DVT in 76 (21%). The type of anticoagulation therapy for initial therapy was low molecular weight heparin in 282 pts (78%), and for long-term therapy was warfarin in 272 (75%). Eighteen (5%) pts received systemic or catheter-directed thrombolytic therapy for their index VTE at the time of initial diagnosis. Median duration of anticoagulation therapy was 2.4 months (range, 0.1–6.0). Fifty four (15%) pts presented with VTE recurrence within the first 6 months of index VTE. The distribution of site at VTE recurrence was 32 (57%) isolated PE, 10 (18%) isolated extremity DVT, 1 (2%) isolated IVT, 10 (18%) combined PE and DVT, 2 (4%) combined DVT and IVT, and 1 (2%) combined PE/DVT and IVT. The 6-month cumulative incidence of VTE recurrence after index VTE was 26.6% (95% CI, 19.7–33.5). In the univariate analysis for cumulative incidence of VTE recurrence, male gender (P=0.022), 2 to 4 of ECOG PS (P=0.002), lung or pancreas of primary site of cancer (P Conclusion: This study demonstrated that the risk of VTE recurrence in Asian patients with recurrent/metastatic solid cancer receiving anticoagulation therapy after prior VTE was substantially high. Pancreas or lung as a cancer site, poor PS, and male gender were strong predictors of VTE recurrence. These may provide basic information to optimize treatment strategies for tailored thromboprophylaxis in recurrent or metastatic solid cancer pts. Further larger studies are needed to confirm our results and to compare with different ethnicities. Disclosures: No relevant conflicts of interest to declare.

Abstract 1990 Introduction: Autologous stem cell transplantation (ASCT) is a standard of care for younger multiple myeloma patients (pts). However, nearly all pts undergoing ASCT will relapse and require salvage therapy. Several investigators have reported 2nd ASCT might be a feasible and effective treatment modality in some pts. However, these studies contained small number of pts with 2nd ASCT and did not compare with outcomes of salvage therapy using novel agents. Thus, the aims of this study are to investigate outcomes of 2nd ASCT in pts relapsed after front-line ASCT and identify the impact of 2nd ASCT compared to modern systemic therapy in the novel agent era. To minimize the heterogeneity between the 2 groups, matched-pair design was chosen. Methods: The data of 48 pts between 1998 and 2010 with 2nd ASCT after relapse of front-line ASCT identified from web-based registry (www.myeloma.or.kr) were analyzed. Pts with tandem ASCT or salvage allo-SCT were excluded. The goal of this study was to perform a matched-pair analysis, each patient with 2nd ASCT was matched to three pts from a cohort of 517 pts treated with systemic chemotherapy after relapse of prior ASCT. The pts were matched for 9 potential prognostic factors: age at relapse (MEL140), response to front-line ASCT (≥VGPR vs Results: The median age at relapse was 55.5 (range, 33.4–68.5) years and 106 pts (55%) were male. The ISS was I(54, 28%)/II(84, 44%)/III(54, 28%). Serum LDH level was elevated in 133 (69%) and sCr ≥2mg/dL was in 35 (18%). The data of conventional cytogenetic analysis was available in 156 pts (79%). Thirty-three (21%) were abnormal. Of these, 26 pts (79%) had complex chromosomal abnormalities, 15 (45%) del(13q), and 6 (18%) hypodiploidy. One hundred sixty (83%) received VAD as induction therapy for first ASCT. Conditioning regimen for first ASCT was MEL 140–200 mg/m2 in 187 (97%). Fifty-six (29%) received maintenance therapy after first ASCT. Response to front-line ASCT was 67 CR (35%), 39 VGPR (20%), 68 PR (35%), 13 MR/SD (7%), 5 PD (3%). The median TTP after first ASCT was 12.0 (range, 1.1–83.8) months, and pts with ≥18 months of TTP after first ASCT were 57 (30%). After matching process, we identified it was successful because the distribution of 9 matching variables and unmatched other variables (ECOG performance status, hypercalcemia, bone lesions) was balanced between 2 groups. 2nd ASCT conditioning consisted of MEL alone in 45 (94%), the remaining 3 had MEL with busulfan or bortezomib. Only one transplant-related death occurred following 2nd ASCT. Novel agents used as salvage therapy in their course of disease were bortezomib in 151 (79%), thalidomide in 138 (72%), and lenalidomide in 6 (3%). Thalidomide was less frequently used in the 2nd ASCT group than the systemic chemotherapy group (58% vs 80%, p=0.016). With a median follow-up of 55.3 (range, 3.4–140.0) months, the 2nd ASCT group revealed significantly better progression-free survival (median, 18.0 [95% CI, 15.2–20.8] months vs 9.1 [6.7-11.5] months, p=0.017, respectively) and overall survival (OS; median, 55.5 [46.2-64.8] months vs 25.4 [16.7-34.1] months, p=0.035, respectively) than the systemic chemotherapy group. In multivariate analysis for OS, Conclusion: The outcomes of salvage 2nd ASCT appear superior to those of systemic chemotherapy, even fewer pts in the 2nd ASCT group received thalidomide. Additionally, 2nd ASCT was an independent prognostic factor for better OS. Considering current low mortality of 2nd ASCT, our results might provide a substantial evidence for performing 2nd ASCT in relapsed myeloma pts and suggest the value of performing a prospective randomized trial comparing 2nd ASCT and systemic chemotherapy in pts relapsed after front-line ASCT. Disclosures: No relevant conflicts of interest to declare.

Abstract 2021 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 non-Hodgkin's lymphoma (NHL), such as BEAM (carmustine, 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 including Korea. Intravenous busulfan containing regimens as conditioining regimen have been used for both allogeneic and autologous stem cell transplantation in patients with hematologic and non –hematologic malignancies. The purpose of this prospective multicenter phase II study was evaluate the efficacy and safety of iv busulfan/melphalan/etoposide regimen as a conditioining regimen for high dose chemotherapy in the patients with relapsed or high risk NHL. Methods: Patients with relapsed or primary refractory NHL or chemosensitive high risk NHL underwent high dose chemotherapy followed by ASCT at 13 centers in Korea. The conditioning regimen consisted of iv busulfan 3.2mg/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. Results: Fifty one patients were enrolled onto the study. Main subgroups were DLBCL (n=25, 49%) and T cell lymphoma (n=19, 37%). At the time of ASCT, the disease status of patients was as follows: 13 patients were high risk in remission, 16 were primarily refractory to inducton therapy, 15 patients were in chemosensitive relapse. All patients had successful stem cell engraftment with a median time to neutrophil recovery of more than 500/mm3 of 10 days (range, 2 to 30 days). Platelet recovery of more than 20,000/mm3 was seen after a median of 10 days (range, 2 to 51 days) with delayed recovery in one patient. Treatment related toxicities included nausea/vomiting in 28 patients (55%), diarrhea in 28 patients (55%) and mucositis in 33 patients (65%), which were grade I or II in the majority of cases. Grade I/II hepatic toxicities occurred in 24% (n=12) and grade III in 6% (n=3). There were no VOD and treatment related death. The median duration of hospitalization for ASCT was 30 days (range, 12 to 80 days). Forty one patients (80%) achieved a complete response 1 month after ASCT, while three patients showed progressive disease. At a median follow up of 14.7 months, 21(41%) patients exhibited a relapse or progression, while 11 patients had died of disease and one patient had died of heart failure. The estimated 2-year overall and progression free survival for all patients was 64% and 40%, respectively. Conclusion: This preliminary analysis suggests that conditioning regimen of i.v. busulfan/melphalan/etoposide would be well tolerated and effective in patients with relapsed or high risk NHL. Accordingly, this regimen may be regarded as an important treatment option to substitute for BEAM regimen. Disclosures: Lee: Novartis: Research Funding.

Abstract 2018 Background: High-dose melphalan and autologous transplantation (HDM-AT) is the most effective treatment for survival benefits in multiple myeloma (MM) patients. However, the relationship between the HDM-AT response and long-term outcome is not clear. In this study we examined the relationship. Method: We analyzed the clinical data of 137 patients treated with HDM-AT in three institutions between 2000 and 2011. The international Myeloma Working Group Uniform Response Criteria was used to evaluate. Results: Out of 137 patients, clinical data of 126 patients were evaluable for treatment response according to the medical records. Their median age was 55 years (range, 36–65 years) and 69 (55%) patients were male. Among the patients who had received induction treatment (IT), 79%(100/126) of the patients were treated with bortezomib-containing regimens. After IT, the response rates were 29% CR, 18% VGPR, 37% PR, 15% SD, and 1% PD. After HDM-AT, response rates were 64% CR, 15% VGPR, 15% PR, 4% SD, and 2% PD. Median follow-up duration was 25 months (range, 5–146 months). 5-year overall survival (OS) and progression-free survival (PFS) were 54% and 43 %, respectively. Multivariate analysis regarding OS showed that CR after HDM-AT compared to ≤CR is an important prognostic factor (5-year OS rate of CR vs ≤CR, 78% vs 29%, respectively, p=0.002). However, CR after HDM-AT is not prognostic factor for PFS. 79 (79/126, 64%) patients showed the CR after HDM-AT. Among the 79 patients, 44 patients did not achieve CR after IT however, turned into CR after HDM-AT; 35 patients already achieved CR after IT. However, there were no significant differences between the two groups of patients (5-year PFS, 44% vs. 45%, P=0.245 and 5-year OS 77% vs. 79%, P=0.690 respectively). Conclusion: Achievement CR after HDM-AT is the only important prognostic factor to obtain the survival benefit regardless of response after IT in MM patients. Disclosures: No relevant conflicts of interest to declare.

Abstract 4477 Peripheral T cell lymphomas (PTCLs) are an aggressive subtype of non-Hodgkins lymphoma and they have shown the shorter survival compared with B cell lymphoma. High-dose chemotherapy (HDT) followed by autologous stem cell transplantation (HDT/ASCT) for PTCLs has a potential meaning of consolidating remission for PTCLs. However, the effectiveness of ASCT on distinct conditioning regimens, the optimal transplant timing in the frontline or relapsed are still unclear. We investigated the clinical outcomes of HDT/ASCT as frontline intensification in 46 patients with newly diagnosed PTCLs except ALK(+) anaplastic large cell lymphoma. Patients underwent ASCT with a uniform conditioning regimen (busulfex, cyclophosphamide and etoposide). The median age was 47 years (17–65). The histological subtypes were 47.9% PTCL-NOS (n=23), 18.8% anaplastic large cell lymphoma (n=9), 4.2% angioimmunoblastic T cell lymphoma (n=2), 25% extranodal NK/T cell, nasal type (n=12), 2.1% hepatosplenic T cell lymphoma (n=1) and 2.1% enteropathy-associated T cell lymphoma. Thirty patients (62.6%) presented with advanced stage disease (III/IV) and 16 (33.3%) had B symptoms. At diagnosis, 21 patients (43.8%) were classified as high-intermediate/high risk by the age-adjusted IPI (aaIPI) and 10 (20.9%) were classified as high-risk (more than 2 factors) by the prognostic index for PTCL (PIT). Thirty-one patients (67%) could undergo HDT/HSCT and disease status at pretransplant consisted of 23 patients (50 %) with CR and 8 patients (17.4%) with PR. 6 out of 8 patients with PR at pretransplantation improved the response to CR after HDT/ASCT. There was no significant difference of the response rate between CHOP alone or CHOP-like chemotherapy and non-anthracycline-based chemotherapeutic regimen. At a median follow-up of 32.9 months, 23 patients (50%) are alive. The 5-year probability of overall and progression-free survival (PFS) was 48.2 ± 8.1 % and 47.4 ± 8.1%, respectively. However, the 5-year OS and PFS rate in transplanted patients was 57.3± 10.2 % and 55.3 ± 11.3 %, respectively. Conclusion: Frontline HDT/ASCT in patients with PTCL could be performed with a high response rates and a substantial impact on improving outcome for PFS. Our findings also indicate that busulfex, cyclophosphamide and etoposide is a feasible conditioning regimen in ASCT for PTCLs. Disclosures: No relevant conflicts of interest to declare.

Abstract 2044 Background: Induction treatment followed by autologous stem cell transplantation (ASCT) is the standard therapy for the newly diagnosed younger patients with multiple myeloma (MM). Although new drugs such as lenalidomide or bortezomib have been shown the promising results as induction treatment, many different type of induction treatment regimens still have been used. We evaluate the efficacy and safety of the short course of high dose dexamethasone (HD dexa) and the response adapted PAD (Bortezomib, Adriamycin, Dexamethasone) or VAD (Vincristine, Adriamycin, Dexamethasone) induction chemotherapy in the newly diagnosed younger patients with MM. Methods: 107 newly diagnosed patients with MM from 21 institutions received 2nd cycles of HD dexa followed by PAD or VAD chemotherapy according to the response to the initial high dose dexamethasone. The primary endpoint was complete response (CR) + near CR rate after ASCT. Among 107 patents enrolled this study from November 2009, 25 patients (23%) have been dropped out. This trial will be continued until total 210 patients will be enrolled. The trial is registered on National Cancer Institute website, number NCT01255514. Results: One hundred seven patients (58 male, 49 female) were enrolled (median age; 56). 26 (24%) light chain disease were included. 31 (29%) patients were D-S stage II and 67 (63%) were stage III. According to the ISS, 23 (22%) patients had stage I, 51 (48%) had stage II and 33 (31%) had stage III. 26 (24%) patients had abnormal cytogenetics. There were 31% del13, 7% del17, 19% t(4;14), 15% t(14;16) and 28% t(11;14) in FISH analysis. Among the 82 evaluable patients, CR + PR rate was 48% (39/82) after 2nd cycles of HD dexa therapy. 39 patients (48%) received subsequent VAD chemotherapy and 43 patients (52%) received PAD chemotherapy. Among the 64 patients finished VAD or PAD chemotherapy, CR + PR rate was 83% (79%, 26/33 in VAD group vs. 87%, 27/31 in PAD group). 56 patients were finished ASCT until now. CR + near CR rate after ASCT were 61% (58% in VAD group vs 63% in PAD group). Mortality rate of this trial was 13% (11/82). The cause of death was disease progression (n=3), bleeding (n=1) and infections (n=7). Among 82 patients in whom VAD or PAD chemotherapy was actually performed, 1 year overall survival (OS) rate was 84.7%. 1 year survival rate was 93.8% versus 77.2% (P=0.049) with VAD versus PAD (median follow-up; 9.1 months). Conclusion: Risk adapted approach using initial steroid response showed good response results after ASCT compared with previous trial (CR + near CR rate of IFM 2005-01trial-Bortezomib+dexa induction & ASCT was 35%, J Clin Oncol. 2010;28:4621–9) The MM patients who had poor response to HD dexa also showed similar good response rate after ASCT compared with the patients who had good response to HD dexa treatment in this trial. PAD re-induction therapy after failure of initial steroid induction treatment might overcome the inferior results in the high risk MM patients. Therefore, initial steroid response adapted strategy might be the more cost-effective approach in the newly diagnosed ASCT eligible MM patients. Disclosures: No relevant conflicts of interest to declare.

Abstract 1516 Background: Front-line combination of imatinib with conventional chemotherapy has demonstrated an improved complete remission (CR) rate, an increased transplantation proceeding rate with CR, and a better survival in adults with Ph+ ALL. However, in the light of disease aggressiveness and recurrence, mainly as a result of the outgrowth of leukemic subclones with imatinib-resistant mutations, an improved strategy to induce more effective leukemic cell clearance is clearly needed. Dasatinib, a potent dual BCR-ABL/SRC family kinase inhibitor, has been shown to be effective in patients with imatinib-resistant chronic myeloid leukemia and Ph+ ALL. Methods: We present the first interim results of the Korean prospective phase II study protocol designed to evaluate the clinical efficacy of first-line dasatinib plus conventional chemotherapy for adults with newly diagnosed Ph+ ALL. This study is registered at www.ClinicalTrials.gov as NCT01004497. The protocol is designed for 51 patients, and recruitment started in March, 2010. The protocol enrolls patients (15–65 years) who receive dasatinib (100 mg once daily for 4 weeks) as an alternative schedule after each conventional chemotherapy course (alternating modified hyper-CVAD and high-dose cytarabine/mitoxantrone). Patients in CR who have a suitable related/unrelated donor undergo allogeneic transplantation as early as possible (depending on the speed of coordination process). Patients without a donor continue to receive dasatinib plus conventional chemotherapy (up to 4 courses; depending on the patient's tolerability) followed by dasatinib maintenance therapy (100 mg once daily for up to 2 years). Minimal residual disease monitoring for BCR-ABL transcript is centrally evaluated by real-time quantitative PCR (4.5 log sensitivity) through handling of bone marrow samples from all patients (Research Institute of Molecular Genetics, The Catholic University of Korea, Seoul, Korea). Results: A total of 36 patients have been enrolled to date. Of these, 3 patients are receiving the first dasatinib cycle (too early); 3 patients died before starting the first dasatinib cycle from infections. Thus, 30 patients are evaluable for assessment of response to dasatinib plus conventional chemotherapy. Median age was 47 years (range, 19 to 64 years). Karyotype analysis revealed additional chromosomal changes in 18 (60%) of the 30 patients. Twenty patients (67%) had m-BCR transcript. All patients (100%) have achieved CR with a decrease in the minimal residual disease by the first dasatinib cycle, and of these, 13 patients (43%) have achieved major molecular response [MMR; including 5 complete molecular response (CMR4.5)]. By the second dasatinib cycle, 25 patients (83%) have achieved MMR (including 11 CMR4.5). So far, no dasatinib-related serious adverse events (≥grade 3 toxicity) have been observed. Twenty-four (80%) of the 30 patients have undergone allogeneic transplantation in CR; 6 patients are receiving continuous dasatinib plus conventional chemotherapy in CR. With a median follow-up duration of 10 months (range, 5 to 17 months), 25 patients are at present alive in continuous CR, and 4 patients have died (2 infections during consolidation chemotherapy, 2 transplant-related complications). Only 1 patient who failed to achieve MMR has relapsed at 11 months from diagnosis (at 5 months after allogeneic transplantation). The estimated probabilities of disease-free survival and overall survival at 1 year were 76% and 83%, respectively. Conclusions: Our interim analysis indicates that first-line combination of dasatinib with conventional chemotherapy appears to be effective in achieving a good quality of molecular response (MMR/CMR4.5) in adults with Ph+ ALL. Whether this would translate to an improved long-term survival remains to be investigated. Disclosures: Lee: Bristol Myers Squibb: Honoraria, Research Funding. Kim:Bristol Myers Squibb: Honoraria, Research Funding.

Abstract 1790 Introduction The addition of rituximab to standard chemotherapy has substantially improved the survival in patients with diffuse large B cell lymphoma (DLBCL). Previous studies in the pre-rituximab era have identified the worse outcomes in primary extranodal DLBCL compared with nodal DLBCL. However, there have been reported conflicting datas about outcomes of primary extranodal DLBCL compared with nodal DLBCL in the rituximab era. Primary breast DLBCL is one of the extremely rare extranodal lymphoma. As in other primary extranodal lymphoma, few clinical studies have been reported for investigating the efficacy of rituximab in patients with primary breast DLBCL. For clarifying this, a large randomized trial comparing survival in patients with primary breast DLBCL is required. However, the rarity of primary breast DLBCL makes large trial virtually difficult in single center or study group. Additionally, retrospective studies for evaluating the role of rituximab in primary breast DLBCL had bias according to the difference of treatment period between CHOP and R-CHOP era. Thus, to investigate the impact of rituximab in primary breast DLBCL, we performed a matched pair analysis following strict matching criteria in patients with primary breast and nodal DLBCL treated with R-CHOP. Materials and methods Primary breast DLBCL patients treated with R-CHOP was identified from 11 hospitals in Korea between May 2004 and August 2009. The eligibility criteria included: (1) histologically confirmed DLBCL, (2) Ann Arbor stage I or II of primary breast DLBCL, defined as isolated breast involvement with or without nodal disease, (3) received front-line treatment with R-CHOP. Each primary breast DLBCL patient was matched to three nodal DLBCL patients treated with R-CHOP during the same period from the data registry of Korean Lymphoma Working Party. The patients were matched for 5 known prognostic factors: age ( Results Twenty-five patients with primary breast DLBCL were identified. The median age at diagnosis was 56 (range, 21–79) years and all patients were female. The Ann Arbor stage was I in 13 patients (52%) and II in 12 patients (48%). ECOG PS was 0 or 1 in 23 patients (92%), B symptom was present in 1 patient (4%), and serum LDH level was elevated in 9 patients (36%). Thus, stage-modified international prognostic index (IPI) was 0 or 1 in 20 patients (80%). Eight patients (32%) were received 3 or 4 cycles of R-CHOP followed by involved field radiotherapy and 17 patients (68%) were treated with 6 to 8 cycles of R-CHOP. After matching process, stage-modified IPI, treatment strategy, radiation dose, and follow-up duration as well as 5 matching factors were not significantly different between primary breast and nodal DLBCL groups. With a median follow-up of 34.3 (range, 4.4–76.2) months, 3-year progression-free survival (PFS; 70.0% [59.9-80.1] vs. 85.2% [79.9-90.5], p=0.145) and overall survival (OS; 82.2% [72.6-92.8] vs. 90.0% [86.0-94.0], p=0.528) was not statistically different between primary breast and nodal DLBCL groups. In multivariate analysis, 2 or 3 risk factors of stage-modified IPI were independent prognostic factor for worse PFS (hazard ratio [HR], 3.18; 95% CI, 1.22–8.30) and OS (HR, 4.88; 95% CI, 1.55–15.33). Comparing 3-year cumulative incidence of progression between primary breast and nodal DLBCL, extranodal progression in the breast or central nervous system (CNS) was significantly higher in the primary breast DLBCL than nodal DLBCL (23.6 ± 9.3% vs. 1.4 ± 1.3%, p Conclusions In the post rituximab era, the survival outcomes of primary breast DLBCL were not significantly inferior to those of nodal DLBCL. These results suggest adding rituximab improve survival in primary breast DLBCL as in nodal DLBCL, so that the results provide evidence to add rituximab in this rare extranodal DLBCL. However, even including rituximab, extranodal progression in the breast or CNS was observed still high. Thus, further larger studies of international collaboration to confirm these results are warranted. Disclosures: No relevant conflicts of interest to declare.