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Treatment of indolent lymphoma has improved significantly in recent decades since the advent of rituximab (anti-CD20 monoclonal antibody). Although, some patients with limited disease can be cured with radiation therapy alone, most patients experience disease progression and recurrence during follow-up despite early initiation of treatment. Thus, watch-and-wait is still regarded the standard for asymptomatic patients. Patients with indolent lymphoma have a significant heterogeneity in terms of tumor burden, symptoms (according to anatomical sites) and the need for instant therapy. Therefore, the initiation of treatment and treatment option should be decided with a clear goal in each patient according to the need for therapy and clinical benefits with the chosen treatment. In this review, we cover the current treatment of follicular lymphoma and marginal zone lymphoma.

Central venous catheters (CVCs) are generally required for chemotherapy in patients with acute leukemia, but catheter-related infection is one of the common causes of neutropenic fever. We investigated the in-hospital mortality according to early removal of CVCs and the factors influencing the mortality in patients with acute leukemia undergoing remission induction chemotherapy. This study retrospectively analyzed the hospital record data of 278 patients with acute leukemia treated with non-tunneled CVCs and remission induction chemotherapy in a single institution. Bloodstream infection was more common (p

Introduction Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma and a heterogeneous disease with a variety of molecular aberrations and diverse clinical outcomes. BCL2 expression has been implicated for a poor prognosis among patients with DLBCL. However, there is no consensus regarding the interpretation of BCL2 expression in DLBCL. In previous studies, the range of BCL2-positive cases, determined by immunohistochemistry (IHC), was highly variable (24 - 80%) due to subjective and semiquantitative interpretation and the absence of the established cutoff value for BCL2 expression. Consequently, the prognostic impact of BCL2 varies between studies. In addition, only the proportion of BCL2 positive tumor cells are considered in determining the BCL2 positivity. We aimed to define BCL2 positivity by quantitative analysis integrating both the intensity and proportion of BCL2 expression. Methods We retrospectively collected formalin-fixed, paraffin-embedded (FFPE) diagnostic biopsies from 221 patients with de novo DLBCL between January 2007 and December 2012 at our institute. All patients were treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) as first-line treatment. A separate validation set included 111 patients with de novo DLBCL who received first-line R-CHOP at another tertiary hospital in South Korea. BCL2 expression was analyzed using the tumor-specific Automated Quantitative Analysis (AQUA) scoring system based on multiplex immunofluorescence. The tumor-specific quantified intensity information in pixels was converted to protein expression information on a cell basis using the AQUA scoring system. The AQUA scores for BCL2 was calculated as the signal intensities of BCL2 in the target compartment divided by the pixel area of the target compartment. Cell of origin (COO) was determined according to the Hans classification using IHC. Results Ninety-eight patients (44.3%) were > 60 years old of age, 126 patients (57.0%) were male and 81 patients (36.7%) had an International Prognostic Index of 3-5 in the training set. With a median follow-up duration of 59 months, the 5-year event-free survival (EFS) and overall survival (OS) rate were 62.2% and 69.0%, respectively. The BCL2 AQUA score of 41.47 was determined as the optimal cutoff value in the ROC analysis. A total of 86 patients (38.9%) were classified as high BCL2 AQUA score group according to the determined cutoff value. High BCL2 AQUA score was significantly associated with worse OS and EFS (P = 0.00015; OS, P = 0.00012; EFS) (Figure 1A, B). Multivariate analysis revealed that high BCL2 AQUA score was a significant poor prognostic factor for both OS and EFS independent of the IPI, and COO (P = 0.01; OS, P = 0.015; EFS). The high BCL2 AQUA score group in the validation set was also significantly associated with worse OS and EFS (P = 0.0075; OS, P = 0.0049; EFS) (Figure 1C, D). The poor prognostic impact of BCL2 AQUA score was also in good correlation with both OS and EFS in the entire cohort (P < 0.0001; OS, P < 0.0001; EFS) (Figure 1E, F). The adverse impact of high BCL2 AQUA score was identified within both low (IPI 0-2) and high IPI (IPI 3-5) groups (Figure 2A-D). The high BCL2 AQUA score was also associated with poor prognosis within both GCB (P = 0.0077; OS, P = 0.0055; EFS) and non-GCB type DLBCL (P = 0.059; OS, P = 0.04; EFS), although a marginal statistical significance was observed regarding OS in the non-GCB type (Figure 2E-H). Conclusion Our study demonstrated that BCL2 expression analyzed by AQUA scoring system, incorporating both intensity and proportion, is an independent prognostic factor for patients with DLBCL. Given the growing clinical implications of BCL2 and the therapeutic progress in targeting BCL2 in hematologic malignancies, the concrete definition of BCL2 positivity in DLBCL holds great promise for the study of the pathophysiology of DLBCL and could be used to establish new therapeutic strategies. Disclosures No relevant conflicts of interest to declare.

Extranodal natural killer (NK)/T cell lymphoma (ENKTL) is a distinct subtype of Non-Hodgkin's lymphoma mainly involving the nasal area. Since the entity was first recognized, treatment strategies have been evolving from anthracycline-based chemotherapy and radiotherapy to L-asparaginase containing regimens and recently immune checkpoint inhibitors. With the currently used combined chemotherapy and radiotherapy, more than 70% of patients with localized disease can be cured. L-asparaginase containing regimens have significantly improved treatment outcomes among patients with advanced disease. However, the treatment outcomes of patients with disease refractory to L-asparaginase containing regimens or who experience recurrence remain poor. In this article, we cover the current treatments for ENKTL and emerging treatment approaches.

The predictive significance of osteolysis-related proteins was evaluated in bortezomib-treated multiple myeloma. The clinicopathological characteristics were collected retrospectively. Immunohistochemistry was performed for analyzing receptor activator of NF-κB ligand (RANKL), osteoprotegerin (OPG), macrophage inflammatory protein 1 alpha (MIP1α), and dickkopf-1 (DKK1) expression. Among clinicopatholgical characteristics, osteolytic lesion was associated with higher response to bortezomib treatment (79% vs. 46%). High DKK1 expression was significantly correlated with osteolytic lesion (

Background: The neutrophil-to-lymphocyte ratio (NLR) is an independent prognostic marker in solid and hematological cancers. While the derived NLR (dNLR) was shown to be non-inferior to the NLR in large cohorts of patients with different cancer types, it has not been validated as a prognostic marker for multiple myeloma (MM) to date. Methods: Between May 22, 2011 and May 29, 2014, 176 patients with MM from 38 centers who were ineligible for autologous stem cell transplantation were analyzed. The dNLR was calculated using complete blood count differential data. The optimal dNLR cut-off value according to receiver operating characteristic analysis of overall survival (OS) was 1.51. All patients were treated with melphalan and prednisone combined with bortezomib. Results: The complete response rate was lower in the high dNLR group compared to the low dNLR group (7 vs. 26.1%, respectively; p = 0.0148); the corresponding 2-year OS rates were 72.2 and 84.7%, respectively (p = 0.0354). A high dNLR was an independent poor prognostic factor for OS (hazard ratio 2.217, 95% CI 1.015–4.842; p = 0.0458). Conclusion: The dNLR is a readily available and cheaply obtained parameter in clinical studies, and shows considerable potential as a new prognostic marker for transplantation-ineligible patients with MM.

Introduction Decitabine has shown clinical benefits in patients with intermediate (INT)-2 or high-risk myelodysplastic syndrome (MDS), determined according to the International Prognostic Scoring System (IPSS), but the benefits have not been well demonstrated in patients with lower-risk (IPSS low or INT-1) disease. Recently, it was proposed that the prognosis for patients with IPSS lower-risk disease is heterogeneous, with a substantial proportion of these patients having poor survival. Patients and Methods This study included patients with IPSS lower-risk MDS from the DRAMA (An Observational Study for Dacogen Long-Term Treatment in Patients With Myelodysplastic Syndrome; NCT01400633 ) and DIVA (A Study for Dacogen Treatment in Patients With Myelodysplastic Syndrome; NCT01041846 ) studies, which were prospective observational studies on the efficacy and safety of decitabine treatment in patients with MDS. Using the Lower-Risk Prognostic Scoring System [LR-PSS], we classified IPSS lower-risk MDS. Patients in each LR-PSS category were divided according to overall response (OR) to decitabine treatment, and survival outcomes were compared. Results One hundred sixteen patients were enrolled: LR-PSS category 1 (n = 12; 10.3%), category 2 (n = 56; 48.3%), and category 3 (n = 48; 41.4%). Survival outcomes differed among the 3 categories (P = .046). The overall survival according to OR showed a significant difference in total patients (P = .008) and category 3 patients (P = .003). We analyzed predictive factors for OR, but no variable was found to significantly affect OR. Conclusion Decitabine treatment showed a survival benefit in the higher-risk group of IPSS lower-risk MDS patients who responded to treatment, and classification using the LR-PSS category was helpful for this subgroup, indicating that decitabine treatment might alter the natural course of disease in these patients.

Natural killer (NK)/T cell lymphoid malignancy comprises extranodal NK/T cell lymphoma (ENKTL) and aggressive NK cell leukemia (ANKL), and the outcomes for advanced or relapsed/refractory ENKTL and ANKL remain poor. Allogeneic stem cell transplantation (SCT) can be used as a frontline consolidation treatment to prevent the relapse of advanced disease or as salvage treatment after chemotherapy for relapsed sensitive disease. We retrospectively analyzed 36 patients (ENKTL, n = 26; ANKL, n = 10) who underwent upfront (n = 19) and salvage allogeneic SCT (n = 17) at 6 hospitals. Patients received myeloablative (n = 25) or reduced-intensity (n =11) conditioning regimens depending on the institute's policy. The median age at the time of allogeneic SCT was 37 years (range, 17 to 62), and more patients with ANKL (8/10) received upfront allogeneic SCT than ENKTL patients (11/26). Disease status before allogeneic SCT, conditioning regimen, and donor source did not differ between upfront and salvage allogeneic SCT groups. Febrile neutropenia (n = 20) and acute graft-versus-host disease (n = 16) were common adverse events. The median overall survival (OS) and progression-free survival (PFS) after allogeneic SCT were 11.8 months and 10.0 months, respectively. Twelve patients died from disease relapse and 12 from nondisease-related causes. Ten deaths occurred within 100 days after allogeneic SCT (10/24); these were mostly related to disease relapse (n = 8). The OS after allogeneic SCT did not differ between ENKTL and ANKL (P = .550) or between upfront and salvage SCT (P = .862). Complete chimerism was significantly associated with better PFS (P.001). No significant differences in PFS were observed based on the conditioning regimen or source of stem cells (P.05). Allogeneic SCT may be beneficial for patients with ENKTL and ANKL given that some patients were able to maintain their remission after allogeneic SCT. However, allogeneic SCT should only be performed in highly selected patients because the risks of disease relapse and nondisease-related mortality remain high.

The prognostic significance of Bcl-2, Bcl-6, p53, topoisomerase II, and β-tubulin expression was evaluated in diffuse large B-cell lymphoma (DLBCL) patients treated with cyclophosphamide, doxorubicin, vincristine, prednisolone, and rituximab. Eight-year progression-free survival (PFS, P = 0.006) and overall survival (OS, P = 0.001) of patients with high Bcl-2 expression were significantly inferior to those of patients with low expression without prognostic significance of Bcl-6, p53, topoisomerase II, and β-tubulin expression. High expression of Bcl-2 was associated with poor PFS (P = 0.045) and OS (P = 0.004) only in patients with low international prognostic index (IPI). In multivariate analysis, high expression of Bcl-2 was a significant independent prognostic factor of poor PFS (P = 0.026) and OS (P = 0.007) along with high IPI. In conclusion, the expression of Bcl-2 may be a useful prognostic factor, especially in DLBCL patients with low IPI.

The hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) regimen has been widely used for lymphoblastic lymphoma (LBL) as a primary treatment. However, there is few data about its treatment outcome in Asian patients. Thus, we conducted this study to evaluate the efficacy of hyper-CVAD induction and stem cell transplantation (SCT) consolidation in LBL patients. The treatment responses of 49 patients treated with the hyper-CVAD regimen were retrospectively analyzed in 13 institutions. Given 24 patients who responded to hyper-CVAD underwent consolidation treatment with SCT, overall survival (OS) and progression-free survival (PFS) of patients who received SCT were compared with patients who did not. The overall response rate was 79 %: 73 % (36/49) complete responses, 6 % (3/49) partial responses, and 4 % (2/49) induction deaths. The major limitation for the delivery of the planned hyper-CVAD cycles was hematological toxicity. Among 39 responders, 24 patients underwent autologous (n = 16) and allogeneic SCT (n = 8) consolidation. Their 3-year OS and PFS rates were 76 and 78 %, respectively, and there was no difference in survival outcomes between autologous and allogeneic SCT. However, 15 patients without SCT consolidation showed poorer PFS even though they all achieved complete response. Thus, only seven patients maintained their response at the time of analysis. In conclusion, the hyper-CVAD regimen is effective for remission induction in LBL, and SCT consolidation after hyper-CVAD induction produced better clinical outcomes than did continuation of hyper-CVAD.

Although recent studies have suggested that cessation of imatinib (IM) in chronic myeloid leukemia patients can be associated with sustained response, further validation is needed to explore predictive factors. In a prospective, multicenter study, chronic phase patients were eligible for cessation of IM therapy after more than 3 years if they had no detectable BCR-ABL1 transcript for at least 2 years. A total of 48 patients with a median age of 47 years (19-74 years) were enrolled. Twenty patients received IM for post-transplant relapse. After a median follow-up of 15.8 months (1.4-28.2 months) after IM discontinuation, nine of the non-transplant group lost undetectable molecular residual disease (UMRD) and major molecular response (MMR), whereas none of the 20 patients in the transplant group experienced UMRD loss. Probabilities for sustained MMR and UMRD were 64.4% and 66.3% in the non-transplant group, respectively. Of nine patients re-treated with IM, eight patients re-achieved MMR at a median of 1.7 months (0.9-2.8 months). Seven of these patients re-achieved UMRD at a median of 5.6 months (2.8-12.1 months). Previous transplantation, IM duration, and UMRD duration were significantly associated with sustained molecular responses. Our data strongly suggest that immunological control contributes to sustained suppression of residual leukemia cell expansion and that IM can be safely discontinued in patients with post-transplant relapse.

Background: Despite the small but significant survival benefit of adjuvant chemotherapy in locally advanced gastric cancer (LAGC), the optimal regimen remains to be determined. We conducted a randomized trial comparing oral (PO) chemoimmunotherapy (CITX) with intravenous (IV) CITX in LAGC patients (stages IB-IIIB) with curative resection (≥ D2 dissection). Methods: The patients were randomized to the IV (5-fluorouracil 500 mg/m2 weekly for 24 weeks, mitomycin-C 8 mg/m2 every 6 weeks × 4) or the PO (uracil-ftorafur (UFT) 400-600 mg/day for 12 months) group. Patients in both groups received PO polysaccharide-K (3 g/day for 4 months). The planned number of patients was 368 for proving the non-inferiority of PO CITX compared to IV CITX for overall survival. Results: The trial was closed prematurely after enrolling 82 patients (44 in the IV group, 38 in the PO group). With a median follow-up of 82 months, there were no significant differences in the 5-year disease-free survival (73% vs. 55%, p = 0.358) and overall survival (77% vs. 66%, p = 0.159) between the 2 groups. The IV group demonstrated a higher incidence of grade 2 or 3 neutropenia, thrombocytopenia, and vomiting. Conclusions: PO CITX with UFT appeared to be at least non-inferior to 5-fluorouracil and mitomycin-C CITX, with lower toxicity in the adjuvant treatment for LAGC.

There has been controversy surrounding Waldeyer’s ring (WR), especially focused on the question of whether it should be regarded as a nodal or an extranodal site. We conducted retrospective analyses of marginal zone B cell lymphomas involving WR (WR-MZLs) to observe their clinical features and prognosis, with specific regard to the nodal-or-extranodal question. A total of 52 patients with histological diagnosis of WR-MZL were retrospectively analyzed. The most common involvement site was the tonsil (40.4 %). Ann Arbor stage III/VI disease was present in 48.1 % (25 of 52). The response rate of the 27 stage I/II patients was 88.9 %, with 21 complete remissions and three partial remissions. The median time to progression (TTP) was 3.7 years (95 % CI 2.5–4.9 years). The estimated 5-year TTP and overall survival rates were 39.4 and 90.5 %, respectively. In a comparison with the historical data regarding extra-WR MALT lymphoma and nodal MZL (N-MZL), MALT lymphoma showed better TTP results than did WR-MZL and N-MZL (P

Purpose: Primary thyroid marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue type (pTY-MZL) is an extremely uncommon form of lymphoma. Due to its rarity, the natural history and optimal treatment modality for this disease have yet to be clearly established. Methods: A total of 27 patients with histologically confirmed pTY-MZL were retrospectively analyzed. Results: The median age of our subjects was 53 years (range 25–82). This study involved 17 females (63.0%) and 10 males (37.0%). Twenty-four out of 27 patients (88.9%) initially presented with localized disease, defined by Ann Arbor stage I/II. Bone marrow involvement was detected in 8.3% of the patients (2 patients), and 91.7% of the patients (25 of 27) were categorized into the low or low-intermediate risk group, according to the International Prognostic Index criteria. Accompanying Hashimoto’s thyroiditis was detected in 72% of the patients, whereas thyroglobulin antibody levels were elevated in 70% of the patients. Twenty-six patients were treated with surgery, radiotherapy or chemotherapy, and 25 patients achieved complete remission. During the follow-up period, only 2 patients evidenced progression, and no deaths occurred over the course of the study. Conclusion: pTY-MZL tends to be an indolent disease. However, unlike other mucosa-associated lymphoid tissue site MZLs, pTY-MZL was well controlled via several treatment modalities, and the patients’ responses were sustained for a prolonged period.

Background: This observational study was conducted to document the efficacy and safety of the use of micafungin (Mycamine) as an empirical antifungal agent in febrile neutropenic patients. Methods: Micafungin was administered for sustained fever (>38.4°C) on days 3–5 following the initiation of empirical antibiotic therapy. The overall success rate and side effects were evaluated. Results: A total of 47 patients with acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome and lymphoma were enrolled in the study. The overall success rate of micafungin was 61.7% (29/47). A total of 3 patients (6.4%) experienced grade 3/4 elevations in their aspartate aminotransferase levels, and 10 patients (21%) experienced grade 3/4 hyperbilirubinemia, 9 of which resolved. Four patients died of septic shock. Younger patients (9/l) also had a better response to micafungin, as did the patients who recovered from their fever or neutropenia. Conclusion: Micafungin has an excellent efficacy (61.7%) and safety profile when used as an empirical antifungal agent in febrile neutropenic patients with hematological disorders.

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

TO THE EDITOR: The International Randomized Interferon versus STI-571 study was the first randomized trial to demonstrate the prognostic significance of monitoring BCR-ABL1 transcripts by real-time quantitative polymerase chain reaction (RT-PCR) [1], and defined a major molecular response (MMR) after treatment as a 3-log10 reduction from the baseline value in the level of measured BCR-ABL1 transcripts [1]. On the other hand, an international scale (IS) was proposed as an absolute value of 0.1% BCR-ABL1, which corresponds to a 3-log10 reduction from the baseline value, for MMR, in an effort made by international experts to standardize BCR-ABL1 quantification [2,3].

Does the timing of adjuvant chemotherapy for gastric cancer influence patient outcome?

The occurrence of granulocytic sarcoma as a pattern of relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is rare. In this paper, we report a rare case of acute myeloid leukemia (AML) relapsed as a granulocytic sarcoma of the donor type. The patient was diagnosed as having AML and underwent an allo-HSCT from his matched sibling donor. Fifty-seven months after allo-HSCT, he developed granulocytic sarcomas of duodenum, jejunum, and left sterno-cleido-mastoid muscle. The bone marrow was normal with 100% donor chimerism. A Y chromosome PCR was performed on the patient's duodenum specimen as well as bone marrow aspirate in order to check the patient-origin cells. The duodenal specimen was found to contain 41.2% SRY-positive cells (from the donor). Repeat endoscopy on day 2 of chemotherapy showed that the granulocytic sarcoma had shrunk dramatically. The patient died of sepsis during the nadir state 35 days after starting salvage chemotherapy.

Background: Febrile neutropenia is considered a medical emergency and generally prompts immediate hospitalization. For this reason, many physicians and researchers have tried some attempts to reduce the duration of febrile neutropenia. Patients with hematologic disorders frequently require the insertion of medium or long-term central venous catheters (CVCs) for stem-cell transplantation, the administration of chemotherapy, or transfusion of blood products. We have already known that the CVC is a major source of bloodstream infections in the neutropenic patients, but, there have been no reports about the duration of febrile neutropenia in the cases with early removal of CVCs except for catheter-related blood stream infections (CRBSIs). In this study, we want to investigate the factors influencing the duration of febrile neutropenia including early removal of CVCs except for CRBSIs in the patients diagnosed with acute myeloid leukemia. Methods: A total of 161 central catheter insertion cases with febrile neutropenia except for CRBSIs in 102 patients were eligible for analysis. CRBSI was defined as the same microorganism grown from at least one percutaneous blood culture and from a culture of the catheter tip (>15 colony-forming units), or a growth of microbes from blood sample drawn from a catheter hub at least 2 hours before microbial growth was detected in a blood sample obtained from a peripheral vein. Patients with blood stream infection (BSI) were defined as those with clinical signs of infection and the microorganism grown from at least one percutaneous blood culture without detecting microorganism from a culture of the catheter tip or from blood sample drawn from a catheter hub. The early removal of CVCs was defined as the removal of CVCs before 21 days from the insertion date of CVC. Duration of fever was investigated according to age, gender, body mass index (BMI), type of chemotherapy, presence of baseline fever, presence of BSI and/or early removal of central catheter by the Kaplan-Meier method and the Log Rank method. Statistical analysis was performed using SPSS software version 13.0 (IBM, Armonk, NY, USA). Results: Baseline characteristics of total cases were described in Table 1. Univariate and multivariate analysis about duration of fever are summarized in Table 2 and Table 3. Age, type of chemotherapy, presence of baseline fever and early removal of central catheter were significant in the univariate analysis and age, type of chemotherapy and early removal of central catheter were also significant, but, baseline fever was not significant in the multivariate analysis. Furthermore, duration of fever in the remission induction chemotherapy was significantly longer than consolidation chemotherapy, on the other hand, not significantly longer than salvage chemotherapy. Conclusion : In this retrospective study, age, type of chemotherapy, presence of baseline fever and early removal of central catheter were significant in the univariate analysis. They were equally significant in the multivariate analysis, only except for the presence of baseline fever. It is noteworthy that the cases with early removal of CVCs except for CRBSIs had significant reduction of the duration of febrile neutropenia. We may need active consideration about the early removal of CVCs in the acute myeloid leukemia patients with febrile neutropenia for the purpose of reduction of the duration of febrile neutropenia. Download : Download high-res image (131KB) Download : Download full-size image Download : Download high-res image (125KB) Download : Download full-size image Download : Download high-res image (111KB) Download : Download full-size image Disclosures No relevant conflicts of interest to declare.

Background: Although continued improvement in survival in multiple myeloma was observed over the past decade with the introduction of new therapeutic options such as the proteasome inhibitors and immunomodulatory drugs, the prognosis of myeloma patients (pts) with relapsed and refractory and primary refractory to those drugs is significantly worse than that of responders. The predictive significance of various clinicopathologic characteristics and expression status of osteolysis-related proteins in terms of therapeutic response to bortezomib were evaluated in multiple myeloma pts. Methods: In 58 pts treated with bortezomib, the clinicopathologic characteristics was retrospectively collected. Pretreatment biopsy samples were analyzed for receptor activator of NF-kB ligand (RANKL), osteoprotegerin (OPG), macrophage inflammatory protein 1 alpha (MIP-1a), and dickkopf-1 (DKK1) expression by immunohistochemistry (Fig 1.). Results: Bortezomib administrated in the fisrt (11 pts), second (29 pts), third (15 pts), fourth (2 pts) and fifth (1 pt) line of chemotherapy. Overall response rate (RR) of bortezomib treatment was 66%. Eight-year overall survival (OS) rate of all pts were 45.3%. Eight-year OS rate of bortezomib non-responders was significantly inferior compared to that of bortezomib responders (24% vs. 62%, p=0.011). The clinicopathologic characteristics including gender, stage, cytogenetic risk stratification by chromosomal aberration and cellularity of bone marrow plasma cell except age and presence of osteolytic lesion were not correlated with response to bortezomib. Median age of bortezomib responders was higher than that of non-responders (65 vs 60, p=0.034). The presence of osteolytic lesion was associated with higher RR of bortezomib treatment (79% vs 46%, p=0.012). High expression of DKK1 was significantly correlated with presence of osteolytic lesion (p=0.003), while expression status of RANKL, OPG and MIP-1a were not associated with presence of osteolytic lesion. In addition, high expression of DKK1 was associated with female gender (p=0.030, Table 1.), increased cellularity of bone marrow plasma cell (p=0.023, Table 1.) and plasmablatic morphology (p=0.007, Table 1.). In multiple myeloma with high DKK1 expression, higher RR was observed (84% vs 44%, p=0.002, Table 1.). In multivariate analysis, high DKK1 expression were independently associated better response to bortezomib (p=0.005). Pts with high DKK1 expression had significantly longer median PFS (23 months versus 6 months, p=0.022, Fig 2A.) and OS (Not reached versus 26 months, p=0.028, Fig 2B.) after bortezomib treatment compared to those with low DKK1 expression. Multivariate analysis revealed that high DKK1 expression was an independent prognostic factor of favorable PFS (p=0.043) and OS (p=0.045). Conclusion : Despite limitation as retrospective analysis with small sample size, our data indicate that expression status of DKK1 may be a useful predictive and prognostic factor in multiple myeloma pts treated with bortezomib. Disclosures No relevant conflicts of interest to declare.

BACKGROUND: According to our prior prospective phase II trial, Rituximab in combination with chemotherapy (R-CVP) has been shown to improve response rate (RR) and progression free survival (PFS) in patients with advanced stage marginal zone lymphoma (MZL) compared with chemotherapy alone (CVP). In spite of better RR and PFS, relapses seem to continue after immunotherapeutic treatment in these patients. Thus, eventual relapse remains an important clinical issue for the majority of patients with indolent lymphoma, and defining further ways to extend the period of remission remains an essential goal. But data from clinical trials evaluating rituximab maintenance treatment in these patients are almost limited. We aimed to evaluate the effect of maintenance treatment with rituximab on the PFS of patients with MZL. METHODS: Histologically confirmed advanced stage MZL patients who did not progress at the end of 6~8 cycles of 1st line Rituximab-CVP (cyclophosphamide 750 mg/m2 and vincristine 1.4 mg/m2 (maximum 2.0 mg), given intravenously on day 1, and oral prednisolone 100 mg on days 1-5) regimen were enrolled. Patients received 2 years of rituximab maintenance therapy (375 mg/m2 every 8 weeks). Primary objection was three year progression free survival. This trial is registered with ClinicalTrials.gov, number NCT012113095. RESULTS Between March 2010 and March 2013, a total of 47 patients were enrolled with informed consent at this trial from 17 institutes in Korea. Among these patients, 1 patient withdrew informed consent, 1 patient was screening failure with combined thyroid cancer. The median age of the evaluated 45 (32 males, 13 females) patients is 54 (range 33-77) years. Fifteen patients (33.3%) evidenced nodal MZL, 30 (66.7%) extranodal MZL (10 patients were lung, 6 ocular, and 5 stomach, in order of frequency). The IPI score were 1 in 13 (28.9%), 2 in 21 (46.7%), 3 in 9 (20%), and 4 in 2 (4.4%) patients. The patients received a total of 6 or 8 cycles of 1st line R-CVP chemotherapy were 10 (22.2%) and 35 (77.8%), respectively. There were 20 CR (44.4%), 22 PR (48.9%), and 3 SD (6.7%). Median treated number of rituximab maintenance followed by R-CVP was 12 (range 1-12). Thirty two patients (71.1%) patients completed planned 12 cycles of rituximab maintenance. Disease progression during rituximab maintenance was 8 patients, 2 patients stopped treatment because of side effects (1 abdominal pain, 1 recurrent pneumonia) 2 patients were follow-up loss. Four patients were expired (each 1 pneumonitis, pneumonia, sepsis, and disease progression). PFS and OS rate at 3 years were 78.9% and 90.6%, respectively. CONCLUSION: 2 years of rituximab maintenance therapy after R-CVP first-line chemotherapy for advanced stage MZL might be improve PFS with tolerable toxicities Disclosures Kim: Celltrion, Inc.: Consultancy, Honoraria. Lee:Amgen: Membership on an entity's Board of Directors or advisory committees.

Acquired hemophilia A is a very rare but life-threatening disorder caused by autoantibody against coagulation factor VIII. The incidence was much rarer in young people. In this case report, a young woman presented with spontaneous muscle hematoma. Because of pain and limited range of motion, she underwent surgery for resolution at first. However, her symptoms and hemorrhage worsened. She was diagnosed with acquired hemophilia A. We started combination treatment with bypassing agent, activated prothrombin complex and immunosuppressants immediately and the results were successful. The acute bleeding was controlled and autoantibody was completely resolved.

Background Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) is a heterogeneous group of aggressive T-cell lymphomas with poor treatment outcomes. The aim of this study was to evaluate whether lymphopenia at diagnosis would have an adverse effect on survival in patients with PTCL-NOS treated with anthracycline-containing chemotherapy. Methods A total of 118 patients with PTCL-NOS treated with anthracycline-containing chemotherapy from 4 Korean institutions were included. Results Thirty-six patients (30.5%) had a low absolute lymphocyte count (ALC, < 1.0 × 109/L) at diagnosis. Patients with lymphopenia had shorter overall survival (OS) and progression-free survival (PFS) rates compared with patients with high ALCs (P = 0.003, P = 0.012, respectively). In multivariate analysis, high-intermediate/high-risk International Prognostic Index (IPI) scores and lymphopenia were both associated with shorter OS and PFS. Treatment-related mortality was 25.0% in the low ALC group and 4.8% in the high ALC group (P = 0.003). In patients considered high-intermediate/high-risk based on IPI scores, lymphopenia was also associated with shorter OS and PFS (P = 0.002, P = 0.001, respectively). Conclusion This study suggests that lymphopenia could be an independent prognostic marker to predict unfavorable OS and PFS in patients with PTCL-NOS treated with anthracycline-containing chemotherapy and can be used to further stratify high-risk patients using IPI scores.

Background: A guideline of central line-related blood stream infection (CRBSI) is only for immune-competent patients with end-stage renal disease on hemodialysis. We need widely acceptable guideline whether remove or maintain a central catheter in febrile neutropenic patients. Method: Medical records from 293 cases (95 patients) of febrile neutropenia with Central Catheterization were obtained retrospectively, and clinical characteristics, particularly duration of fever, were analyzed according to the early removal of central catheterization under anti-cancer chemotherapy for acute leukemia. Results: Forty-eight cases (16.4%) have already baseline fever and 25 cases (8.5%) showed baseline pneumonic infiltration prior to chemotherapy. The insertion sites of catheterization were subclavian (85.3%), internal jugular (12.6%), and others (2.0%). Early removal of central catheter was done at 93 cases (31.7%) and the cause of early removal was fever (63.4%), malfunction (11.8%), and others (24.7%). The duration of fever was significantly shortened by early removal of central catheterization (5.4 vs 7.5 days, p=0.003, Figure 1A). In addition, the duration of fever was related with age, diagnosis, type of chemotherapy, presence of baseline fever or pneumonic consolidation in univariate analysis. The site of central access or body mass index as well as existence of CRBSI did not affect duration of fever. In multivariate analysis, early removal of central catheter was independently associated with short duration of fever (OR=0.619, 95% CI=0.46-0.83, p=0.001, Table 1). The effect of early removal of central catheter was highlighted when micro-organisms were documented (Figure 1B). Summary: In patients with febrile neutropenia, early removal of central catheter can shorten the duration of fever particularly when BSI was documented. Disclosures No relevant conflicts of interest to declare.

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.

Background: There is no standard treatment strategy for maintaining first complete remission (CR1) status after several cycles of consolidation chemotherapy in acute myeloid leukemia (AML) patients who are not suitable for transplantation. Maintenance chemotherapy has failed to document the cure rate or prolongation of survivals in patients with acute myeloid leukemia (AML) except for acute promyelocytic leukemia (APL). In this study, we retrospectively compared leukemia free (LFS) and overall survival (OS) of patients with or without maintenance therapy. Methods: Maintenance chemotherapy consisted of daily 6-mercaptopurine and weekly methotrexate per os and lasted for 2 years. Patients who maintained CR1 status after completion of consolidation therapy started maintenance chemotherapy. Results: Fifty two patients (not suitable for transplantation) who completed at least 1 cycle of consolidation therapy were eligible for analysis. Twenty seven patients agreed to administrate oral maintenance chemotherapy whereas 25 patients refused. Median age was 52 years and 24 patients were male. According to the FAB classification, 7.7, 9.6, 40.4, 38.5, 1.9 and 1.9% of patients are AML M0, M1, M2, M4, M6 and M7, respectively. Myelodysplastic syndrome (MDS) related and chemotherapy-related secondary AML patients were 5.6 and 9.6%, respectively. Favorable, intermediate and unfavorable cytogenetic risk groups were 32.7, 63.5 and 2%, respectively. Of 33 patients with intermediate risk, 84.8, 12.1 and 3% were normal karyotype, other not-defined and +8 alone, respectively. Two patients with unfavorable risk were complex karyotype and inv(3). There was no significant difference in the patients' characteristics between non-maintenance and maintenance group. Almost of all patients (96.4%) received remission induction therapy with a same protocol (7-3 regimen). Relapse was observed in 27 patients (51.9%) after achieving CR1. Median LFS and OS was 28 (95% CI, 2–54) and 29 months (95% CI, 6–52), respectively. The OS was 19 (95% CI, 8–30) and 43 months (95% CI, 19–67) in non-maintenance and maintenance group, respectively (p = 0.044, Fig 1A), whereas LFS was not significantly different. In multivariate analysis, the presence of maintenance therapy was an independent prognostic factor for better LFS (p = 0.044) and OS (p = 0.042, Table 1.). In subgroup analysis (Table 2.)., statistically significant clinical benefit from maintenance chemotherapy was observed in patients with older age (>= 60 years) (p = 0.024), intermediate or unfavorable cytogenetic results (p = 0.004, Fig 1B.), initial higher WBC count (>= 50,000/mm3) (p = 0.005), secondary AML (p = 0.009), and receiving less than 2 cycles of consolidation therapy (p = 0.006). Conclusions: Despite limitation as retrospective analysis with small sample size, our data indicate that maintenance chemotherapy with oral 6-MP and MTX can prolong survivals of patients with AML (except APL) who are not suitable for transplantation as a post-remission therapy particularly with older age, intermediate or unfavorable cytogenetics, initial higher WBC count, secondary AML or receiving less than 2 cycles of consolidation therapy. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Background: Micafungin, one of the powerful ecchinocandins, needs to be clarified its efficacy and safety of empirical therapy on febrile neutropenic patients compared with other anti-fungal drugs such as azole compounds. Methods: A randomized, multi-center, prospective study (age-, sex-, diagnosis-, risk-controlled) was conducted for a comparison of efficacy and safety between micafungin and intravenous itraconazole as an empirical therapy on febrile neutropenic patients with acute leukemia. Anti-fungal drugs (study drug, micafungin; control drug, itraconazole) were administrated for sustained high fever following appropriate empirical antibiotic therapy (°Ã 3 days of combination antibiotics). The overall success rate [if the patient meets all of the following criteria: (1) no breakthrough fungal infection; (2) survived for 7 days past the end of the therapy; (3) no premature discontinuation; (4) disappearance of fever during neutropenia; (5) successfully treated base-line fungal infection] and side effects were evaluated. And duration of fever and neutropenic fever were estimated and compared between two groups. Results: A total of 134 patients with acute leukemia were enrolled in the study (86 patients with AML, 41 patients with ALL, 7 patients with secondary leukemia). The overall success rate of micafungin and itraconazole was 63.6% and 53.2%, respectively (p = NS) (Figure 2). However, duration of fever and duration of neutropenic fever were significantly shorter in micafungin group (p = 0.0007, p = 0.0118, respectively) and survival benefit was marginal (OS, median months, 10.93 vs. 4.77, p = NS) (Figure 1). Grade III-IV adverse events including hyperbilirubinemia (2 vs. 7), elevation of transaminase level (2 vs. 4), electrolytes imbalance (1 vs. 2), atrial fibrillation (1 vs. 0), and anaphylaxis (1 vs. 0) occurred at 7 and 13 patients in micafungin (10.4%) and itraconazole (18.8%) group, respectively. All adverse events were manageable however, 4 patients died of progression of infection in each group. Conclusion: This randomized, controlled, prospective study documented that micafungin, when compared with itraconazole, showed significantly superior effect on shortening the duration of fever and neutropenic fever, resulting in marginal survival benefit on acute leukemia patients who are suffering from life-threatening neutropenic period under anti-leukemic therapy. Disclosures No relevant conflicts of interest to declare.

Background Patients (pts) with DLBCL who have received rituximab (R) antibody in the first-line setting, have poorer treatment outcomes when they are re-treated with R-chemotherapy in the salvage setting. Resistance to R may have developed. Ofatumumab (O) is a human monoclonal antibody against CD 20 that targets a different epitope than R. We hypothesized that replacing R with O in second line setting may overcome R resistance. The primary end-point of this ongoing phase II study is the objective response rate (ORR) following two cycles of O in combination with ICE (Ifosfamide, Carboplatin and Etoposide) or O-ICE. Secondary end points include the assessments of the safety and tolerability of the combination, progression-free (PFS) and overall survival (OS). Methods This was a multi-center, non-randomized phase II open label study. Pts with histologically confirmed DLBCL who failed or were refractory to first line R-based anthracycline therapy were eligible. Pts were accrued according to a 2-stage Simon’s Optimal Design at the National Cancer Centre Singapore and 3 medical centres in South Korea; Samsung Medical Centre, Ajou University Hospital and Soonchunhyang University Hospital. Stage 1 will enrol 24 pts and if 14 or more pts respond, we will proceed to stage 2 where another 37 pts would be recruited. Pts receive 3-weekly ICE (Ifosfamide 5g/m2 on day 2, Carboplatin AUC = 5 on day 2, Etoposide 100 mg/m2 day 1-3) and O (1000 mg), infused on day 1 and 8 of cycle 1, and thereafter only on day 1 of each cycle. A restaging scan is performed after cycle 2. Pts who are candidates for high dose chemotherapy (HDC) and autologous stem cell rescue (ASCR) would receive additional 1 or 2 more cycles of O-ICE before stem cell mobilization. Pts who are not candidates for HDC and ASCR would receive up to 6 cycles of O-ICE. Results A total of 24 pts with a median age of 54.5 years (27-75) were enrolled. Among them, 14 (58%) were male and 14 (58%) had stage III/IV disease. A median of 4 (2-6) courses of O-ICE was administered and 11 pts underwent HDC+ASCR. The ORR after 2 cycles was 58.3%; complete response (CR) 29.2% and partial response (PR) 29.2%. On treatment completion, the best ORR became 62.5% (CR = 37.5%, PR = 25%). Grade 1/2 non-hematologic toxicities, independent of relation to study drug, occurring in at least 20% of pts included nausea (50%), pain (50%), fatigue (42%), rash (42%), anorexia (33%), vomiting (33%), diarrhea (25%), edema (29%), fever (21%), pruritus (21%), cough (21%) and paresthesia (21%). Grade 3/4 toxicities included neutropenia (50%), thrombocytopenia (71%) and 4 anemia (54%). Febrile neutropenia occurred in 12.5% and no treatment related deaths were reported. The median follow up time was 8.2months (95% CI 5.3-14.0). The median PFS was 8.2months (95% CI 4.2-17.8) and the median OS was not reached (95% CI 8.6-not reached). Conclusion The study regimen met the predefined threshold of 14 responding pts in stage 1. The ORR of O-ICE was comparable to that of RICE in the CORAL study and this result is significant considering that all pts in this study had received R prior to study entry. Together with the tolerability data and promising activity, continuation of study enrolment in stage 2 has started. Disclosures Tao: Medscape: Honoraria; Takeda: Honoraria. Quek:Novartis: Consultancy, Honoraria; Bayer: Honoraria. Kim:Novartis: Research Funding; Cellgene: Research Funding; Takeda: 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 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.

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.

BACKGROUND Acute promyelocytic leukemia (APL) can be life threatening, necessitating emergency therapy with prompt diagnosis by morphologic findings, immunophenotyping, cytogenetic analysis, or molecular studies. This study aimed to assess the current routine practices in APL and the clinico-pathologic features of APL. METHODS We reviewed the medical records of 48 Korean patients (25 men, 23 women; median age, 51 (20-80) years) diagnosed with APL in 5 university hospitals between March 2007 and February 2012. RESULTS The WBC count at diagnosis and platelet count varied from 0.4 to 81.0 (median 2.0)×10(9)/L and 2.7 to 124.0 (median 54.5)×10(9)/L, respectively. The median values for prothrombin time and activated partial thromboplastin time were 14.7 (11.3-44.1) s and 29 (24-62) s, respectively. All but 2 patients (96%) showed a fibrin/fibrinogen degradation product value of >20 µg/mL. The D-dimer median value was 5,000 (686-55,630) ng/mL. The t(15;17)(q22;q12 and PML-RARA fusion was found in all patients by chromosome analysis and/or multiplex reverse transcriptase-polymerase chain reaction (RT-PCR), with turnaround times of 8 (2-19) d and 7 (2-13) d, respectively. All patients received induction chemotherapy: all-trans retinoic acid (ATRA) alone (N=11, 26%), ATRA+idarubicin (N=25, 58%), ATRA+cytarabine (N=3, 7%), ATRA+idarubicin+cytarabine (N=4, 9%). CONCLUSION Since APL is a medical emergency and an accurate diagnosis is a prerequisite for prompt treatment, laboratory support to implement faster diagnostic tools to confirm the presence of PML-RARA is required.

Abstract 5084 Background: Waldeyer's ring (WR) is circular band of lymphoid tissue located at the opening of the respiratory and digestive tract. There is controversy as to whether WR should be considered as a nodal or extranodal site. In this study, we conducted retrospective analyses of WR involving MZLs (WR-MZLs) to identify their clinical features, treatment, prognosis- favor nodal or extranodal. And we want to get additional information about specific organ relationship between WR-MZL and other MALT sites. Patients and Methods: From 1987 to 2010, 124 patients who were histologically confirmed as a MZL arising from head and neck (H&N) area was including WR (47 patients) were reviewed. Primary orbit and ocular adnexa MZL patient was excluded this data collection. Results: The male/female ratio of the 47 patients was 23 to 24. The median age was 53 years (range, 17–77). The commonly involving sites were tonsil (53.2%) followed by nasopharyn (40.4%). Fourteen patients (29.7%) were accompanied with extra-WR area MALT site- gastrointestinal tract (14.9%), ocular and adnexa (12.8%). Ann Arbor stage I/II disease was present in 50% (23 out of 46). Thirty-nine patients were categorized into the low/low-intermediate risk group (84.8%) according to International Prognostic Index (IPI). Complete and partial remissions were achieved in 18 (78.3%) and 2 (8.7%) of the 23 stage I/II patients. In 23 patients with stage III/IV, CR and PR were achieved in 15 (65.2%) and 4 (17.4%), respectively. The median progression-free survival (PFS) was 3.6 years (95% CI, 2.4–4.8 years). The estimated 5-year overall survival (OS) was 88%. Compared with H&N MALT site MZLs, WR-MZLs were significantly poor in PFS and OS (P=0.005 and P=0.007). Conclusion: WR-MZLs were also an indolent disease like general MZL. But, WR-MZL patients presented with more advanced stage and poorer survivals than other site H&N MZL patients. Therefore, even though WR has been considered histologically extranodal MALT organ, clinically it is closer to nodal MZL. Disclosures: No relevant conflicts of interest to declare.

Abstract 4548 Background: Treatment strategy for steroid-refractory acute graft versus host disease (aGvHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is to be standardized. We report our clinical experience of Etanercept, recombinant human soluble tumor necrosis factor receptor fusion protein, on steroid-refractory aGvHD, retrospectively. Method: A total of 18 patients who received allo-HSCT and presented with steroid-refractory aGvHD in Ajou University Hospital were studied retrospectively. Twenty five miligram of Etanercept was given subcutaneously twice weekly for 4 weeks. Clinical responses were checked with regard to the severity of aGvHD. Results: Median age was 43.5 years. Patients with AML, myeloma, ALL, aplastic anemia, myelodysplastic syndrome and idiopathic myelofibrosis were studied. The engraftment kinetics was adequate and no one failed to engraft. Before Etanercept, grade 4, grade 3, grade 2 and grade 1 of aGvHD occurred in 7, 6, 5, and zero patients, respectively however the number of patients were changed to 4, 5, 5, and 4 after Etanercept, respectively (p = .005). Eighty percent of grade II and 57% of grade IV patients showed partial response, so did in 14% of grade III patients. Skin and gut aGvHD was well controlled with Etanercept, whereas hepatic GvHD was not. Three patients died of severe infection. There was no factor affecting clinical outcome of Etanercept. All the non-responders died but 56.6% of the responders survived (p = 0.003). Conclusion: Etanercept can be one of the effective anti-aGvHD drugs for steroid-refractory cases after allo-HSCT considering tolerable side effects and tolerable cost. Disclosures: No relevant conflicts of interest to declare.

Abstract 4661 Introduction Invasive or possible fungal infection is often fatal and its incidence is increasing in febrile neutropenic patients with hematological malignancies. Thus, empirical antifungal agent should be carefully selected for those patients. Patients and Methods The study was conducted as a prospective multicenter trial to document the efficacy and safety of micafungin (Mycamine®), a class of echinocandin, as an empirical antifungal agent in febrile neutropenic patients. Micafungin was administrated for sustained fever (>38.4°C) on day 3 - 5 after initiation of empirical antibiotic therapy. The overall success rate according to the composite score (no breakthrough fungal infection, survival for seven days beyond the end of therapy, did not discontinue therapy prematurely, had resolution of fever during the period of neutropenia, and successfully treated a documented base-line fungal infection) and side effects were evaluated. Results A total of 47 patients with AML, ALL, MDS or lymphomas were enrolled. The overall success rate was 61.7% (29/47). Three patients (6.4 %) experienced grade 3/4 elevated aspartate aminotransferase and ten patients (21 %) showed grade 3/4 hyperbilirubinemia and nine of which resolved, and four patients died of septic shock. Patients with young age (< 50 yr) and ALL rather than AML showed a better response to micafungin. Less profoundly neutropenic (≥50 /mm3) patients revealed a better response, as did the patients who recovered from fever or neutropenia. Conclusions Micafungin has been reported to have an excellent efficacy (61.7 %) and safety profile when used as an empirical antifungal agent to treat febrile neutropenic patients with hematological disorders. Disclosures: No relevant conflicts of interest to declare.

Abstract 4365 Background Ovarian cancer is one of the most chemotherapy sensitive solid tumors. However, the role of dose intensity in the chemotherapy of advanced epithelial ovarian cancer has remained controversial. Accordingly, the current study attempted to analyze the outcome of high dose chemotherapy and autologous peripheral blood stem cell transplantation for ovarian cancer retrospectively. Methods Clinical data were collected retrospectively from 6 transplant centers in Korea between January 1996 and July 2008. Results Twenty three patients of total 6 centers were analyzed. The median age of the patients was 52 years (40-62 years). Nineteen patients (82.6%) were platinum sensitive and 4 patients were not. The conditioning regimens were reported to be ICE (ifosfamide, carboplatin, and etoposide) in 43.5 %, CTM (cyclophospamide, thiotepa, and melphalan) in 26.1 %, melphalan in 13%, other in 17.4 %. The median time to attain a neutrophil count greater than 500/mm3, following the transplantation, was 13 days (4∼38), and to attain a platelet count greater than 20,000/mm3, was 13 days (4∼38 days). There was primary graft failure of platelet in 3 patients. The median duration of progression free survival and overall survival were 6.3 months (95% CI, 0-19.3) and 19.7 months (95% CI, 10-29.4). The median overall survival was 25.9 months in the platinum sensitive patients and 17.4 months in the platinum resistant patients, however, there was no statistically significant difference in PFS between two groups. Poor prognostic factor for survival which retained statistical significance at multivariate level were platinum resistance (p=0.06, RR 3.99; 95% CI, 0.94-16.97) and clear cell type (p=0.015, RR 9.63; 95% CI, 1.56-59.45). Conclusion Some subgroups (non clear cell types, platinum sensitive groups) of patients with ovarian cancer seem to have good outcomes after high dose chemotherapy with autologous stem cell transplantation, although several biases may have affected these observations. Disclosures: No relevant conflicts of interest to declare.

Abstract 4450 Acquired hemophilia is a rare bleeding disorder caused by autoantibodies directed against the coagulation factor VIII (FVIII). Usually acquired hemophilia is found in the elderly person, autoimmune disorder or women in the postpartum. Incontrast to alloantibody inhibitors of hereditary hemophilia, acquired inhibitor is presumably due to a spontaneous autoimmune disorder in which patients with previously normal hemostasis develop autoantibodies against FVIII. However, the precise cause of the antibody formation remains obscure and the possibility of abnormal FVIII protein derived from the FVIII gene mutation might have caused the antibody formation was investigated by direct FVIII gene sequencing method. Blood samples were obtained from a 72 year old male who initially presented with a large hematoma in the Rt. Shoulder, and had a prolonged aPTT (46 sec), FVIII level of 14%, and VIII inhibitor titer 2∼5 BU/ml. Direct sequencing of FVIII was performed via amplification for all 26 exons, including the 5′-UTR and 3′-UTR region, using the 35 synthesized primers. Sequencing was conducted using BigDye Terminator cycle sequencing kit on an ABI 3730XL DNA analyzer (Applied Biosystems, Foster City, CA). Sequence variations were analyzed with CLC main workbench program (CLC, Aarhus. Denmark). Firstly, we analyzed translational region of FVIII gene. But we couldn't find any sequence variation. Then we analyzed the sequence of untranslationed region, 5′-UTR and 3′-UTR. As a result, we identified gene variation of substitution to c.8889G>A in the 3′-UTR. We speculate that this variation may have affected the RNA processing or mRNA stability. Thus we need to study about the relationship between this sequence variation and FVIII function. Also, we will investigate whether this gene variation is functional mutation. The cause of acquired hemophilia remains obscure. Variations in FVIII molecules including in untranslatable 5′- or 3′-region should be studied further to delineate the cause of antibodies in acquired HA. We expect that the accumulation of sequence variation can help to understand the cause of acquired hemophilia through this study. Disclosures: No relevant conflicts of interest to declare.

Lymphomas of mucosa-associated lymphoid tissue (MALT) comprise 7% of all newly diagnosed non-Hodgkin’s lymphomas. Helicobacter pylori (H. pylori) negative gastric MALT lymphomas account for 28 to 45% of gastric MALT lymphomas. H. pylori infection has a close relationship with most gastric low-grade B cell lymphomas of the MALT type. Monoclonal gammopathy can be seen in 36% of the patients and negatively associated with responses to eradication of H. pylori in gastric MALT lymphoma. Here, we describe a case of H. pylori negative MALT lymphoma that arose from the stomach with massive plasmacytic differentiation mimicking an extramedullary plasmacytoma with monoclonal gammopathy, and that was cured by total gastrectomy, chemotherapy and radiotherapy.

Purpose: On performing umbilical cord blood (UCB) transplantation, faster engraftment may lead better clinical outcome. Because transplanted viable cell count in UCB is related to the engraftment, we examined cryopreserved UCB cells with several methods after thawing. Methods: Viability of cryopreserved cells were examined with trypan blue, DNA contents analysis, caspase-3 activation test, intracellular esterase activity and Annexin-V/PI staining. Results: A total of 60 samples were used in this study. After thawing, 89% of the total MNCs and 84% of CD34+ cells were viable as identified by trypan blue exclusion assay. In the CD34+ cell population, the cell death rate was found to be 47 % by Annexin-V/PI staining and less than 5 % by DNA contents analysis. Caspase-3 activity failed to document apoptosis. The intracellular esterase activity test also showed a cell death rate of about 10–20 % at 2, 4, and 6 hours after thawing. Conclusion: Viable cells in UCB should be measured by several compensatory techniques rather than a single method. Discordance among Annexin-V/PI staining versus trypan blue exclusion, DNA contents analysis, and the caspase-3 activation test or intracellular esterase activity should be clarified in order to apply these techniques for actual cord blood transplantation.

Summary To clarify the usefulness of multiplex reverse transcription polymerase chain reaction (mRT-PCR) in diagnosing acute leukemia, mRT-PCR detecting 28 different translocations was performed on bone marrow aspirates of 156 patients with acute leukemia, and the results were compared with conventional chromosomal karyotypes. About 113 of 156 patients had acute myeloid leukemia (AML), and 36 had acute lymphoid leukemia (ALL) with patients’ ages ranging from 1 to 84 (median: 34.5). Concordance rate between karyotyping and mRT-PCR was 50% (51% in AML and 44% in ALL). Karyotype revealed chromosomal abnormalities in 70 patients (45%) while mRT-PCR showed some aberrations in 59 patients (38%). mRT-PCR detected t(1;19), t(4;11), t(9;11), t(10;11), t(11;19), t(12;21), and TAL1d, which were not detected by G-banding. In addition, 10 patients with t(15;17), one patient with t(8;21), and four patients with t(9;22) detected by mRT-PCR revealed normal karyotypes. However, mRT-PCR did not detect numerical abnormalities, deletions, and translocations other than the 28 translocations included in the assay as expected. In conclusion, although it cannot be a substitute of the conventional chromosome analysis, mRT-PCR could be a complementary diagnostic strategy of acute leukemia.

Background: It is still obscure how dendritic cells (DCs) can orchestrate whole immune reactions according to the host age. We studied changes of murine splenic DCs after total body irradiation (TBI), with regards to age. Methods: Young (8∼14 wk) and old (12∼16 mo) C57Bl/6 mice were irradiated with a dose of 1,100 cGy and were assessed 6 h later for phenotypic and functional changes of the DCs. The mean fluorescence intensities and cytokine producing cell proportions were analyz ed with the student's t-test. Results: Interleukin-12 (IL-12), interferon (IFNγ) and tumor necrosis factor (TNFα) producing classical DCs (cDCs) were more numerous in the young untreated mice than in the old mice. However, the number of these cells decreased in the young mice and increased in the old mice after TBI. IL-12, IFNγ and TNFα producing plasmacytoid DCs (pDCs) were more frequent in the old mice than in the young mice before TBI both mice showed an increased frequency of cells producing these cytokines after TBI. Overall, the highest numbers of cDCs and pDCs producing IL-12, IFNγ and TNFα were present in the old mice after TBI. In both the cDC and pDC populations, the old mice had a higher frequency of IL-10+ cells prior to TBI. After irradiation, the young mice had a higher frequency of IL-10+ cells. Conclusion: With TBI, the DCs showed dramatic differences between young and old mice. Young mice turned to an immuno-suppressive response whereas the old mice changed to an immuno-stimulation of DCs after TBI. From these dramatic aging effects, we hope to explain the different frequencies and severities of acute GvHD after allogeneic hematopoietic stem cell transplantation according to host age.

Micafungin, a clinically important echinocandin antifungal drug, needs to be investigated as empirical therapy in febrile neutropenia in comparison with azole compounds. A prospective randomized study was conducted to compare clinical outcomes between micafungin and intravenous itraconazole as an empirical therapy for febrile neutropenia in hematological malignancies. The antifungal drug (micafungin 100 mg or itraconazole 200 mg IV once daily) was given for high fever that was sustained despite the administration of appropriate antibiotics. Treatment success was determined by composite end points based on breakthrough invasive fungal infection (IFI), survival, premature discontinuation, defervescence, and treatment of baseline fungal infection. Duration of fever, hospital stay, and overall survival (OS) were studied. A total of 153 patients were randomized to receive micafungin or itraconazole. The overall success rate was 7.1 % point higher in the micafungin group (64.4 vs. 57.3 %, p = 0.404), satisfying the statistical criteria for the non-inferiority of micafungin. The duration of fever and hospital stay were significantly shorter in the micafungin group (6 vs. 7 days, p = 0.014; 22 vs. 27 days, p = 0.033, respectively). Grade 3 adverse events including hyperbilirubinemia (2 vs. 7), elevation of transaminase levels (2 vs. 4), electrolyte imbalance (1 vs. 2), atrial fibrillation (1 vs. 0), and anaphylaxis (1 vs. 0) occurred in 7 and 13 patients in the micafungin (10.4 %) and itraconazole (18.8 %) groups, respectively. Micafungin, when compared with itraconazole, had favorably comparable success rate and toxicity profiles on febrile neutropenia in patients with hematological malignancies. In addition, it showed superior effect on shortening the hospital stay.