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Background JAK2 mutation status is a well-known risk factor for thrombosis in patients with myeloproliferative neoplasms. However, the clinical usefulness of JAK2 allele burden is under investigation. Methods We retrospectively evaluated the impact of the JAK2 V617F allele burden on clinical characteristics and outcomes of JAK2 V617F-positive polycythemia vera (PV) and essential thrombocythemia (ET). The JAK2 V617F allele burden was measured using sequencing. Results Altogether, 127 patients with JAK2 V617F mutation (PV, N=61; ET, N=66) were included in this study. JAK2 V617F allele burdens were positively correlated with white blood cell counts, hemoglobin values, lactate dehydrogenase levels, and platelet counts. The median values of JAK2 V617F allele burden in patients with PV and ET were 58% and 30%, respectively. A JAK2 V617F allele burden of ≥30%, older age, and a higher hemoglobin level were risk factors for thrombotic events in ET. In patients with PV, older age was the only thrombotic risk factor. The 8-year probabilities of overall survival (OS) were 82.9% in all patients. A high JAK2 V617F allele burden (≥58%) was associated with poor OS in patients with PV. For the patients with ET, the difference in 8- year OS based on the JAK2 V617F allele burden was not significant. Conclusion The JAK2 V617F allele burden was correlated with hematologic parameters and clinical outcomes. Assessing the JAK2 V617F allele burden can be helpful in predicting the thrombotic risk and disease course in patients with JAK2 V617F-positive PV and ET.

Venous thromboembolism (VTE), which includes pulmonary embolism and deep vein thrombosis, is a condition characterized by abnormal blood clot formation in the pulmonary arteries and the deep venous vasculature. It is often serious and sometimes even fatal if not promptly and appropriately treated. Moreover, the later consequences of VTE may result in reduced quality of life. The treatment of VTE depends on various factors, including the type, cause, and patient comorbidities. Furthermore, bleeding may occur as a side effect of VTE treatment. Thus, it is necessary to carefully weigh the benefits versus the risks of VTE treatment and to actively monitor patients undergoing treatment. Asian populations are known to have lower VTE incidences than Western populations, but recent studies have shown an increase in the incidence of VTE in Asia. A variety of treatment options are currently available owing to the introduction of direct oral anticoagulants. The current VTE treatment recommendation is based on evidence from previous studies, but it should be applied with careful consideration of the racial, genetic, and social characteristics in the Korean population.

Several high-dose therapy (HDT) conditioning regimens have been used to treat non-Hodgkin's lymphoma (NHL), such as bis-chloroethylnitrosourea (BCNU)/etoposide/cytosine arabinoside/melphalan (BEAM), BCNU/etoposide/cytosine arabinoside/cyclophosphamide (BEAC), and cyclophosphamide/BCNU/etoposide (CBV). BCNU is an active drug in HDT of NHL, but the supply is limited in some countries, including Korea. Busulfan has been used in allogeneic and autologous stem cell transplantation (ASCT). This phase II study evaluated the efficacy of busulfan/melphalan/etoposide (BuME) as a conditioning regimen for HDT in relapsed or high-risk NHL. The regimen consisted of intravenous busulfan (3.2 mg/kg/day) on days -8, -7, and -6, etoposide (400 mg/m2 /day) on days -5 and -4, and melphalan (50 mg/m2 /day) on days -3 and -2. A total of 46 patients were included in the study, with 36 (78.3%) achieving a complete response after ASCT. The 2-year progression-free survival (PFS) and overall survival (OS) rates for all patients were 46.7% (95% CI, 31.8-60.4%) and 63.7% (95% CI, 47.7-76.0%), respectively. There was no development of veno-occlusive disease and no treatment-related deaths within 100 days after ASCT. These results indicate that a BuME regimen is well-tolerated and effective for patients with relapsed or high-risk NHL, and may be comparable to some previously used regimens. This regimen may be useful as a substitute for BCNU-containing regimens.

Background A high number of focal lesions (FL) detected using PET/CT at diagnosis were found to be associated with adverse prognosis along with Revised International Staging System (R-ISS). In present study, we combined R-ISS with FL using PET/CT to design a reliable and easily applicable risk stratification system in patients with newly diagnosed MM (NDMM). Methods In training cohort, the data of 380 patients with NDMM who underwent 18F-fluorodeoxyglucose (18F-FDG) PET/CT upon diagnosis from 10 hospitals of the Korean Multiple Myeloma Working Party were retrospectively analyzed. All patients were classified by R-ISS and were treated by frontline therapy with proteasome inhibitors (PI) and/or immunomodulatory drugs (IMiD). The K-adaptive partitioning algorithm was adopted to develop the new risk groups with homogeneous survival. Sixty-seven patients in external validation cohort were additionally collected to confirm reproducibility of the new risk groups. Results In the training cohort, 199 patients (52.4%) showed FL > 3 using PET/CT at diagnosis. R-ISS stages I, II, and III were 78 patients (20.5%), 230 (60.5%), and 72 (18.9%), respectively. The combined R-ISS with PET/CT newly allocated NDMM patients into four groups: R-ISS/PET stage I (n=30; R-ISS I with FL≤3), stage II (n=149; R-ISS I with FL>3 and R-ISS II with FL≤3), stage III (n=166; R-ISS II with FL>3 and R-ISS III with FL≤3), and stage IV (n=35; R-ISS III with FL>3). The new R-ISS/PET showed significantly pronounced survival differences according to stages. Two-year overall survival (OS) rates were 96.6%, 89.5%, 75.0%, and 57.9% (p < 0.001), and 2-year progression-free survival (PFS) rates were 86.9%, 65.1%, 41.9%, and 15.2% (p < 0.001) in stages I, II, III, and IV, respectively. The prognostic role of the R-ISS/PET for survival outcomes was also confirmed in different subgroups classified by transplant eligibility and by types of treatments. In the external validation cohort, the new R-ISS/PET was successfully implemented. Two-year OS rates for were 100%, 89.9%, 82.6%, and 42.0% for R-ISS/PET I, II, III, and IV, respectively (p = 0.001). PFS rates at 2 years for each R-ISS/PET were 100%, 74.5%, 57.9%, and 25.6%, respectively (p = 0.004). In the multivariate Cox analysis for survival outcome, R-ISS/PET was a significant factor and could predict long-term outcomes with regard to OS: stage II vs. I (HR 2.50, p = 0.215), (ii) stage III vs. I (HR 5.11, p = 0.025), and (iii) stage IV vs. I (HR 10.3, p = 0.003) and PFS: (i) stage II vs. I (HR 2.21, p = 0.005), (ii) stage III vs. I (HR 4.57, p < 0.001), and (iii) stage IV vs. I (HR 9.48, p < 0.001). Conclusion The new R-ISS/PET had a remarkable prognostic power for estimating the survival outcomes of patients with NDMM. This system helps discriminate patients with a good prognosis from those with a poor prognosis more precisely. Thus, R-ISS/PET is applicable for identifying heterogeneous manifestation of clinical MM. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Venous thromboembolism (VTE) may lead to diminished quality of life and ultimately worse prognosis in cancer patients, but there is limited data on the incidence, risk factors and mortality impact of VTE in Asian primary central nervous system lymphoma (PCNSL) patients.To report the incidence, risk factors and mortality impact of VTE in Asian PCNSL patients.From 7 academic centers in Korea, 235 newly diagnosed PCNSL patients undergoing chemotherapy were retrospectively identified during period of January 2004 to September 2018.All patients but 12 (6 T-cell, 6 other B-cell) had diffuse large B-cell lymphoma. During the median follow-up of 21 months, 33 patient (14.0%) developed VTE. Of the VTE events, 11 (33.3%) were deep vein thrombosis (DVT), 15 (45.5%) were pulmonary thromboembolism (PTE), and 7 (21.2%) were DVT with PTE. The median time to VTE was 2 months and the one-year actuarial incidence was 11.7%. On multivariate analysis, ECOG performance ≥2, age60 years, female sex, and Hb10 g/dL were independently associated with VTE. The patients with VTE were associated with shorter disease specific survival (P = 0.046) and overall survival (P = 0.022).Overall, the incidence of VTE in Asian PCNSL seems to be lower compared to Western population. As VTE development is associated with overall survival and indicative of relapse, careful close monitoring is warranted.

Objective: We aimed to evaluate the effect of stem cell source and dose on the survival of various donor subgroups, such as matched sibling donor (MSDs) and alternative donors (ADs), upon bone marrow (BM) or peripheral blood stem cell (PBSC) infusion in aplastic anemia (AA). Methods: We retrospectively investigated the effects of stem cell source and dose on allogeneic hematopoietic stem cell transplantation (alloHSCT) in AA. Results: A total of 267 patients were included in this analysis. The BM-treated group showed an association with low incidence of any-grade acute graft versus host disease (GvHD) (p < 0.001). A higher stem cell dose was related with a low incidence of extensive chronic GvHD in MSDs (p = 0.025). Multivariate analysis for overall survival (OS) revealed that only age at alloHSCT p = 0.010) and prior platelet transfusion p = 0.046) in MSDs and higher stem cell dose (hazard ratio = 2.596, p = 0.045) in ADs were favorable prognostic factors. Conclusion: PBSCs could be preferred in AD because high stem cell dose may be easily achieved to improve the OS at the expense of acute GvHD. However, BM stem cells are preferred in MSDs.

Bortezomib/thalidomide/dexamethasone (VTD) induction therapy followed by autologous stem cell transplantation (ASCT) is one of the standard therapies for newly diagnosed multiple myeloma (NDMM). However, the appropriate depth of response to induction therapy and timing of upfront ASCT are still debated. We investigated if two additional cycles of VTD (VTD6) improved the responses and progression-free survival (PFS) compared with four cycles of VTD (VTD4). We retrospectively reviewed outcomes of 190 NDMM patients treated with at least four cycles of VTD followed by ASCT between September 2014 and August 2017 [VTD4, n = 129 (67.9%); VTD6, n = 61 (32.1%)]. The VTD6 group had a higher pre-ASCT complete response (CR) rate than the VTD4 group (31.1% versus 10.1%, P 2-microglobulin, and pre-ASCT CR as important factors for PFS. Two additional cycles of VTD prolonged PFS in patients with PR only after VTD4 [Hazard ratio (HR) = 0.29, P = 0.016] or those with Revised International Staging System stage I/II (HR = 0.36, P = 0.039). In conclusion, two additional VTD cycles may be helpful for patients with PR only after VTD4 but high risk MM needs the other treatment options.

Ultra-deep sequencing detects low-frequency genetic mutations with high sensitivity. We used this approach to prospectively examine mutations in the BCR/ABL1 tyrosine kinase from patients with newly diagnosed, chronic-phase chronic myeloid leukemia (CML) treated with the tyrosine kinase inhibitor nilotinib. Between May 2013 and November 2014, 50 patients from 18 institutions were enrolled in the study. We screened 103 somatic mutations and found that mutations in the P-loop domain were the most frequent (173/454 mutations in the P-loop) and noted the presence of the V299 L mutation (dasatinib-resistant/nilotinib-sensitive) in 98 % of patients (49/50). No patients had Y253H, E255 V, or F359 V/C/I mutations, which would recommend dasatinib rather than nilotinib treatment. The S417Y mutation was associated with lower achievement of a major molecular response (MMR) at 6 months, and the V371A mutation was associated with reduced MMR and MR4.5 durations (MMR for 2 years: 100 % for no mutation vs. 75 % for mutation, P=0.039; MR4.5 for 15 months: 94.1 % vs. 25 %, P=0.002). Patients with known nilotinib-resistant mutations had lower rates of MR4.5 achievement. In conclusion, ultra-deep sequencing is a sensitive method for genetic-based treatment decisions. Based on the results of these mutational analyses, nilotinib treatment is a promising option for Korean patients with CML.

Old age alone does not reflect an intolerability to chemotherapy. However, upfront dose reduction (UDR) of the first cycle of first-line palliative chemotherapy has sometimes been chosen by physicians for older adults with metastatic cancer due to concerns regarding adverse events. The development of predictive factors for UDR of palliative chemotherapy would be helpful for treatment planning among older adults. This was a secondary analysis of a study on predicting adverse events of first-line palliative chemotherapy in 296 patients (&ge, 70 years) with solid cancer. We assessed the prevalence of UDR of the first cycle of first-line chemotherapy and the association of UDR with the variables of geriatric assessment (GA) and chemotherapy compliance. Among the 296 patients, 177 (59.8%) patients were treated with UDR. The mean percentage of UDR for the total patient group was 19.2% (range: 4&ndash, 47%) of the standard dose. In a multivariate analysis, poor performance status (PS) and living without a spouse were independent predictive factors of UDR of first-line palliative chemotherapy in older adults. Patients with UDR showed fewer grade 3&ndash, 5 adverse events versus the standard dose group. Study completion as planned was significantly higher in the UDR group versus the standard dose group. Older adults with UDR better tolerated chemotherapy than patients with a standard dose.

In 2016, the World Health Organization revised the diagnostic criteria for myeloproliferative neoplasms (MPNs) based on the discovery of disease-driving genetic aberrations and extensive analysis of the clinical characteristics of patients with MPNs. Recent studies have suggested that additional somatic mutations have a clinical impact on the prognosis of patients harboring these genetic ab normalities. Treatment strategies have also advanced with the introduction of JAK inhibitors, one of which has been approved for the treatment of patients with myelofibrosis and those with hydroxyurea-resistant or intolerant polycythemia vera. Recently developed drugs aim to elicit hematologic responses, as well as symptomatic and molecular responses, and the response criteria were refined ac cordingly. Based on these changes, we have revised the guidelines and present the diagnosis, treatment, and risk stratification of MPNs encountered in Korea.

Background/Aims This study evaluated the role of hypomethylating agents (HMA) compared to best supportive care (BSC) for patients with high or very-high (H/VH) risk myelodysplastic syndrome (MDS) according to the Revised International Prognostic Scoring System. Methods A total of 279 H/VH risk MDS patients registered in the Korean MDS Working Party database were retrospectively analyzed. Results HMA therapy was administered to 205 patients (73.5%), including 31 patients (11.1%) who then received allogeneic hematopoietic cell transplantation (allo-HCT), while 74 patients (26.5%) received BSC or allo-HCT without HMA. The 3-year overall survival (OS) rates were 53.1% ± 10.7% for allo-HCT with HMA, 75% ± 21.7% for allo-HCT without HMA, 17.3% ± 3.6% for HMA, and 20.8% ± 6.9% for BSC groups (p < 0.001). In the multivariate analysis, only allo-HCT was related with favorable OS (hazard ratio [HR], 0.356; p = 0.002), while very poor cytogenetic risk (HR, 5.696; p = 0.042), age ≥ 65 years (HR, 1.578; p = 0.022), Eastern Cooperative Oncology Group performance status (ECOG PS) 2 to 4 (HR, 2.837; p < 0.001), and transformation to acute myeloid leukemia (AML) (HR, 1.901; p = 0.001) all had an adverse effect on OS. Conclusions For the H/VH risk group, very poor cytogenetic risk, age ≥ 65 years, ECOG PS 2 to 4, and AML transformation were poor prognostic factors. HMA showed no benefit in terms of OS when compared to BSC. Allo-HCT was the only factor predicting a favorable long-term outcome. The use of HMA therapy did not seem to have an adverse effect on the transplantation outcomes. However, the conclusion of this study should be carefully interpreted and proven by large scale research in the future.

Predictive factors for initiating hypomethylating agents’ (HMAs) treatment and the survival benefit of HMAs for lower-risk myelodysplastic syndrome (LR-MDS) are still unknown. This study evaluated the factors affecting the use of HMAs and compared long-term outcomes between best supportive care (BSC) and HMA groups after matching baseline clinical factors. Data of 353 patients diagnosed with LR-MDS by International Prognostic Scoring System between October 1992 and July 2013 were retrospectively analyzed. HMAs were administered continuously until a clinical response or progression. HMAs were administered to 243 patients with median 45 days (range 0–7078 days) after diagnosis, while 110 patients were treated with BSC. HMAs were administered over a median of 5 cycles and overall response was achieved in 104 patients (42.8%). The cumulative incidence of HMA treatment increased in higher-risk groups by other risk scoring systems. Three-year overall survival (OS) rate was higher in BSC group (69.1%) than HMA responders (47.4%, p = 0.065) or HMA non-responders (46.3%, p = 0.005). Among 162 case-matched cohorts, 3-year OS rates were comparable between the BSC group (67.1%) and HMA responders (58.1%, p = 0.914), while that of HMA non-responder was low (32.2%, p

Background Older patients have increased risk of toxicity from chemotherapy. Current prediction tools do not provide information on cumulative risk. Methods Patients aged ≥ 70 years with solid cancer were prospectively enrolled. A prediction model was developed for adverse events (AEs) ≥ Grade 3 (G3), based on geriatric assessment (GA), laboratory, and clinical variables. Results 301 patients were enrolled (median age, 75 years). Median number of chemotherapy cycles was 4. During first-line chemotherapy, 53.8% of patients experienced AEs ≥ G3. Serum protein < 6.7 g/dL, initial full-dose chemotherapy, psychological stress or acute disease in the past 3 months, water consumption < 3 cups/day, unable to obey a simple command, and self-perception of poor health were significantly related with AEs ≥ G3. A predicting model with these six variables ranging 0–8 points was selected with the highest discriminatory ability (c-statistic= 0.646), which could classify patients into four risk groups. Predicted cumulative incidence of AEs ≥ G3 was discriminated according to risk groups. Conclusions This prediction tool could identify the risk of AEs ≥ G3 after chemotherapy and provide information on the cumulative incidence of AEs in each cycle. Clinical Trial Id WHO ICTRP number, KCT0001071

Although nilotinib has improved efficacy compared to imatinib, suboptimal response and intolerable adverse events (AEs) limit its effectiveness in many patients with chronic myeloid leukemia in chronic phase (CML‐CP). We investigated the 2‐year efficacy and safety of nilotinib and their relationships with plasma nilotinib concentrations (PNCs). In this open‐label, multi‐institutional phase 4 study, 110 Philadelphia chromosome‐positive CML‐CP patients were treated with nilotinib at a starting dose of 300 mg twice daily. Molecular responses (MRs) and AEs were monitored for up to 24 months. The 24‐month cumulative MR 4.5 rate was evaluated as the primary endpoint. Plasma samples were collected from 94 patients to determine PNCs, and the per‐patient mean was used to categorize them into four mean PNC (MPNC) groups. Cumulative MR rates and safety were compared between groups. With a median follow‐up of 22.2 months, the 24‐month cumulative MR 4.5 rate was 56.2% (95% confidence interval, 44.0%–8.3%), and the median time to MR 4.5 was 23.3 months. There were no significant differences in the cumulative rates of major molecular response, MR 4, and MR 4.5 between MPNC groups. One patient died due to acute viral hepatitis, and two developed hematological or cytogenetic relapse, while no progression to accelerated or blast phase was observed. Safety results were consistent with previous studies with no new safety signal identified. Across the MPNC groups, there was no significant linear trend in the frequency of AEs. Nilotinib is highly effective for the treatment of CML‐CP with manageable AEs. The measurement of PNC has no predictive value for patient outcomes and is thus not found to be clinically useful. This study is registered with clinicaltrials.gov, Number NCT03332511.

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.

Purpose We compared two induction regimens, idarubicin (12 mg/m2/d for 3 days) versus high-dose daunorubicin (90 mg/m2/d for 3 days), in young adults with newly diagnosed acute myeloid leukemia (AML). Patients and Methods A total of 299 patients (149 randomly assigned to cytarabine plus idarubicin [AI] and 150 assigned to cytarabine plus high-dose daunorubicin [AD]) were analyzed. All patients received cytarabine (200 mg/m2/d for 7 days). Results Complete remission (CR) was induced in 232 patients (77.6%), with no difference in CR rates between the AI and AD arms (80.5% v 74.7%, respectively; P = .224). At a median follow-up time of 34.9 months, survival and relapse rates did not differ between the AI and AD arms (4-year overall survival, 51.1% v 54.7%, respectively; P = .756; cumulative incidence of relapse, 35.2% v 25.1%, respectively; P = .194; event-free survival, 45.5% v 50.8%, respectively; P = .772). Toxicity profiles were also similar in the two arms. Interestingly, overall and event-free survival times of patients with FLT3 internal tandem duplication (ITD) mutation were significantly different (AI v AD: median overall survival, 15.5 months v not reached, respectively; P = .030; event-free survival, 11.9 months v not reached, respectively; P = .028). Conclusion This phase III trial comparing idarubicin with high-dose daunorubicin did not find significant differences in CR rates, relapse, and survival. Significant interaction between the treatment arm and the FLT3-ITD mutation was found, and high-dose daunorubicin was more effective than idarubicin in patients with FLT3-ITD mutation.

// Da Jung Kim 1 , Ho Sup Lee 1 , Joon-Ho Moon 2 , Sang Kyun Sohn 2 , Hyeoung Joon Kim 3 , June-Won Cheong 4 , Deog-Yeon Jo 5 , Hawk Kim 6 , Hyewon Lee 7 , Soo-Mee Bang 8 , Won Sik Lee 9 , Yong Park 10 , Mark Hong Lee 11 , Jae Hoon Lee 12 , Sung Hwa Bae 13 , Min Kyoung Kim 14 and The Korean Society of Hematology AML/MDS Working Party 1 Department of Internal Medicine, Kosin University College of Medicine, Kosin University Gospel Hospital, Busan, South Korea 2 Department of Hematology/Oncology, Kyungpook National University Hospital, Daegu, South Korea 3 Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, Hwasun, Jeollanamdo, South Korea 4 Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea 5 Department of Internal Medicine, Chungnam National University Hospital, Chungnam National University, Daejeon, South Korea 6 Division of Hematology and Cellular Therapy, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, South Korea 7 Department of Hematology-Oncology, Center for Hematologic Malignancy, National Cancer Center, Goyang, South Korea 8 Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul, South Korea 9 Department of Internal Medicine, Busan Paik Hospital, Busan, South Korea 10 Department of Internal Medicine, Korea University College of Medicine, Seoul, South Korea 11 Division of Hematology-Oncology, Department of Internal Medicine, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, South Korea 12 Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, South Korea 13 Department of Internal Medicine, Daegu Catholic University Medical Center, Daegu, South Korea 14 Department of Hematology-Oncology, Yeungnam University Medical Center, Yeungnam University School of Medicine, Daegu, South Korea Correspondence to: Ho Sup Lee, email: hs52silver@gmail.com Keywords: myelodysplastic syndrome, discontinuation, survival, decitabine, azacitidine Received: March 17, 2017 Accepted: April 28, 2017 Published: May 29, 2017 ABSTRACT It is often difficult to continue treatment with hypomethylating agent(HMA) in clinical practice because of problems such as toxicities, poor economics, etc. We compared clinical outcomes of those patients who continued HMA and those who discontinued HMA because of other causes, and evaluated factors associated with survival in those patients who discontinued HMA. Patients were divided into two groups: treatment failure, those who stopped treatment due to disease progression; and discontinuation, those who discontinued treatment because of other causes. The median progression free survival(PFS) was 9.2 months (range 7.7 – 10.7 months) vs 28.9 months (range 22.6 – 35.2) in the treatment failure and discontinuation groups, respectively ( P < 0.001). In a multivariate analysis, a lower risk by WPSS was an independent predictive factor for a longer PFS, and a lower risk by WPSS and median number of HMA cycles greater than seven were independent predictive factors for longer overall survival(OS) only in the discontinuation group. Patients who discontinued HMA without disease progression showed a prolonged survival than those who failed HMA treatment. Especially, a lower risk by WPSS and longer duration of HMA treatment may be predictive factors for a longer PFS and OS in patients who discontinued HMA.

Bortezomib-melphalan-prednisone (VMP) showed superior efficacy versus MP as first-line treatment for transplantation-ineligible multiple myeloma (MM). This study investigated the efficacy of VMP for Korean patients with MM. Overall, 177 MM patients received 9 cycles of VMP in this prospective, multicenter, observational study. The primary endpoint was 2-year progression-free survival (PFS). Thirty-nine (22%) patients were aged ≥ 75 years and 83 (47.4%) patients had International Staging System stage III. A median of 5 cycles were delivered. Overall response rate (ORR) was 72.9%, and complete response (CR) rate was 20.3%. With a median follow-up of 11.9 months, median PFS was 17 months. The 2-year PFS and overall survival (OS) rates were 29.2% and 80.0%, respectively. Median OS was not reached. PFS was significantly different depending on performance status (Eastern Cooperative Oncology Group < 2 vs. ≥ 2; p = 0.0002), β2-microglobulin level (< 5.5 vs. ≥ 5.5 mg/L; p = 0.0481), and cumulative dose of bortezomib (< 35.1 vs. ≥ 35.1 mg/m2; p < 0001). The common adverse events (AEs) were in line with the well-known toxicity profiles associated with VMP. In conclusion, VMP is a feasible and effective front-line treatment for transplant-ineligible older patients with MM in Korea. Continuing therapy with prompt adjustment of treatment according to AEs may be important to improve outcomes of elderly patients.

// Dok Hyun Yoon 1,* , Seok Jin Kim 2,* , Seong Hyun Jeong 3 , Dong-Yeop Shin 4 , Sung Hwa Bae 5 , Junshik Hong 6 , Seong Kyu Park 7 , Ho-Young Yhim 8 , Deok-Hwan Yang 9 , Hyewon Lee 10 , Hye Jin Kang 11 , Mark Hong Lee 12 , Hyeon-Seok Eom 10 , Jae-Yong Kwak 8 , Jae Hoon Lee 6 , Cheolwon Suh 1 and Won Seog Kim 2 1 Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea 2 Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 3 Department of Hematology-Oncology, Ajou University School of Medicine, Suwon, Korea 4 Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea 5 Department of Internal Medicine, Catholic University of Daegu School of Medicine, Daegu, Korea 6 Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Korea 7 Department of Hematology/Oncology, Soonchunhyang University Bucheon Hospital, Bucheon, Korea 8 Department of Internal Medicine, Chonbuk National University School of Medicine, Jeonju, Korea 9 Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea 10 Center for Hematologic Malignancies, National Cancer Center, Goyang, Korea 11 Department of Internal Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea 12 Department of Hematology-Oncology, Konkuk University Medical Center, Seoul, Korea * These authors have contributed equally to this work Correspondence to: Won Seog Kim, email: // Keywords : extranodal NK/T-cell lymphoma, nasal type; concurrent chemoradiotherapy; L-asparaginase; methotrexate; treatment Received : May15, 2016 Accepted : August 11, 2016 Published : August 16, 2016 Abstract We designed a new treatment protocol incorporating concurrent administration of L-asparaginase (to reduce the probability of systemic progression during concurrent chemoradiotherapy (CCRT)) plus high-dose methotrexate to consolidation chemotherapy to intensify the regimen for treating localized extranodal NK/T cell lymphoma, nasal type (ENKTL). CCRT comprised radiation (36–44 Gy) with weekly cisplatin (30 mg/m 2 ) and tri-weekly L-asparaginase (4 000 IU). Chemotherapy—MIDLE (methotrexate 3 g/m 2 on day 1, etoposide 100 mg/m 2 and Ifosfamide 1 000 mg/m 2 on days 2–3, dexamethasone 40 mg on days 1–4, and L-asparaginase 6 000 IU/m 2 on days 4, 6, 8, 10)—was repeated every 28 days for two cycles. One of the 28 patients developed distant lesions after CCRT. The final complete response rate was 82.1%. Four patients dropped out during or after their first MIDLE cycle due to toxicities (recurrent G3 hyperbilirubinemia [n = 1], G3-5 increased creatinine [n = 2], and G5 infection [n = 1]). With a median follow-up of 46 months (95% CI: 39–47 months), the estimated 3-year progression-free survival rate and overall survival rate were 74.1% and 81.5%, respectively. This MIDLE protocol may be effective for localized ENKTL. However, concurrent administration of L-asparaginase during CCRT does not seem to provide additional benefits.

Aim We performed a phase II study to evaluate the efficacy of combination chemotherapy consisting of gemcitabine, dexamethasone and oxaliplatin (GemDOx) as a biweekly regimen and salvage therapy in patients with relapsed or refractory aggressive non-Hodgkin lymphoma (NHL). Methods Gemcitabine (1000 mg/m2) and oxaliplatin (85 mg/m2) were administered intravenously on days 1 and 15, and dexamethasone (40 mg) was administered orally on days 1–4. Results Twenty-nine patients were enrolled, and most patients had diffuse large B-cell lymphoma (n = 18). The median age of the patients and median prior number of chemotherapy cycles were 53 (range, 26–74) years and 1 (range, 1–4) cycle, respectively. Only 17 (58.6%) and 9 (31.0%) patients completed two or more and four or more cycles, respectively, and the median number of received cycles was two (range, 1–8). Overall response rates were 27.6% (complete response in 13.8%) among intent-to-treat patients and 47.1% (complete response in 23.5%) among patients who had received at least two GemDOx cycles. Median progression-free survival and median overall survival were 3.9 and 20.5 months, respectively. The most-frequent grade 3 or 4 toxicity was neutropenia (22.9%), and no grade 3 or 4 peripheral neurotoxicity was noted. Conclusion GemDOx chemotherapy, therefore, showed modest activity against relapsed or refractory aggressive NHL, although toxicities were acceptable.

We performed a study on allogeneic hematopoietic cell transplantation (alloHCT) from an HLA-haplo-identical familial donor (haploFD) using a busulfan-fludarabine-antithymocyte globulin conditioning regimen for severe aplastic anemia (sAA) and hypoplastic myelodysplastic syndrome. For the comparison between a haploFD and an alternative donor (AD; matched unrelated or partially matched donor) for sAA in adults, we collected haploFD data retrospectively and prospectively. Forty-eight AD cases were selected for the comparison with 16 haploFD cases. All transplantation outcomes except for extensive chronic graft versus host disease (GvHD) were similar. The frequencies of hepatic sinusoidal obstruction syndrome (p = 1.000), acute GvHD (p = 0.769), grade 3/4 acute GvHD (p = 0.258), chronic GvHD (p = 0.173), extensive chronic GvHD (p = 0.099), primary neutrophil engraftment failure (p = 1.000), secondary graft failure (p = 1.000) and platelet engraftment failure (p = 0.505) were similar. Time to neutrophil engraftment was faster in haploFD (p = 0.003), while the cumulative incidence of platelet engraftment was similar (p = 0.505). Overall survival was also similar between AD and haploFD (p = 0.730). In conclusion, alloHCT from haploFD in sAA was comparable with alloHCT from AD, but extensive chronic GvHD seemed frequent in haploFD. Therefore alloHCT from haploFD could be an alternative approach for alloHCT from AD in adult sAA.

581 Copyrightc 2015 The Korean Association of Internal Medicine This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Received: 2014. 11. 28 Revised: 2015. 3. 4 Accepted: 2015. 4. 29

The effects of imatinib plus chemotherapy were assessed in 87 patients with newly diagnosed Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). Imatinib was administered continuously, starting from the eighth day of remission induction chemotherapy, then through five courses of consolidation or until allogeneic hematopoietic cell transplantation (HCT). Patients who were not transplanted were maintained on imatinib for 2 years. Eighty-two patients (94.3%) achieved complete remission (CR). Among these 82 CR patients, 40 experienced recurrence of leukemia. The 5-year relapse free survival (RFS) rate and overall survival (OS) rates were 39.0% and 33.4%, respectively. In total, 56 patients underwent allogeneic HCT in first CR. The 5-year cumulative incidence of relapse and OS rate of them were 59.1% and 52.6%, respectively. Six of seven patients who were maintained on imatinib after completion of consolidation relapsed and the median time of RFS was 40.7 months. In total patient, cumulative molecular CR rate was 88.5% and median time of molecular CR duration was 13 months. Initial imatinib dose intensity was significantly associated with median CR duration (P

Relapsed or refractory acute myeloid leukemia (R/R AML) in elderly (≥60 yr old) patients were eligible. Induction chemotherapy consisted fludarabine and cytarabine (ARAC) as a 24-hr CI without idarubicin (C-FLAG), which was compared with the results of C-FLAG with idarubicin (CI-FLAG2) in younger patients' trial. A total of 33 and 68 patients were enrolled in C-FLAG and CI-FLAG2, respectively. CR, CRp, and CRi were achieved in 10 (30.3%), 3 (9.1%), and 2 (6.1%), respectively. When comparing outcomes between C-FLAG and CI-FLAG2, there were no difference in terms of CR rate (P = 0.572) and objective response rate (ORR; P = 0.899). Favorable predictors on ORR in C-FLAG were PB WBC ≤ 20K/uL at salvage (P = 0.024) and early evaluation peripheral BLAST = 0% (P = 0.013) on multivariate analysis. The overall survival of patients who achieve CR/CRp/CRi showed significantly prolonged survival compared with patients who did not in C-FLAG (P

BACKGROUND Patients receiving red blood cell (RBC) transfusions are at risk of iron overload, which can cause significant organ damage and is an important cause of morbidity and mortality. STUDY DESIGN AND METHODS This study was an open-label, single-arm, prospective clinical study to evaluate the efficacy and safety of deferasirox (DFX) in patients with aplastic anemia (AA), myelodysplastic syndrome (MDS), or acute myeloid leukemia (AML). Patients with serum ferritin levels of at least 1000 ng/mL and ongoing transfusion requirements were enrolled. DFX was administered for up to 1 year. A total of 100 patients were enrolled. RESULTS Serum ferritin levels decreased significantly following treatment (from 2000 to 1650 ng/mL, p = 0.004). The median absolute reduction in serum ferritin levels was −65 ng/mL in AA (p = 0.037), −647 ng/mL in lower-risk MDS (MDS-LR; p = 0.007), and −552 ng/mL in higher-risk MDS (MDS-HR)/AML (p = 0.482). Mean labile plasma iron (LPI) levels decreased from 0.24 μmol/L at baseline to 0.03 μmol/L at 1 year in all patients (p = 0.036). The mean LPI reduction in each group was −0.17 μmol/L in AA, −0.21 μmol/L in MDS-LR, and −0.30 μmol/L in MDS-HR/AML. Gastrointestinal disorders were commonly observed among groups (16.0%). DFX was temporarily skipped for adverse events in seven patients (7.0%) and was permanently discontinued in 11 patients (11.0%). CONCLUSION DFX reduced serum ferritin and LPI levels in patients with transfusional iron overload. Despite the relatively high percentage of gastrointestinal side effects, DFX was tolerable in all subgroups.

The National Comprehensive Cancer Network (NCCN)-International Prognostic Index (IPI) and GELTAMO (Grupo Espanol de Linfomas/Trasplante Autologo de Medula Osea)-IPI were developed to enable better risk prediction of patients with diffuse large B-cell lymphoma (DLBCL). The present study compared the effectiveness of risk prediction between IPI, NCCN-IPI, and GELTAMO-IPI in patients with DLBCL particularly in terms of determining high-risk patients. Among 439 patients who were enrolled to a prospective DLBCL cohort treated with R-CHOP immunochemotherapy, risk groups were classified according to the three IPIs and the prognostic significance of individual IPI factors and IPI models were analyzed and compared. All three IPI effectively separated the analyzed patients into four risk groups according to overall survival (OS). Estimated 5-year OS of patients classified as high-risk according to the IPI was 45.7%, suggesting that the IPI is limited in the selection of patients who are expected to have a poor outcome. In contrast, the 5-year OS of patients stratified as high-risk according to NCCN- and GELTAMO-IPI was 31.4% and 21.9%, respectively. The results indicate that NCCN- and GELTAMO-IPI are better than the IPI in predicting patients with poor prognosis, suggesting the superiority of enhanced, next-generation IPIs for DLBCL.

We previously assessed continuous infusion (CI) of fludarabine and cytarabine plus idarubicin (CI-FLAG1) for patients under 65 years of age with resistant acute myeloid leukemia. Induction chemotherapy consisted of idarubicin (IDA) plus fludarabine and cytarabine (ARAC) as a 24-hour CI. In response to induction, 31.6% of patients achieved complete remission (CR) and in 68.4% the treatment failed. We concluded that CI-FLAG1 carried a high risk of toxicity and reduced CI-FLAG doses were recommended. Therefore, we revised the protocol (CI-FLAG2) by reducing the dose of IDA and ARAC. In total, 38 and 68 patients were enrolled into CI-FLAG1 and CI-FLAG2, respectively. When comparing outcomes between CI-FLAG1 and CI-FLAG2, there were no differences in terms of the CR rate (p = 0.306) and the overall response rate (ORR; p = 0.206). The treatment failure patterns were different between CI-FLAG1 and CI-FLAG2. The median overall survival showed only a trend towards longer survival in CI-FLAG2 (p = 0.074). Among intermediate-risk patients, there were high response rates favoring CI-FLAG2 in terms of the CR rate (p = 0.108), the ORR (p = 0.031), and overall survival (p = 0.033). This represented a relatively improved response rate compared to our previous study. There was decreased aplasia with dose reductions at the expense of increased resistance. A reduced dose of CI-FLAG might be most beneficial for intermediate-risk groups.

This multicenter phase II clinical trial was designed to evaluate the efficacy and safety of weekly Genexol-PM® and gemcitabine combination chemotherapy in patients with unresectable or metastatic biliary tract cancer. Patients and methods Patients received 100 mg/m2 Genexol-PM® and 1,000 mg/m2 gemcitabine intravenously on days 1 and 8 every 21 days. Results Out of 39 patients, there were 10 partial responses (25.6%) and 18 with stable diseases (46.2%) were confirmed with median response duration 4.1 months. The median progression-free survival was 5.9±1.6 months and overall survival 11.9±1.4 months. The median number of cycles administered was 4.0 (range=1-10). Grade 3 or more neutropenia occurred in 12 patients (26.7%). The most common grade 3/4 non-hematological toxicities were febrile neutropenia (13.4%) and elevation of liver enzymes (6.7%). Conclusion Weekly Genexol-PM® combined with gemcitabine demonstrated sufficient antitumor activity to warrant further development when used as first-line chemotherapy for advanced biliary tract cancer.

B ackground The advent of new agents has contributed to the prolonged survival of multiple myeloma (MM) patients. From the Durie-Salmon staging system, international staging system (ISS) and recently, revised ISS (R-ISS) have been developed to better prognosticate the survival of MM. R-ISS includes chromosomal abnormalities (CA) detected by interphase fluorescent in situ hybridization (iFISH) and lactate dehydrogenase (LDH) in addition to the ISS. However, the R-ISS has still some limitations in the real clinical settings, as it has enrolled patients exclusively on clinical trials which includes more young patients (age < 65 years old), contains non-standardized iFISH results and has short median follow-up duration. The first-line drugs used in the patients could also affect the prognosis. Therefore, a more detailed and standardized but also convenient prognostic system is needed with clinical findings commonly observed in MM patients treated with new agents in the real clinical world. Patient and Method Adult patients who were confirmed multiple myeloma between January, 2011 to December, 2017 and patients who had received thalidomide and/or bortezomib or lenalidomide-based chemotherapy as a first-line treatment were included for the analysis. A total of 861 patients from 13 centers participating Korean multiple myeloma working party were analyzed. Baseline serum albumin, serum ß2-microglobulin, cytogenetics by iFISH, LDH (lactate dehydrogenase), ALC (absolute lymphocyte count), CRP (C-reactive protein) and ferritin were measured within 4 weeks before beginning the first line of chemotherapy. Each factors of age ≥ 65 years, serum ß2-microglobulin ≥ 5.5 mg/L, LDH > normal, cytogenetic high risk by FISH (del17p, t(4;14), t(14;16)), ALC < 1500/mm3, CRP ≥ 1.5 mg/dL, and ferritin ≥ 500 ng/mL were defined as abnormal findings, which were given 1 point (Table 1) and the sum of points were used to discriminate inflammatory factor-based staging system (IFBSS). IFBSS were defined as follows: Stage I (point 0), stage II (point 2-3), stage III (point 4-5), and stage IV (point 5-7). Overall survival (OS) was defined by the date of MM diagnosis to the date of death by any cause or follow-up loss. Results Baseline characteristics of the patients were as listed in Table 2. With a median follow-up duration of 22.70 months (range, 0.20-86.80 months), age ≥ 65 years, serum ß2-microglobulin ≥ 5.5 mg/L, LDH > normal, cytogenetic high risk by FISH (del17p, t(4;14), t(14;16)), ALC < 1500/mm3, CRP ≥ 1.5 mg/dL, and ferritin ≥ 500 ng/mL showed significant higher OS by univariate and multivariate analysis. Albumin < 3.5 mg/dL were excluded into the staging system due the unpredictability to OS in univariate analysis (Table 3). Study groups of inflammatory factor-based scoring system comprised of 61 patients in stage I, 395 patients in stage II, 189 patients in stage III and 36 patients in stage IV. The median OS were not reached in stage I and II, stage III and IV showed a median OS of 36.57 months (95%CI, 33.96-.39.18) and 17.60 months (95%CI, 9.16-.26.04). The OS according to the IFBSS showed significant differences (P < 0.001), which predicted OS better compared with conventional ISS and R-ISS (Table 4). Conclusion In the new agent era, inflammatory factors incorporated into the staging system can better discriminate prognosis of multiple myeloma patients compared to the ISS or R-ISS. Validation of this finding in a larger cohort is needed to expand usage of this new staging system. Disclosures Yoon: Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Kyowa Hako Kirin: Research Funding; Janssen: Consultancy; Yuhan Pharma: Research Funding; Genentech, Inc.: Research Funding; MSD: Consultancy.

Purpose We investigated the clinical outcome of bone marrow (BM) involvement in patients with diffuse large B-cell lymphoma (DLBCL) who received rituximab-based therapy. Materials and Methods A total of 567 consecutive patients with newly diagnosed DLBCL treated with rituximab-CHOP (RCHOP) between November 2001 and March 2010 were included in the current study. All of the patients underwent a BM study at the initial staging and the clinical characteristics and prognosis of these patients with or without BM involvement were analyzed retrospectively. Results The total cohort included 567 patients. The overall incidence of BM involvement was 8.5%. With a median follow-up duration of 33.2 months (range, 0.1 to 80.7 months) for patients who were alive at the last follow-up, the five-year overall survival (OS) and event-free survival (EFS) rate in patients without BM involvement (76.3% and 67.5%, p

The clinical outcomes of acute promyelocytic leukemia (APL) have improved greatly, but treatment failure still occurs. Identification of patients with poor prognosis is fundamental, and we propose a new clinical prognostic system (CBC-score) consisting of WBC, platelet count, and hemoglobin level. Between 1995 and 2009, 156 patients with APL from seven institutes in Korea were retrospectively reviewed. In the new CBC-score system, each of the following (WBC ≥10 × 109/L, platelet

Central nervous system involvement remains a challenging issue in the treatment of patients with diffuse large B-cell lymphoma. We conducted a prospective cohort study with newly diagnosed diffuse large B-cell lymphoma patients receiving rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone to identify incidence and risk factors for central nervous system involvement. Among 595 patients, 279 patients received pre-treatment central nervous system evaluation, and 14 patients had central nervous system involvement at diagnosis (2.3% out of entire patients and 5.0% out of the 279 patients). For those patients, median follow-up duration was 38.2 months and some of them achieved long-term survival. Out of 581 patients who did not have central nervous system involvement at diagnosis, 26 patients underwent secondary central nervous system relapse with a median follow-up of 35 months, and the median time to central nervous system involvement was 10.4 months (range: 3.4-29.2). Serum lactate dehydrogenase > ×3 upper limit of normal range, the Eastern Cooperative Oncology Group performance status ≥ 2, and involvement of sinonasal tract or testis, were independent risk factors for central nervous system relapse in multivariate analysis. Our study suggests that enhanced stratification of serum lactate dehydrogenase according to the National Comprehensive Cancer Network-International Prognostic Index may contribute to better prediction for central nervous system relapse in patients with diffuse large B-cell lymphoma. This trial was registered at clinicaltrials.gov identifier: 01202448.

Background To investigate the efficacy, safety, and tolerability of weekly docetaxel treatment in advanced non-small cell lung cancer (NSCLC) patients in Korea. Methods This prospective observational study included Korean advanced NSCLC patients with Eastern Cooperative Oncology Group performance status

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

Objective: To evaluate the effectiveness of OROS® hydromorphone in reducing breakthrough pain (BTP) medication frequency in Korean patients with chronic cancer pain. Settings and Design: Multicenter, prospective, open-label, phase IV study. Participants: Patients with chronic malignant pain using immediate-release oxycodone more than two times per day for BTP. Interventions: Patients were stabilized on their ongoing drug for 3 days immediately before baseline measurements (day 0). Medication was changed to OROS® hydromorphone at a dose equianalgesic to oxycodone using a 2.5:1 controlledrelease oxycodone to hydromorphone hydrochloride conversion ratio; the patients were observed for 7 days. Dose was titrated, if required, and the patients were observed for another 7 days. Effectiveness and safety parameters were measured at baseline, day 7, and day 14. Main Outcomes: BTP medication frequency on days 7 and 14, compared to baseline. Results: Of the 141 patients screened, 114 received study drug and 98 completed the study. Compared to day 0, daily BTP medication frequency on day 14 decreased from 2.93 to 2.00 (p < 0.0001), daily BTP frequency decreased from 3.67 to 2.44 (p < 0.0001), and end-of-dose pain frequency decreased by 44 percent. Pain was controlled adequately during daytime and night-time. Pain intensity decreased by 11 percent as assessed using the Korean Brief Pain Inventory and by 17 percent as assessed using the numerical rating scale. About 61.2 percent patients and 60.2 percent physicians were satisfied with the treatment. Common adverse events, which occurred in 91.2 percent patients, were constipation, somnolence, and dizziness. Conclusion: Once-daily OROS® hydromorphone is efficient in the reduction of cancer pain-related BTP episodes, including end-of-dose pain.

One of the members of the tyrosine kinase receptor family is the protein product of the c-met proto-oncogene, which is the receptor for hepatocyte growth factor (HGF). HGF is known as a potent mitogen and motogen for many kinds of carcinoma cells, and has been found to simulate the growth and progression of gastric cancer cells through HGF-receptors. In addition, the urokinase-type plasminogen activator (uPA) and receptor (uPAR) also play important roles in the invasion and metastasis.The expression of c-met protein was investigated using immunohistochemical staining of 50 paraffin embedded gastric cancers, and by measuring the serum uPAR levels, before and after an operation, in gastric cancer patients using an ELISA assay.Of the 50 cases, 32 (64%) expressed the c-met protein. The c-met protein expression was significantly correlated with the TNM staging (p0.05), but the other prognostic factors were not significant variables. According to a Kaplan-Meier's plot, the one and three year overall survival rates were 94 and 70% in patients not expressing the c-met protein, and 81 and 33% in those that did, and the Survival curves revealed a significantly different prognosis (p=0.04). Elevated serum uPAR levels (or=3257.8 pg/ml, control+/-mean 2SD) were observed in 9 (34.6%) of 26 gastric cancer patients, but in none of control subjects. Average serum uPAR levels were 2980.8+/-616.2 pg/ml before the operation and 2404.7+/-455.9 pg/ml after, and decreased significantly after surgical resection (p0.05). The serum uPAR level correlated significantly with lymph node metastasis and vessel invasion (p0.05).The expression of c-met protein, and the level of uPAR, may be prognostic factors in gastric cancer.

We conducted a phase 3 randomized trial comparing 2 different doses of daunorubicin as induction chemotherapy in young adults (60 years of age or younger) with acute myeloid leukemia (AML). Of 383 patients who were analyzed, 189 received standard-dose daunorubicin (SD-DN, 45 mg/m2 per day times 3 days) and 194 received high-dose daunorubicin (HD-DN, 90 mg/m2 per day times 3 days) in addition to cytarabine (200 mg/m2 per day times 7 days) to induce complete remission (CR). The CR rates were 72.0% in the SD-DN arm and 82.5% in the HD-DN arm (P = .014). At a median follow-up of 52.6 months, overall (OS) and event-free (EFS) survival were higher in the HD-DN arm than in the SD-DN arm (OS, 46.8% vs 34.6%, P = .030; EFS, 40.8% vs 28.4%, P = .030). Differences in CR rate and both OS and EFS remained significant after adjusting for other variables (CR, hazard ratio [HR], 1.802, P = .024; OS, HR, 0.739, P = .032; EFS, HR, 0.774, P = .048). The survival benefits of HD-DN therapy were evident principally in patients with intermediate-risk cytogenetic features. The toxicity profiles were similar in the 2 arms. In conclusion, HD-DN improved both the CR rate and survival duration compared with SD-DN in young adults with AML. This study is registered at www.clinicaltrials.gov as #NCT00474006.

Introduction Diffuse large B cell lymphoma (DLBCL) of primary nodal (PN) or primary extranodal (PEN) origin may differ immunophenotypically, in that PEN lymphoma cells may originate from activated rather than germinal center B (GCB) cells. We evaluated the relationship between DLBCL clinicopathological features, including expression of B-cell differentiation markers, and primary tumor site. Patients and Methods Expression of CD10, Bcl-6, Bcl-2, and MUM1 was determined in paraffin-embedded tissues from 123 patients with DLBCL. Results Of the 123 patients with DLBCL, 40 (32.5%) had the GCB and 83 (67.5%) had the non-GCB phenotype. Fifty-one patients (42%) showed disease involvement at PEN sites, including 29 with disease in the gastrointestinal (GI) tract (14 in the stomach, 15 in the intestine). Of these 51 patients, 16 (31.4%) were classified with the GCB and 35 (68.5%) with the non-GCB subtype. There were no differences in the frequencies of GCB and non-GCB subtypes among primary sites. Of the 72 patients with PN DLBCL, 22 (31%) had the GCB and 50 (69%) had the non-GCB subtype. There were no differences in the frequencies of GCB and non-GCB subtypes between patients with PN and PEN DLBCL. Although lactate dehydrogenase (LDH) concentration > normal, stage >II, and rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP) treatment were independent predictors of overall survival (OS), GCB subtype, and presence of PEN disease failed to predict survival upon multivariate analysis. Conclusion There was no difference in GCB and non-GCB phenotypes between patients with PN and PEN DLBCLs. Additional studies are needed to further assess molecular differences between the two groups.

Upfront allogeneic hematopoietic cell transplantation (alloHCT) as first line therapy for older than 40 or 50 years is not usually recommended for severe aplastic anemia patients even though there are suitable matched sibling donors because they usually have poor outcomes after alloHCT. Therefore, first line immune suppression therapy (IST) is recommended. However, current outstanding alloHCT outcome can make it possible to try upfront alloHCT even in older AA patients. The purpose of this retrospective study is to determine the transplantation-related results in AA patients older than 40 years. This study collected data retrospectively for older AA patients. Congenital bone marrow failure was excluded from this study. alloHCT was divided as upfront and second alloHCT according to prior IST. Total 129 patients were enrolled in this study from 2001 to 2017. Age at diagnosis and at alloHCT were 25 to 63 (median 48.0) years and 40.3-64.9 (median 49.1) years, respectively. Median time from diagnosis to alloHCT was 5.2 (range, 1-234.1) months. Upfront and second alloHCT were 42 and 87 patients, respectively. Upfront alloHCT received more stem cells from related donors, more BM stem cells and more fludarabine conditioning compared with second alloHCT (83.3% vs. 58.6%, p=0.005; 52.4% vs. 74.7%, p=0.011; 52.4% vs. 30.2%, p=0.015, respectively). However, ABO mismatching (p=0.747), TBI conditioning (p=0.547), cyclophosphamide conditioning (p=0.114), ATG conditioning (p=0.483) were similar between upfront and second alloHCT. Any engraftment failure, neutrophil engraftment failure and platelet engraftment failure were similar between upfront and second alloHCT (28.6% vs. 28.7%, p=0.985; 19.0% vs. 18.4%, p=0.928; 19.0% vs. 34.5%, p=0.072). Hepatic SOS, acute GvHD and chronic GvHD were also similar between upfront and second alloHCT (4.8% vs. 5.7%, p=0.817; 28.6% vs. 36.5%, p=0.376; 19.0% vs. 19.5%, p=0.947). Survival rates at 1Y, 2Y, 3Y and 5Y were 90.7, 82.2, 73.5 and 64.3%, respectively. Survival rates at 5 years in upfront and second alloHCT were 76.2 and 54.1%, respectively (p=0.059). Survival rates at 5 years (5YSR) in age 40-50y, 50-60y, and older than 60y were 64.1, 62.4 and 50.0%, respectively (p=0.349). alloHCT from matched related donor or other donors had similar survival rates (p=0.404). However, upfront alloHCT showed superior survival rate (5YSR 76.5% vs. 53.2%, p=0.114) without statistical significance compared with second alloHCT even in matched related donor subgroup. This trend is similar in alternative donor subgroup (5YSR 75.0% in upfront alloHCT vs. 54.9% in second alloHCT, p=0.459). alloHCT in older AA showed promising results even in patient older than 60 years although upfront alloHCT showed marginal statistical superiority. In conclusion, upfront alloHCT in older AA needs further confirmation by prospective studies. Disclosures No relevant conflicts of interest to declare.

Introduction Four cycles of bortezomib/thalidomide/dexamethasone (VTD) induction therapy followed by autologous stem cell transplantation (ASCT) is one of the standard therapy for patients aged less than 65 years with newly diagnosed multiple myeloma (NDMM). Complete remission (CR) status before ASCT is an important prognostic factor for progression-free survival (PFS). We analyzed whether two additional cycles of VTD improved the pre- and post-transplant responses as well as PFS compared to the four cycles of VTD induction therapy. Methods A total of 222 patients with NDMM between September 2014 and August 2016 from eleven hospitals in South Korea were included in the current study. The patients received at least four or more cycles of VTD induction therapy before administration of high-dose therapy (HDT, melphalan 200mg/m2) followed by ASCT. VTD regimen was consisted of bortezomib subcutaneous infusion (1.3 mg/m2 on days 1, 4, 8, and 11), thalidomide (100 mg daily), and dexamethasone (40 mg on days 1-4, 8-11), which was administered every 4 weeks. Results The median age was 57 years (range 30−64 years), and 120 patients (61.9%) were male. Revised international scoring system (R-ISS) classified 59 (30.4%), 86 (44.3%), and 49 patients (25.3%) as stage I, II, and III, respectively. VTD induction was administered 4 cycles in 194 patients (VTD4, 67.5%) and more than 4 cycles in 63 (VTD6, 32.5%) before HDT. Patient characteristics at diagnosis did not differ between VTD4 and VTD6. CR rate before HDT was significantly higher in VTD6 than VTD4 (31.7% vs 13.0%, P = 0.003). However, CR rate after HDT/ASCT was similar between VTD4 and VTD6 (69.0% vs 65.5%, P = 0.726). There was no difference in the incidence of peripheral neuropathy (PN) (≥ grade 2 or that required dose reduction) between two groups. The median follow-up duration was 18.0 months (range 7.0-43.8 months). The 2-year PFS did not differ between the two groups (51.7 ±5.7% in VTD4 and 62.1±8.6% in VTD6, P = 0.240). Multivariate analysis revealed that the achievement of CR was a favorable prognostic factor for PFS (HR 0.27 [0.08−0.90], P = 0.034). Deletion 17p (HR 2.87 [1.01−7.92], P = 0.048) and t(4;14) (HR 3.38 [1.76−6.48], P < 0.001) in FISH were adverse prognostic factors for PFS. Patients with stage I/II by R-ISS receiving additional two cycles of VTD showed prolonged PFS (median PFS not reached vs. 27.6 months, P = 0.034). In the multivariate analysis, VTD6 was a favorable prognostic factor for PFS for patients with stage I/II by R-ISS, (HR 0.11 [0.02−0.52], P = 0.005). Conclusion CR rates increased with additional cycles of VTD induction therapy for NDMM. However, the PFS benefit was observed only in patients with R-ISS stage I/II. For patients with high-risk MM, intensive induction therapy that overcome poor prognostic factors should be administered to improve long-term outcomes. Figure. Figure. Disclosures No relevant conflicts of interest to declare.

The present study was conducted to evaluate the efficacy and safety of a combination regimen of S-1, paclitaxel plus cisplatin in patients with advanced gastric cancer.Patients with previously untreated metastatic or recurrent, measurable gastric cancer received intravenous paclitaxel 80 mg/m² plus cisplatin 30 mg/m² on days 1, 8 and S-1 35 mg/m² orally twice daily on days 1-14 based on a 3-week cycle.Forty-four patients were enrolled in the current study, among whom 38 were assessable for efficacy and all assessable for toxicity. Two complete response and 24 partial responses were confirmed, giving an overall response rate of 59.1%. At a median follow-up of 11.4 months, the median time to progression and median overall survival was 9.4 (95% CI 6.8-12.1) months and 11.2 (95% CI 7.6-14.8) months, respectively. Grade 3/4 neutropenia occurred in 45 events (20.9%) and febrile neutropenia was observed in five events (2.3%). The common non-hematologic toxicity was nausea (grade 1/2, 27.2%) and diarrhea (grade 1/2, 9.0%).The combination of S-1, paclitaxel and cisplatin was found to be well tolerated and effective in patients with advanced gastric cancer.

The present study analyzed the polymorphisms of DNA repair genes and their impact on the response to chemotherapy and survival of patients with colorectal cancer.A total of 94 patients with recurrent or metastatic colorectal cancer treated with oxaliplatin-based combination chemotherapy were enrolled in the present study. The single nucleotide polymorphisms of 16 DNA repair genes were determined using a PCR-RFLP assay.During the median follow-up duration of 15.9 (2.1-53.0) months, 67 (71.3%) progressions and 29 (30.9%) deaths were observed. Among the 60 patients assessable for response, response to the oxaliplatin-based regimens was found in 27 (45%) patients (9 CR and 18 PR). In a logistic regression analysis adjusted to age, sex, primary site, disease status, and regimen, the POLR2C rs4937 and MSH2 rs3732183 polymorphisms were statistically associated with the response to the oxaliplatin-based chemotherapy. A multivariate survival analysis showed that the TT genotype of the MGMT (rs1625649) -535GT polymorphism was found to correlate with a worse progression-free survival (PFS) than the combined GG + GT genotypes (HR = 3.137; 95% CI = 1.423-6.914; P = 0.005), which was also observed among the 60 evaluable patients (HR = 2.653; 95% CI = 1.101-6.392; P = 0.030) For the clinical parameters, curative resection was the most significant prognostic factor in a Cox model for PFS and overall survival (HR = 0.229 and 0.205; P0.001 and 0.001, respectively).The MGMT -535GT polymorphism (rs1625649) was found to be correlated with PFS in patients with advanced colorectal cancer treated with oxaliplatin-based chemotherapy.

Objective This prospective multicenter study conducted by the Korean Cancer Study Group evaluated the efficacy and safety of pemetrexed in Korean patients with advanced non-small cell lung cancer (NSCLC) who had prior chemotherapy. Patients and methods: Patients with stage IIIB or IV NSCLC in whom prior chemotherapy failed received pemetrexed 500mg/m 2 every 3 weeks with folic acid and vitamin B12 supplementation until disease progression or the development of intolerable toxicity. Eighty-one patients were enrolled. Results The overall response rate for 78 evaluable patients was 5.1% [95% confidence interval (CI) 1.4–12.6; partial response 4/78, no complete response]. The disease control rate including complete, partial response and stable disease was 46.2% (36/78, 95% CI 34.8–57.8). With a median 8.7 months follow-up, the median time to progression was 3.1 months (95% CI 1.17–5.03) and the median overall survival (OS) was 7.8 months (95% CI 5.19–10.35). The median OS for patients with adenocarcinoma histology was 18.7 months compared to 6.1 months for non-adenocarcinoma. In a multivariate analysis, Eastern Cooperative Oncology Group performance status 0–1 [hazards ratio (HR)=0.331, 95% CI 0.135–0.814] and adenocarcinoma (HR=0.504, 95% CI 0.283–0.899) were independent factors for prolongation of overall survival.Conclusions Pemetrexed monotherapy has promising efficacy in patients with advanced NSCLC as a second-line therapy with less hematologic and non-hematologic toxicity, especially in those with adenocarcinoma histology.

The objective of this study was to evaluate the efficacy and toxicity of docetaxel and cisplatin combination chemotherapy in patients with metastatic esophageal cancer.Patients with untreated metastatic squamous cell esophageal cancer, which was histologically proven with at least one measurable lesion, were eligible for the study. Docetaxel 70 mg/m(2) and cisplatin 70 mg/m(2) were intravenously given on day 1 of 21 days schedule.From December 2004 to December 2007, total of 39 patients (M/F = 39/0) were enrolled. The median age was 65 years. Thirty-four patients were evaluable for response. There were 3 (7.7%) complete remission, 10 (25.6%) partial remission, 11 (28.2%) stable disease, and 10 (25.6%) progression disease. The objective tumor response rate was 33.3% in intention-to-treat (ITT). Median PFS was 5.0 months and median survival was 8.3 months. Median number of cycles administered was 3. The relative dose intensity of docetaxel and cisplatin was 92 and 91%, respectively. This treatment was comparatively tolerated with grade 3/4 neutropenia in 20.5%/10.3%, grade 3 infection in 2.6% of patients.Docetaxel plus cisplatin combination chemotherapy showed promising antitumor activity with manageable toxicities in patients with metastatic squamous esophageal cancer.

SummaryEvaluation of the Janus kinase 2 (JAK2) V617F mutation has been widely used for the diagnosis of myeloproliferative neoplasms (MPN). However, its prognostic relevance to clinical outcome is not completely understood. We investigated the association of JAK2 V617F with vascular events in Korean patients with myeloproliferative neoplasms (MPN). We studied 283 patients from 15 centers, who were diagnosed with MPN. The JAK2 V617F status was evaluated by allele-specific polymerase chain reaction (PCR) and sequencing. The patients’ diagnoses were essential thrombocythemia (ET n=146), polycythemia vera (PV n=120), primary myelofibrosis (n=12), and unclassifiable MPN (MPNu n=5). JAK2 V617F was detected in 89 (61%) patients with ET, 103 (86%) with PV, four (33%) with myelofibrosis, and four (80%) with MPNu. A higher number of leukocytes, haemoglobin levels and BM cellularity as well as an older age, lower platelet counts, and diagnosis of PV were significantly correlated with JAK2 V617F. Eighty-three and 43 episodes of thrombosis and bleeding occurred in 100 patients each before and after the diagnosis. Vascular events more frequently occurred in 37% of patients with JAK2 V617F than in 29% of those without the mutation (p=0.045). Among 175 patients whose samples were available for sequencing, 28 patients with homozygous JAK2 V617F had vascular events more frequently (57%) than those who were heterozygotes (39%) or had the wild type (27%) (p=0.03). The multivariate analysis showed that a JAK2 homozygous mutation, hypercholesterolemia and older age were independent risk factors for a vascular event. The results of this study showed that Korean patients with MPN had a similar JAK2 mutation rate and frequency of vascular events when compared to Western patients. The presence of V617F was significantly related to vascular events. Therefore, initial evaluation for the JAK2 mutation and careful monitoring for vascular events should be performed in MPN patients.

The present study was conducted to evaluate the efficacy and safety of a combination regimen of docetaxel plus oxaliplatin in patients with advanced gastric cancer. Patients with previously untreated metastatic or recurrent, measurable gastric cancer received intravenous docetaxel 65 mg m(-2) plus oxaliplatin 120 mg m(-2) on day 1 based on a 3-week cycle. Forty-two patients were enrolled in the current study, among whom 39 were assessable for efficacy and all assessable for toxicity. One complete response and 18 partial responses were confirmed, giving an overall response rate of 45.2% (95% confidence interval (CI); 31.7-59.7%). At a median follow-up of 7.7 months, the median time to progression and median overall survival was 5.7 (95% CI; 4.3-7.2) months and 9.9 (95% CI; 7.8-12.0) months, respectively. Grade 3/4 neutropenia occurred in 11 patients (26.1%) and febrile neutropenia was observed in four patients (9.5%). The common non-haematologic toxicity was fatigue (grade 1/2, 61.9%) and nausea (grade 1/2, 47.7%). The combination of docetaxel and oxaliplatin was found to be well tolerated and effective in patients with advanced gastric cancer.

Primary retroperitoneal mucinous cystadenocarcinoma is a rare tumor. Only about 30 such cases have been reported in the worldwide literature, and a few Korean cases have been reported. The pathogenesis is not clear, and coelomic metaplasia of the retroperitoneal mesothelium has gained wide support. There is no consensus on the appropriate treatment, but surgical exploration is needed for the diagnosis and treatment, and adjuvant chemotherapy may be recommended following complete surgical excision. The long-term prognosis has not been established. We report here on a 32-year-old woman who was diagnosed as having a retroperitoneal mucinous cystadenocarcinoma with mural nodules of sarcomatoid change. Tumor excision and adjuvant chemotherapy were done and the patient is doing well without any evidence of recurrence at 42 months postoperatively.

The objective of this study was to review the natural history of extrapulmonary small cell carcinoma (EPSCC) with specific emphasis on clinical features, response to treatment and survival. The records of all patients (n=34) with EPSCC treated at Yeungnam University Medical Center and Catholic University of Daegu Medical Center between 1998 and 2005 were retrieved and reviewed. The primary sites of tumor were the esophagus and thymus in 6 patients (17.6%) each, pancreas and stomach in 5 patients each (14.7%); other sites included were the cervix, abdominal lymph nodes, abdominal wall, bladder, colon, maxillary sinus, nasal cavity, ovary, parotid gland and liver. Twenty three patients out of 34 had limited disease. The median survival of all patients was 14 months. Independent prognostic factors included stage and primary tumor location. The prognosis for the patients with extensive disease and in the gastrointestinal group was unfavorable. EPSCC is a non homogeneous disease entity. As a result of its frequent recurrence, multimodal therapy has a better outcome even in cases of limited disease. Combination chemotherapy plays a central role for treatment of extensive disease in EPSCC. Further multicenter studies are now needed to determine more details regarding disease sub-class and optimal treatment modality.