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Background Bortezomib has significantly advanced the treatment of patients with multiple myeloma (MM). However, considering that most patients with MM are elderly, bortezomib-related morbidity should be thoroughly studied to ensure the safe use of this drug. Herpes zoster has been reported as a possible adverse event associated with bortezomib because a major target of bortezomib, nuclear factor—κB, is known to be involved with T-cell immunity. Patients and Methods We performed a retrospective analysis of the incidence of herpes zoster among 282 patients treated with a bortezomib-containing regimen. Results During the patients' pre-bortezomib treatment (median, 2.14 years), the incidence of herpes zoster was 11% (31 of 282 patients). However, after the patients were treated with bortezomib, the incidence increased to 22.3% (63 of 282 patients), of which almost all occurrences were within the first 3 cycles (median duration, 41 days). The time interval from diagnosis to bortezomib initiation date was shorter in herpes zoster—positive patients than in herpes zoster—negative patients (2.14 ± 1.87 years vs. 3.38 ± 2.95 years; P = .002). Disease duration, previous herpes zoster infection, disease stage and type of myeloma, and the type and intensity of previous treatments failed to show any relationship with herpes zoster. These findings suggest that longer history of disease and treatments did not affect the occurrence of herpes zoster, nor did the type of bortezomib regimens or their toxicities. Conclusion Bortezomib can increase the incidence of herpes zoster regardless of disease duration, previous treatments, and concomitantly administered drugs. Thus, the occurrence of herpes zoster should be monitored during bortezomib treatment.

The standard beneficial chemotherapy proven for patients with advanced pancreatic cancer is a regimen containing gemcitabine. In the pregemcitabine era, 5-fluorouracil (5-FU) was the standard agent. Oral 5-FU can be added to gemcitabine to improve the efficacy of chemotherapy and to provide better patient convenience. The possibility to improve efficacy of gemcitabine by fixed dose rate infusion (FDRI) was proposed in addition to combining it with 5-FU. We tried a new chemotherapy combining FDRI of gemcitabine with doxifluridine and leucovorin. Eligibility criteria were pathologically proven, chemotherapy-naïve, and metastatic or nonoperable advanced pancreatic cancer. Gemcitabine 1,000 mg/m2 was infused over 100 min (days 1, 8 and 15). Doxifluridine 200 mg/m2 t.i.d. and leucovorin 15 mg b.i.d. were given orally (days 1–21). Chemotherapy was repeated every 28 days until a patient had received 6 cycles or progression was found. Twenty-nine patients were enrolled from October 2002 to December 2004. A total of 78 cycles were given at a mean of 2.7 cycles per patient. Response could be evaluated in 26 patients. Responses were partial remission in 4/26 patients (15.4%), stable disease in 8/26 (30.8%) and progression in 14/26 (53.8%). All patients progressed except for 2 in partial remission and 2 in stable disease. Toxicities could be assessed in 23 patients. Maximal hematological toxicities greater than grade 2 were leucopenia in 3 patients (11.5%), neutropenia in 2 (7.7%), anemia in 2 (7.7%), thrombocytopenia in 1 (3.8%) and febrile neutropenia in 3 (11.5%). Maximal nonhematological grade 3 or 4 toxicities were asthenia in 1 patient (3.8%), anorexia in 1 (3.8%), vomiting in 1 (3.8%), diarrhea in 2 (7.7%), allergic reaction in 1 (3.8%), hand-foot syndrome in 1 (3.8%) and hyperbilirubinemia in 1 (3.8%). All 29 patients were dead on last follow-up. Median progression-free survival was 3.91 months in 26 evaluable patients and median overall survival was 5.59 months in all patients. Combination chemotherapy including FDRI of gemcitabine seems minimally active for patients with advanced, nonoperable pancreatic cancer. Further research to improve effectiveness of chemotherapy for advanced pancreatic cancer is mandatory.

The benefits of intensive post-remission chemotherapy have not been verified in elderly patients with acute myeloid leukemia (AML). To reduce fatal complications caused by intensive post-remission therapy, we performed a prospective phase II multicenter trial of standard induction chemotherapy (‘7+3’ of cytarabine plus daunorubicin), followed by two cycles of attenuated consolidation therapy (‘5+1’ of cytarabine plus daunorubicin) for elderly patients with AML, excluding those with M3. Of the 41 patients enrolled in the study, 24 (58.5%) attained CR. Of these 24, 17 (70.8%) completed both planned cycles of consolidation therapy. After a median follow-up of 566 days (range, 63–1190 days) among surviving patients, 15 relapsed, with an actuarial 3-year disease-free survival rate of 22.5%. There were no fatal complications during consolidation therapy. Actuarial 3-year overall survival was 17.0%. These findings suggest that, when compared with previous findings using more intensive consolidation therapy, attenuated consolidation therapy does not compromise outcomes in elderly AML patients.

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

INTRODUCTION Patients receiving red blood cell (RBC) transfusions are at risk of iron overload. Humans do not have a physiologic mechanism to excrete excess iron, and total body iron is regulated primarily by the rate of absorption. Transfusion induced Iron overload can cause significant organ damage and is an important cause of morbidity and mortality. METHODS This study was an open-label, single-arm, prospective, phase 4, multicenter clinical study to evaluate the efficacy and safety of deferasirox (DFX) in patients with aplastic anemia (AA), myelodysplastic syndrome (MDS), or hematologic malignancy (HM). Eligibility criteria were serum ferritin (SF) levels ≥1000 ng/mL and ongoing transfusion requirements. For evaluation of the iron overload, SF and transferrin saturation (TFST) were measured every 4 weeks, and labile plasma iron (LPI) levels were regularly followed once every 6 months. Patients received DFX at an initial dose of 20 mg/kg/day for up to 1 year. RESULTS A total of 109 patients were enrolled. SF levels decreased significantly following treatment (from 2000 to 1650 ng/mL, p=0.003). The median absolute reduction in SF levels was -389 ng/mL (range -5428 to 3788) in AA (p=0.029), -567 ng/mL (range -3040 to 4969) in MDS (p=0.136), and -552 ng/mL (range -2899 to 5451) in HM (p=0.057). Median TFST reduction was -14.9% (range -69.4 to 71.0) in all patients (n = 65, p = 0.064). In the MDS and HM groups, TFST decreased significantly from baseline: -14.9% (range -57.4 to 52.2) in the MDS group (p = 0.040) and -16.3% (range -69.2 to 20.8) in the HM group (p = 0.005), while TFST reduction in the AA group was -7.4% (range -58.3 to 71.0) (p = 0.790). Baseline LPI levels were within normal laboratory ranges in all groups. Mean LPI levels decreased from 0.24 μmol/L at baseline to 0.03 μmol/L at 1 year in all patients (p=0.035). The mean LPI reduction in each group was -0.23±0.41 μmol/L (p=0.220) in AA, -0.26±0.51 μmol/L (p=0.110) in MDS, and -0.19±0.70 μmol/L (p=0.336) in HM. All of the AEs related with DFX were grade 1 or 2, and there were no severe AEs (grade ≥3) reported during the study period. Gastrointestinal disorders were commonly observed among groups (n=32, 29.4%), including diarrhea in 8.3%, nausea in 7.4%, and abdominal discomfort in 5.5% of patients. Overall differences in end organ function, including heart, pancreas, thyroid, and gonad, between baseline and 1-year follow up were not statistically significant. No significant differences in LVEF at 1-year after DFX treatment were seen (p = 0.103). Pancreatic dysfunction measured by FBS (p = 0.480) and C-peptide (p = 0.096) levels did not appear to be affected by iron overload during DFX treatment. The results of thyroid function tests (TFT) were not significantly different between the pre- and post-treatment periods in terms of TSH (p = 0.207), free T3 (p = 0.259), or free T4 (p = 0.654) levels. Gonadal dysfunction was not observed during the DFX treatment. DISCUSSION ICT may be an appropriate option for patients with HM or higher risk MDS. In the current study, DFX successfully reduced serum ferritin and LPI levels in HM from baseline to 1 year of treatment. The roles of ICT or DFX during treatment for HM on infection risk and survival benefits need to be elucidated in prospective studies. In 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 patients. Disclosures No relevant conflicts of interest to declare.

Background; Accelerated phase of chronic myeloid leukemia (AP-CML) is not clearly defined yet. There are different definitions to classify AP. In European Leukemia Net (ELN) 2013 recommendation, considerable therapeutic approach of de novo AP would be hematopoietic stem cell transplantation (HSCT) followed by frontline tyrosine kinase inhibitor (TKI). To explore long-term efficacy of frontline imatinib (IM) treatment and early predictors of long-term outcome, we analyzed a total of 73 patients who received frontline IM.. Method; AP defined as a definition of ELN recommendation.. A progression to blastic phase and loss of response were considered as progression. Patients who had received HCT were censored at the time of HCT when calculating overall survival (OS) and progression-free survival (PFS). Results; Of 83 patients who diagnosed as AP, 73 patients received IM and other 10 patients had HSCT (n=7) or no treatment (n=3). Of 73 IM-treated patients, 36 patients maintained IM therapy and 37 patients discontinued IM with switch to 2G TKI (n=23) or HSCT (n=14). Analysis of baseline characteristics revealed prior cytogenetic response (CyR), and molecular response at 6 and 12 months for prediction of survivals. Clinical factors for better survival including Sokal score (p=0.203), Hasford sore (p=0.832), peripheral blood (PB) basophil count (p=0.374), spleen size (p=0.656), bone marrow (BM) promelocyte (p=0.839), BM basophil (p=0.478 were not significant. PB blast5% (p=0.031), platelet count >20x109/L (p=0.008), PB promyelocyte20x109/L at diagnosis (p=0.002), achieving CCyR (p=0.007) and MR2.0 at 12M (p=0.048) were significant prognostic factors in multivariate analysis. Probability of 10Y OS for patients who acheived CCyR vs. no CCyR were 85.2% vs. 0% (p Conclusion: Achievement of CCyR or achievement of MR1.0 at 12M was important goals not only in progression but also in survival. Therefore if a patient doesnÕt achieve the goals, the treatments need to be changed. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

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

Introduction: The effect of imatinib plus combination chemotherapy were assessed in 87 patients, aged 16-71 years, with newly diagnosed Philadelphia Chromosome-Positive (Ph+) acute lymphoblastic leukemia (ALL). Methods: Imatinib (600 mg/day orally) was administered continuously with combination chemotherapy, starting from eighth day of remission induction treatment, then through 5 courses of consolidation or until allogeneic hematopoietic cell transplantation (HCT). Patients who were not transplanted were maintained on imatinib for 2 years. Molecular response monitoring was performed at the central lab (Asan Medical Center) with quantitative RT-PCR assays for peripheral blood or bone marrow BCR-ABL RNA in serial; at the time of diagnosis, at hematologic complete remission (HCR), and every 3 months thereafter. The molecular response was defined as complete (MCR) if the BCR-ABL/G6PDH ratio was less than 1x10-5. Results: Between October 2005 and February 2009, total 89 patients with newly diagnosed Ph+ALL were enrolled. With median follow-up of 5 years among survivors (range: 2.6-8.9 years) and data were frozen up in July, 2014. Two patients were not assessed, one due to a final diagnosis of CML blastic phase and one for refusal of the protocol treatment 4 months after enrollment. Eighty-two patients (94%) achieved HCR at a median 25 days (range, 14-69 days). Among these 82 HCR patients, 40 experienced recurrence of leukemia and 5-year relapse free survival (RFS) rate was 36.8%. Median time of RFS was 33 months (95% CI 20-46 months). In all, 24 patients died without leukemia progression or recurrence. Causes of treatment related morality were infection (n=5), bleeding (n=2), and HCT related complication (n=17). The 5-year overall survival (OS) rate was 33.4% and the median time of OS was 22.9 months (95% CI, 7.95-37.97 months). In total, 56 patients (68%) underwent allogeneic HCT in first HCR and had received a median 2 courses (range, 0-5 courses) of consolidation prior to HCT. At a median follow-up of 5-years (range, 2.1-8.4 years) after HCT, 23 patients experienced leukemia recurrence (cumulative incidence, 59.1%; 95% CI, 49.7%-68.5%). Of these 23 patients, 17 showed new molecular evidence of disease recurrence before hematologic relapse. Six patients, however, experienced hematologic recurrence without preceding molecular evidence of leukemia recurrence. The 5-year OS rate of patient underwent allogeneic HCT at first HCR was 52.6% and the median time of OS was 72.0 months (95% CI, 17.49-126.50 months). In the patients who completed the five cycles of consolidation, 7 patients were maintained on imatinib. Among these 7 patients, four patients finished 2-year imatinib maintenance. At median follow-up of 4 years (range, 1.9-7.4 years) after maintenance, 6 patients relapsed. The median time of RFS of patient who received maintain therapy was 40.7 months (95% CI, 24.38-57.19 months). One patient with relapse received HCT at second HCR after salvage therapy and two patients died with leukemia recurrence. Cumulative MCR rate was 88.5%, and median time to MCR was 54 days (range, 13-384 days). Median time of MCR duration was 13 months (range, 0.9-60.3 months). MCR achievement within 3months after remission induction was significant predictor of RFS (P=0.004) and OS (P=0.003). Thirty two patients who lost of MCR had significantly inferior RFS (P90% vs. ¡Â90%; was significantly associated with median HCR duration (44 vs. 13 months, P=0.001, Fig. 1), median overall survival (39 vs. 10 months, P80% vs. ¡Â80%; was 57% (95% CI, 43.0-75.5%) and 33% (95% CI, 12.3-55.4%), respectively (P=0.05). Conclusions: The higher imatinib dose intensity is correlated with the better molecular response and the superior overall outcome. The quantitative monitoring of BCR-ABL transcript levels is useful in identifying subgroups of Ph+ALL patients at a high risk of relapse. Figure 1 Figure 1. Figure 2 Figure 2. Figure 3 Figure 3. Disclosures No relevant conflicts of interest to declare.

Our previous study showed that a less toxic regimen comprising reduced cyclophosphamide (Cy), fludarabine and anti-thymocyte globulin (ATG) (Cy-Flu-ATG), was less toxic for allogeneic hematopoietic cell transplantation (alloHCT) compared with standard Cy-ATG in patients with adult severe aplastic anemia (AA). We postulated that replacing Cy with Flu (Flu-ATG) would be more beneficial. Therefore we performed a randomized phase III study to compare the regimen-related toxicities (RRTs) of two different conditioning regimens: Cy-ATG vs. Flu-ATG. We present the interim alaysis. Patients in the Cy-ATG arm received Cy at 200 mg/kg. Those in the Flu-ATG arm received fludarabine (Flu) at 180 mg/m2. A total of 36 patients (21 in the Cy-ATG and 15 in the Flu-ATG) were enrolled. The basic patientsÕ characteristics were similar between both arms except for donor type and HLA-matching. There were more unrelated donor (38.1% vs. 73.3%; p=0.037) and HLA mis-matching (0% vs. 40%; p=0.001) in Flu-ATG arm. All predefined RRTs were similar between Cy-ATG and Flu-ATG (33.3% vs. 33.3%; p=1.000). There was no primary engraftment failure in both arms and only one patients in Cy-ATG died of treatment-related hepatic toxicity before engraftment. Also there were no differences between Cy-ATG and Flu-ATG arms in terms of secondary engraftment failure (20% vs. 20%; p=1.000), hepatic sinusoidal obstruction syndrome (0% vs. 0%; p=1.000), hemorrhagic cystitis (4.8% vs. 0%; p=1.000), pulmonary complications (12.5% vs. 16.7%; p=1.000). The incidence of acute graft-versus-host disease (GvHD) (14.3% vs. 20.0%; p=0.677) and chronic GvHD (11.8% vs. 7.7% ; p=1.000) were also similar. The 3-year survival rate did not differ (77.3% vs. 77.0%; p=0.995; Figure 1). Flu-ATG can be Figure 1 promising in terms of RRT without increasing engraftment failure in Flu-ATG arm when considering more unrelated and HLA-mismaching patients were enrolled. We will continue this phase III trial. Figure 1. promising in terms of RRT without increasing engraftment failure in Flu-ATG arm when considering more unrelated and HLA-mismaching patients were enrolled. We will continue this phase III trial. Disclosures No relevant conflicts of interest to declare.

Forty-one of 792 acute leukemia patients suffered fatal intracranial hemorrhage (FICH). Acute promyelocytic leukemia was the most common subtype. Achievement of complete remission in AML was significantly influenced by FICH. FICH accounts for about half of deaths from hemorrhage and this proportion has not changed despite improvements in leukemia management.

Dastinib (BMS-354825) is a FDA-approved small compound that was developed for chronic myeloid leukemia as a multi-targeted kinase inhibitor of wild-type BCR-ABL and SRC family kinases. Valproic acid (VPA; Orfiril) has been a well-known anti-epileptic drug worldwidely, and belong to the class I histone deacetylase inhibitor. The aim of this research is to determine the anti-leukemic effects of combination of dasatinib and VPA or their mechanism in acute myeloid leukemia (AML) cells. In this study, dasatinib showed potent inhibitory effects on VPA-treated AML cells that were associated with induced G1 phase cell cycle arrest and also apoptosis including the cleavage of PARP, caspase-3, -7 and -9. Moreover, inhibitors of caspase-3 and -9 (Z-DEVD-FMK and LEHD-CHO) efficiently inhibited dasatinib-induced apoptosis in VPA-treated AML cells. Therefore, dasatinib/VPA-induced cell death occurred via caspase-dependent apoptosis. Also, inhibitors of MEK/ERK (U0126 and PD98059) and p38 MAPK (SB203580) efficiently inhibited dasatinib/VPA-induced apoptosis. The combination of dasatinib and VPA differentiation capacity of AML cells is more powerful than each drug alone. So the combination is enough to push AML cells to death strongly by G1 cell cycle arrest and caspase-dependent apoptosis. In addition, MEK/ERK and p38 MAPK controls dasatinib/VPA-induced apoptosis as an upstream regulator. Finally, co-treatment of dasatinib and VPA is contributed to AML cell death by regulation of differentiation capacity. Taken together, these results indicate that dasatinib and VPA together have a potential for anti-leukemic therapy. Citation Format: Sook-Kyoung Heo, Eui-Kyu Noh, Dong-Joon Yoon, Jae-Cheol Jo, Jae-Hoo Park, Hawk Kim. Dasatinib accelerates valproic acid-induced acute myeloid leukemia cells death by regulation of differentiation capacity. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 347. doi:10.1158/1538-7445.AM2014-347

Dasatinib is a compound developed for chronic myeloid leukemia as a multi-targeted kinase inhibitor against wild-type BCR-ABL and SRC family kinases. Valproic acid (VPA) is an anti-epileptic drug that also acts as a class I histone deacetylase inhibitor. The aim of this research was to determine the anti-leukemic effects of dasatinib and VPA in combination and to identify their mechanism of action in acute myeloid leukemia (AML) cells. Dasatinib was found to exert potent synergistic inhibitory effects on VPA-treated AML cells in association with G1 phase cell cycle arrest and apoptosis induction involving the cleavage of poly (ADP-ribose) polymerase and caspase-3, -7 and -9. Dasatinib/VPA-induced cell death thus occurred via caspase-dependent apoptosis. Moreover, MEK/ERK and p38 MAPK inhibitors efficiently inhibited dasatinib/VPA-induced apoptosis. The combined effect of dasatinib and VPA on the differentiation capacity of AML cells was more powerful than the effect of each drug alone, being sufficiently strong to promote AML cell death through G1 cell cycle arrest and caspase-dependent apoptosis. MEK/ERK and p38 MAPK were found to control dasatinib/VPA-induced apoptosis as upstream regulators, and co-treatment with dasatinib and VPA to contribute to AML cell death through the regulation of differentiation capacity. Taken together, these results indicate that combined dasatinib and VPA treatment has a potential role in anti-leukemic therapy.

117 Background: Adjuvant chemotherapy for gastric cancer after gastrectomy with D2 dissection can be recommended. However, there are limited data of survival benefit in the elderly. We sought to investigate the use of adjuvant chemotherapy for patient ≥70 years old with stage II or III gastric cancer and identify its impact on survival. Methods: Patient ≥70 diagnosed with stage II or III gastric cancer at the Ulsan University Hospital from 2008-2012 were identified. A retrospective analysis of electronic and paper patient records was performed to identify baseline characteristics, chemotherapy used, toxicity, and survival. Results: A total of 277 patients ≥70 years old underwent gastrectomy with D2 dissection from 2008-2012. Of these, 94 patients were pathologically diagnosed as stage II or III gastric cancer. Among the 94 patients, 58.5% of patients (n=55) received adjuvant chemotherapy and 39 patients received regular check-up without chemotherapy. Fluoropyrimidine alone regimens including TS-1 (n=26) and Didox (n=22) were more commonly used compared with fluroropyrimidine-platinum combination regimens (n=7). With median follow-up of 30.9 (range, 0.8-65.5 months), the median relapse-free survival (RFS) of patients with adjuvant chemotherapy or regular follow-up only was 39.1 and 26.1 months (P = 0.027). Multivariate analysis revealed that the adjuvant chemotherapy was associated with longer RFS (hazard ratio 0.51; 95% confidence interval 0.27 – 0.98). There was a trend toward improved overall survival (OS) in the adjuvant chemotherapy group, with a median OS of 51.2 months compared with that of 44.5 months in the regular follow-up only group (P= 0.242). Toxicities in adjuvant chemotherapy were generally tolerated. Conclusions: In elderly patients (aged 70 or older) with stage II or III gastric cancer after gastrectomy with D2 dissection, adjuvant chemotherapy may carry a potential survival benefit for those who receive it. Further well-designed prospective studies are needed to confirm these finding.

A comprehensive defect analysis scheme has been described here incorporating defect monitoring, classification and review tools. The integration scheme is presented pictorially, and described in detail in the body of this paper. This paper will also describe CMP defects gathered using this new defect detection methodology.

Although eosinophilic fasciitis (EF) may precede hematologic malignancy or Hodgkin's disease, association with peripheral T-cell lymphoma (PTCL) is extremely rare. Only four cases of EF preceding or concomitant PTCL have been reported in the world literature. We experienced the first Korean case of EF complicated by the later relapse of peripheral T-cell lymphoma. A 63-year-old Korean male has been followed at our outpatient clinic periodically after treatment for stage IV PTCL. He had been in complete remission for seven and a half years when he developed edema of both lower extremities followed by sclerodermatous skin change in both hands with peripheral eosinophilia. Biopsy from the left hand showed fibrous thickening of the fascia with lymphoplasmacytic and eosinophilic infiltrate, consistent with EF. Twenty-five months later, a newly developed lymph node from the left neck showed recurrence of PTCL. EF may occur as a paraneoplastic syndrome associated with the relapse of PTCL. Therefore, in a patient with EF, the possibility of coexisting and/or future occurrence of hematologic neoplasm should be considered.

To determine whether the p53 expression might be a predictor for treatment response and overall survival in nodal non-Hodgkin's lymphoma (NHL), we analyzed the expression of p53 in 69 NHL patients. p53 protein expression was analyzed by immunohistochemistry with long-term follow up (1-148 months: median 12.2). p53 expression was noted in 23/69 (33.3%) patients. Complete response (CR) rate to systemic chemotherapy was correlated with stage (I/II) (p=0.038), but not with p53 expression (p=0.2856). Poor overall survival was associated with stage (p=0.0010) or IPI score (p=0.0076), but not with p53 expression (p=0.8601). From stratification analysis by stage, in stage III/IV patients, the p53 positive group had a trend to be associated with poor overall survival than the p53 negative group. Multivariate analysis revealed that p53 positive group was associated with less CR rate compared to the p53 negative group (p=0.046), whereas overall survival was correlated with stage (p=0.0320), not with p53 status. p53 expression was associated with less CR rate in patients with DLBL. Further studies with large numbers of samples and homogenous group of NHL are needed to determine the prognostic value of cell cycle regulator, p53 in NHL.

Allogeneic hematopoeitic cell transplantation (alloHCT) is a curative therapy for severe/very severe aplastic anemia (sAA) in adult. alloHCT from haplo-identical family donor (HD) is an alternative approach while alloHCT from matched sibling donor (MSD) is the choice of therapy. Our previous study suggested that alloHCT from matched unrelated donor (MUD) were comparable with MSD when pre-transplantation conditions were well-matched. It means poor outcome of MUD might come from poor pre-transplantation clinical factors such as delayed alloHCT. Same will be applied to HD. In this study we compared HD with alternative donors (AD; MUD or mismatched family donor) by matched case study. We selected AD cases from KSBMT2007-01 study population who had comparable pre-transplantation clinical factors with HD by propensity-score matching. Pre-tranplatation clinical factors such as age, ATG conditioning or ABO-compatibility were matched. Therefore 48 AD cases were selected for the comparison with 16 HD cases. Male (p=0.009) and female to male transplantation (p=0.002) were more frequent in HD. AD received prior immune suppression therapy (IST) frequently (p=0.092). Cyclophosphamide (p500/μL, days°×18 (15.4-20.6)13 (11.2-14.8)0.003Time to platelet>20K/μL, day°×s25 (21.4-28.6)15 (5.7-24.3)0.772CI of aGvHD, days°×-86 (19.4-152.6)0.378CI of grade 3/4 aGvHD, days°×--0.255CI of cGvHD, months°×-10.4 (0-35.3)0.202CI of extensive cGvHD, months°×9.5 (5.1-13.9)7.3 (1.9-12.8)0.918°× Median (95% confidence interval), calculated by Gray's testAbbreviations: SOS, sinusoidal obstruction syndrome; aGvHD, acute graft-versus-host disease; cGvHD, chronic graft-versus-host disease; ANC, absolute neutrophil count, CI, cumulative incidenceFigure 1Overall survivalFigure 1. Overall survival In conclusion, alloHCT from HD in sAA is comparable with alloHCT from AD when pre-transplantation clinical factors were similar although extensive chronic GvHD seemed frequent in HD. Therefore alloHCT from sAA could be alternative approach of alloHCT from MUD in adult sAA. Disclosures: No relevant conflicts of interest to declare.

We previously reported the interim analysis on the clinical outcome of nilotinib (Tasigna®, Novartis Pharma, Basel, Switzerland), when combined with multi-agent chemotherapy for newly diagnosed Philadelphia-positive acute lymphoblastic leukemia (Ph+ALL) in adults. Herein, we reported the final results of the multicenter prospective phase2 trial of Adult Acute Lymphoblastic Leukemia Working Party, the Korean Society of Hematology. Newly diagnosed Ph+ALL patients aged 18 years old or more were eligible when they had adequate organ function. Diagnosis of Ph+ALL was performed via confirmation of the presence of Ph chromosome by conventional GTL-band technique, and/or positive molecular analysis with nested RT PCR for detection of BCR-ABL fusion transcripts. Written informed consent was obtained from all subjects. All patients received induction treatment consisting of vincristine, daunorubicin, oral or parenteral prednisolone, and nilotinib. After achieving complete remission (CR), subjects received either 5 courses of consolidation followed by 2-year maintenance with nilotinib, or allogeneic hematopoietic cell transplantation (alloHCT) depending on the donor availability, his/her tolerability, and patient’s wish. Nilotinib was administered twice a day with a single dose of 400mg (800mg per day) from day8 of induction until the initiation of conditioning for alloHCT or the end of maintenance therapy. Minimal residual disease (MRD) monitoring was performed at the central lab with quantitative RT-PCR assays for peripheral blood BCR-ABL RNA using LightCycler® Technology in serial; at the time of diagnosis, at hematologic CR(HCR), and every 3 months thereafter. BCR-ABL quantification was expressed relative to the amount of glucose-6-phosphate dehydrogenase (G6PDH) mRNA. The molecular response was defined as complete (MCR, MRD-negative) if the BCR-ABL/G6PDH ratio was less than 1x10-6. Toxicity was graded according to National Cancer Institute Common Toxicity Criteria (version 2.0). Subjects had been followed up for 2 years after alloHCT or during maintenance therapy. Data were frozen up in June, 2013. A total of 91 subjects (male: female = 45: 46) were enrolled onto the study between January 2009 and May 2012. The median age was 47 (range 18-71) years old. Type of BCR breakpoint was minor (e1a2) in 71% of patients. The median BCR-ABL/G6PDH ratio was 6.09 (bone marrow) and 3.28 (peripheral blood) at diagnosis. During induction, all subjects required blood product transfusion, and incidence of nonhematologic adverse events (AE) over grade 3 was 17% (jaundice), 18% (ALT elevation), 13% (lipase elevation), and 2% (pancreatitis). Neither QTc prolongation over 500ms nor significant arrhythmia happened among any subject and any cycle. HCR rate was 90% and median time to HCR was 27 days (range, 13-72); most of failure was due to death in aplasia (n=8). MCR rate at HCR was 55%, Cumulative MCR rate was 84%, and median time to MCR was 1.1 months (range, 0.6-15.8). Most common cause of dropout from study was treatment-related death (n=22; during induction/consolidation vs. after alloHCT = 12 vs. 10), and HREL (n=15). Nilotinib was interrupted 75 times among 64 subjects, reduced 14 times among 12 subjects, and discontinued permanently due to hematologic relapse (HREL, n=14), AE (n=6, over gr3:3), and other cause (n=2). Fifty nine patients underwent alloHCT, 34 with myeloablative and 25 with reduced-intensity conditioning. Incidences of acute graft-versus-host disease (GVHD) and chronic GVHD were 41% and 29%, respectively. With a median follow-up of 20.7 months of surviving subjects, estimated hematologic relapse-free survival (RFS), and overall survival (OS) rate at 2 years were 74% and 70%, respectively. Among subject achieving MCR, 2-year molecular RFS rate was 56%. When events were defined as ‘dropout due to AE, isolated molecular / extramedullary relapse, HREL, and death from any cause’, median event-free survival was 12.5 months. In this prospective study, nilotinib was shown to be effective for adult Ph+ALL, and concurrent administration of nilotinib with cytotoxic drug was well-tolerable, although death in aplasia during induction was the most common cause of failure of achieving HCR. In terms of MRD, potential of nilotinib to achieve and maintain MRD negativity were satisfactory (Clinicaltrials.gov NCT00844298). Disclosures: Off Label Use: Nilotinib for Ph+ALL-sientific and academic purpose.

Background Since the first case report of Gimaz et al., several investigators have reported that the secondary immune thrombocytopenia (ITP) can occur in patients with Helicobactor pylori (H. pylori) infection. Eradication of H. pylori has been shown to result in improvement in thrombocytopenia. In one systematic review of 696 patients with H. pylori infection it showed 50.3% overall response (platelet count >= 30 X 109/L and at least a doubling of the base line count) after H. pylori eradication. Under these results, ASH 2011 guidelines for ITP recommended that eradication therapy be administered in adult patients who are found to have H. pylori infection (grade 1b). But also they recommended that treatment be administered for newly diagnosed patients with a platelet count < 30 X 109/L. To the best of our knowledge, there was no prospective study to evaluate the efficacy of H. pylori eradication for ITP patient with moderate thrombocytopenia and positive H. pylori. In Korea, the prevalence of H. pylori was reported as high as 60 – 65% in general adult population. The response rate and price of 1st line triple regimen for H. pylori eradication were known to be 70 - 80% and around 100 US dollars in Korea. With these circumstances, tolerable treatment like H. pylori eradication for ITP patients with platelet count >=30 X 109/L is challengeable. Thus, we performed the prospective multicenter phase II study to evaluate the efficacy of H. pylori eradication for the 1st line treatment of persistent or chronic ITP patients with moderate thrombocytopenia. Methods We enrolled patients with persistent (3 to 12 months from diagnosis) or chronic (lasting for more than 12 months) ITP defined by international working group. The platelet counts of patients were between 30 X 109/L and 70 X 109/L. And all patients had positive result of C13-urea breath test (UBT) and had never been treated for ITP or H. pylori. Patients with other secondary ITP could not be enrolled. Patients received lansoprazole 30mg twice daily, amoxicillin 1000mg twice daily and clarithromycin 500mg, twice daily for one week. Eradication of H. pylori was evaluated at eighth week after treatment by UBT. Platelet counts were monitored at 2 weeks and after then at every month for a year. Complete response (CR) was defined as a platelet count >= 100 X 109/L. Partial response (PR) was defined as a platelet increase of >= 30 X 109/L and at least a doubling of the base line count. The primary endpoint was CR rate at 3 months after treatment. All patients provided written informed consents and this trial was registered at www.ClinicalTrials.gov (NCT01255332). Results Twenty-six patients were enrolled between November 2010 and May 2013 from 6 medical centers in Korea. Two patients with HCV infection and one patient with more than 70 X 109/L of platelet counts were excluded from analysis. The mean initial platelet counts of 23 patients (7 males, 16 females, median age 43 years and range 19 - 58 years) was 52.7 ± 9.5 X 109/L (range 39 – 68 X 109/L). All patients except one checked UBT after treatment and H. pylori eradication was achieved in 86.3% (19/22) of patients. CR was obtained in 13 of 23 patients (56.5%) within 3 months after treatment. And no PR was found until this time point. The median time to CR after initiating treatment was 4 weeks (range 2 – 8 weeks). CR rate of the patients who achieved H. pylori eradication was 63.2% (12/19). Unlike other reports, there was no significant difference on initial platelet counts among CR group and non-responder group and no significant correlation on the platelet levels between baseline and initial 3 months (Fig 1). Only 2 of 26 patients could not continue medication due to nausea and diarrhea, respectively. There was no other significant adverse event. Conclusion The eradication of H. pylori is an effective first line treatment for persistent or chronic ITP with moderate thrombocytopenia with high CR rate and rapid onset. And it has acceptable toxicity and relatively low cost. This study supports routine detection and eradication of H. pylori infection in ITP patients especially in populations with a high prevalence of this infection. Disclosures: No relevant conflicts of interest to declare.

Background Approximately 50% of CP CML patients achieve undetectable molecular residual disease (UMRD) at 6-7 years of first-line imatinib (IM) therapy. Although imatinib therapy is effective in chronic myeloid leukemia (CML) patients and a substantial portion of patients achieve UMRD with prolonged IM therapy, up to 10^7 leukemic cells can still be present in the absence of detectable BCR-ABL1 in RQ-PCR assay due to the sensitivity limit of current RQ-PCR technology. The recent several reports to assess whether IM can be discontinued in CML patients have shown that IM discontinuation can be employed based on clinical study in patients who had enough IM therapy and UMRD durations prior to IM discontinuation. In our previous report, the 12-month probability of sustained UMRD of 48 patients was 80.8% (78.4% in 37 patients with at least 12 months follow-up), a higher rate than that reported by the ‘STIM’ (Stop Imatinib) trial. To identify predictors for safer, successful IM discontinuation and to explore additional contributing factors for sustained molecular responses (MRs), this multicenter prospective Korean Imatinib Discontinuation Study (KIDS) is on-going. Methods Patients who were treated with IM for more than 3 years and whose BCR-ABL1 was undetectable in RQ-PCR for at least 2 years were enrolled in this study. After discontinuation, molecular response was monitored using RQ-PCR assay every month up to 6 month follow-up, every 2 months up to 12 month follow-up, and every 3 months thereafter. In case of relapse, defined as loss of MMR on 2 consecutive assessments, IM therapy was re-introduced and molecular response after resumption was observed every month using RQ-PCR. Our primary objectives were to evaluate the probability of persistent UMRD at 12 month follow-up after discontinuation, and to measure the duration of persistent UMRD after discontinuation. The secondary objective was to evaluate the probability of major molecular response (MMR) loss and the time taken to lose MMR after discontinuation. Results Of the 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.

8521 Background: Combination chemotherapy of IMEP was active as a first-line as well as a second-line treatment for NTCL in a retrospective analysis. Thus, we conducted a prospective, multicenter, phase II study of IMEP chemotherapy in previously, untreated stage I/II NTCL. Methods: Patients with chemo-naïve stage I/II NTCL were enrolled between December 2004 and February 2009 and they received 6 cycles of IMEP (ifosfamide 1.5 g/m2 on days 1 to 3; methotrextate 30mg/m2 on days 3 and 10; etoposide 100mg/m2 on days 1 to 3; and prednisolone 60mg/m2/day on days 1 to 5) followed by involved field radiotherapy (IFRT). Response was evaluated every 2 cycles of chemotherapy and 4 to 8 weeks after completion of IFRT using modified Response Evaluation Criteria in Solid Tumors. Results: Overall, 44 patients including 29 males were analyzed by the intent-to-treat principle. Overall response rates were 73% (complete remission [CR], 11 [27%] of 41 evaluable patients) after IMEP chemotherapy and 78% (CR, 18 [67%] of 27) after IMEP followed by IFRT. Grade 3 to 4 neutropenia and thrombocytopenia were documented in 33 (75%) and 7 (16%) patients, respectively. Only 8 (18%) patients experienced grade 3 febrile neutropenia. 2-year progression-free survival (PFS) and overall survival (OS) were 56% and 66%, respectively. High Ki-67 (≥ 70%) and Ann Arbor stage II independently reduced PFS (hazard ration [HR]=5.6, 95% confidence interval [CI] 1.8-17.6; P=.004) and OS (HR=4.8, 95% CI 1.9-12.2; P=.001), respectively. Conclusions: IMEP followed by IFRT is active and safe against patients with previously untreated stage I/II NTCL.

Correspondence to Hawk Kim, M.D., Ph.D. Division of Hematology and Hematological Malignancies, Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, 877 Bangeojinsunhwando-ro, Dong-gu, Ulsan 682-714, Korea Tel: +82-52-250-8892, Fax: +82-52-251-8235, E-mail: kimhawkmd@gmail.com Copyrightc 2013 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. Alemtuzumab을 이용한 이차성 순적혈구 빈혈의 치료

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

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

Abstract 3628 Introduction: We conducted a randomized trial comparing two different doses of daunorubicin as induction chemotherapy in young adults with acute myeloid leukemia (AML) and showed intensification of induction therapy using a high daily dose of daunorubicin (90 mg/m2/d × 3d) improved both complete remission (CR) rate and survival duration compared to standard daunorubicin dose (45 mg/m2/d × 3d) (Lee JH et al. Blood 2011;118:3832). Our results confirmed the ECOG work (Fernandez HF et al. N Engl J Med 2009;361:1249). Thus, high-dose daunorubicin (90 mg/m2/d) for 3 days should be the future standard of care for induction of patients with AML. However, it is not known whether a dose of 90 mg/m2/d is superior to a dose of 45–90 mg/m2/d. It is also necessary to compare the effects of high-dose daunorubicin with that of other agents, especially idarubicin. For these reasons, we began another randomized trial comparing two induction regimens in young adults with AML: idarubicin vs. high-dose daunorubicin. This study is now recruiting patients (ClinicalTrials.gov #NCT01145846). Here, we present the results of interim analysis of the study. Methods: This study began on May 2010 and target number of patient's accrual is 300. A total of 161 patients (65 years or younger) with newly diagnosed AML except acute promyelocytic leukemia were registered in this study as of March 22, 2012. Four patients were removed from the study (patient's refusal to be randomized in 2 and change of diagnosis in 2) and the remaining 157 patients were analyzed. After random assignments, 81 patients received idarubicin (AI, 12 mg/m2/d × 3d) and 76 patients received high-dose daunorubicin (AD, 90 mg/m2/d × 3d) in addition to cytarabine (200 mg/m2/d × 7d) for induction of CR. Patients with persistent leukemia received the second attempt of induction chemotherapy, consisting of idarubicin (AI, 12 mg/m2/d × 2d) or daunorubicin (AD, 45 mg/m2/d × 2d) plus cytarabine (5d). Patients who attained CR received 4 cycles of high-dose cytarabine (3 g/m2 × 6 doses) in patients with good- or intermediate-risk cytogenetics and 4 cycles of cytarabine (1 g/m2 × 6d) plus etoposide (150 mg/m2 × 3d) in those with high-risk cytogenetics. Hematopoietic cell transplantation (HCT) was performed according to attending physician's discretion. Results: CR was induced in 123 (78.3%) of 157 patients. Reasons for induction failure were resistant disease in 26, hypoplastic death in 2, and indeterminate cause in 6. As postremission therapy, 3 patients received no further treatment, 35 received consolidation chemotherapy without HCT, 73 underwent allogeneic HCT, and 12 underwent autologous HCT. The CR rates were not significantly different between two arms: 77.8% (63 of 81, AI) vs. 78.9% (60 of 76, AD) (P=0.859). With a median follow-up of 285 days, overall survival probabilities at 18 months were 65.6% in AI vs. 72.6% in AD (P=0.278). The probabilities at 18 months for relapse-free survival were 78.5% in AI vs. 86.2% in AD (P=0.563) and those for event-free survival were 61.5% in AI vs. 67.7% in AD (P=0.078). Toxicity profiles were similar between two arms. Conclusions: The results of interim analysis of this ongoing phase 3 trial, which compares idarubicin (12 mg/m2/d × 3d) with high-dose daunorubicin (90 mg/m2/d × 3d), did not show significant differences in the outcomes of patients. It appears that the effects of two drugs with the doses in current study are equivalent as an induction chemotherapeutic agent in regards to CR rates and overall, relapse-free or event-free survivals. Disclosures: No relevant conflicts of interest to declare.

Abstract 3515 Background: The core binding factor (CBF) AML can be achieved long-term remission with high dose cytarabine-based chemotherapy alone. However, those with C-KIT gene mutation (esp. D816 C-KIT mutation) showed worse treatment outcomes compared to those with wild type C-KIT gene. The remaining cases without D816 C-KIT mutation is around 75% of CBF AML, which implies requirement of more sophisticated dissection of the patients according to their prognosis. Single nucleotide polymorphism (SNP) array (SNP-A) could detect cryptic abnormal genomic lesions, not identified by metaphase cytogenetics(MC). In this study, we analyzed the prognostic value of SNP-A based karyotyping combined with MC and its association with C-KIT mutation to facilitate further stratification of CBF AML patients. Methods and Materials: A total of 98 CBF AML patients were included and of whom, 63 (64%) and 35 patients (36%) were t(8;21) and inv(16)/t(16;16), respectively. Genome-Wide Human SNP 6.0 Array (Affymetrix, CA, USA) was performed using DNAs from marrow samples taken at diagnosis. Results: A total of 40 abnormal genomic lesions in 25 patients (26%) were detected by SNP-A karyotyping analysis, with a mean of 1.6 lesions per affected case (median size 33.6 Mb; range 0.4–145.9 Mb), including 3 CN-LOH lesions, 17 gain lesions, and 20 loss lesions. Survival of the patients with abnormal lesion(s) detected by SNP-A or/and MC was worse than those without any lesions in terms of 2 years' overall survival (OS; 57.5% vs 76.4%, p=0.028), event-free (EFS; 45.7% vs 66.2%, p=0.072) and leukemia free survival (LFS; 49.0% vs 77.4%, p=0.015). In contrast, MC alone could not stratify patients according to their long-term prognosis. Especially, in the subgroup with inv(16)/t(16;16), survival of patients with abnormal SNP-A/MC lesion showed worse than that of those without lesion (40.9±12.7% vs 80.2±10.4% at 2 yrs, p=0.040), but not in the subgroup with t(8;21) (66.85±9.1% vs 74.4±7.8% at 2 yrs, p=0.240). As for the subgroup with D816 C-KIT mutation, there were no differences of OS (p=0.417), EFS (p=0.380) and LFS (p=0.218) according to the presence of abnormal lesions detected by either SNP-A or MC. However, in the subgroup without D816 C-KIT mutation, those with abnormal lesions detected by either SNP-A or MC showed worse survival compared to those without abnormal lesions with respect to OS (61.6±8.7% vs 82.7±5.6% at 2 yrs, p=0.038). Multivariate analysis confirmed prognostic impact of abnormal SNP/MC lesions on OS (HR 2.743, p=0.020), EFS (HR 2.434, p=0.025), and LFS (HR 3.350, p=0.012). Conclusion: This study suggests that combined use of SNP-A with MC in the initial evaluation of CBF AML can provide an important prognostic value, especially in the inv(16)/t(16;16) subgroup or in the patients without having D816 C-KIT mutation. Disclosures: No relevant conflicts of interest to declare.

Abstract 1517 Background: Incorporation of imatinib into classical cytotoxic chemotherapy has improved the response and survival of patients with Philadelphia chromosome-positive (Ph+) adult acute lymphoblastic leukemia (ALL). Nilotinib (Tasigna, Novartis Pharma, Basel, Switzerland), a second-generation tyrosine kinase inhibitor with enhanced in-vitro inhibition of BCR-ABL kinase, showed faster and deeper responses than imatinib among patients with chronic myeloid leukemia. Moreover, less serious gastrointestinal adverse effects of nilotinib may be beneficial to combination with intensive chemotherapy in Ph+ ALL when compared with imatinib. Herein, we report interim results of a prospective single-arm multicenter phase-2 study evaluating the safety and efficacy of nilotinib-combined multi-agent chemotherapy in Ph+ ALL. Methods: Patients aged over 18 years old were eligible if they had newly diagnosed Ph+ ALL, and adequate hepatic/renal/cardiac function. Diagnosis of Ph+ ALL was dependent upon confirmation of t(9;22) with cytogenetics by conventional GTL-band technique, and/or positive molecular analysis with nested RT PCR for detection of BCR-ABL fusion transcripts. Written informed consent was obtained from all patients. All patients received induction treatment consisting of vincristine, daunorubicin, oral prednisolone, and nilotinib. After achieving complete remission (CR), patients received either 5 courses of consolidation followed by 2-year maintenance with 6-mercaptopurine plus methotrexate, or allogeneic hematopoietic cell transplantation (alloHCT) according to the donor availability and his/her general condition. Nilotinib was administered twice a day with a single dose of 400mg (800mg per day) from day8 of induction until the initiation of alloHCT or the end of maintenance therapy. Quantitative RT-PCR assays were performed at the central lab with Light-Cycler Technology at the time of diagnosis, at CR, and every 3 months thereafter. BCR-ABL quantification was expressed relative to the amount of glucose-6-phosphate dehydrogenase (G6PDH) mRNA. The molecular response was defined as complete (MCR) if the BCR-ABL/G6PDH ratio was less than 1×10−6. Toxicity was graded according to National Cancer Institute Common Toxicity Criteria (version 2.0). For interim analysis, outcome was updated as of July 1, 2011. Results: A total of 50 consecutive patients (male: female = 22: 28) were enrolled onto the study between January 2009 and December 2010. The median age was 44.5 (range 18–71) years old. Type of BCR breakpoint was minor (e1a2) in 66% of patients. The median BCR-ABL/G6PDH ratio was 6.09 (bone marrow) and 3.08 (peripheral blood) at the diagnosis. Except five patients who died in aplasia during induction, 45 (90%) patients achieved hematologic remission (HCR), and MCR rate was 54% at the time of HCR. During the whole treatment periods, administration of nilotinib was interrupted 50 times among 30 patients, and dose was reduced among 6 ones. Of 45 patients who achieved HCR, median dose intensity (DI) of nilotinib between day8 and day of confirmation of HCR was 769.2mg (range 160–800), and MCR rates were not different among two subgroups when dichotomized using the median dose intensity (60.9% vs. 59.1%). During the induction, 20% of patients experienced ≥grade 3 jaundice, which were all reversible, and 2% experienced pancreatitis. Thirty three patients underwent alloHCT, 19 with myeloablative and 14 with non-myeloablative conditioning. Incidences of ≥grade 3 acute graft-versus-host disease (GVHD) and extensive chronic GVHD were 9% and 3%, respectively. With a median follow-up of 17.4 months (range, 6.9–29.1), estimated relapse-free survival (RFS), event-free survival (EFS), and overall survival (OS) at 2 years were 71.1%, 49.4%, and 66.2%, respectively. Of 33 patients who underwent alloHCT, 2-year RFS, EFS, and OS rate were 70.5%, 60.0%, and 83.2%, respectively. Achievement of MCR and DI of nilotinib were not associated with outcome. Conclusion: Nilotinib was tolerable in combination with intensive chemotherapy for adult patients with Ph+ ALL, and the outcomes were comparable to previous results based on imatinib combination. Patient recruitment is ongoing currently based on this interim analysis, and the final results are expected in 2014. Disclosures: Off Label Use: Nilotinib is used as 'off-label drug' for Philadelphia chromosome-positive acute lymphoblastic leukemia in this trial. We have achieved the permission for the use of this drug in this clinical trial from the Korean FDA.

Abstract 967 A PROGNOSTIC MODEL OF THERAPY-RELATED MYELODYSPLASTIC SYNDROME FOR PREDICTING SURVIVAL AND TRANSFORMATION TO ACUTE MYELOID LEUKEMIA Alfonso Quintás-Cardama, Hawk Kim, Elias Jabbour, Stefan Faderl, William Wierda, Farhad Ravandi, Tapan Kadia, Sa Wang, Sherry Pierce, Jianqin Shan, Hagop Kantarjian, Guillermo Garcia-Manero Background: A significant fraction of patients with MDS have a prior history of an antecedent malignancy treated with chemotherapy and/or radiotherapy. Therapy related MDS (t-MDS) differs from de novo MDS in its high frequency of chromosomal abnormalities (typically in the context of complex karyotypes), high rate of transformation to acute myeloid leukemia (AML), and high resistance to standard MDS therapy. MDS prognostic models (e.g., IPSS, WPSS) have been developed based primarily on cohorts of patients with de novo MDS. We evaluated the characteristics of a large cohort of patients with t-MDS and created a specific t-MDS prognostic model. Patients and methods: From 1998 to 2007, we identified 1950 patients with MDS of which 438 (22%) (RAEB-T by FAB were excluded) had a history of one or more prior malignancies and treatment for their malignancies prior to a diagnosis of MDS. Of those, 279 (64%) had received prior chemotherapy and/or radiotherapy, and therefore were categorized as t-MDS. Potential prognostic factors were determined by univariate analyses and validated by multivariate analysis. The final prognostic factors were incorporated into a novel prognostic model. Results: Univariate analysis identified significant factors in association with overall survival. They included hepatomegaly (no vs. yes; p=0.02), hemoglobin (5 years; p=0.06), number of lines of therapy (1 vs. ≥2; p=0.06), serum albumin (≥4 vs. 3mg/L; p=0.05), ECOG performance status (0–1 vs. ≥2; p Conclusion: We propose a prognostic model specific for patients with t-MDS that predicts overall and leukemia-free survivals. This model may facilitate the development of risk-adapted therapeutic strategies. Disclosures: No relevant conflicts of interest to declare.

Abstract 2763 Approximately 50% of CP CML patients achieve complete molecular response (CMR) at 6–7 years of first-line imatinib therapy. Although imatinib therapy is effective in CML patients and a substantial portion of patients achieve CMR with prolonged imatinib therapy, up to 10^7 leukemic cells can still be present in the absence of detectable BCR-ABL in RQ-PCR assay due to the sensitivity limit of current RQ-PCR technology. The recent data from STIM (Stop Imatinib) trial showed that the probability of persistent CMR at 12 month follow-up after imatinib discontinuation was 41%, and the conclusion was that imatinib can be safely discontinued, at least in some patients with persistent CMR. However, it is still not clearly defined whether discontinuation of imatinib therapy can be safely employed in patients with sustained CMR. In our prospective study, we examined if imatinib therapy can be safely discontinued in CML patients with sustained CMR4.5 according to strict PCR sensitivity criteria, and CMR4.5 was defined as undetectable BCR-ABL using RQ-PCR assay with at least 4.5-log sensitivity. CML patients who were treated with imatinib for more than 3 years and whose BCR-ABL was undetectable in RQ-PCR for at least 2 years were enrolled in this study. Our primary objectives were to evaluate the probability of persistent CMR4.5 at 12 month follow-up after discontinuation, and to measure the duration of persistent CMR4.5 after discontinuation. The secondary objective was to evaluate the probability of major molecular response (MMR) loss and the time taken to lose MMR at 12 month follow-up after discontinuation. In patients with loss of MMR, the probability of re-achieving MMR/CMR4.5 and the time taken to re-achieve MMR/CMR4.5 after imatinib resumption were also evaluated. 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. Digital PCR methodology with higher sensitivity compared to RQ-PCR assay was also applied before discontinuation and every year after discontinuation for more accurate estimation of BCR-ABL transcript levels. In case of relapse, defined as loss of MMR on 2 consecutive assessments, imatinib therapy was re-introduced and molecular response after resumption was observed using both RQ-PCR and digital PCR assays. As of data cut-off date of 15 Jul 2011, 20 patients (13 females, 7 males) who were diagnosed in Seoul St. Mary's Hospital between 20 Mar 1996 and 25 Apr 2005 were enrolled in this study with a median follow-up of 7 months (range, 2–9), and informed consents were obtained from all patients prior to participation. With a median age of 44 years (range, 25–67), the percentages of patients with low, intermediate and high Sokal risk scores were 30%, 30% and 15%, respectively with unknown Sokal risk scores in 25%. Ten patients (50%) received SCT and/or interferon therapy prior to imatinib therapy, while 10 patients (50%) received first-line imatinib therapy. The median time on imatinib therapy and the median duration of sustained CMR4.5 were 91 months (range, 40–112) and 60 months (range, 23–104), respectively, prior to discontinuation. Since discontinuation of imatinib therapy, all of 20 patients remained off therapy at the last follow-up with persistent CMR4.5 in 18 patients (90%) and loss of CMR in 2 patients (10%). Although loss of CMR was observed in 2 patients, both patients have not resumed imatinib therapy as MMR was maintained at the last follow-up. Our preliminary data show lower relapse rate after discontinuation compared to previous discontinuation studies. Strict PCR sensitivity criteria should be employed to assess the accurate measurement of BCR-ABL transcript levels prior to discontinuation, and then it might be possible to safely stop imatinib therapy in CML patients with stable CMR4.5. Through further clinical investigation on a large patient population and longer period of observation, more concrete conclusion can be made regarding the outcome of imatinib discontinuation. Updated data with longer follow-up duration will be presented in the meeting. Disclosures: No relevant conflicts of interest to declare.

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

Abstract 3012FN2 The hepatic sinusoidal obstruction syndrome (SOS; veno-occlusive disease [VOD]) is an acute complication after allogeneic hematopoietic stem cell transplantation (alloHSCT). However, the actual incidence and outcomes after alloHSCT in patients with adult acquired aplastic anemia (AA) was not defined yet. We investigated the incidence, risk factors and outcomes of SOS in AA. Data was taken from our previous retrospective study comparing matched sibling donors versus alternative donors (KSBMT07-02 study) and prospective randomized phase III study comparing cyclophosphamide (Cy)-ATG and Cy-fludarabine (Flu)-ATG (COSAH C-004A study) in patients with adult acquired AA. Total 260 patients were included in this analysis. SOS developed in 7.3% (n=19/260). SOS patients were male in 13 (68.4%), related donors in 84.2%, HLA full-matched in 73.7%, same donor-recipient sex matching in 63.2% patients. There were no TBI containing conditioning regimen and all patients received Cy containing conditioning regimen. The majority (94.7%) received ATG as condition regimen; horse ATG in 73.7% and rabbit ATG in 21.1% patients. Classical Cy (200mg/m2)-ATG was the most common conditioning regimen (84.2%). Sixteen patients (84.2%) received preventive medication of SOS and the major drug was heparin (78.9%). Among the diagnostic criteria of SOS, weight gain was observed in 17 (89.5%); hepatomegaly in 14 (73.7%); hyperbilirubinemia in 17 (89.5%) patients. The average total bilirubin was 6.65 (range 1.8–26.9) mg/dL. The severity of SOS was mild in 10 (52.6%), moderate in 6 (31.6%) and severe in 3 (15.8%) patients. Treatment for SOS were supportive care (72.2%), UDCA (16.7%) and corticosteroid (11.1%). All severe cases died of SOS and one moderate case died of multiple organ failure combined with infection without recovery of SOS. Therefore the mortality of SOS was 4/19 (21.1%). The probability of mortality by SOS had no correlation with weight gain (p=1.000), hepatomegaly (p=0.524), hyperbilirubinemia (p=1.000), maximal total bilirubin (p=0.239) or maximal direct bilirubin value (p=0.184). The frequencies of SOS were not significant in male (p=0.126), older than 31y (p=9.8%), prior IST (n=10/116, 8.6%; p=0.465), prior ATG usage for IST (p=0.846), unrelated donor (p=0.216), HLA mismatch (p=0.340), female to male matching (n=3/46, 6.5%; p=0.935), ABO incompatible (n=10/125, 8.0%; p=0.680), TBI conditioning (p=0.232), cyclophosphamide (p=1.000), ATG conditioning (p=0.325), fludarabine condition (p=0.221), busulfan conditioning (p=1.000), cyclosporine prophylaxis for GvHD (p=0.272), methotrexate prophylaxis for GvHD (p=0.170), bone marrow as a stem cell source (p=1.000). However, Cy 200mg/m2 conditioning (p=0.035), classical Cy-ATG condition (p=0.007) and horse ATG conditioning (p In conclusion, SOS is a relatively rate acute complication of alloHSCT in AA (7.3%). However the mortality of SOS is still high under supportive care. Horse ATG conditioning regimen was a significant risk factor for developing SOS. Disclosures: No relevant conflicts of interest to declare.

Abstract 4952 Gemcitabine (GEM) and oxaliplatin (OX) are commonly used as weekly or biweekly therapy. In this regard, dose dense biweekly schedule seems of reasonable investigational value in GEM and OX combination for non-Hodgkin lymphoma (NHL). We conducted phase II study to evaluate the efficacy of the combination chemotherapy consisting of GEM, OX and dexamethasone (GemDOx) as a biweekly regimen in patients with relapsed or refractory NHL. Primary end point was objective response rate and secondary end points were toxicities, progression-free survival, overall survival, ASCC efficacy, rate for proceeding to ASCT. The inclusion criteria were relapsed or refractory malignant aggressive NHL of any histological subtypes: Patients who have refractory to first-line CHOP-like regimen; Patients who have first relapsed after first-line CHOP-like regimen or upfront autologous or allogeneic hematopoietic stem cell transplantation Chemotherapy was repeated every 4 weeks. Gemcitabine 1000 mg/m2 in NS 500 mL was administered IV as a fixed dose rate infusion (FDRI, 10 mg/m2/min) on days 1 and 15. OX 85 mg/m2/d in 5DW 500 mL was administered IV over 6 hour on day 1 and 15. Dexamethasone 40 mg was admistered orally on day 1 through 4. All 29 patients were enrolled in this phase II study. Patients were male in 18 (62.1%), DLBCL in 16 (55.2%), stage III/IV in 25 (79.3%) and relapsed NHL in 23 (79.3) patients. Five (17.2%) patients had relapsed after upfront autologous/allogeneic stem cell transplantation. The most common prior chemotherapy was R-CHOP (n=16, 55.2%) and 17 (58.6%) were exposed to rituximab as prior chemotherapy. The median age and median prior chemotherapy were 53 (range 26–74) years old and 1 (range 1–4) cycle, respectively. IPI at relapse were 3/4 in 11 (37.9%). Only 17 (58.6%) and 9 (31.0%) patients could finish 2 or more and 4 or more cycles, respectively, and median received cycle was 2 (range 0.5–8). Four patients completed planned all 6 or more cycles, and 4 patients stopped GemDOx after 4 cycles for ASCT, and 1 patient lost initial response and progressed after 4 cycles. The reasons of drop-out were progressed disease in 15 (51.7%), lost to follow-up in 4 (13.8%), discrete of attending physician in 1 (3.4%) and withdraw of consent in 1 (3.4%). Maximal response rate was 27.9% (CR in 13.8%; PR in 13.8%) in intent-to-treat basis and 47.0% (CR in 23.5% and PR in 23.5%) among patients who had received at least 2 cycles of GemDOx. Stable disease was observed in 6 (20.7%) in intent-to-treat basis and 5 (29.4%) among patients who had received at least 2 cycles of GemDOx. Among patients who received 2 or more cycles, ORR was 53.4% (CR in 26.7% and PR in 26.7%) in relapsed NHL and 0% (SD in 50% and PD in 50%) in refractory NHL. Median survival and median progression-free survival were 20.526 (95% CI, 8.945–32.108) and 3.947 (95% CI, 0–10.358), respectively in all patients (Figure 1). Among patients who had completed 2 or more cycles, median survival and median progression-free survival were not reached and 10.625 (95% CI, 0–21.575), respectively. In conclusion, dose-dense biweekly GemDOx showed activity against highly unfavorable relapsed NHL, but failed to show superior overall response rate especially against refractory NHL. The main cause of failure was progressive disease although considering high drop-out rate. Disclosures: No relevant conflicts of interest to declare.

e18514 Background: We investigated the prognostic impact of bone marrow (BM) involvement in patients with diffuse large B-cell lymphoma (DLBCL) who received rituximab-based therapy. Methods: Thus, ...

Abstract 4371 Background: Although the introduction of all-trans retinoic acid (ATRA) and combined chemotherapy improved clinical outcomes of acute promyelocytic leukemia (APL), treatment failure still occur due to early death or disease relapse. The PETHEMA study suggested that the risk adopted stratification of disease risk into 3 groups (low, intermediate and high risk) according to the white blood cell (WBC; 10×109/L) and platelet counts (40×109/L) could improve treatment outcomes of APL patients. However, this stratification system needs to be validated in an independent cohort of patients. The current study attempted to validate the prognostic system based on WBC and platelet counts, hemoglobin level, risk stratification system by PETHEMA and proposed prognostic system consisting of WBC and platelet counts and hemoglobin level. Methods and patients: Total of 164 patients was included retrospectively from 5 institutes in Republic of Korea. In patients receiving Idarubicin/ATRA based combination chemotherapy. Consolidation therapy was given with Idarubicin monotherapy in 79 patients, or Idarubicin plus cytarabine in 42 patients. Result: With median follow-up of 2.94 years, the CR rate following remission induction treatment was 83.9% in overall patients, while the 3 years OS, TRM and relapse rate was 77.6±3.5%, 20.4±3.3, and 9.6±3.1%, respectively. The combined prognostic system provided better stratification of APL patients according to their prognosis compared to single variable comparison such as WBC counts, platelet counts or hemoglobin level. In addition, the risk stratification system by PETHEMA could predict OS (p=0.06) and TRM (p=0.05), but not CR rates (p=0.1) or relapse (p=0.7). However, the proposed 3 score prognostic system could provide better stratification of APL patients in term of the CR rates (p=0.01 vs 0.1 between 3 score system vs PETHEMA risk stratification), OS (p=0.02 vs. 0.06) and TRM (p=0.006 vs 0.05), but not of relapse risk (p=0.9 vs 0.7). Conclusion: This retrospective study suggested that the proposed 3 score prognostic system could provide better stratification of APL patients in term of the CR rates, OS and TRM, but not of relapse the risk. Further study will be needed to reach a clear conclusion of better prognostic stratification of APL patients with large number of patients. Disclosures: No relevant conflicts of interest to declare.

Abstract 2272 To test the correlation of trough plasma Imatinib Mesylate (IM) levels and pharmacogenomic variation with cytogenetic or molecular responses, we measured trough plasma IM levels and analyzed various genetic polymorphisms in newly diagnosed CML patients at 6 months of IM treatment and compared them with the likelihood of achieving cytogenetic complete response (CyCR) or major molecular response to standard dose of IM. Newly diagnosed 94 CML patients were prospectively enrolled in the current study. CyCR was achieved in 71 patients (75.5%). Eighty-four patients (89.4%) showed optimal response (CyCR + cytogenetic partial response CyPR) at 6 months. Trough plasma IM levels were highly variable ranging from 203 to 4980 ng/ml: mean (±SD) was 1392±78.8 ng/ml. Among 47 patients with trough plasma IM level of The impact of single nucleotide polymorphisms (SNPs) in cytochrome P450 (CYP) genes (CYP2D6, CYP3A4, CYP3A5, CYP2C9, CYP2C19, CYP2B6, CYP2C8, CYP1A2) and transporter genes (hOCT1, hOCT2, hOCT3, ABCG2, ABCC2, SLCO1B1, ABCB1) potentially associated with IM trough level was also investigated. The AA genotype in CYP2C19*2 (681G>A) was significantly associated with higher IM trough level than dominant genotype (p=0.021), whereas transporter genes did not show any significant results. The CC genotype of ABCG2 (421C>A) gene was related with CCyR (OR 3.47, 95% CI 1.09–11.05; p=0.030). In conclusion, the incidence of optimal responses in newly diagnosed CML patients who had been treated with standard dose of IM for 6 months was significantly higher in the patient group with trough plasma IM level of ≥1320 ng/ml than the group with Disclosures: No relevant conflicts of interest to declare.

Abstract 1315 Younger age is an important favorable prognostic factor to undergo HSCT in adult patients with AA, however what makes the poor survival in elderly patients is not well known. In this study we analyzed the age factor on HSCT in adult AA. A total 225 adult AA patients who had undergone HSCT were enrolled in this study. The age at the time of HSCT in 57 patients were over 40 yrs (elderly group) and 168 patients were less than 40 years (younger group). Adult over than 40 years had poor survival (5 year survival rate [5YSR] 55.1% vs. 76%; p=0.003) and this tendency maintained not only in MRD setting (5YSR 58.2 vs. 82.1%; p=0.003) but also in AD setting (4YSR 43.2% vs. 63.2%; p=0.109). We explored the prognostic factors of age over 40 years. Gender (p=0.642), prior IST (p=1.0), time from diagnosis to HSCT (p=0.348), donor type (p=0.479), HLA matching (p=0.311), ABO incompatibility (p=0.504), conditioning regimen (p=0.412), use of BM as stem cell source (p=0.456), infused CD34+ cells (p=0.478) were not different between elderly and younger groups. Compared with younger group, patients in elderly group had similar HSCT results in terms of engraft failure (p=0.848), neutrophil engraftment (p=1.0), platelet engraftment (p=0.104), SOS (p=0.591), aGvHD (p=0.445), cGvHD (p=0.105), grade of cGvHD (p=0.321), resolution of cGvHD (p=0.503) and relapse after HSCT (p=0.754). The causes of death had no statistical differences between 2 groups; infection (84.2% vs. 69.7%; p=0.328), engraft failure (5.3% vs. 21.2%; p=0.232), GvHD (20.0% vs. 18.2%; p=1.0). The more units of PC transfusion (p=0.061), more female to male matching (p=0.089), delayed time to ANC>500/μ(median 17 vs. 15 days; p=0.012) and delayed time to ANC>1000/μ(median 19 vs. 17 days; p=0.008) were noted in elderly group. Days for platelet engraftment were not different (p=0.485). Univariate analysis for survival in elderly group showed followings: gender (p=0.406); prior IST (p=0.104); donor type (p=0.475); HLA matching (p=0.052); female to male (p=0.857); ABO incompatibility (p=0.943); BM as a stem cell source (p=0.697); TBI as conditioning (p=0.467); ATG as conditioning (p=0.989); engraft failure (p=0.006); SOS (p=0.001); aGvHD (p=0.689); G3/4 aGvHD (p=0.024); cGvHD (p=0.545); extensive cGvHD (0.701). Mutivariate analysis revealed engraft failure (HR 2.839, 95% CI 1.012–7.967; p=0.047) and VOD (HR 5.972, 95% CI 1.597–22.331; p=0.008) were significant prognostic factors for survival. No prior IST, HLA full matching, successful engraftment, no SOS and no grade 3/4 aGvHD were the predictors of favorable survival in patients over 40 years old with AA. In conclusion, to prolong the HSCT survival for adult over 40 years in AA, HSCT without IST, full HLA matching, the prevention of engraft failure by using PB as a stem cell source and active management of SOS and effective GvHD prevention should be considered. Disclosures: No relevant conflicts of interest to declare.

Abstract 3687 Background: Prednisolone at a dose of 1 mg/kg/day (PRD) for 2 to 4 weeks is administered as front-line therapy to most adult patients with immune thrombocytopenia (ITP) who need to be treated. Recent results from 2 large single arm studies suggest high dose dexamethasone (DEX) as first-line treatment may produce a high sustained response rate. Therefore, we conducted prospective randomized trial comparing DEX with PRD as initial treatment of adult patients with newly diagnosed ITP. Methods: We did a randomized multicentre trial based on a 1:1 design. We enrolled treatment-naïve patients, 16 years or older, with a diagnosis of ITP according to the practice guidelines of the American Society of Hematology and a platelet count of 30×109/L or less. Patients with ITP were randomly assigned to receive either DEX 40 mg/day on day 1–4 (If the platelet count dropped below 3×109/L within the first six months, another four-day course of DEX was given) or PRD 1mg/kg/day for 4 weeks. The primary object of this study was the sustained response (platelet count>30×109/L after 6 months) rate. Second objectives are response rate at 4 weeks, predictors of steroid response, and toxicity. This study is registered at http://clinicaltrials.gov as NCT00451594. Results: From September 2005 to December 2009, 151 adults with ITP were randomly assigned (76 patients in the DEX arm, 75 patients in the PRD arm). Overall demographics were balanced between arms; Median age 44 years old (DEX:PRD 44 years old:44 years old); 69.5% female (DEX:PRD 73.7%:65.3%); median initial platelet count 17×109/L (DEX:PRD 16×109/L:17×109/L). Of 151 enrolled patients, 117 patients (57 patients in the DEX arm, 60 patients in the PRD arm) were evaluable in terms of sustained response. Sustained response rate by intention-to-treat (ITT) and per protocol were 25.0% and 33.3% in the DEX arm, 36.0% and 45.0% in the PRD arm, respectively (p=0.33 by ITT). Eight patients in the DEX arm and 17 patients in the PRD arm had a sustained platelet counts more than100×109/L. Fifteen patients had a sustained response after a single course of DEX and 6 patients among them required no further treatment during two to four year follow up. Median time to relapse in patients who had a sustained response was 1320 days and 1140 days, respectively. The response rate at day 28 was 68.2% in the DEX arm and 81.2% in the PRD arm. Pre-treatment platelet count was higher in patients who achieved sustained response (responder vs. non-responder: 17.1±7.8×109/L vs. 15.9±8.9×109/L). Eleven patients in the DEX arm and 8 patients in the PRD arm received splenectomy. Both treatments were well tolerated. Three patients represented side effects that were severe enough to discontinue the treatment in the PRD arm, including pneumonia (1), hyperglycemia (1), and myalgia (1). Six patients receiving DEX and 5 patients receiving PRD had G3 or more hyperglycemia. Conclusion: One or two courses of DEX were not more effective than PRD in adults with ITP. However, 19.7% of adult ITP had a sustained response with a single course of DEX. Initial treatment with DEX could be useful for identifying patients who may not require prolonged steroid treatment. Disclosures: No relevant conflicts of interest to declare.

Abstract 34 We performed randomized phase III study to compare the regimen related toxicities (RRT) of two different conditioning regimens, cyclophosphamide (CyATG) vs. cyclophosphamide plus fludarabine (CyFluATG) given in addition to anti-thymocyte globulin (ATG) for allogeneic hematopoietic cell transplantation (alloHSCT) for bone marrow failure syndrome including severe aplastic anemia (AA) and hypoplastic myelodysplastic syndrome (MDS). CyATG consisted of Cyclophosphamide (Cy) 50 mg/kg (D –5 to –2). CyFluATG arm received fludarabine (Flu) 30 mg/m2 (D –6 to –2) and Cy 50 mg/kg (D –3 to –2). Thymoglobuline 3 mg/kg, lymphoglobulin 15 mg/kg on days -4 to -2 or alemtuzumab 20mg on day -4 were infused in both arms. Patients were stratified by stem cell donor (related vs. unrelated). Total 83 patients (40 patients to Cy-ATG and 43 patients to Cy-Flu-ATG) were enrolled from February 2003. All patients except for one patient, who had assigned to Cy-Flu-ATG arm and died during conditioning, received full planed regimen and all planned patients were included in this analysis. Median age was 34 (15-60) years and male patients were 42/83 (50.6%). AA patients were 79 and MDS were 4. Matched sibling donors were 53 (63.9%). ATG was used in form of thymoglobulin (n=75, 90.4%), and some patients had received ALG (n=5, 6.0%) or alemtuzumab (n=3, 3.6%). Median duration from diagnosis to transplantation was 4.7 (0.2-177.7) months. Age, gender, donor type were not different in both arms (Table 1). Various TRT were similar between Cy-ATG and Cy-Flu-ATG (Table 2); granulocyte graft failure rate (p=0.959), platelet graft failure rate (p=0.625), acute GvHD (p=0.388), chronic GvHD (p=0.991), CMV antigenemia (p=0.550), hematuria (p=0.480). However, pulmonary complications (p=0.005) was significantly lower in CyFluATG arm. Infection rate (p=0.130) and sinusoidal obstruction syndrome (SOS, p=0.101) seemed lower in CyFluATG arm but were not statistically significant. Any RRTs were significantly higher in CyATG arm (80.0% vs. 39.5%; p In conclusion, overall treatment-related complications and survival were similar between CyATG CyFluATG, however, CyFluATG seemed superior over CyATG in terms of pulmonary complications and RRT.Table 1.Characteristics of patients between Cy-ATG and Cy-Flu-ATGCharacteristicsCy-ATGCy-Flu-ATGp-valueGender, n (%)0.586Male19 (47.5)23 (53.5)Female21 (52.5)20 (46.5)Age, median (range)34.5 (15±59)34.0 (18±60)0.365Months from diagnosis to SCT, median (range)4.8 (0.2–147.2)4.6 (0.9–177.7)0.982Diagnosis, n (%)0.617AA39 (97.5)40 (93.0)MDS1 (1.9)3 (7.0)Infused CD34+ cell dose (?106/kg), mean±SD5.76±4.895.25±5.300.449ATG, n (%)0.360Thymoglobulin38 (95.0)37 (86.0)ALG1 (2.5)4 (9.3)Alemtuzumab1 (2.5)2 (4.7)HLA-A, B, C and DR molecular matching, n (%)0.699Full matched30 (75.0)30 (69.8)1 locus mismatched3 (7.5)3 (7.0)2 loci mismatched3 (7.5)2 (4.7)Not determined4 (10.0)8 (18.6)Donor, n (%)0.834MSD26 (65.0)27 (62.8)AD14 (35.0)16 (37.2)Table 2.The comparison of treatment-related toxicities between Cy-ATG and Cy-Flu-ATGFactorsCy-ATGCy-Flu-ATGp-valueGraft failure, n (%)5 (12.5)7 (16.3)0.625Granulocyte1 (2.5)1 (2.3)0.959Platelet5 (12.6)7 (16.3)0.625Acute GvHD, n (%)Any grades6 (15.0)10 (23.3)0.388Grade 3/42 (5.0)1 (2.3)0.514Chronic GvHD, n (%)Any5 (12.5)5 (11.6)0.991Extensive4 (10.0)3 (7.0)0.369CMV antigenemia, n (%)24 (60.0)23 (53.5)0.550Infection, n (%)32 (80.0)28 (65.1)0.130Interstitial pneumonitis, n (%)0 (0.0)0 (0.0)–Pulmonary complications, n (%)14 (35.0)4 (9.3)0.005SOS, n (%)5 (12.5)1 (2.3)0.101Hematuria, n (%)10 (8.7)8 (29.6)0.480Any regimen-related toxicities, n (%)32 (80.0)17 (39.5) Disclosures: Off Label Use: Cyclophosphamide, Fludarabine and thymoglobulin were used in conditioning regimens of this phase III clinical trial.

Arsenic trioxide (ATO) treatment has been used in recent decades to achieve clinical remission in patients with acute promyelocytic leukemia (APL). The biological basis for ATO treatment has been explained as being mediated through anti-proliferation, anti-angiogenesis, and apoptosis in both APL and solid tumor cells. Arsenic trioxide has been shown to affect microtubules such that dysfunction of the cellular cytoskeleton is induced, which ultimately leads to cell death. In this study, we reported that ATO disrupts tubulin assembly and results in microtubule dysfunction, inducing cell death in an APL cell line. ATO markedly enhanced the depolymerization of microtubules. Analysis of posttranslational modifications of microtubules also revealed that ATO decreased modified forms of the polymerized tubulin portion in adose-dependent manner. Immunocytochemical investigation showed that ATO changed the cellular microtubule network and inhibited the formation of polymerized microtubules. These alterations in microtubules suggest that ATO increases the depolymerized form of tubulin in the cells, potentially through its effect on the attenuation of spindle dynamics. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2513.

Gefitinib (Iressa, ZD1839), a selective epidermal growth factor receptor tyrosine kinase inhibitor, inhibits growth, invasion and colony formation of various cancer cells. However, little is known about the effect of combination of gefitinib and arsenic trioxide (ATO) on differentiation of acute promyelocytic leukemia (APL). Therefore, we investigated whether gefitinib had any role in the ATO-induced differentiation of NB4 cells (APL cell line). Gefitinib induced the expression of differentiation markers including CD11b and CD14 in ATO-treated NB4 cells and facilitated ATO-induced morphologic changes and ROS generation. The results were evident that the combination of gefitinib and ATO could induce more effectively functional differentiation of leukemic cells to macrophage-like cells. Moreover, the extracellular-signal regulated kinase (ERK) pathway was necessary for the enhancement of gefitinib in ATO-induced differentiation, measured by CD11b and CD14 expression on NB4 cells. Therefore, our data indicated that gefitinib can play a potential role as an adjunctive differentiation agent in APL. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5477.

Abstract 1151 Poster Board I-173 Introduction The mainstay of treatment for chronic graft-versus-host disease (GVHD) is steroid. However, there is limited treatment option for steroid-refractory chronic GVHD. Although the pathogenesis of chronic GVHD is still uncertain, the possible relation of auto-antibodies with chronic GVHD (Patriarca F, et al. Exp Hematol 389-96, 2006) and the result from a previous pilot study (Cutler C, et al. Blood 756-762, 2006) suggested that a treatment strategy targeting against B cells might become another effective therapy for chronic GVHD. Thus, we performed a study to determine the efficacy of rituximab (Mabthera®, Roche), an anti-CD20 monoclonal chimeric antibody in patients with steroid-refractory chronic GVHD. Patients and methods This is a multicenter, open-labeled prospective phase II study performed by the Korean Society of Blood and Marrow Transplantation (NCT00472225). Patients should be diagnosed as chronic GVHD according to the criteria for clinical trials in chronic GVHD proposed by National Institutes of Health Consensus Development Project (Filipovich AH, et al. Biol Blood Marrow Transplant 945-56, 2005). The steroid-refractoriness was defined as the same severity during the last one month while patients received the equivalent of prednisone ≥0.5mg/kg per day or 1mg/kg every other day at least for 30 days or longer. The treatment schedule consists of induction (rituximab 375mg/m2 weekly IV for 4 consecutive weeks) and maintenance (rituximab 375mg/m2 monthly IV for 4 consecutive months). The response and the quality of life (SF36 questionnaire) were evaluated during the follow-up. Results 37 patients (20 male, 17 female) were evaluated, and their median age was 29 years (range 8-57 years, 7 patients from pediatrics and 30 from internal medicine). The time interval between transplantation and rituximab treatment was from 4.0 to 45.7 months. The most commonly involved organs were skin, oral cavity, eyes and lungs. The average number of involved organ per each patient was three and their average severity was grade 2-3. The median potential follow-up was 12.3 months (95% confidence interval: 12.06-12.54 months). The maximum response during follow-up was as follows: 8 complete response (21.6%), 22 partial response (59.5%), 6 no response (16.2%), and 1 disease progression (2.7%). Thus, the overall response rate was 81.1%. The dosage of steroid was reduced in all responders including complete withdrawal of steroid. The quality of life was improved in terms of physical health and mental/emotional health after treatment. However, 5 responders showed the progression of disease activity during follow-up, and infectious complications were life-threatening, thus, 8 patients died due to infections including pneumonia. The involvement of skin and oral cavity showed better response than the involvement of lungs and eyes. Conclusion The weekly administration of rituximab followed by monthly maintenance rituximab may be an effective treatment for steroid-refractory chronic GVHD, however, the active prophylaxis against infection should be considered. Disclosures No relevant conflicts of interest to declare.

Abstract 4881 Introduction The Korean Multiple Myeloma Working Party (KMMWP) initiated a nationwide registration of myeloma patients via a web page designated the “Korean Myeloma Registry.” This registry includes demographic features, characteristics of disease, treatment outcomes, and survival status. Herein, we retrospectively reviewed data representing 3,209 Korean myeloma patients. Methods Members of the registry committee of the KMMWP designed the web-based registration site for the “Korean Myeloma Registry (www.myeloma.or.kr).” A total of 3,209 patients were registered from 39 hospitals. Each one of participated hospitals registered their patients who were diagnosed as MM between the years 1999 and 2009. The approximate duration of registration was from May 2005 until March 2009; following collection, the data was downloaded for analysis. Results The median age at diagnosis was 64 years (range, 20 – 93 years) with 84 patients ' 40 years of age; this included three patients < 30 years of age (ages 20, 28, and 29 years old). Poor performance status (ECOG grade 2-3), anemia (Hgb < 10 g/dL), hypoalbuminemia (< 3.5 g/dL), and elevated serum β2 microglobulin (> 5.5 mg/dL) were more frequently observed in the > 65 years of age group than in the groups '65 years of age. Thus, an advanced ISS stage was more common in patients older than 65 years. The most common idiotype of myeloma was IgG (46.0%, 1475/3209), followed by IgA type (18.6%). Non-secretory myeloma accounted for 4.4% of cases, with IgD, IgM, and IgE subtypes being very rare. However, patients ' 40 years of age demonstrated a tendency toward a higher incidence of the IgD type (7.1%, 6/84) and light chain disease (22.6%, 19/84) compared to the other age groups. Other characteristics, including the presence of extramedullary plasmacytoma, demonstrated a similar pattern among the groups. Chromosomal studies of bone marrow aspirates were performed in 1,943 patients with 499 patients (25.7%) demonstrating abnormalities. In 60.9% of patients (1,954/3,209), an objective response to induction treatment included complete response (CR), partial response (PR), and minimal response (MR) (Table 4); 463 patients demonstrated progressive disease (PD) during induction treatment. Response could not be evaluated in 300 patients (9.3%) due to early drop out, including follow-up loss and early death. Eight hundred four patients (25.1%) received SCT. The majority of patients (23.1%, 741 patients) received autologous SCT within one year of diagnosis; designated as “early transplantation.” Autologous SCT was performed in those patients who achieved an objective response following induction treatment. Sixty three patients (2.0%) underwent autologous SCT after relapse; designated as “delayed transplantation.” Five hundred eighty patients received single autologous SCT. Tandem autologous SCT was performed in 134 patients. Allogeneic SCT was performed for 63 patients following autologous SCT. The median OS was 50.13 months (95% confidence interval (CI) of 46.20 – 54.06 months). When OS was compared according to age strata, patients '40 years of age demonstrated a prolonged OS (median OS of 71.13 months) compared with patients > 65 years of age (median OS of 36.73 months, P < 0.001). When we compared the survival of patients who received novel agents such as bortezomib or thalidomide at any time during the course of their treatments with patients who did not receive novel agents, there was a significant difference of OS between two groups (median OS 42.23 versus 55.50 months, P < 0.001). Tandem autologous SCT produced a superior OS when compared with single autologous SCT. Furthermore, patients who underwent delayed SCT demonstrated a longer OS compared with early SCT (P = 0.017). Multivariate analysis found that age > 65 years, poor performance status, platelet count < 100,000/μL, serum albumin < 3.5 g/dL, serum creatinine ≥ 2.0 mg/dL, serum β2 microglobulin ≥ 3.5 mg/dL, the presence of extramedullary plasmacytoma, and the presence of chromosomal abnormalities were all found to be independent prognostic factors for OS. Conclusion In this study, we demonstrate improved survival of patients with multiple myeloma after the introduction of novel agents and autologous stem cell transplantation. Disclosures No relevant conflicts of interest to declare.

Abstract 3796 Poster Board III-732 Therapy-related myelodysplastic syndrome (Tx-MDS) is a poorly defined disease entity with in general a poor prognosis. The natural history of Tx-MDS is not well understood. In this analysis, we evaluated patient characteristics in an attempt to define the natural history and create a prognostic model of Tx-MDS. This analysis focuses on patients with Tx-MDS that have been previously treated for other malignancies. We identified a total of 438 patients who had a history of one or more malignancies prior to diagnosis of Tx-MDS evaluated at MD Anderson Cancer Center between 1997 to 2007. Finally, 281 Tx-MDS patients were selected by identifying those that had received prior chemotherapy (CTx) and/or radiation therapy (RTx) with a prior history of other malignancy, and by eliminating non-MDS entities from WHO classification such as RAEB-T. Patient characteristics are as follows: male sex was 165 (58.7%), median age at diagnosis of MDS was 66.2 years (range 13.4-89.4). IPSS was low in n=30 (11%), INT-1 in n=87 (31.0%), INT-2 in n=120 (42.7%) and high in n=35 (12.5%). The most common cytogenetic abnormality was -5 and/or -7 (n=149, 53.1%). Seventy five patients (26.7%) were diploid. Prior cancers included: head and neck (n=7, 2.5%), thyroid (n=3, 1.1%), lung (n=7, 2.5%), breast (n=32, 11.4%), gastrointestinal (n=13, 4.6%), prostate (n=34, 12.1%), other genitourinary or gynecological (n=16, 5.7%), melanoma/skin cancers (n=5, 1.8%), sarcomas (n=8, 2.8%), other solid cancers (n=2, 0.7%), lymphoma (n=102, 36.3%), CML/CLL (n=6, 2.1%), AML/ALL (n=5, 1.8%), multiple myeloma (n=11, 3.9%) and multiple cancers (n=30, 10.7%). Prior Tx was CTx only (n=107, 38.1%), RTx only (n=73, 26.0%) or both CTx and RTx (n=101, 35.9%). A total of 54 patients had received hematopoietic stem cell transplantation (HSCT) (autologous n=52 (18.5%); allogeneic n=2 (0.7%)). Potential prognostic factors were selected by univariate analyses and validated by multivariate analysis. The final prognostic factors were incorported into a prognostic model of Tx-MDS. We also evaluated the impact of specific forms of therapy in outcome in Tx-MDS. Univariate analyses for better survival revealed that presence of hepatomeglay (no hepatomegaly vs. hepatomegaly; Median 10.7 vs. 1.7 months (M); 95% confidence interval [CI] 0-5.8 vs. 8.7-12.7M; p=0.023), chromosome alterations (8+, 20q-, Y-, normal vs. others; median 22.1M vs. 8.2M ; 95% CI 17.0-27.2 vs. 6.9-9.5M; p6Y; median 13.3 vs. 10.6; 95% CI 5.4-21.2 vs. 6.8-14.4; p=0.027), treatment line(s) of therapy (1 vs. ≥2; median 14.4 vs. 8.6M; 95% CI 10.1-18.8 vs. 5.5-11.7M; p=0.011), serum albumin (≥4 vs. 3mg/L; median 12.2 vs. 9.1M; 95% CI 8.2-16.2 vs. 6.3-11.8M; p=0.015), serum creatitine (≤1 vs. >1mg/dL; median 11.9 vs. 10.2M; 95% CI 7.1-16.7 vs. 8.1-12.3M; p=0.061), ECOG performance status (0-1 vs. ≥2; median 11.8 vs. 5.5M; 95% CI 9.7-14.0 vs. 2.4-8.6M; p Disclosures: No relevant conflicts of interest to declare.