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Background Low-dose metronomic cyclophosphamide chemotherapy is an emerging strategy offering a potentially less toxic yet effective treatment modality. We evaluated the efficacy and safety of low-dose metronomic cyclophosphamide in patients with low grade non-Hodgkin lymphoma (NHL) by retrospectively reviewing the data. Method The patients received oral cyclophosphamide (50 mg per day) and/or oral methotrexate (2.5 mg twice weekly) until disease progression or unacceptable toxicity was noted. Results Of the 36 patients, 17 (47.2%) were male, median age was 66.4 years (range, 37-91 years), and subtypes of NHL were mucosa associated lymphoid tissue lymphoma (55.6%), small lymphocytic lymphoma (13.9%), follicular lymphoma (11.1%), mantle cell lymphoma (8.3%), nodal marginal zone lymphoma (4.5%), splenic marginal zone lymphoma (2.8%), and lymphoplasmacytic lymphoma (2.8%). The stage I, II, III, IV were 38.9%, 13.9%, 11.1%, 36.1%, respectively and 55.6% of patients received this regimen as the first-line treatment, mainly due to frailty, refusal to standard chemotherapy. The overall best response rate (ORR) was 73.5% (12 complete responses, CRs and 13 partial responses, PRs), with 29.1 months of the median duration of response and the disease control rate was 88.2%. The median treatment duration was 8.8 months (range, 0.1-38.4 months); the median progression-free survival (PFS) was 43.5 months, and the median overall survival (OS) was not yet reached. Especially, the ORR in patients who were treated with metronomic cyclophosphamide as the first line treatment and as more than the second line treatment were 78.9% (10 CRs, 5 PRs) and 66.6% (2 CRs, 9 PRs), respectively. The median PFS were not reached in the first line cyclophosphamide treatment group and 26.5 months (range, 5.7-47.2 months) in the other group (p=0.110), and similarly, the median OS were not reached and 64.4 months (0-135.7 months) (p=0.058), respectively. The regimen was generally well tolerated, with small numbers of grade 3-4 toxicities; neutropenia (2%), anemia (3%), thrombocytopenia (3%), fatigue (4%), and anorexia (1%). Conclusion We concluded that low-dose metronomic cyclophosphamide represents efficacious and well-tolerated treatment for low-grade NHL patients. Disclosures No relevant conflicts of interest to declare.

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

Introduction Dasatinib, a second-generation tyrosine kinase inhibitor (TKI), has been administered at a fixed starting dose of 100 mg once daily for patients with chronic myeloid leukemia in chronic phase (CP-CML). However, the relationships between TKI exposure, and safety and efficacy responses suggest that such fixed dosing may not be optimal for many Asian patients. In this study, the relationships between the starting dose of dasatinib adjusted for BW (Dose/BW), and dose limiting toxicities (DLTs) and molecular responses (MRs) were evaluated to develop an initial dosing strategy of dasatinib. Methods The safety and efficacy responses of dasatinib therapy were explored from the clinical data obtained in patients newly diagnosed with CP-CML at seventeen hospitals in South Korea. The safety response was assessed as the occurrence of first DLTs by 36 months that required an interruption in dasatinib therapy. The efficacy responses were evaluated as the achievement of MR at 3 months (MR1), 6 months (MR2), 12 months (major molecular response, MMR) and 24 months (deep molecular response, MR4.5). The rates and patterns of DLT occurrence and MR achievement by 36 months were examined using a Kaplan-Meier method. A logistic regression method was used to determine the effect of the Dose/BW of dasatinib on the occurrence of first DLTs or the achievement of MRs. A chi-square test for trend was used to assess the trend of DLT occurrence and MR achievement in patient subgroups divided into quartiles (Q1 to Q4) based on Dose/BW. Results The clinical data were obtained from a total of 102 Asian patients with CP-CML whose median BW was 64.0 kg (range, 37.8 to 106.0 kg) and Dose/BW 1.60 mg/kg (1.00 to 2.80 mg/kg). Safety. The most frequent DLTs were thrombocytopenia (46%), pericardial or pleural effusion (31%) and anemia (7%); the median time of occurrence for the DLTs were 29 days (range, 7 to 417 days), 336 days (7 to 681 days) and 35 days (10 to 140 days), respectively. The rate of DLT occurred first increased rapidly by four months of starting dasatinib therapy and then steadily by 28 months until reaching approximately 56% in the Kaplan-Meier curve. Patients with higher Dose/BW had a greater risk of DLT occurrence by 36 months as determined using a logistic regression (logit [P] = 1.58 × [Dose/BW] - 2.27, p = 0.03). As Dose/BW increases from Q1 to Q4 (median Dose/BW; 1.23, 1.45, 1.65 and 2.00 mg/kg, respectively), the rate of DLTs rises from 43.5% (Q1) to 66.7% (Q4) with a statistically significant trend of increment (p = 0.03). The median dose that would produce the lowest rate of DLTs is 78.7 mg as calculated by multiplying the median Dose/BW of Q1 (1.23 mg/kg) by the median BW of patients (64.0 kg). Efficacy. The achievement rates of MMR and MR4.5 increased continuously and reached 82% and 43%, respectively, by 36 months of starting dasatinib therapy. The Dose/BW of dasatinib did not affect the rates of MR achievements based on a logistic regression analysis. Even though Dose/BW increased, the achievement rates of MR1, MR2 and MMR demonstrated neither an increasing nor a decreasing trend from Q1 to Q4. Conclusion The higher the starting Dose/BW of dasatinib, the greater is the risk of DLT occurrence without improving the potential for MR achievement. Therefore, in order to minimize the risk of DLTs without compromising MRs, a lower starting dose of dasatinib 80 mg once daily is suggested for Asian patients with CP-CML especially with lighter BW. Disclosures Kim: ILYANG: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sun Pharma.: Research Funding.

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

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

Background: Reactivation of hepatitis B virus (HBV) is a well-recognized complication in patients with chronic HBV infection undergoing cytotoxic or immunosuppressive therapy. Currently, BCR-ABL1 tyrosine kinase inhibitors (TKIs) have been a standard of first-line treatment for chronic myeloid leukemia (CML) about last two decades. As there have been several case reports of HBV reactivation in CML patients treated with TKIs, the test for hepatitis B infection before initiating TKIs is recommended. Therefore, this study aimed to evaluate the risk of HBV reactivation in a large cohort of CML patients on TKIs treatment. Methods: We retrospectively reviewed the medical records of 1817 patients, who were diagnosed with CML and had available HBV serology between 2001 and 2017 from St. Mary's Hospital, Seoul, Korea. Results: Among 1817 patients, 76 patients (4.2%) were HBs-antigen (HBs-Ag) positive and 1741 (95.2%) were HBs-Ag negative. 302 patients (17.3%) of 1741 HBs-Ag negative patients were HBc-antibody positive indicating past infection of HBV. After exclusion of 7 patients who did not receive TKIs treatment, 69 patients were analyzed for HBV reactivation. The median age at diagnosis of CML was 42 (range 21-73) years and 44 (64%) were males. Median duration of follow-up from the recognition of HBs-Ag was 66.7 months (range, 2.4 - 192.7 months). Of 69 patients, a patient had been on antiviral therapy for chronic HBV infection before the diagnosis of CML. Eighteen patients (26% of 68) received antiviral prophylaxis prior to or concomitantly with the initiation of TKIs. Additional 4 patients were simultaneously initiated antiviral treatment with TKIs due to the evidence of active HBV infection such as the high titer of HBV DNA or elevated level of Alanine aminotransferase. Among 46 patients who did not receive antiviral prophylaxis, 12 patients (26%; 95% CI, 12-36%) eventually required antiviral treatment due to the development of active HBV hepatitis while on TKI therapy. HBV reactivation according to each TKI treatment was developed in 7 patients with imatinib, 2 patients in dasatinib, 1 patient in nilotinib, and 1 patient in radotinib therapy. One patient developed HBV reactivation permanently discontinued TKI therapy. Median time to HBV reactivation from CML diagnosis was 22.1 (range, 6.3-124.6 months) months. Median duration of antiviral therapy of 35 patients who received antiviral therapy was 38.2 months (95% CI, 25.7 ~ 50.7 months). 9 patients were off antiviral therapy at the last follow-up, 5 patients from prophylaxis group and 4 patients from treatment group. There was no difference in the duration of antiviral treatment between prophylactic and treatment groups. The initial choice of antiviral therapy as prophylaxis or treatment were entecavir for 14 (41% of 34), lamivudine for 8 (24%), tenofovir for 8 (24%), telbivudine for 3 (9%), and adefovir for 1 (3%). Conclusion: We evaluated HBV reactivation in a large cohort of HBs-Ag positive patients with CML from a single center, who received TKIs treatment. The reactivation rate of HBV was high at 26% without antiviral prophylaxis, which strongly support the routine screening of HBV serology prior to initiation of TKI therapy to identify HBs-Ag positive patients and the close monitoring of hepatic functions and HBV serology during TKI therapy. Given the high incidence of HBV reactivation with TKI treatment, concomitant antiviral prophylaxis with TKIs should be considered in HBs-Ag positive patients receiving TKI treatment. Figure. Figure. Disclosures Kim: Ilyang: Research Funding; Novartis: Research Funding; BMS: Research Funding; Pfizer: Research Funding.

Background: Although several studies have demonstrated that BCR-ABL1 transcript levels at 3 months were prognostically significant in patients treated with frontline imatinib (IM) and second-generation tyrosine kinase inhibitors (2G-TKIs), the decision to change treatment based on early molecular response (EMR) status remain under investigaiton. Because CML patients currently have multiple treatment options, the impact of early molecular milestones on long-term outcomes needs to be determined in each agent treated patients. Aims: The aim of this study is to evaluate the impact of 3-month early molecular response (EMR) on long-term outcomes of CML patients treated with IM and different 2G-TKIs, as additional information to guide clinical decisions on switching to a different TKI. Methods: 734 new CP CML patients who were treated with frontline IM (n = 366) or 2G TKIs (n = 368) were analyzed. Molecular responses were monitored using qRT-PCR assay in 3 month intervals by achieving major molecular response (MMR), and then 6 month intervals after achieving MMR. Main study objectives were to evaluate the long-term outcomes, including failure-free survival (FFS), progression-free survival (PFS), and overall survival (OS), according to 3-month EMR. FFS was measured from the date of treatment start until death, progression to AP or BP, or ELN failure on treatment, whichever came first. PFS and OS collected survivals on patients who were treated with other TKIs after frontline therapy discontinuation. Results: A total of 734 patients were treated with imatinib (IM; n = 366), dasatinib (DAS; n = 141), nilotinib (NIL; n = 89), and radotinib (RAD; n = 138). The median age was 43 years (range, 11-87). The percentages of patients with low, intermediate, and high Sokal risk scores were 37%, 38% and 23%, respectively, with 2% unknown risk. With a median follow-up of 85.6 (IM; range, 4.4-207.5) and 38.9 (2G-TKIs; range, 11.6-130.2) months, 460 (62.7%; 182 IM and 218 2G-TKIs) patients continue on the frontline therapy and 274 (37.3%) patients were permanently discontinued or changed to other TKIs due to intolerance (73 IM, 38 DAS, 2 NIL, 28 RAD), ELN failure (32 IM, 3 DAS, 2 NIL, 3 RAD), progression (3 IM, 1 DAS, 1 RAD), and others (60 warning, 3 pregnancy, 14 treatment-free remission study, and 9 follow-up loss). In 366 patients treated with IM, patients achieving BCR-ABL1 ≤ 10% at 3 months (n = 275, 75.1%) had a better outcomes in terms of 8-y OS (97.4% vs 89.7%, P 10%. In 368 patients treated with 2G-TKIs, achievement of 3-month EMR (n = 331, 90.0%) was associated with a higher 8-y OS (98.6% vs 91.9%, P Conclusions: Our data showed that EMR failure at 3 months could translate into poor survival outcomes in patients treated with frontline IM and 2G-TKIs.However, to confirm the benefit of an early switch of therapy, further investigations in a larger patient population with longer follow-up are needed. Disclosures Kim: Pfizer: Research Funding; BMS: Research Funding; Novartis: Research Funding; Ilyang: Research Funding.

Background With first-line imatinib (IM) therapy, approximately 50% of CP CML patients achieve undetectable molecular residual disease (UMRD). The recent several discontinuation clinical trials have demonstrated 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, we have reported that of 90 patients with follow-up ≥12 months, the probability of sustained major molecular response (MMR) at 12 months and 24 months was 62.2% and 58.5%, respectively. However, currently, the issue on the occurrence of late relapse with a long-term follow-up after IM discontinuation is important. Therefore, here we analyzed the long-term follow-up results of the KID study. Methods CP CML patients who were treated with IM for more than 3 years and had undetectable levels of BCR-ABL1 transcripts determined by quantitative reverse transcriptase polymerase chain reaction for at least 2 years were eligible for KID study. After IM discontinuation, the molecular response was monitored using the following schedule: every month for the first 6 months, every 2 months up to 12 months, and every 3 months thereafter. In cases of MMR loss after 2 consecutive assessments (molecular relapse), IM treatment was re-introduced. Results Between October 2010 and June 2015, a total of 126 patients (70 females, 56 males) were enrolled on KID Study, with a median age of 47 years (range, 18 - 82), the percentages of patients with low, intermediate and high Sokal risk scores were 33%, 25% and 15%, respectively with unknown Sokal risk scores in 27%. And the median time on IM therapy and the median duration of sustained UMRD prior to discontinuation were 83 months (range, 32 - 141) and 41 months (range, 22 - 131), respectively. After a median follow-up of 43 months (range, 4.9 - 93.6) after IM discontinuation, 55 patients lost MMR in 2 consecutive analyses at a median time of 3 months (range, 0.9 - 53.2 months). The 12-month and overall probability of sustained MMR was 61.9 ± 4.3% and 55.1 ± 4.6%, respectively. UMRD (P = 0.001) and IM duration on treatment (P = 0.003) were associated with the probability of sustained MMR. Out of 55 patients with molecular relapse, 53 patients (except 2 patients with follow-up loss) were re-treated with IM for a median of 31.7 months (range, 5.8 - 82.9 months), 51 patients re-achieved MMR at a median of 1.9 months (range, 0.0 - 5.4 months) after resuming IM therapy and 48 of these patients re-achieved UMRD at a median of 5.8 months (range, 0.9 - 19.7 months). 2 patients who re-achieving of MMR after resuming IM therapy lost MMR again; One patient with 45.8 and 40.3 months of IM therapy duration and sustained UMRD duration prior to discontinuation, respectively lost MMR at 7.4 months after IM discontinuation and re-achieved MMR 1.7 later after IM restarting, but MMR was lost again on the assessment 8 months later. Another patient with 122.2 and 30.4 months of IM therapy duration and sustained UMRD duration prior to discontinuation, respectively relapsed at 53.2 months after IM discontinuation. Despite re-achieving MMR 1.4 later after IM restarting, the patient suddenly progressed to blast crisis at 6 months after restarting IM. Conclusions Our results showed that IM discontinuation can be applied with approximately 55% of probability of sustained MMR in the long term. Although sudden blast crisis occurring in responding patients with CML has already been reported in IM therapy, event of progression to BC in a clinical trial of IM discontinuation deserves to be followed-up with caution. Overall, both UMRD and IM duration on treatment were the most important predictors for successful IM-off. Disclosures Kim: Pfizer: Research Funding; Ilyang: Research Funding; Novartis: Research Funding; BMS: Research Funding.

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

Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL), a member of the tumor necrosis factor (TNF) family, binds to several cell-surface receptors with distinct functions (agonistic receptors 1 and 2 [TRAIL-R1, TRAIL-R2]; decoy receptors 3 and 4 [TRAIL-R3, TRAIL-R4]). Expression and function was characterized in patients with myelodysplastic syndromes (MDSs). While normal marrow showed negligible expression of TRAIL and receptors (except TRAIL-R3), TRAIL and all receptors were constitutively expressed in MDS marrow. Following TRAIL exposure, MDS marrow showed significant increases in apoptosis, whereas normal marrow, except for a subset of CD34+ precursors, did not (P = .012). Marrow from 21 patients with MDS was then propagated in long-term cultures in the presence or absence of TRAIL. While in advanced MDS (refractory anemia with excess blasts in transformation [RAEB-T] and tAML [MDS transformed into AML]), colony numbers decreased in the presence of TRAIL (63.0% ± 10.4% of untreated group [100%]), numbers increased in patients with RA or RAEB (160.2% ± 90.5% of untreated group). TRAIL eliminated preferentially clonally abnormal cells as identified by chromosomal markers. Thus, TRAIL and receptor expression differed significantly between normal and MDS marrow, and TRAIL modulated in vitro hemopoiesis in MDS dependent upon disease stage but not, to a detectable extent, in normal marrow.

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

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

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 x 3d) improved both complete remission (CR) rate and survival duration compared to standard daunorubicin dose (45 mg/m2/d x 3d) (Lee JH et al. Blood 2011;118:3832). As it is necessary to compare the effects of high-dose daunorubicin with that of other agents, especially idarubicin, we performed another randomized trial comparing two induction regimens in young adults with AML: idarubicin vs. high-dose daunorubicin (ClinicalTrials.gov #NCT01145846). Here, we present final results of the study. Methods: Between May 2010 and March 2014, a total of 316 patients (65 years or younger) with newly diagnosed AML except acute promyelocytic leukemia were registered in this study. Seventeen patients were removed from the study (change of diagnosis in 11, patient's refusal to be randomized in 3 and other in 3) and the remaining 299 patients were analyzed. After random assignments, 149 patients received idarubicin (AI, 12 mg/m2/d x 3d) and 150 patients received high-dose daunorubicin (AD, 90 mg/m2/d x 3d) in addition to cytarabine (200 mg/m2/d x 7d) for induction of CR. Patients with persistent leukemia received the second attempt of induction chemotherapy, consisting of idarubicin (AI, 12 mg/m2/d x 2d) or daunorubicin (AD, 45 mg/m2/d x 2d) plus cytarabine (5d). Patients who attained CR received 4 cycles of high-dose cytarabine (3 g/m2 x 6 doses) in patients with good- or intermediate-risk cytogenetics and 4 cycles of cytarabine (1 g/m2 x 6d) plus etoposide (150 mg/m2 x 3d) in those with high-risk cytogenetics. Hematopoietic cell transplantation (HCT) was performed according to attending physician's discretion after one or two cycles of consolidation chemotherapy in most transplant cases. Results: CR was induced in 232 (77.6%) of 299 patients. Reasons for induction failure were resistant disease in 50, hypoplastic death in 5, and indeterminate cause in 12. As postremission therapy, 3 patients received no further treatment, 71 received consolidation chemotherapy without HCT, 137 underwent allogeneic HCT, and 21 underwent autologous HCT. The CR rates were not significantly different between two arms: 80.5% (120 of 149, AI) vs. 74.7% (112 of 150, AD) (P=0.224). With a median follow-up of 1046 days, overall survival probabilities at 4 years were 51.1% in AI vs. 54.7% in AD (P=0.756). The probabilities at 4 years for relapse-free survival were 63.5% in AI vs. 74.2% in AD (P=0.181) and those for event-free survival were 44.8% in AI vs. 50.7% in AD (P=0.738). Toxicity profiles were similar between two arms. Interestingly, overall and event-free survivals of 44 patients with FLT-ITD mutants (27 in AI and 17 in AD) were significantly different according to the induction regimens (AI vs AD; overall survival, 30.8% vs. 61.9%, P=0.030; event-free survival, 31.4% vs. 61.9%, P=0.025). Conclusions: The results of this phase 3 trial, which compared idarubicin (12 mg/m2/d x 3d) with high-dose daunorubicin (90 mg/m2/d x 3d), did not show significant differences between two arms in the outcomes of patients in terms of CR rates and overall, relapse-free or event-free survivals. In subset analysis, high-dose daunorubicin seems to be more effective than idarubicin in patients with FLT-ITD mutants. Disclosures Kim: Celgene: Research Funding; Alexion Pharmaceuticals: Research Funding; Il-Yang: Research Funding; Novartis: Research Funding.

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

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

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

Background: Uncontrolled complement activation has a major role in the pathogenesis of atypical HUS (aHUS) and the restraint of this process by eculizumab is life saving. However, the evidence of complement dysregulation in the pathogenesis of Thrombotic Thrombocytopenic Purpura (TTP) is still unclear. In this study we examined the presence of complement activation biomarkers in patients with aHUS and TTP and the levels were compared to normal healthy controls . Patients and Methods: Patients with thrombotic microangiopathic thrombocytopenia diagnosed either as TTP with low ADAMTS13 activity less than 10% or aHUS with impaired renal function, Cr> 2mg/dL and normal ADAMTS13 activity were chosen from the Korean TTP registry from February 2012 to June 2014. Prospective plasma and serum samples prior to intervention were collected from newly diagnosed patients with TTP (n=20), aHUS (n=20), and 20 healthy controls and frozen at -700C. Complement activation products (C3a, Bb as alternative pathway; C4d as classic pathway; C5a, C5b-9; terminal pathway) were measured by ELISA. Results: Significantly increased levels of Bb and C5b-9 were observed in TTP (median [range], ng/mL; Bb, 1220 [540.0 – 16560], p=0.048; C5b - 9, 390.1 [238.5 - 938.7], p Conclusion: Complement biomarkers are activated to a similar level in both newly diagnosed cases of TTP and aHUS. Complement activation product levels did not differentiate aHUS from TTP. 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.

Abstract 1691 Dasatinib and nilotinib have been founded to be effective and well-tolerated in patients who develop resistance or intolerance to imatinib. Not enough data are currently available to recommend one over the other as the preferred second-line therapy based on efficacy data. Therefore we planned a multicenter retrospective study to analyze the efficacy and safety of dasatinib and nilotinib in patients with imatinib-resistant or –intolerant chronic myeloid leukemia in chronic phase. In this Korean multicenter study, 126 patients imatinib-resistant or –intolerant chronic myeloid leukemia in chronic phase were treated with dasatinib (n=76) or nilotinib (n=50) The purpose of this study was to compare rates of cytogenetic and molecular response rate, event-free survival (EFS), progression-free survival (PFS) and overall survival (OS), and toxicities of nilotinib and dasatinib treatment of imatinib-resistant or –intolerant chronic myeloid leukemia in chronic phase. PFS was defined as the time from the start of treatment to the earliest date of any of following event: loss of complete hematologic response (CHR), loss of major cytogenetic response (MCyR), progression to accelerated phase (AP) or blastic phase (BP), discontinuation due to treatment failure as assessed by the clinician, and death from any cause on therapy. Event was defined by any one of the following: loss of CHR, loss of MCyR, progression to AP or BP, discontinuation due to treatment failure as assessed by the clinician, treatment discontinuation due to toxicity, and death from any cause on therapy. For dasatinib and nilotinib group, median ages (51 years old vs. 53), median durations of CML (23.7 months vs. 19.8 ) before receiving dasatinib or nilotinib and duration of prior imatinib treatment (21.7 months vs 17.7) were comparable. Nilotinib group had a higher proportion of intermediate and high sokal scores at the time of diagnosis than dasatinib group (41.5 vs 29.3% (high), 41.5% vs 32.5%(intermediate), 17.1% vs 37.9(low), p= 0.04). After median follow-up durations of 20.2 months of dasatinib group and 25.3 months of nilotinib group, the rates of major molecular response were 50.0% for dasatinib group and 59.6% for nilotinib group (p=NS) and the rates of MCyR (complete and partial cytogenetic response) were 78.4% for dasatinib group and 74.5% for nilotinib group (p=NS). The estimated EFS at 24 months was 67% and 48% in dasatinib and nilotinib group, respectively. (p Disclosures: No relevant conflicts of interest to declare.

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

Abstract 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 2765 In CML, achievement of major molecular response (MMR) is a significant prognostic factor as it has been shown to be associated with longer duration of complete cytogenetic response (CCyR) and long-term progression-free survival. In IRIS study, patients who achieved both CCyR and MMR showed higher progression-free survival rates, compared to those who had CCyR without MMR. Higher doses of imatinib are expected to yield higher CCyR and MMR rates, compared to standard dose of imatinib, and second-generation tyrosine kinase inhibitor, nilotinib also produces high CCyR and MMR rates in patients with CP CML who are resistant to imatinib. In this prospective study, the efficacy of nilotinib and high-dose imatinib was investigated in suboptimal molecular responders who received standard-dose imatinib as first-line therapy. Early CP CML patients who have achieved CCyR but no MMR after at least 18 months and up to 24 months (≥ 18 to ≤ 24 months) on first-line imatinib therapy at a daily dose of 400 mg were enrolled in this clinical trial, and informed consents were obtained from all patients prior to participation. In nilotinib arm, patients received oral dose of 400 mg BID (800 mg/day), and patients received 800 mg/day administrated as 400 mg BID in imatinib dose-escalation arm. To assess the drug efficacy, cytogenetics and RQ-PCR analysis were performed at regular intervals, and baseline mutational analysis was conducted for every patient with subsequent mutational analyses performed in patients demonstrating either lack of response or disease progression. Primary endpoint is to evaluate the cumulative MMR rates by 12 months, and secondary endpoints are to evaluate the cumulative CMR rates and time to and duration of MMR and CMR during further 24 month follow-up. Progression-free survival and safety profiles will also be assessed as secondary endpoints. Patients showing lack of response (lack of complete hematologic response (CHR) at 6 months, increasing WBC, no major cytogenetic response (MCyR) at 24 months), loss of response (loss of CHR or MCyR) or severe intolerance to treatment were allowed to crossover to the alternative treatment arm. With a data cut-off date of 18 Jul 2011, a total of 30 patients were randomized into nilotinib arm (n =13) or imatinib arm (n = 17), and 6 patients have crossed-over to nilotinib arm due to lack of response. With a median follow-up of 11 months (range, 0.2–28 mos), all patients have maintained CCyR without progression to advanced disease, and progressive decrease in BCR-ABL transcript levels was observed in all patients. Cumulative MMR rates at 20 months were significantly higher in nilotinib arm compared to imatinib dose-escalation arm (59.00% vs. 27.40%, P = 0.047), and patients treated with nilotinib also showed faster molecular response rates, with 5 patients achieving MMR within 3 months of nilotinib therapy. At the last follow-up, 7/13 (53.85%) and 2/11 (18.18%) patients achieved MMR in nilotinib arm and in high-dose imatinib arm, respectively, with 1 patient in nilotinib arm achieving 4-log reduction of BCR-ABL transcripts. Although toxicity was observed more frequently in imatinib dose-escalation arm, all patients currently maintain the initial dose (except 1 patient who interrupted imatinib therapy due to neurosurgical operation), and based on the toxicity data, no additional or serious adverse events were developed except for pre-existing toxicities before randomization. These preliminary results demonstrate that early intervention using nilotinib or dose escalation of imatinib could be recommended in suboptimal molecular responders, with nilotinib being more preferable. Through further clinical investigation on a large patient population and longer period of observation, efficacy and safety of early intervention of suboptimal molecular response using nilotinib or dose escalation of imatinib will be assessed. Updated data with longer follow-up duration will be presented in the meeting. Disclosures: Woodman: Novartis: Employment, Equity Ownership. Szczudlo:Novartis: Employment, Equity Ownership. Kim:Novartis: Employment.

Abstract 2661 Background. In lymphoma, bone marrow (BM) involvement is a sign of extensive disease and BM biopsy is a standard method in the evaluation of BM infiltration by disease. Because of patchy BM involvement pattern by lymphoma, the reported rates of unilateral involvement in bilateral biopsies range from 10% to 50%. However BM biopsy is an invasive and painful procedure. The value of unilateral versus bilateral BM biopsy remains controversial. Fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET-CT) is a noninvasive imaging technique and currently it shows potential to detect BM involvement by lymphoma. Aims. We assess the abilities of FDG PET-CT to ascertain the presence of BM involvement in diffuse large B cell lymphoma (DLBCL) patients and to define the possibility that bilateral BM biopsies could be replaced by unilateral biopsy for DLBCL staging workup. Methods. We retrospectively reviewed medical records of histologically proven DLBCL patients from 2004 through 2010 at the Asan Medical Center and Hallym University Medical Center. All patients were examined by FDG PET-CT and bilateral BM biopsy at both posterior iliac crests for initial staging workup. Evaluation of PET studies was performed by board-certified nuclear medicine physicians of each institution. Quantitative analysis of FDG uptake was not performed. Data were expressed in terms of sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for FDG PET-CT in evaluation of BM involvement by DLBCL, using BM biopsy as the reference standard. Two sets (right & left biopsy site) of pathologic and imaging data were analyzed separately. Results. Study population comprised 478 patients (median age 57, range 17–85 years; 269 male) with newly diagnosed DLBCL. Ann Arbor stage I, II, III and IV patients were 96, 120, 40 and 222, respectively. Overall, BM involvement by DLBCL that confirmed by bilateral BM biopsy occurred in 63 patients (13.2%, 15, 12, and 36 at right, left and both side biopsy, respectively). From the data of right side biopsy and FDG PET-CT images, comparison of the former and the later results revealed concordant positive findings in 22 cases (4.6%) and concordant negative findings in another 418 cases (87.4%). In 29 patients (6.1%) in whom FDG PET-CT returned findings of normal marrow, iliac crest BM biopsy revealed lymphomatous infiltration. On the other hand, in 9 patients (1.9%) in whom bilateral iliac crest BM biopsy had failed to reveal any abnormality, FDG PET-CT showed increased uptake. The calculated values for FDG PET-CT in evaluation of right BM infiltration were 43.1% (22/51) of sensitivity, 97.9% (418/427) of specificity, 71% (22/31) of PPV and 93.5% (418/447) of NPV. The values oriented from left BM biopsy and FDG PET-CT images were similar (sensitivity 41.7% (20/48), specificity 97.9% (421/430), PPV 69% (20/29), NPV 93.7% (421/449)). Conclusions. This study has the largest DLBCL cases among ever reported articles, and demonstrates not excellent sensitivity of FDG PET-CT against the results of BM biopsy for the detection of BM involvement in DLBCL patients. BM biopsy could not be completely replaced with FDG PET-CT. But it has relatively good PPV, FDG PET-CT will be a useful tool for image-guided biopsy for DLBCL staging. And in daily practice, clinicians could consider the possibility to do efficient unilateral BM biopsy for DLBCL patients who have increased posterior iliac crest FDG uptake, instead of bilateral biopsy. Disclosures: Kim: Novartis: Research Funding.

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 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.

Abstract 2778 Poster Board II-754 Introduction: Interstitial deletions involving the long arm of chromosome 5, one of the good prognostic factors, are the most common chromosomal abnormality either as a sole or in combination with other abnormalities in myelodysplastic syndromes (MDS). However, the prognostic impact of del(5q) accompanied by additional chromosome abnormalities remains controversial. We investigated the hematologic, cytogenetic and prognostic features of del(5q) in MDS. Also, we mapped the deleted region on 5q by fluorescence in situ hybridization (FISH), whether the difference of deleted region between 5q- syndrome and MDS with del(5q) accompanied by additional abnormalities makes the clinical and prognostic differences. Methods: 137 adult patients, newly diagnosed as de novo MDS in Seoul National University Hospital from April 2000 through March 2009, were enrolled. We reclassified MDS subtypes according to WHO classification 2008. To compare the hematologic, cytogenetic and prognostic features according to presence of del(5q), we categorized the patients with del(5q) into 3 groups: patients with additional chromosomal abnormalities with del(5q) as 'MDS with del(5q)'; patients with other chromosomal abnormalities other than del(5q) as 'MDS with other chromosomal abnormalities (CA)'; and patients with isolated del(5q) as '5q- syndrome'. Also, the mapping with FISH for EGR1, CSF1R, and PDGFRβ on 5q, was performed in conjunction with G-banding to all patients and additional 16 patients with alleged del(5q) by G-banding from Korean MDS working party. Results: According to the new WHO classification of 2008, the 33 refractory anemia patients according to the previous WHO classification of 2001 were reclassified into refractory cytopenias with unilineage dysplasia (13 patients), refractory cytopenia with multilineage dysplasia (six patients) and MDS - unclassified (14 patients) (Fig 1). The median age of Korean MDS was 59 years, and the frequencies of 5q- syndrome and 5q deletion was 2.2% (3/137 patients) and 15.3%, respectively. Among 137 patients, 17 patients were grouped into 'MDS with del(5q)', and 53 patients into 'MDS with other CA'. The 'MDS with del(5q)' were significantly older and showed higher % of blasts in PB and BM than 'MDS with other CA'. And, they were categorized into higher risk group according to the International Prognostic Scoring System (IPSS) (Table 1). As a results of mapping for EGR1, PDGFRβ and CSF1R, deletion of all 3 regions was 93.3% in patients of 'MDS with del(5q)' and 66.7% in patients of '5q- syndrome', showing no difference in deleted genes between the two groups. Half (53%) of patients of 'MDS with del(5q)' accompanied complex abnormalities including chromosome 7 abnormalities. The del(5q) was detected only by FISH, showing discrepant results between G-banding and FISH analysis. Especially, marker chromosomes by G-banding in some patients were proved to be chromosome 5 with del(5q) by FISH. Conclusion: The biologic and prognostic features of MDS in Korea seem to be markedly different from those of Caucasian; younger age and low frequency of 5q- syndrome. The incidence of complex cytogenetic abnormalities including del(5q) was higher than that of Caucasian, while that of isolated del(5q) was quite low in Korea, which can explain that higher proportion of MDS with del(5q) belongs to higher risk IPSS group. And, we suggest FISH for del(5q) at initial diagnosis and during follow-up after treatment of MDS with alleged del(5q), since the presence of del(5q) in MDS is important for choosing the lenalidomide treatment. Disclosures: No relevant conflicts of interest to declare.

Abstract 2072 Poster Board II-49 Backgrounds Currently, there are many efforts to design risk-adapted strategies in newly diagnosed acute promyelocytic leukemia (APL) by modulating treatment intensity and those seem to be an efficient approach to minimize treatment-related morbidity and mortality (TRM) while maintain the potential in cure for each relapse-risk group. We had postulated that maintaining of Ara-C during induction therapy might have acceptable toxicities yet obtaining good CR in newly diagnosed APL, and idarubicin alone during consolidation periods might have excellent LFS and OS with low relapse rate. Patients and Methods Eighty six patients with newly diagnosed APL were enrolled in the “multicenter AML-2000 trial” after informed consents were obtained during the period of January 2000 to July 2007. For remission induction therapy, patients received oral ATRA (45mg/m2/d, maintained until CR) combined with idarubicin (12mg/m2/d, D1-D3) plus Ara-C (100mg/m2/d, D1-D7). After CR achievement, patients received 3 monthly consolidation courses consisting of idarubicin (12mg/m2/d, D1-D3) alone and maintenance therapy with ATRA (45mg/m2/d, D1-D15, every 2 month) alone had continued for 2 years. Total patients were divided into low-risk, intermediate-risk and high-risk groups according to a predictive model for relapse risk (Sanz score) based on pretreatment WBC and platelet count and the treatment outcomes were compared in the different risk groups. Results The median age of our cohort was 40 years old (range; 6-80) and median follow-up was 27 months (range; 1-90). The distribution of patients in the 3 risk groups was as follows ; 28 (32.6%) patients in low-risk, 40 (46.5%) in intermediate-risk and 18 (20.9%) in high-risk. Overall, CR was achieved in 78 (90.7%) of 86 patients. The CR rate according risk groups was 96.4% in low-risk, 87.5% in intermediate-risk, and 88.9% in high-risk group and there was no significant statistical difference among the different risk groups. During induction therapy, 48 (55.8%) patients experienced grade 3-4 treatment-related toxicity (TRT), mostly fever and infection (38.8% of all patients) and 6 (7.0%) patients died of treatment-related complications. During 3 consolidation courses, 25 (29.1%) of 78 patients experienced grade 3-4 TRT in 1st course, 27 (36.0%) of 75 patients in 2nd course, and 14 (28.0%) of 50 patients in 3rd course. Overall, 3 (3.5%) patients died of treatment-related complications in CR. The incidence of TRT and treatment-related mortality (TRM) during induction or consolidation therapy showed no significant statistical difference among the different risk groups. The relapse occurred in 6 (7.0%) patients; 2 cases in intermediate-risk and 4 cases in high-risk. However, none had relapsed in low risk group, 5 patients of relapsed patients relapsed during consolidation courses and only one patient, however, relapsed during maintenance therapy. The overall survival (OS) and leukemia-free survival (LFS) rate at 7 years in all of patients was 76.7% and 83.5%, respectively. The OS rate at 7 years was 92.9% in low-risk, 78.6% in intermediate-risk and 53.6% in high-risk group (P:0.04) and the LFS rate at 7 years was 96.4%, 83.4% and 62.2% respectively, showing the significant difference between 3 different risk groups (P:0.046). Conclusions This study indicates that our protocol composed of induction therapy with “3+7” chemotherapy plus ATRA followed by consolidations with three courses of idarubicin alone and maintenance therapy with ATRA alone yields a high CR rate and low relapse rate but minimal acceptable toxicities. Despite of adding Ara-C during induction therapy, we did not find much significant toxicities but having good CR rates, and despite of not adding any additional low/intermediate dose chemotherapies(ie, 6MP), we were able to observe significantly high relapse rate in low and intermediate risk group with excellent LFS and OS. Meanwhile, in high-risk group, the relapse rate was significantly higher than other risk groups and most of the relapses occurred in the middle of consolidation courses. This data suggests that our consolidation therapy composed of anthracycline alone may be not enough to minimize risk of relapse in high-risk group in contrast with the low and intermediate-risk groups. More intensive consolidation therapy combined with other effective, but get tolerable chemotherapies or hematopoietic stem cell transplantation in first CR or the combination of arsenic trioxide or others in front-line therapy should be considered in the patients with high-risk of relapse. Disclosures: No relevant conflicts of interest to declare.

Cytogenetics is still being considered the most powerful single prognostic factor, which is useful to determine the types of post-remission therapy in AML, though various molecular markers are available for predicting the prognosis of AML patients. Most phase III studies have failed to demonstrate a clear advantage of allografting over chemotherapy in terms of overall survival because of significant risk of transplant-related mortality. Optimal post-remission therapies in terms of frequencies (number of treatment) or intensities are not decided yet. In this study, since 2000, we investigated that outcomes of post-remission therapies(high-dose cytarabine (HDAC) vs autologous stem cell transplantation (AutoSCT) vs allogeneic stem cell transplantation from sibling or unrelated donors (AlloSCT)) based on cytogenetic risk (GPG, Good prognosis group; IPG, Intermediate prognosis group; PPG, Poor prognosis group by MRC definition) on the AML patients who achieved complete remission after induction chemotherapy. The aims of this prospective intention to treat analysis was to compare the CR, recovery kinetics, DFS and OS in the different prognostic groups. Three plus seven (idarubicin 12mg/m2, D1–D3; cytarabine 100mg/m2, D1–D7) were given to de novo AML, secondary AML and therapy-related AML. Then, HDAC or AutoSCT was given after intermediate dose (8gm/m2) of cytarabine to the patients with GPG. Three times of post-remission therapy including HDAC, or AutoSCT followed by two times of post-remission therapy were given to IPG or PPG. If HLA-identical sibling was available, then AlloSCT underwent after 1st post-remission therapy. Since January, 2000, 506 patients(18 centers) were enrolled up to December, 2007. Among them, 92.3% was de novo AML, and GPG, IPG and PPG were, 23.1%, 62.1% and 14.8% respectively. Over all complete remission rate after 1st induction was 79.0% and CR rate in GPG, IPG, PPG were 92.0%, 81.0% and 43.9% respectively(P

Introduction Imatinib mesylate (IMT) dose escalation has been proposed as a therapeutic option in patients (Pts) with chronic myeloid leukemia (CML) who failed to achieve optimal response with standard dose IMT. We report the results of prospective multi-center single arm phase ¥≥study evaluating efficacy of escalated dose IMT. We intended to identify patterns of molecular change using serial quantitative RT-PCR and its relationship with clinical outcome. We also planned to find predictive markers for outcome with array comparative genomic hybridization (aCGH) and epigenetic study of bcr gene in addition to BCR/ABL mutation. Patient and methods Pts in chronic phase (CP) CML who failed to achieve optimal response by European LeukemiaNET with adequate organ function were enrolled. Pts in accelerated phase (AP) or blast crisis (BC) who failed to achieve complete hematologic response after 3 months of IMT were also eligible. CP Pts received 600mg daily, while Pts in AP or BC received 600 or 800mg IMT daily. Pts received IMT for at least 12 months or until the appearance of a progressive disease, intolerable toxicity. Along with cytogenetic response (CyR), molecular response (MR) was assessed with BCR-ABL/ABL gene ratio of peripheral blood or bone marrow aspirate. Baseline BCR/ABL gene mutation test was performed using Matrix-assisted laser desorption/ionization time of flight mass spectrometry. Genome-wide screening for regions of genetic gains and losses with baseline blood samples was performed for 38 Pts using aCGH. Methylation status of 4 CpG sites in bcr gene promoter region was tested for 40 Pts and average methylation level was used for analysis. Blood samples at baseline and 6 months after dose escalation were tested. 29 optimal responders to standard dose IMT and 38 healthy donors were also tested for bcr methylation status for additional comparison. Results 71 Pts (median age 49.0 years, M:F=50:21) received escalated dose IMT. Median time to treatment failure (TTTFx) was 18.0 months and toxicities were manageable. 44 and 52 Pts were evaluable for FISH at 6 months and 1 year, where 16 and 17 Pts showed complete CyR (CCyR) respectively. For 61 Pts with serial MR data, TTTFx was longer in Pts who achieved molecular reduction of more than 50% within 6 months (Molecular early responder: MER) than who didn’t (p Conclusion Escalated dose IMT is a reasonable option for CML Pts showing less than optimal response to standard IMT. MER after escalated dose IMT is a useful early predictive marker for long term response. Mutational status of BCR-ABL at baseline is possibly important for response. Chromosome 16p11.2, 22q11.23 and 17q12 are potential locations related to IMT response and GSTT1 CN loss may be a genetic change affecting clinical outcome. bcr methylation status is an epigenetic marker associated with IMT response, where decreased bcr methylation status is related to poor IMT response.

Introduction: The myelodysplastic syndrome (MDS) is frequently associated with various chromosomal abnormalities. ‘5q− syndrome’ is low-risk MDS known as good responder of lenalidomide recently. However, the patients with other abnormalities in chromosome 5 showed quite different clinical features from those with ‘5q− syndrome’. The aim of this study was a retrospective evaluation for Korean MDS patients with abnormalities in chromosome 5 other than ‘5q− syndrome’. Materials and Methods: Among 456 patients with MDS diagnosed at 16 hospitals in Korea between 1996 and 2006, 370 with available cytogenetic data entered the study. Univariate and multivariate analysis were performed. Results: Ninety three patients (25.1%) showed abnormalities in chromosome 5 and the ‘5q− syndorme’ was only 10 patients (2.7%). Among the rest, 39 patients (10.5%) had various abnormalities other than 5q deletion such as translocation or 5 monosomy, 38 (10.3%) had complex abnormalities with 5q−, and 2 had mosaic pattern with normal chromosome. Four patients had isolated 5q− but blasts in marrow were over 5%. The deletion of 5q was interstitial but with a predominance for 5q13-33 deletions (34.8%). MDS patients with chromosome 5 abnormalities other than ‘5q− syndrome’ didn’t share the clinical features with ‘5q− syndrome’. There was no leukemic transformation in ‘5q− syndrome’ group, but 18 (21.7%) with other abnormalities in chromosome 5 finally transformed to acute leukemia. Five year overall survival was significantly inferior in non-’5q− syndrome’ patients than ‘5q− syndrome’ (14.3% vs. 79.6%, P=0.0115). Conclusions: Patients with isolated 5q− and excess blast (>5%), other abnormalities than isolated 5q−, or mosaic chromosome with isolated 5q− and normal chromosome didn’t share the clinical features such as lower rate of leukemic transformation and long survival.

The effectiveness of anthracycline dose intensification for induction of CR in AML has not been studied in a randomized fashion. We conducted a prospective randomized trial to compare the therapeutic efficacy and toxicity of two different doses of daunorubicin in combination with cytarabine in AML. This study began on August 2001 and 293 adult patients (younger than 60 years) with newly diagnosed AML except M3 have been enrolled. Fourteen patients were removed from the study and the remaining 279 patients were analyzed. After random assignments, 135 patients received standard-dose daunorubicin (SD-DN, 45 mg/m2/d × 3 d) and 144 patients received high-dose daunorubicin (HD-DN, 90 mg/m2/d × 3 d) in addition to cytarabine (200 mg/m2/d × 7 d) for induction of CR. Patients with persistent leukemia received the second attempt of induction chemotherapy, consisting of standard-dose daunorubicin (2 d) plus cytarabine (5 d). Patients who attained CR received 4 cycles of high-dose cytarabine (3 g/m2 × 6 doses) and 2 cycles of daunorubicin (1 d) plus cytarabine (5 d). For patients in intermediate- or high-risk cytogenetic groups, allogeneic hematopoietic cell transplantation was performed if there was a suitable donor. CR was induced in 98 of 135 patients (72.6%) in SD-DN arm and 119 of 144 (82.6%) in HD-DN arm (P = 0.044). The impact of daunorubicin dose intensification on the CR rates were different by cytogenetic risk group: the CR rates for SD-DN vs. HD-DN arm were 24/25 (96.0%) vs. 35/36 (97.2%) for good-risk group, 63/88 (71.6%) vs. 64/83 (77.1%) for intermediate-risk group, and 10/20 (50.0%) vs. 19/24 (79.2%) for poor-risk group. With a median follow-up of 596 days for surviving patients, the 4-year probabilities of overall survival, disease-free survival, and relapse-free survival were similar between SD-DN and HD-DN arm. Two different doses of daunorubicin (SD-DN vs. HD-DN) showed similar toxicity profiles regarding recovery times from myelosuppression, transfusion requirements, severe toxicities (grades III to IV) classified by NCI-CTC ver 2.0 including cardiac toxicities, and duration of antibiotics administration. In conclusion, high-dose daunorubicin showed higher CR rates in AML patients of intermediate- and poor- cytogenetic risk groups without increase of toxicities compared to standard-dose daunorubicin.

Backgrounds: The discovery of Janus kinase 2 (JAK2) mutation make it easy to diagnose polycythemia vera (PV) in which the prevalence of this mutation is reported up to 96%. The latent PV is defined in patients who show the lower hemoglobin than WHO criteria at the time of diagnosis without any cause of secondary erythrocytosis; 17~18.5g/dL in male and 15 ~16.5g/dL in female. We investigated the mutational status of JAK2 in polycythemia vera either of latent or manifest type and secondary polycythemia. Methods : We reviewed the clinical records of 182 patients from 8 centers, who underwent bone marrow (BM) examination with a suspicion of non-BCR/ABL myeloproliferative diseases (nMPD). JAK2 mutation was examined by allele-specific PCR in 110 patients. Results : The positive rate of JAK2 mutation was 69% of 48 patients with PV, 54% in 41 patients with essential thrombocythemia (ET), 25% of 8 patients with chronic idiopathic myelofibrosis and 100% of 1 patient with unclassifiable MPD. JAK2 mutation was not detected in 7 patients with secondary polycythemia and 5 with reactive thrombocytosis. The number of patients with latent PV was eleven (23%) among the 48 PV patients. Nine of these 11 patients were positive for JAK2 mutation. Finally, sensitivity of JAK2 mutation was 69% (33/48) in all PV, 82% (9/11) in latent PV, and 65% (24/37) in manifest PV. The specificity of JAK2 mutation was 100% for secondary polycythemia. Among the 41 patients with ET, four patient had high hemoglobin met the latent PV criteria. Only one patient among them showed JAK2 mutation. The presence of a JAK2 mutation was closely correlated with the diagnosis of PV (p=0.006), leukocytosis (p=0.000), increased megakaryocytes (p=0.013), and decreased serum EPO (p=0.034) in 98 nMPD patients. In these patients, vascular events before or after the diagnosis and survival were not affected according to JAK2 status during the median follow-up of 25 months (range; 0~211). Conclusions : The JAK2 mutation help diagnose PV with higher sensitivity in latent PV than manifest PV. This finding can be adopted in the diagnosis of PV in newly visited polycythemic patient whose hemoglobin were under the criteria and condition could be excluded for secondary erythrocytosis. Therefore, JAK2 mutation should be incorporated into the work-up of nMPD including PV for accurate diagnosis. In the meeting, we can present the additional JAK2 data of untested 72 patients.

Systemic capillary leak syndrome (SCLS) is a rare condition characterized by episodic capillary hyperpermeability. The manifestations of this syndrome are generalized edema, hypotension, hypoalbuminemia, hemoconcentration, renal shut-down and monoclonal gammopathy. The pathogenesis of SCLS is still unclear. The treatment of SCLS is empirical, including theophylline, terbutaline, steroids, loop diuretics, plasmapheresis and BMT. Some patients were diagnosed multiple myeloma during follow-up. Death during the acute attack from cardiopulmonary collapse or diuresis phase from pulmonary edema occurs in approximately one third of the cases. Therefore initial fluid therapy is one of critical care point, but there is no information what is the adequate volume expander during acute attack. We experienced two cases of SCLS with severe acute attack and showed rapid improvement of hypotension by 10% pentastarch. Case 1: A 36-year-old woman visited our hospital with systolic blood pressure (SBP) 50 mmHg, resting dyspnea, oliguria and anasarca. The laboratory findings showed Hb 19.2 g/dL, hematocrit (Hct) 53%, total protein / albumin 3.7 / 1.7 g/dL, BUN / creatinine 32.6 / 1.9 mg/dL and monoclonal IgG-kappa. There was no evidence of multiple myeloma. We diagnosed the patient as having SCLS and started intravenous infusionof 9 L of normal saline (NS), dexamethasone, aminophylline and inotropics for 8 hours. Despite massive fluid therapy, SBP was not increased, and respiratory failure due to pulmonary edema was developed. After infusion of 10% pentastarch 0.5 L every 8 hours, SBP was gradually increased to normal within 12 hours without NS infusion. From the next day, diuresis phase started, other clinical and laboratory findings became normal range. There was no long-term sequale, and no more attack for 1 year follow-up. Case 2: A 36-year-old woman was referred to our hospital with severe hypovolemic shock and anasarca. The laboratory findings showed typical SCLS with the presence of monoclonal IgG-kappa. There was no evidence of multiple myeloma. She had histories of similar several episodes for 3 years, was managed with infusion of albumin, NS and suffered from pulmonary edema. At this time, clinical and laboratory findings were severe: confusion, anuria, SBP 40 mmHg, Hb 21.1 g/dL, Hct 63%, BUN / creatinine 22.6 / 2.8 mg/dL, total protein / albumin 4.4 / 2.5 g/dL. Two hours after using 0.5 L of 10% pentastarch and 2 L of NS, SBP and urine output increased to 127 mmHg and 50 ml/hour, respectively. Other clinical and laboratory findings restored and diuresis phase started within 1 day and there was no pulmonary edema. Acute management during hypotensive attack is very important to reduce mortality of SCLS. Because shift of fluid and protein by capillary hyperpermeability is the pathophysiology of this syndrome, total body fluid is not decreased. Thus massive crystalloid fluid, albumin infusion would not effective during hypotensive phase of SCLS and exacerbate edema. Hypoalbuminemia (molecular weight (MW) 69,000 dalton) is very common manifestation of SCLS, and Atkinson et al (Medicine1997; 56;225–39) reported that egress from vascular compartment was limited to proteins of MW up to 200,000 dalton. Under this knowledge, we used pentastarch (MW 240,000 dalton) during acute SCLS attacks and it showed dramatic responses. Pentastarch would be a very effective treatment for acute attack and might decrease acute mortality of SCLS.

Biphenotypic acute leukemia (BAL) is a rare yet defined type of acute leukemia. We investigated the incidence, clinicopathologic characteristics, and clinical outcomes of BAL in Korean adults. The present study retrospectively analyzed clinicopathological and clinical data from 43 adult patients with BAL, defined using the EGIL scoring system, from 11 Korean institutes. The incidence of BAL was 2.1% among acute leukemias; 2.3% in male and 1.9% in female. Median age of 43 BAL patients, 25 males and 18 females, was 38 years (range, 16–74). The immunophenotype was myeloid/B-lymphoid (M+B) in 31 (72.1%), myeloid/T-lymphoid (M+T) in 10 (23.3%), and B/T-lymphoid (B+T) and myeloid/B/T-lymphoid (M+B+T) in one (2.3%) each. 37 patients had the results of cytogenetic analyses and Ph chromosome (n=14, 37.8%) was the single most common abnormal finding. Intensive induction chemotherapy was given in 36 of 43 patients: AML-type in 13 (36.1%), ALL-type in 8 (22.2%), and combined type in 15 (41.7%). Complete remission (CR) was induced in 29 patients (80.6%). The CR rate was significantly lower in M+T (5 of 9, 55.6%) than M+B (22 of 25, 88.0%) (P=0.039). Other unfavorable factors for CR were absence of CD19 (P=0.029) or CD20 (P=0.046), and presence of CD2 (P=0.040). The CR rates were not significantly different according to cytogenetic finding or type of induction chemotherapy. After median follow-up duration of 712 days among surviving patients, 11 patients relapsed with median relapse-free survival (RFS) of 3.08 years and 4-y RFS of 38.3% and 18 patients died with median overall survival (OS) of 2.49 years and 4-y OS of 30.1%. Multivariate analysis showed that high leukocyte counts (≥ 30,000/μl) at diagnosis (OR, 5.922; 95% CI, 1.379–25.429; P=0.017) was an independent unfavorable prognostic factor for RFS, and high leukocyte counts at diagnosis (OR, 9.348; 95% CI, 3.014–28.993; P

Compared to younger patients with acute myeloid leukemia (AML), elderly patients are associated with poorer prognosis and only a few survive long-term. Although several randomized trials demonstrate that elderly patients benefit from full-dose application of cytarabine plus anthracyclines rather than less intensive chemotherapy for induction therapy, optimal post-remission therapy remains to be determined. We performed a prospective phase II multicenter trial of standard induction therapy (7+3 of cytarabine plus daunorubicin) followed by 2 cycles of attenuated consolidation therapy (5+1 of cytarabine plus daunorubicin) for elderly AML patients excluding M3. This study was designed to reduce fatal complications by intensive post-remission therapy, benefits of which have not been evidenced in elderly patients. Induction therapy consisted of cytarabine (200 mg/m2/d x 7) and daunorubicin (45 mg/m2/d x 3). If interim bone marrow examination, which was done at 14 days after the start of induction therapy, showed persistent leukemia, the second attempt of induction therapy was tried with the same doses of cytarabine for 5 days and daunorubicin for 2 days. The patients who attained complete remission (CR) by induction therapy received 2 cycles of attenuated dose consolidation therapy (cytarabine 200 mg/m2/d x 5 plus daunorubicin 45 mg/m2/d x 1). Forty-one patients, 25 males and 16 females, were enrolled into the study between Jan 2002 and Dec 2004. Median age was 66 years (range, 60–78 years). Thirty-seven patients received the planned dose of induction therapy and 4 did not complete it due to intolerance in 3 or tumor lysis syndrome in 1. CR was attained in 16 patients after a first attempt of induction therapy. A second attempt of induction therapy was administered to 16 patients, 8 of whom attained CR. Overall, 24 (58.5%; 95% CI, 43.5–73.6%) of 41 enrolled patients achieved CR at a median of 34 days (range, 21–86 days). In the 17 patients who did not achieve CR, the cause of treatment failure was resistant leukemia in 15, complications of aplasia in 1, and indeterminate in 1. Of 24 CR patients, 17 completed all 2 cycles of consolidation therapy, 3 received 1 cycle, and 4 did not receive consolidation therapy. During induction therapy, most common non-hematologic toxicities (≥ grade 3) were febrile neutropenia (83%) and metabolic abnormalities (44%). During consolidation therapy, non-hematologic toxicities (≥ grade 3) were infrequent except febrile neutropenia (45% for the first consolidation and 41% for the second consolidation). There were no fatal complications during consolidation therapy. After a median follow-up duration of 566 days (range, 63–1190 days) among surviving patients, 27 died and actuarial 3-year overall survival was 17.0%. No patient died in remission. Fifteen of 24 CR patients relapsed and actuarial 3-year disease-free survival was 22.5%. Our study suggests that attenuated consolidation does not compromise the outcomes of elderly AML patients, compared to the results from previous reports using more intensive consolidation therapy.