ALBERT

Description: Background; Accelerated phase of chronic myeloid leukemia (AP-CML) is not clearly defined yet. There are different definitions to classify AP. In European Leukemia Net (ELN) 2013 recommendation, considerable therapeutic approach of de novo AP would be hematopoietic stem cell transplantation (HSCT) followed by frontline tyrosine kinase inhibitor (TKI). To explore long-term efficacy of frontline imatinib (IM) treatment and early predictors of long-term outcome, we analyzed a total of 73 patients who received frontline IM.. Method; AP defined as a definition of ELN recommendation.. A progression to blastic phase and loss of response were considered as progression. Patients who had received HCT were censored at the time of HCT when calculating overall survival (OS) and progression-free survival (PFS). Results; Of 83 patients who diagnosed as AP, 73 patients received IM and other 10 patients had HSCT (n=7) or no treatment (n=3). Of 73 IM-treated patients, 36 patients maintained IM therapy and 37 patients discontinued IM with switch to 2G TKI (n=23) or HSCT (n=14). Analysis of baseline characteristics revealed prior cytogenetic response (CyR), and molecular response at 6 and 12 months for prediction of survivals. Clinical factors for better survival including Sokal score (p=0.203), Hasford sore (p=0.832), peripheral blood (PB) basophil count (p=0.374), spleen size (p=0.656), bone marrow (BM) promelocyte (p=0.839), BM basophil (p=0.478 were not significant. PB blast5% (p=0.031), platelet count 〉20x109/L (p=0.008), PB promyelocyte

Description: 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.

Description: Allogeneic hematopoeitic cell transplantation (alloHCT) is a curative therapy for severe/very severe aplastic anemia (sAA) in adult. alloHCT from haplo-identical family donor (HD) is an alternative approach while alloHCT from matched sibling donor (MSD) is the choice of therapy. Our previous study suggested that alloHCT from matched unrelated donor (MUD) were comparable with MSD when pre-transplantation conditions were well-matched. It means poor outcome of MUD might come from poor pre-transplantation clinical factors such as delayed alloHCT. Same will be applied to HD. In this study we compared HD with alternative donors (AD; MUD or mismatched family donor) by matched case study. We selected AD cases from KSBMT2007-01 study population who had comparable pre-transplantation clinical factors with HD by propensity-score matching. Pre-tranplatation clinical factors such as age, ATG conditioning or ABO-compatibility were matched. Therefore 48 AD cases were selected for the comparison with 16 HD cases. Male (p=0.009) and female to male transplantation (p=0.002) were more frequent in HD. AD received prior immune suppression therapy (IST) frequently (p=0.092). Cyclophosphamide (p

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

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

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

Description: Relapsed/refractory acute myeloid leukemia (R/R AML) is hard to treat especially in elderly patients. We previously assessed continuous infusion (CI) of fludarabine and cytarabine plus idarubicin (CI-FLAG2) for patients under 65-years old with R/R AML. Also we started prospective phase II study of attenuated version of CI-FLAG2 for elderly patients (C-FLAG). R/R AML in elderly (¡Ã60 years old) patients were eligible. Induction chemotherapy consisted fludarabine and cytarabine (ARAC) as a 24-hr CI without idarubicin. Total 38 and 68 patients were enrolled in CI-FLAG1 and CI-FLAG2, respectively. There were no differences in terms of patients’ characteristics except for median age (p20K/uL at salvage (p=0.004) and PB blast〉40% at salvage, all which factors were unfavorable in C-FLAG. When comparing outcomes between CI-FLAG2 and C-FLAG, there were no difference in terms of CR rate (p=0.572) and objective response rate (ORR; p=0.899). Treatment failure patterns were also similar between C-FLAG and CI-FLAG2 (p=0.742). The most common treatment failure was resistant (66.7%) in C-FLAG. There were more frequent HCT in CI-FLAG2 (p20K/uL at salvage (p=0.024) and PB blast 〉0% on early evaluation (p=0.013) by multivariate analysis. The overall survival of patients who achieve CR/CRp/CRi showed significantly prolonged survival compared with patients who did not in C-CLAG (p

Description: Abstract 2275 Background: Dasatinib is known to induce large granular lymphocyte (LGL) expansion, which correlates with better clinical efficacy. The current retrospective study attempted to investigate the incidence of lymphocytosis following second-line dasatinib therapy in chronic myeloid leukemia (CML) and to analyze the clinical factors predictive of the development of lymphocytosis, as well as association with treatment outcomes. Method: Fifty CML patients who failed imatinib treatment and received dasatinib for 3 months or more, were enrolled from 9 centers in the Republic of Korea. The cumulative incidence of lymphocytosis was assessed, and cytogenetic and molecular response, treatment failure, loss of response, progression to advanced disease, and survival were evaluated and analyzed according to the development of lymphocytosis. Results: After a median of 17 months of dasatinib therapy, complete cytogenetic (CCR) and major molecular response (MMR) was noted in 23 and 16 patients, respectively. Twenty three patients (46%) developed lymphocytosis following dasatinib therapy (median onset 4 months). No clinical predictive factor for the development of lymphocytosis was found. The cytogenetic response was significantly better in the group that developed lymphocytosis (LC+), as compared to the group without lymphocytosis (LC-); the LC+ group showed a higher complete cytogenetic response (CCyR; 78.3% vs. 29.6%, p=0.001) and major molecular response (MMR; 52.2% vs. 14.8%, p=0.005), in comparison to the LC- group. The development of lymphocytosis after dasatinib was identified as a favorable independent marker for predicting a CCyR (p=0.002) or MMR following dasatinib therapy (p=0.003). Conclusion: The present study suggested that 1) lymphocytosis following dasatinib therapy is not rare phenomenon with incidence of 46%; 2) it might be associated with higher response following dasatinib therapy. Further study is necessary to identify which subset of lymphocytes was expanded and to reveal the exact mechanism by which dasatinib induces lymphocyte expansion. Disclosures: No relevant conflicts of interest to declare.

Description: Background: Many prognostic factors have been studied with the development of treatments for multiple myeloma (MM). Serologic inflammatory markers, such as serum beta2-microglobulin (B2MG), albumin, absolute lymphocyte count (ALC), C-reactive protein (CRP), lactate dehydrogenase (LDH), and serum ferritin level, which are easily tested in patients to determine disease status, have been reported to be correlated with prognosis in many studies. Therefore, the purpose of this study is to estimate the correlation between the frequency of the combined inflammatory parameters of ALC, LDH, B2MG, albumin, CRP, and ferritin and the prognosis for survival in patients with MM treated with induction chemotherapy containing thalidomide and who underwent autologous stem cell transplantation (ASCT). Methods: Data from patients at 13 university hospitals in South Korea between December 2005 and May 2013 were collected retrospectively. The patients were those who had been treated with thalidomide-containing chemotherapy and then underwent ASCT. An inflammatory score was determined for each inflammatory parameter, where an ALC level less than 1000/L, a B2MG level greater than 3.5 mg/L, a serum albumin level less than 3.5 g/dL and an LDH level greater than 450 IU/L were each assigned a score of 1 point, and the sum of these points was used as the total inflammatory score ranging from 0 to 4 points. Results: The median age of the 232 patients was 57 years (range, 33-82 years) and the male to female ratio was 1.09:1. The achieved response rates before and after ASCT were as follows: complete response (CR) or stringent CR (sCR) in 81 (34.9%) and 142 (60.2%) patients, very good partial response (VGPR) in 61 (26.3%) and 47 (20.3%), partial response (PR) in 79 (34.1%) and 32 (13.8%), and 〈 PR in 7 (3.1%) and 5 (2.3%). The reason for the higher overall response rate (ORR) in this study compared to other studies was that it included patients who were treated with thalidomide induction chemotherapy and who underwent ASCT. The median progression free survival (PFS) was 31.93 months (range, 25.116 – 38.750) and the median overall survival (OS) was not reached during the follow-up duration. In the univariate analysis, the following factors were associated with a greater than 3-year PFS: lower B2MG (〈 3.5 mg/L vs. ≥ 3.5 mg/L; 49.7% vs. 40.4%, p=0.022), lower LDH (〈 450 IU/L vs. ≥ 450 IU/L; 47.9% vs. 31.5%, p=0.009), lower cytogenetic risks (standard vs. intermediate vs. high; 51.4% vs 26.2% vs 52.7%, p=0.022) and a lower inflammatory score (〈 2 vs. ≥ 2; 53.6% vs. 35.1%, p=0.004). The following factors were associated with a greater than 3-year OS (Table 2): higher hemoglobin level (〈 10 g/dL vs. ≥ 10 g/dL; 81.0% vs. 92.8%, p=0.042), higher platelet count (

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