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Abstract 4314 Backgrounds Neurologic complications after allogeneic hematopoietic stem cell transplantation (HSCT) have not been clearly described, especially in children. Methods We analyzed the medical records of 194 consecutive children (median: 7.2 years, range: 6 months-18.4 years) who underwent allogeneic HSCT for malignant or non-malignant hematologic disorders at Asan Medical Center between 1998 and 2009. Results Donors were matched siblings in 64, unrelated volunteers in 127 and haploidentical mothers in 3. Twenty-eight children (14%, 95% confidence interval[CI]: 9-19) developed neurologic complications within the first 6 months of HSCT. Calcineurin inhibitor associated-neurotoxicity was the most common neurologic complication (n=14), followed by cerebrovascular events (n=6), thrombotic microangiopathy-associated abnormalities (n=2), hypoxic-ischemic brain injury (n=2), CNS infection (n=1), metabolic encephalopathy (n=1), and events of undetermined cause (n=2). Univariate analysis showed that transplant from unrelated donor, peripheral blood grafts and occurrence of acute GVHD (>grade 1) were associated with significant increased risk of neurologic complications. In multivariate analysis, development of acute GVHD (>grade 1) was identified as an independent risk factor for early neurologic complications. Survival at 1-year was significantly inferior in patients who developed neurologic complications within 6 months of transplant (42% [95% CI: 23-61] versus 82% [95% CI: 76-88], p Conclusion Neurologic complications are significant clinical problems among children receiving HSCT, contributing to early death after transplant. Immediate diagnostic efforts to detect neurologic events are required in patients with clinically suspicious symptoms. Disclosures: No relevant conflicts of interest to declare.

Abstract 4513 Introduction Severe chronic neutropenia (SCN) is a rare hematologic disorder defined by an absolute neutrophil count less than 0.5×109/L for several months or years. They usually suffer from recurrent infections. Principal subtypes of SCN are congenital, cyclic, idiopathic and primary autoimmune neutropenia (AIN). Patients and Methods Medical records collected from a national survey were retrospectively analyzed on newly diagnosed SCN patients in Korea between January, 1999 and December, 2008 in respect to the diagnosis, clinical manifestations, treatments and prognosis of the patients. Results There were 64 patients (Male, 20; Female 44) reported from 16 hospitals: congenital, 19; cyclic, 16; idiopathic, 25; and immune in origin, 4. The main clinical manifestation was various types of bacterial infections. Two cases (1 congenital, 1 cyclic) were diagnosed by family histories. The median age at diagnosis was 12 months (11 days-158 months). A bone marrow examination was done in 45 patients (70.3 %) at the median age of 26 months (1 day-158 months), with the interval between the initial CBC and BM study being 7.3 months (9 days-138 months). The ELA2 mutation, done in 6 patients, was not detected. Only one patient with congenital SCN evolved to AML at 54 months after diagnosis, who is under chemotherapy. Most patients were treated with G-CSF (5-10 μg/kg/day) during infection episodes. The median follow up duration was 23 months (11 days – 176 months). Two patients of congenital SCN died of infection (pneumonia, meningitis) and 8 patients were lost to follow up, and the remaining are alive. Conclusions SCN is a rare hematologic disease with inherent vulnerability to infections, thus early detection with proper management should be important for survival of SCN patients. We propose a nation-wide, prospective study to delineate the prevalence, molecular diagnosis, natural history, the optimal use of G-CSF, and prognostic factors in Korean patients with SCN. 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.

Abstract 4517 Background Hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS), whether primary or secondary, is a serious and potentially life- threatening histiocytic disorder and generally fatal without immune modulating chemotherapy. This study aimed to define the clinical spectrum and treatment outcome in Korean children. Patients and Method Patients who were diagnosed with HLH/MAS at Asan Medical Center between October 1997 and April 2009 were identified and charts were reviewed. Results Twenty-six patients (16 male, 10 female) were evaluated during 13 - year period. Median age at diagnosis was 29.5 months (range: 0 - 180 months). Twelve patients had HLH secondary to underlying disorders, including viral infection, autoimmune disease. Epstein-Barr virus (EBV) - associated HLH was present in 9 patients, 1 of whom died, while 4 of 17 non-EBV associated patients died. Initial treatment with intravenous immunoglobulin (IVIG) was given to 9 patients and they had no response to IVIG. Eventually, all the patients except two underwent full protocol therapy (HLH 1994/2004) and the 2 patients died of rapid disease progression with delayed diagnosis. Seven patients revealed disease reactivation, median 3 months from HLH protocol therapy, and further treatment using the same regimen induced second remission of short duration. Seven patients (26.9%) had evidence of central nervous system disease at the time of diagnosis and neurological symptoms consisted of seizure, irritability, vomiting. Five of them are long-term survivors including one who received allogeneic stem cell transplantation (SCT) and all 5 patients show normal neurological function after treatment. The familial form of HLH was identified in 3 patients and all received allogeneic SCT from unrelated donor in second remission. They are still alive without relapse. At a median follow-up of 17.5 months, the estimated one-year overall survival rate was 82.8 ± 7.9 %. Conclusion Treatment outcomes using HLH 1994/2004 protocols in Korean children have become comparable to those reported in an international collaborative study. And allogeneic SCT represents a curative treatment for familial form of HLH. Further studies are required to more precisely define clinical spectrum and treatment outcome. Disclosures: No relevant conflicts of interest to declare.

Abstract 4348 Background Hematopoietic stem cell transplantation (HSCT) from matched sibling donor is the standard first-line treatment for children with severe aplastic anemia (SAA). However, the management of SAA lacking a suitable donor remains a great challenge. For those children, HSCT using unrelated donor or mismatched related donor could be a therapeutic alternative. The purpose of this study is to evaluate the outcome in children with SAA who received HSCT from donors other than matched sibling. Patients and Method Between March 2003 and July 2009, 17 patients received HSCT from alternative donors (AD) at Asan Medical Center. We reviewed their medical records and analyzed their transplant-related parameters and outcome. Results Of a total of 17 patients, 11 were male and the median age at HSCT was 9.0 years, ranging from 3.0 to 16.7 years. Four patients had Fanconi anemia and 13 had acquired SAA including 2 who developed SAA after liver transplantation. Donors included unrelated bone marrow (U-BM) in 5, unrelated peripheral blood (U-PB) in 6, unrelated cord blood (U-CB) in 2 and related haploidentical peripheral blood (H-PB) in 4. Of 17 patients, 15 (88%) achieved sustained engraftment. Of 15 with engraftment, only 1 patient who received HSCT from U-CB died of severe GI GVHD and the other 14 patients remain on stable normal counts without transfusion support. All 2 patients (1 U-BM, 1 H-PB) who failed to engraft were dead despite DLI or 2nd HSCT. With a median follow-up of 31.9 months, the Kaplan-Meier estimated overall survival at 2 years was 76.6%. Conclusion In children with SAA, HSCT from AD including haploidentical family donor could be considered as a treatment option if the patients have no matched sibling donor. Given the limitation of this study such as small number of patients and short follow-up period, further trial will be necessary. Disclosures: No relevant conflicts of interest to declare.

Familial hemophagocytic lymphohistiocytosis (FHL) is a rare and genetically heterogeneous disorder characterized by immune dysregulation with a defect in apoptosis triggering and in natural killer and cytotoxic T lymphocyte cellular cytotoxicity. It occurs mostly in infancy and early childhood, and without treatment, is invariably fatal with a median survival of less than 2 months after diagnosis. Only early hematopoietic stem cell transplantation (HSCT) has been shown to cure the disease. The molecular genetic defect causing FHL has been intensively investigated for recent years and classification of FHL according to the genetic abnormality has been tried. It has been noted that some mutations appear to be more frequent in patients from a certain geographical region, but there is no data available for the genetic background of Korean FHL patients. The aim of this study was to identify causative gene(s) and mutation(s) by mutation analyses of three known HLH causative genes, namely PRF1, UNC13D, and STX11 in Korean FHL patients. We also analyzed whether there were genotype-phenotype correlations among these genetic subtypes, and intended to provide critical information for the decision making for timely and most appropriate treatment of FHL patients. Fifteen patients with suspected FHL were recruited from the Korean National Registry of HLH between January 2007 and March 2008. By using genomic DNA samples extracted from peripheral blood leukocytes, direct sequencing was performed in all the exons and their flanking intronic sequences of the PRF1 gene, UNC13D gene, and STX11 gene by genetic analyzer. The correlation between clinical features and genetic subtypes was investigated. Of the 15 HLH patients, 8 mutations of UNC13D gene were found in 5 patients, and 5 of the 8 mutations were novel (Q98X, IVS24+1G>A, IVS21-2A>G, IVS30+5G>A, c.1693delG). Neither PRF1 nor STX11 mutation was identified. IVS9-1G>C, one of the previously reported UNC13D mutations, was found in 3 patients. The clinical features of the patients with UNC13D mutation were associated with earlier age of disease onset (median: 2 months, versus 21 months), more frequent involvement of central nervous system (60% versus 20%), and poorer treatment response (complete response rate 20% versus 70%) than those of FHL patients without UNC13D mutation. This study is the first report to indicate UNC13D mutations as a molecular genetic cause in Korean patients with FHL by direct gene sequencing. The novel UNC13D mutations found in Korean FHL patients implicate the possible presence of an ethnical difference in the genetic background of FHL development. Further study with a larger number of FHL patients would be needed to identify other potential causative genes and mutations and to clarify the genotype-phenotype correlation for each mutation. Moreover, earlier detection of UNC13D mutation on the basis of this study in a suspected FHL patient would provide important information for the decision making for timely HSCT.

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

Objective: Chemoimmunotherapy based treatments improved the survival of patients with hemophagocytic lymphohistiocytosis (HLH), but the outcome is still unsatisfactory. We analyzed the outcome of pediatric patients with HLH after hematopoietic stem cell transplantation (HSCT) in a nation-wide HLH registry. Methods: Retrospective nation-wide data recruitment for HLH pediatric patients diagnosed between 1996 and 2005 was carried out by Histiocytosis Working Party of the KSH and KSPHO. Sixteen patients who received HSCT among enrolled 129 pediatric patients with HLH were analyzed for transplant related variables and events. Results: The probability of 3-year survival after HSCT was 81.2% with median follow-up of 27.5 months compared to the 35.2% for patients who were treated with chemoimmunotherapy only (P=0.03). The reasons for HSCT were active disease at 2 months after treatment (n=8), relapsed disease (n=5), and familial HLH (n=3). Eight patients received transplants from matched unrelated donors, 5 from matched siblings and 3 using unrelated cord blood units. Stem cell sources were bone marrow for all the 13 allogeneic transplants other than 3 cord blood transplants. Conditioning regimens were busulphan, cytoxan, and VP-16 with (5) or without (7) antithymocyte globulin (ATG) in 12 patients, fludarabin and melphalan in 3, and other regimen in 1. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine (CSA) + MTX in 11 patients, CSA +MMF in 2, and others in 2. Twelve patients are alive in complete remission state, 3 patients died of infection and graft failure at early post-transplant period, and 1 patient relapsed at post-transplant 30 days. The relapsed patient developed tuberculous encephalitis after retreatment with chemoimmunotherapy, and alive with supportive care. After HSCT, acute GVHD developed in 5 patients, infection in 5, veno-occlusive disease (VOD) in 2, graft failure in 2, and post-transplant lymphoproliferative disease (PTLD) in 1. Acute lymphoblastic leukemia developed in 1 patient about 2 years after HSCT. Variables such as age at diagnosis, etiology of HLH (familial or secondary), central nervous system (CNS) involvement, disease state after 8 weeks of initial treatment, conditioning regimens, and stem cell sources were not associated with significant difference with regard to 3-year overall survival after HSCT. Conclusion: HSCT revealed excellent outcome for patients with familial, relapsed, or severe and persistent secondary HLH in Korean nation-wide HLH registry.

Infection is one of the most important causes of morbidity and mortality after hematopoietic stem cell transplantation. We assessed the incidence and characteristics of infections in 163 cord blood stem cell transplantation (CBT) recipients from 13 transplant centers of Korea between October, 1996 and April, 2005. The patients underwent CBT with standardized conditioning, GVHD prophylaxis and supportive care including pre-emptive ganciclovir therapy for cytomegalovirus (CMV) antigenemia. The median time to neutrophil engraftment was 19 days (10–62 days) and to platelet engraftment was 45 days (14–394 days). Within the post-transplant day 0 to day 30, 81.6% of patients (133/163) experienced febrile episodes with 11.7% (19/163) of clinically documented infection (CDI) and 19.6% (32/163) of microbiologically documented infection (MDI). The neutrophil engraftment was delayed in the patients with CDI and MDI rather than without CDI and MDI (day 26.3 vs day 21.5, P=0.03) before day 30. In the time period of day 30 to 100, febrile episodes, CDI and MDI occurred in 54.3% (82/151), 14.6% (42/151) and 13.2% (20/151), respectively. After day 100, 38.5% of patients (45/117) experienced febrile episodes with 17.9% (21/117) of CDI and 7.7% (9/117) of MDI. Although the incidence of febrile episodes before day 30 was significantly higher than after day 30, the incidence of CDI and MDI was comparable. There were no significant differences of infection rate according to the infused cell dose, the degree of HLA disparity, acute GVHD and chronic GVHD. The overall mortality rate after CBT was 40% (65/163). Infection was considered the primary cause of transplant-related mortality and represented 18.4% (106/163) of the causes of death with the median day of 96.5 (1∼1,081 days). The incidence of pre-transplant CMV-seropositivity was 85.5% of the patients (106/123) and CMV antigenemia developed in 52.7% of CMV-seropositive patients compared to 11.8% of CMV-seronegative patients (P=0.002). CMV disease developed in 25.7% of CMV-seropositive patients and 6.7% of CMV-seronegative patients, which showed statistiacally not significant. Pre-transplant conditioning regimens such as antithymocyte globulin did not affect on the incidence of CMV antigenemia or CMV disease. Based on our study, the infection was still the primary cause of mortality after CBT, particularly in patients with delayed neutrophil engraftment. The high prevalence of CMV seropositive patients in Korea was associated with increased incidence of CMV antigenemia, not with CMV disease.

Chemotherapy and immunotherapy based treatments improved survival of patients with hemophagocytic lymphohistiocytosis(HLH), but the outcome is still unsatisfactory. We analyzed the putative prognostic factors in a nationwide cohort of patients with HLH. Retrospective data recruitment for the patients diagnosed as HLH during the past 10-year period from 1996 to 2005 was carried out by the Histiocytosis Working Party of the Korean Society of Hematology. The HLH diagnostic criteria of the Histiocyte Society were strictly applied to confirm the eligibility of patients for this study. We analyzed the outcome of pediatric patients with HLH according to the age at diagnosis, sex, central nervous system(CNS) involvement, disease condition(familial or secondary), treatment modalities and disease state after 2 months of initial treatment. One hundred twenty nine patients from 19 centers fulfilled the diagnostic criteria(n=112) and/or had affected siblings together with some of the criteria(n=17). The male to female ratio was 0.95:1. The probability of 3 year overall survival(OS) in HLH patients was 41% with a median follow-up of 51 months. The 3 year OS in patients under 12 months of age at presentation(n=23) was 21.7%, and 44.3% in those over 12 months of age(n=106)(p=0.001). The 3 year OS in patients with CNS involvement(n=16) was 29.1%, and 44.4% in patients without CNS involvement(n=112)(p=0.01). The 3 year OS in patients with active state after 2 months of initial treatment(n=63) was 14.1% compared to 77.2% in those with inactive state(n=61)(p=0.0001). The 3 year OS in patients who received hematopoietic stem cell transplantation(HSCT)(n=17) was 82.3%, and 35.2% in patients treated with chemoimmunotherapy only(n=112)(p=0.03). Among the HSCT patients, complete remission was obtained in 14 patients except 3 other patients who died of infection and graft failure at early post-transplant period. The reasons for HSCT were active disease after chemoimmunotherapy(n=8), relapsed disease(n=5), and familial HLH(n=4). Other prognostic factors were not significantly correlated with outcome in our survey. The age and CNS involvement at diagnosis, disease state after 2 months of initial treatment were important prognostic factors which affected the outcome of HLH significantly in this cohort. This survey also demonstrated excellent outcome of familial or relapsed, persistent secondary HLH after HSCT compared to chemoimmunotherapy only.

The prognostic significance of multidrug resistance (MDR) gene expression is controversial. We investigated whether multidrug resistance gene 1 (MDR1), multidrug resistance-related protein (MRP) and lung resistance protein (LRP) mRNA expression are associated with outcomes in acute leukemia patients. At diagnosis we examined MDR1, MRP and LRP mRNA expression in bone marrow samples from 71 acute leukemia patients (AML 39, ALL 32) using nested reverse transcription polymerase chain reaction (RT-PCR). The expression of each of these genes was then expressed as a ratio in relation to ß-actin gene expression, and the three genes were categorized as being either not expressed (0), weakly expressed (1+), moderately expressed (2+) or strongly expressed (3+). MDR1, MRP and LRP mRNA expression was detected in 23.9%, 83.1% and 45.1%, respectively, of acute leukemia patients. LRP mRNA expression was significantly associated with resistance to induction chemotherapy in acute leukemia patients, and in the AML proportion of these patients, compared to LRP-negative patients (p=0.02 and p=0.03, respectively). MRP and high MDR1 mRNA expression was associated with poorer 2-year survival (P=0.049 and p=0.04, respectively) compared to MRP-negative and non-high MDR1 mRNA-expressing patients, respectively. Patients expressing both MRP and LRP mRNA had poorer outcomes in response to induction chemotherapy and had worse 2-year survival compared to patients not expressing both genes. The present data suggest that MDR gene expression affects CR and survival rates in acute leukemia patients. Thus, determination of MDR gene expression at diagnosis appears likely to provide useful prognostic information for acute leukemia patients.