Search

Chemoimmunotherapy-based treatments have improved the survival of patients with HLH, but outcomes of the patients are still unsatisfactory. We report here the outcome of Korean children with HLH who underwent HSCT, which was analyzed from the data of a nation-wide HLH registry. Retrospective nation-wide data recruitment for the pediatric HLH patients diagnosed between 1996 and 2008 was carried out by the Histiocytosis Working Party of the Korean Society of Hematology. Nineteen patients who received HSCT among the total of 148 enrolled children with HLH were analyzed for the transplant-related variables and events. The probability of five-yr survival after HSCT was 73.3% with a median follow-up of 57. Two months compared to 54.3% for the patients who were treated with chemoimmunotherapy only (p = 0.05). The reasons for HSCT were active disease after eight wk of initial treatment (n = 9), relapsed disease (n = 5), and FHL (n = 5). Fourteen patients are currently alive without disease after HSCT, four patients died of treatment-related events (infection in two and graft failure in two) at early post-transplant period, and one patient died of relapse at one yr post transplantation. The survival of patients who were transplanted because of active disease after eight wk of initial treatment was worse compared to those patients who had inactive state at that time (60.6% vs. 100%, respectively, p = 0.06). Of the four patients who received transplants using cord blood, three died of graft failure (n = 2) and relapse (n = 1). The five-yr probability of survival after HSCT according to the donor type was 85.7% for the MRDs (n = 6), 87.5% for the MUDs (n = 8), and 40% for the MMUDs (n = 5) (p = 0.03). Other variables such as age, CNS involvement at the time of diagnosis, the etiology of HLH (familial or secondary), and the conditioning regimens had no influence on the five-yr OS of the HLH patients who underwent HSCT. HSCT improved the survival of the patients who had familial, relapsed, or severe and persistent SHLH in the Korean nation-wide HLH registry. Although numbers were small, these results are similar to other reports in the literature. The disease state after initial treatment, the stem cell source of the transplant, and the donor type were the important prognostic factors that affected the OS of the HLH patients who underwent HSCT.

Purpose : Cisplatin is highly effective for the treatment of solid tumors in children. However, the clinical use of cisplatin is limited by its ototoxicity. The aim of this study was to evaluate the ototoxicity in children treated with cisplatin. Methods : We performed a single institution retrospective analysis of pediatric oncology patients who received cisplatin therapy between January 2001 and January 2008. Thirty-seven patients with sufficient medical and audiologic data were included in this study. Results : The median age at the time of diagnosis was 10.7 (range 3.8–16.7) years. There were 16 males and 21 females. The underlying diseases were osteosarcoma (15 cases), medulloblastoma (14 cases), germ cell tumors (7 cases), and hepatoblastoma (1 case). The median individual dose was 100 mg/m2/cycle (56-200). The median cumulative dose was 480 mg/m2 (200-1,490). Sixteen patients (43%) received cranial radiotherapy. Of the 37 patients, 17 developed hearing loss, leading to an overall incidence of 46%. Logistic regression showed that age at treatment (P=0.04) and cumulative dose of cisplatin (P=0.005) were the significant risk factors in predicting hearing loss in children treated with cisplatin. In all the patients who had hearing loss, there was neither improvement nor aggravation during the follow-up (3–68 months). Conclusion : The cumulative dose of cisplatin (>500 mg/m2) and younger age at treatment (

CMV infection is one of the major causes of morbidity and mortality after HSCT. The aim of this single center retrospective study was to analyze risk factors for CMV infection in pediatric patients who underwent HSCT. We retrospectively reviewed the medical records of 117 pediatric patients who underwent allogeneic HSCT at Asan Medical Center between December 2000 and January 2007. After HSCT, CMV antigenemia was detected by identifying CMV pp65 early antigen in white blood cells. The incidence of CMV antigenemia was 24% (28/117) at a median of 38 days (range: 19–123 days) after HSCT. In multivariate analysis, CMV antigenemia occurred significantly more often in CMV seropositive recipients, patients who received grafts from alternative donors, T-cell depleted grafts, patients on ATG-containing conditioning regimens, or patients who received steroid for acute GVHD (p

Background Hyperuricemia accompanying tumor lysis syndrome is a serious complication in neoplasia with rapid proliferation and destruction. To confirm the efficacy of recombinant urate oxidase (rasburicase) and its safety profile, a phase IV compassionate use prospective study was performed in Korean pediatric patients with hematologic malignancies. Procedure Rasburicase was administered at 0.2 mg/kg/day once daily for 3–5 days (twice daily allowed during the first 72 hr) by intravenous route for hyperuricemia (uric acid > 7.5 mg/dl). The study period was 5 weeks and consisted of a baseline assessment within 48 hr before the administration of rasburicase, 3–5 days of assessment during treatment and a follow-up assessment at 4 weeks after its final administration. Results The uric acid endpoint (≤7.0 mg/dl) was reached in 97.3% (36/37) of the patients and uric acid levels were significantly reduced in all patients (P

Purpose: To evaluate the usefulness of whole-body (WB) MRI for detecting metastases from paediatric malignant tumours in comparison with conventional oncological imaging methods. Materials and methods: Using a 1.5-T system, a coronal short tau inversion recovery (STIR) sequence was obtained in all patients. In addition, sagittal fat-suppressed T2-weighted, sagittal STIR, or coronal fat-suppressed pre-contrast and post-contrast T1-weighted sequences were performed. Patients who underwent WB MRI and conventional oncological imaging within 15 days were enrolled in the study. In total, 58 bone scintigraphies, 26 iodine-123 (123I) meta-iodo-benzylguanidine (MIBG) scintigraphies, and 48 CT scans were available for comparison in 36 patients (median age 3.5 years; 21 boys, 15 girls) who underwent 82 WB MRI examinations. Skeletal and extraskeletal metastases were evaluated for a variety of tumour types. Results: Concordance rate of WB MRI between two readers was 74%. In detecting metastases, WB MRI had higher sensitivity (99%) and PPV (94%) than bone scintigraphy (26 and 76%, respectively). In detecting skeletal metastases, WB MRI revealed higher sensitivity (100%) than 123I-MIBG scintigraphy (25%) and CT (10%). In contrast, WB MRI showed lower PPV in detecting skeletal and extraskeletal metastases (8 and 57%, respectively) than 123I-MIBG scintigraphy (100%), and lower sensitivity (60%) in detecting extraskeletal metastases than CT (100%). In 2 of 11 untreated patients, tumour staging was upgraded from stage 3 to 4 according to WB MRI findings. In 3 patients, WB MRI revealed early treatment responses (

Chemoimmunotherapy-based treatments have improved the survival of patients with HLH, but outcomes of the patients are still unsatisfactory. We report here the outcome of Korean children with HLH who underwent HSCT, which was analyzed from the data of a nation-wide HLH registry. Retrospective nation-wide data recruitment for the pediatric HLH patients diagnosed between 1996 and 2008 was carried out by the Histiocytosis Working Party of the Korean Society of Hematology. Nineteen patients who received HSCT among the total of 148 enrolled children with HLH were analyzed for the transplant-related variables and events. The probability of five-yr survival after HSCT was 73.3% with a median follow-up of 57. Two months compared to 54.3% for the patients who were treated with chemoimmunotherapy only (p = 0.05). The reasons for HSCT were active disease after eight wk of initial treatment (n = 9), relapsed disease (n = 5), and FHL (n = 5). Fourteen patients are currently alive without disease after HSCT, four patients died of treatment-related events (infection in two and graft failure in two) at early post-transplant period, and one patient died of relapse at one yr post transplantation. The survival of patients who were transplanted because of active disease after eight wk of initial treatment was worse compared to those patients who had inactive state at that time (60.6% vs. 100%, respectively, p = 0.06). Of the four patients who received transplants using cord blood, three died of graft failure (n = 2) and relapse (n = 1). The five-yr probability of survival after HSCT according to the donor type was 85.7% for the MRDs (n = 6), 87.5% for the MUDs (n = 8), and 40% for the MMUDs (n = 5) (p = 0.03). Other variables such as age, CNS involvement at the time of diagnosis, the etiology of HLH (familial or secondary), and the conditioning regimens had no influence on the five-yr OS of the HLH patients who underwent HSCT. HSCT improved the survival of the patients who had familial, relapsed, or severe and persistent SHLH in the Korean nation-wide HLH registry. Although numbers were small, these results are similar to other reports in the literature. The disease state after initial treatment, the stem cell source of the transplant, and the donor type were the important prognostic factors that affected the OS of the HLH patients who underwent HSCT.

Infantile hemangioendothelioma (IHE) is a rare benign vascular tumor with potentially life-threatening complications. Various therapeutic options have been recommended according to the site, extent, and behavior of the IHE. Because of the slow and unpredictable response to treatment with using a single drug in critically ill patients, there is a tendency to administer drugs in combination to treat this disease. Here, we report on a 1-month-old female infant who had a retroperitoneal IHE with Kasabach-Merritt syndrome and she was successfully treated with a combination of steroid, interferon-alpha, and vincristine.

Summary Objective Little is known about the incidence and survival outcomes of pediatric patients with head and neck (HN) lymphomas in Asian populations. This study sought to identify the incidence of HN involvement of pediatric lymphomas and to identify factors prognostic of patient survival. Methods We reviewed the medical records of all children aged 0–14 years with previously untreated lymphomas of HN region and compared patient clinicopathologic characteristics and final outcomes in patients with Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL). Potential prognostic factors for patient survival were investigated. Results Of 106 eligible lymphoma patients, 45 (42.5%; 31 boys and 14 girls) showed HN involvement. Overall, NHL (n = 37) showed more unusual and aggressive presentations than did HD (n = 8) in the head and neck region. Cervical lymphadenopathy was frequently observed (30/45, 66.7%) in these patients. Involvement of extralymphatic head and neck sites was found in 15 of 37 NHL patients (40.5%) but not in any HD patients (p = 0.027). Five-year disease-free survival (DFS) of all HN lymphoma patients was 76.0%. On multivariate analysis, advanced stage and absence of complete remission following 3 cycles of chemotherapy were poor prognostic indicators of patient survival (p Conclusions The incidence of HN involvement in pediatric lymphomas was 42.5% in the studied population. Stage of the lesion and early response to chemotherapy were independent factors prognostic of patient survival.

Studies investigating the effect of prophylactic drugs on hepatic veno-occlusive disease (VOD) development are rare in children that have undergone allogeneic hematopoietic stem cell transplantation (HSCT). This study examined risk factors for VOD, the effect of prophylactic low-dose heparin or lipo-prostaglandin E1 (lipo-PGE1) and the survival rate at day +100 in children undergoing allogeneic HSCT. Eighty five children underwent HSCT between June 1997 and September 2004. Patients were diagnosed and classified as having mild, moderate or severe VOD according to Seattle clinical criteria. Among 85 patients, 25 (29%) developed VOD. VOD occurred more frequently in patients receiving busulfan-based conditioning (24/65, 37%) than in those receiving TBI-based (1/10, 10%) or other (0/10, 0%) regimens (p

In Langerhans cell histiocytosis (LCH) evaluation of the extent of disease is one of the major predictors of patient outcome. Historically this is undertaken using plain radiography and bone scintigraphy. Recently, whole-body (WB) MRI has been reported to be useful in detecting skeletal and extraskeletal metastases in both adults and children. To evaluate the usefulness of WB MRI in patients with LCH in comparison with plain radiography and bone scintigraphy. In nine children (1–7 years of age; mean 3.3 years) who had a pathological diagnosis of LCH and had either plain radiography or bone scintigraphy for comparison, 43 WB MR examinations were performed. Skeletal and extraskeletal lesions of the disease on WB MRI were compared with those on plain radiography and bone scintigraphy. LCH showed unifocal single-system involvement in one patient, multifocal single-system involvement in three, and multifocal multisystem disease in five. WB MRI identified additional skeletal lesions in three (38%) of eight patients, compared with plain radiography, and in two (25%) of eight, compared with bone scintigraphy. WB MRI detected extraskeletal lesions of the disease in five (56%) of the nine patients exclusively, except for one patient whose lung lesions were also detected on plain radiography. In two patients, treatment was changed according to WB MRI findings. WB MRI is a useful initial and follow-up diagnostic method to assess the extent of LCH because WB MRI not only identifies more skeletal lesions of the disease than do plain radiography and bone scintigraphy, but also detects extraskeletal lesions of the disease.

Pneumocystis carinii is the most important opportunistic pathogen of humans in the world. Pneumocystis carinii is experimentally detected in the lungs of rats, mice, rabbits, and monkeys, however, the organisms from different mammals are identical in microscopic morphology. The present study tried to find out more mammalian hosts of P. carinii and also to differentiate the organisms from different mammals by karyotyping. Rats, mice, hamsters, rabbits, cats, and dogs were successfully infected by P. carinii, but guinea pigs and pigs were not. Karyotype of P. carinii from rabbits showed similar size range of chromosomes with that of the prototype, but in different pattern. The patterns from cats and dogs were also different from that of rats. The present study confirms that cats and dogs are infected by P. carinii and at least total three karyotype strains of P. carinii are proven in Korea.

Purpose: Several complications can occur in patients who received bone marrow transplantation (BMT) during childhood and adolescence. This study aims to investigate endocrine dysfunctions after BMT so that better care can be provided to care for long-term survivors of BMT. Methods: One hundred patients (61 males, 39 females) were included in this study. Clinical parameters such as initial diagnosis, age at BMT, conditioning regimen, presence of graft-versus-host disease (GVHD), growth pattern, thyroid func- tion, and pubertal status were retrospectively reviewed to evaluate risk factors associated with endocrine dysfunction. Results :Height standard deviation score (SDS) at BMT, after 1 year of BMT, and at the last visit were 0.08±1.04, -0.09± 1.02, and -0.27±1.18, respectively (P=0.001). Height SDS significantly decreased in patients who received total body irra- diation (TBI) (P=0.017). One of the patients who received TBI demonstrated growth hormone deficiency. Thirty (31.9%) of 94 patients had compensated hypothyroidism. Incidence of compensated hypothyroidism was higher among those who had GVHD (odds ratio 2.82, P=0.025). Of the 32 patients (17 males, 15 females) who were over 14 years in male and 13 years in female at the last visit, 16 (3 males, 13 females) had increased luteinizing hormone (LH) or follicle-stimulating hormone (FSH). Abnormal elevation of LH or FSH was more common in females (odds ratio 30.3, P=0.001). Conclusion :The most common endocrine dysfunction was ovarian insufficiency. Regular check-up for endocrine function needs to be required due to high incidence of endocrine dysfunction in patients with BMT. (Korean J Pediatr 2010;53: 420-427)

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.

We evaluate the outcomes in children with acute leukemia who received allogeneic hematopoietic stem cell transplantation (HCT) using unrelated donor. Fifty-six children in complete remission (CR) received HCT from unrelated donors between 2000 and 2007. Thirty-five had acute myeloid leukemia, and 21 had acute lymphoid leukemia. Stem cell sources included bone marrow in 38, peripheral blood in 4, and cord blood (CB) in 14. Four patients died before engraftment and 52 engrafted. Twenty patients developed grade II-IV acute graft-versus-host disease (GVHD) and 8 developed extensive chronic GVHD. With median follow-up of 39.1 months, event free survival and overall survival were 60.4% and 67.5%, respectively, at 5 yr. Events included relapse in 10 and treatment-related mortality (TRM) in 10. The causes of TRM included sepsis in 4, GVHD in 4 (1 acute GVHD and 3 chronic GVHD), veno-occlusive disease in 1 and fulminant hepatitis in 1. Patients transplanted with CB had event free survival of 57.1%, comparable to 63.2% for those transplanted with other than CB. In conclusion, HCT with unrelated donors is effective treatment modality for children with acute leukemia. In children with acute leukemia candidate for HCT but lack suitable sibling donor, unrelated HCT may be a possible treatment option at the adequate time of their disease.

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.

Background: Bloodstream infection is one of the important causes of mortality, and morbidity in pediatric patients with hemato-oncologic disease. The purpose of this stu dy was to identify the risk factors related to mortality in patients who suffered from a bloodstream infection. Methods: We retrospectively reviewed and analyzed the medical records of 133 pediatric patients with hemato-oncologic diseases who had episodes of bloodstream infection documented at Asan Medical Center from June 2002 through May 2005. Results: A total of 288 pathogens were isolated, and there were 17 episodes of polymicrobial infections. Among the episodes of bloodstream infection, 93.4% were caused by bacteria of which 60.1% were gram-positive bacteria, and 33.3% were gram-negative bacteria. Fungal infections accounted for 6.6% of the infections. The main pathogens included Staphylococcus epidermidis (31.3%), Pseudomonas aeru- ginosa (8.3%), and Klebsiella pneumoniae (7.3%). Gram-positive organisms were isolated more frequently than gram-negative organisms, and non-albicans Candida species were documented more frequently than C. albicans in our study. Infection related mortality was 8.3% (11 of 133 patients). The pulmonary infiltration on chest X-ray (CXR) (P=0.001), and a low absolute neutrophil count ( ≤500/μL) (P=0.017) at the time of blood culture were significantly associated with mortality. Gram-negative bacterial infection (especially with Stenotrophomonas maltophilia) and fungal infection often progressed to the septic shock or death. Conclusion: This study revealed that the presence of pulmonary infiltration on a CXR, neutropenia ( ≤ 500/μL), and gram-negative bacterial infection might be important risk factors of mortality in pediatric patients with hemato-oncologic diseases necessitating more aggressive and vigilant supportive care.

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.

Background: Non-Hodgkin's lymphoma (NHL) accounts for over 80% of pediatric malignant lymphoma in Korea; the event free survival (EFS) of advanced stage NHL has been reported to be 60 to 70%. We accessed the outcome of advanced stage pediatric NHL at a single institution. Methods: Pediatric patients who were diagnosed as stage 3 or 4 with NHL from May 1991 to June 2004 at Asan Medical Center were analyzed for outcomes according to histopathology, gender, age at present, involvement of bone marrow or central nervous system (CNS), and serum level of lactate dehydrogenase (LDH). Results: Sixty-three patients were enrolled in this study. The head and neck were the most common primary site. The five-year EFS and overall survival (OS) were 68% and 78%, respectively. Five-year EFS for lymphoblastic, Burkitt, anaplastic large cell and diffu se large B cell lymphoma were 62%, 86%, 74% and 63%, respectively. Five-year EFS and OS for patients with LDH≤500IU/L were 85% and 100%, while those with LDH>500IU/L were 64% and 72% (P=0.04). There was no significant difference in EFS or OS with regard to other factors. Sixteen out of the 63 patients relapsed, and the five-year OS for those who relapsed was 44%. Conclusion: The outcome of patients with advanced stage NHL treated at our institution was comparable with previous reports. High serum level of LDH at diagnosis proved to be a poor prognostic factor. New effective treatment regimens are needed to improve the outcome of pediatric patients with relapsed NHL.

Background: Hematopoietic stem cell transplantation (HSCT) is one of the most important armamentarium against various hematologic malignancies or some solid tumors. We investigated the number of patients who might need transplants and compared with that of actual transplants to conceptualize current status and circumstances of HSCTs in Korean children. Methods: Questionnaires were sent to Korean Society of Hematopoietic Stem Cell Transplantation (KSHSCT) members who were taking care of children with malignancies or hematologic diseases. Almost all of the newly diagnosed patients between Jan, 1st and Dec, 31st, 2003 were enrolled in the study. Results: Seven hundred forty eight children (male to female ratio = 1.4：1) were enrolled. The median age was 6.1 years old (8 days～28.8 years old). Malignant diseases consisted of 695 cases (92.9%), and among them almost half were hematologic malignancies. The participating members speculated that HSCTs should be indicated in 285 children (38.1%) which included 209 allogeneic, and 76 autologous transplants. In reality, however, allogeneic HSCTs were performed only in 140 children (67.0%) with the median interval of 5.9 month, and autologous transplants in 44 children (57.9%) with 8.3 month. In autologous setting, all the patients received peripheral blood stem cells (PBSCs), whereas bone marrow (61%), cord blood (34%), and PBSC (5%) were used in allogeneic HSCTs. Donor types were as follows: unrelated donor (37%), cord blood (34%), sibling donor (25%), and family (4%). The reasons for not performing HSCTs were unfavorable disease status or death, no availability of suitable donor, economical situation, and refusal by parental preferences. Under the strict insurance regulations, many transplants were not covered by insurance. More autologous transplants were performed without insurance coverage than allogeneic HSCTs (P=0.013). Those cases were advanced cases and HLA mismatch transplants for allogeneic setting, and relatively rare diseases still awaiting favorable results of transplants for autologous setting. Conclusion: HSCTs are essential part of treatment strategies for children with various diseases. Unfortunately, however, a third of patients who were in need of transplants did not receive HSCTs due to various reasons. It is necessary to expand unrelated donor pool or cord blood banks for the cases lacking HLA-identical sibling donors. Also medical insurances should cover HSCTs for rare diseases as well as for less favorable but novel situations where there are no suitable alternatives.

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.

Soluble protein of purified Pneumocvstis cnrinii was prepared from experimentally infected rats. SDS-PAGE of the crude antigen resolved about 20 protein bands from 20 to 200 kDa. Out of thenl, 116 kDa band strongly reacted and 45-55 and 100 kDa bands reacted weakly to the positive reference human serum from U.S.A. Western blot analysis with sera of 130 normal children and 15 newborns in Korea revealed specific IgG antibody reaction to 40-55 and 116 kDa protein bands. Forty percent (40.0%) of the 145 sera were positive with any of the antigenic protein bands of R corinii. The positive rate was 56% in 50 males and 33.3% in 48 females. The protein bands 40-55 and 116 kDa from rat P. carinii were confirmed to cross-react with human sera in Korea. Key words: pneumocvstis carinii, Western blot, antigenic protein bands, IgG antibody, normal children