Long-term follow-up results of cytarabine-containing chemotherapy for acute promyelocytic leukemia

Background/Aims@#We evaluated the feasibility and long-term efficacy of the combination of cytarabine, idarubicin, and all-trans retinoic acid (ATRA) for treating patients with newly diagnosed acute promyelocytic leukemia (APL). @*Methods@#We included 87 patients with newly diagnosed acute myeloid leukemia and a t(15;17) or promyelocytic leukemia/retinoic acid receptor alpha (PML-RARα) mutation. Patients received 12 mg/m2/day idarubicin intravenously for 3 days and 100 mg/m2/day cytarabine for 7 days, plus 45 mg/m2/day ATRA. Clinical outcomes included complete remission (CR), relapse-free survival (RFS), overall survival (OS), and the secondary malignancy incidence during a 20-year follow-up. @*Results@#The CR, 10-year RFS, and 10-year OS rates were 89.7%, 94.1%, and 73.8%, respectively, for all patients. The 10-year OS rate was 100% for patients that achieved CR. Subjects were classified according to the white blood cell (WBC) count in peripheral blood at diagnosis (low-risk, WBC < 10,000/mm3; high-risk, WBC ≥ 10,000/mm3). The low-risk group had significantly higher RFS and OS rates than the high-risk group, but the outcomes were not superior to the current standard treatment (arsenic trioxide plus ATRA). Toxicities were similar to those observed with anthracycline plus ATRA, and higher than those observed with arsenic trioxide plus ATRA. The secondary malignancy incidence after APL treatment was 2.7%, among the 75 patients that achieved CR, and 5.0% among the 40 patients that survived more than 5 years after the APL diagnosis. @*Conclusions@#Adding cytarabine to anthracycline plus ATRA was not inferior to anthracycline plus ATRA alone, but it was not comparable to arsenic trioxide plus ATRA. The probability of secondary malignancy was low.

Endocrine dysfunction after bone marrow transplantation during childhood and adolescence / 소아과

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 function, 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 irradiation (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.

Ototoxicity in children receiving cisplatin chemotherapy / 소아과

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. Method: 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 (<12 years) were 2 most important risk factors for ototoxicity in patients treated with cisplatin. Serial audiometric evaluations are needed in the patients with risk factors during and after cisplatin treatment.

Unrelated Hematopoietic Stem Cell Transplantation for Children with Acute Leukemia: Experience at a Single Institution

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.

Risk Factors of Bloodstream Infection Associated Mortality in Pediatric Patients with Hemato-oncologic Disease / 대한혈액학회지

BACKGROUND: Bloodstream infection is one of the important causes of mortality, and morbidity in pediatric patients with hemato-oncologic disease. The purpose of this study 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 aeruginosa (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 (< or = 500/micorL) (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 (< or = 500/microL), 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.

Relationship between In Vitro Chemosensitivity assessed with MTT Assay and Clinical Outcomes in 103 Patients with Acute Leukemia / 대한진단검사의학회지

BACKGROUND: Cellular drug resistance is supposed to play a major role in chemotherapy failure or relapse. The purpose of this study was to analyze the relationship between in vitro chemosensitivity test results using a 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and clinical response on chemotherapy, and to find the possibility of optimizing the treatment protocol for individual patients according to their actual drug resistance. METHODS: For MTT assay, we obtained bone marrow aspirates from 103 patients with acute leukemia at the time of initial diagnosis or relapse. The following drugs were tested: cytarabine, vincristine, methotrexate, daunorubicin, dexamethasone, L-asparaginase, and mitoxantrone. To evaluate clinical responses after induction chemotherapy, we followed up on their bone marrow study. RESULTS: In our study, in vitro chemosensitivity test with the MTT assay significantly predicted whether patients with AML remained continuous complete remission or went into relapse. It also predicted whether or not child patients with ALL would acquire complete remission after induction chemotherapy. CONCLUSIONS: Although it does not provide the insight into the mechanisms that cause drug resistance, the MTT assay may be a useful tool in individually optimizing the chemotherapy of patients with acute leukemia.

Treatment Outcome and Prognostic Factors for Children with Advanced Non-Hodgkin's Lymphoma at a Single Institution / 대한혈액학회지

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 diffuse large B cell lymphoma were 62%, 86%, 74% and 63%, respectively. Five-year EFS and OS for patients 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.

Current Status of Hematopoietic Stem Cell Transplantation in Korean Children / 대한혈액학회지

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.

Prognostic Significance of Multidrug Resistance Gene 1 (MDR1), Multidrug Resistance-related Protein (MRP) and Lung Resistance Protein (LRP) mRNA Expression in Acute Leukemia

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 (39 myeloid, 32 lymphoblastic) using nested RT-PCR. The expression of each of these genes was then expressed as a ratio in relation to beta-actin gene expression, and the three genes were categorized as being either 0, 1+, 2+ or 3+. MDR1, MRP and LRP mRNA expression was detected in 23.9%, 83.1% and 45.1 %, respectively. LRP mRNA expression was significantly associated with resistance to induction chemotherapy in acute leukemia patients, and in the AML proportion (p=0.02 and p=0.03, respectively). MRP and high MDR1 mRNA expression was associated with poorer 2-yr survival (p=0.049 and p=0.04, respectively). Patients expressing both MRP and LRP mRNA had poorer outcomes and had worse 2-yr survival. The present data suggest that MDR expression affects complete remission 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.

Prophylactic Low-dose Heparin or Prostaglandin E1 may Prevent Severe Veno-occlusive Disease of the Liver after Allogeneic Hematopoietic Stem Cell Transplantation in Korean Children

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<0.05). The incidence of VOD was lower in patients with non-malignant disease compared to those with malignant disease (p<0.05). Survival at day +100 for non-VOD patients was better than that for VOD patients (92% vs. 76%, p<0.05). No patients receiving prophylactic heparin or lipo-PGE1 were found to develop severe VOD, whereas 5 of 35 patients not receiving such prophylaxis developed severe VOD. Given severe VOD is associated with a high mortality rate, this study indicates that prophylactic heparin or lipo-PGE1 may decrease mortality in children undergoing HSCT.

Hematopoietic Stem Cell Transplantation for Children with Malignant Lymphoma in Korea: Multicenter Retrospective Study / 대한소아혈액종양학회지

PURPOSE: Children with Malignant lymphoma who is in the advanced stage at diagnosis or relapses during treatment have a poor prognosis. Recently, hematopoietic stem cell transplantation (HSCT) for advanced stage or refractory/relapsed lymphoma performed frequently. However, the role for HSCT for children with malignant lymphoma is still controversial. In this study, we reviewed children with malignant lymphoma who received HSCT and analyzed the results. METHODS: Questionnaires were made and sent to a group of teaching hospitals, with a return of 37 questionnaires from 11 hospitals. 33 patients with Non-Hodgkin lymphoma (NHL) and 4 patients with Hodgkin disease (HD) who received HSCT from 1997 to 2004 in Korea were enrolled in this study. Disease state at diagnosis, relapses during treatment, disease state at HSCT, and survival record were analyzed. All Data were reviewed with the questionnaires from the 11 teaching hospitals. RESULTS: Four patients with HD received HSCT at the 2nd complete remission after relapse. Survival rate for HD was 100% and their follow up duration ranged from 0.2 to 6.2 years (median 2.4 years). The 2-year survival rate for NHL was 68.1+/-9.0% and their follow up duration ranged from 0.1 to 7.6 years (median 1.5 years). The 2-year survival rate in patients with advanced stage at diagnosis and in relapsed/refractory patients were 83.6+/-1.1% and 55.9+/-12.9%, respectively (P=0.12). The mortality asssociated with HSCT was only 1 case, and most of the transplantation related complications did not resulted in death. CONCLUSION: Our results suggest that high dose chemotherapy followed by HSCT in children with malignant lymphoma is a safe procedure, which at the same time improves the results of standard treatment.

Treatment Outcome of Childhood B-cell Lymphoma and L3 Acute Lymphoblastic Leukemia from a Single Institution / 대한소아혈액종양학회지

PURPOSE: High survival rate can be obtained in B-cell lymphoma (Burkitt's lymphoma, diffuse large B-cell lymphoma) and L3 acute lymphoblastic leukemia (ALL) with multiagent chemotherapy. Objectives of this study were to evaluate the treatment outcomes of B-cell lymphoma and L3 ALL diagnosed at the Department of Pediatrics, Asan Medical Center. METHODS: The medical records of 32 children who were diagnosed with Burkitt's lymphoma, diffuse large B-cell lymphoma and L3 ALL from March 1992 to July 2004 at Asan Medical Center were reviewed retrospectively. The 5 year event free survival (EFS) according to the diagnosis, age, risk group and lactic dehydrogenase (LDH) level were analyzed. RESULTS: There were 23 boys and 9 girls. Age ranged from 9 months to 14.4 years old with a median of 7.1 years. Fourteen patients had L3 ALL, 11 had Burkitt's lymphoma and 7 had diffuse large B-cell lymphoma. Five patients (15.6%) had CNS involvement and 5 with B-cell lymphoma (27.8%, 5/18) had BM involvement. All patients who received appropriate chemotherapy achieved a complete remission (CR), but 18.8% (6/32) relapsed. Among 6 relapsed patients, 5 achieved CR after reinduction chemotherapy. One who had no response to secondary chemotherapy and 2 with isolated CNS relapse died due to disease progression. The most common treatment-related toxicity was myelosuppression (87.5%) followed by neutropenic fever (81.3%). Median follow up is 25 months (3 months to 74 months). Four patients who achieved CR after proper induction therapy (4/32, 12.5%) died, 3 due to relapse and 1 due to toxicity-related complication (neutropenia and sepsis). The 5 year EFS for all patients was 77.5+/-7.5% and the 5 year overall survival was 84.6+/-7.3%. The 5 year EFS of B-cell lymphoma compared with that of L3, ALL was 94.4+/-5.4% versus 55.1+/-13.9% (P=0.012) and 5 year overall survival of relapsed patients was 50.0+/-13.9%. CNS disease at diagnosis, age, LDH had no significant influence on EFS. CONCLUSION: High survival rate of childhood B-cell lymphomas and L3 ALL was obtained with recent intensive multiagent chemotherapy and about 50% of relapsed patients were salvaged with reinduction. High incidence of the treatment-related toxicity such as myelosuppression, neutropenic fever and TLS was observed, but the treatment-related mortality was very low with recent supportive therapies. Survival rate was improved with prompt and appropriate management for the treatment-related toxicity of the intensive chemotherapy.

Hemophagocytic Syndrome Presenting as Severe Acute Hepatitis / 대한소아소화기영양학회지

PURPOSE: Hemophagocytic syndrome (HPS) is characterized by persistent high fever, hepatosplenomegaly, cytopenias, hypertriglyceridemia, and/or hypofibrinogenemia. Hepatic manifestations including overt hepatic failure and fulminant hepatitis are common in HPS. Liver transplantation (LT) should be considered in a case of fulminant hepatitis by other than HPS, but LT is contraindicated and complete cure is possible by chemotherapy in HPS. Therefore, we conducted this study to define the characteristics of HPS presenting as severe acute hepatitis. METHODS: Among the total of 23 patients diagnosed as HPS by bone marrow examination between 1994 and 2005 in Asan Medical Center, 11 cases presented as severe acute hepatitis were enrolled in this study. We analyzed the clinical features, laboratory findings and outcome retrospectively. RESULTS: Seven (64%) of the 11 children with HPS and hepatitis were referred to pediatric gastroenterologist at first. The mean age of onset was 50 months. There was no case with family history of primary HPS. Epstein-Barr virus was positive in 4, and herpes Simplex virus was positive simultaneously in 1 case. As the presenting symptoms and signs, fever was present in 10, hepatosplenomagaly was noted in all and jaundice in 10. Anemia was observed in 10, thrombocytopenia in 10, leukopenia in 8, hypertriglyceridemia in 9, hypofibrinogenemia in 8 and hyperferritinemia in 7 cases, respectively. Nine children received chemotherapy including etopside. The overall mortality rate was 72% (8/11). CONCLUSION: HPS, which needs chemotherapy, should be considered as a cause of severe acute hepatitis especially when accompanied with prolonged high fever and cytopenias.

Prognostic Significance of WT1 Gene Expression in Patients with Acute Leukemia / 대한진단검사의학회지

BACKGROUND: The Wilms' tumor gene (WT1) is located on chromosome 11p13. Several authors have shown that the expression of WT1 gene is associated with prognosis of acute leukemia. It was the aim of this study to investigate the relationship between WT1 positivity and the response to treatment in terms of rate of complete remissions (CR), and survival and to evaluate the prognostic value of WT1 expression in patients with acute leukemia. METHODS: We examined the presence of WT1 specific mRNA in bone marrow samples of 71 patients with acute leukemia at diagnosis (AML 39, ALL 32) by nested RT-PCR. The integrity and the amount of RNA were analyzed by amplification of the -actin gene as an internal control. The relative ratio of WT1 gene expression/ -actin was calculated and classified as not amplified (0), weakly amplified (1+), moderately amplified (2+), or strongly amplified (3+). RESULTS: Thirty-four (47.9%) of the patients with acute leukemia at diagnosis were WT1 PCR positive. Among the WT1 positive patients, 10 patients (14.1%) showed 1+, 20 patients (28.2%) 2+, and 4 patients (5.6%) 3+. The patients with WT1 mRNA expression were younger than those without it in AML. There was a tendency of a higher CR rates in WT1 negative patients than in WT1 positive ones (AML 61.9% vs. 50%, ALL 75.0% vs. 68.8%). The probability of 5 year survival was 62.2% for WT1 negative group and 44.1% for WT1 positive group in all patients. The median survival days accord-ing to levels of WT1 expression was 709 days for negative group, 310 days for 1+ or 2+ groups and 294 days for 3+ group. CONCLUSIONS: The present data suggest a clinical relevance of WT1 expression for the achieve-ment of CR and long term survival in acute leukemia. Analysis of WT1 expression with bone mar-row aspirates at the diagnosis of acute leukemia may be useful to predict prognosis.

Epidemiology and Clinical Outcomes in Children with Malignant Lymphoma in Korea: Retrospective Study / 대한소아혈액종양학회지

PURPOSE: Malignant lymphoma is the primary malignant tumor derived from lymphoid organs. It is composed of Hodgkin's disease and non-Hodgkin lymphoma. Recently, survival rate is on the rise due to improved combination chemotherapy, radiotherapy and high dose chemotherapy followed by hematopoietic stem cell transplantation. In South Korea, no epidemiologic studies concerning malignant lymphoma in the pediatric age group has been performed. Therefore, the Korean Society of Pediatric Hematology-Oncology retrospectively analyzed the incidence, pathologic subtypes, treatment strategies, and survival rates of pediatric malignant lymphomas in South Korea. METHOD: Questionnaires were made and sent to a group of training hospitals, with a return of 580 questionnaires from 24 hospitals. Among them, 517 reports were suitable for analysis. RESULTS: Among the 517 cases, Hodgkin's disease accounted for 58 cases and non-Hodgkin's lymphoma for 459 cases. Male to female ratio for malignant lymphoma was 2.7. Mean age at diagnosis was 8.3 years. Among the pathologic subtypes, mixed cellularity was the most frequent subtype for Hodgkin's disease. Most (70.7%) cases of non-Hodgkins lymphoma belonged to high grade NHL. Burkitt lymphoma accounted for 102 cases, and lymphoblastic lymphoma was found in 58 cases. Peripheral lymphadenopathy was the most common presenting sign upon diagnosis. B symptoms were significantly more frequent in Hodgkin's disease patients than in non-Hodgkin lymphoma patients. The Complete response rate was 62.1% for non-Hodgkin's lymphoma, and 82.8% for Hodgkin's disease. Overall 5 year survival rate was 60.0% in non-hodgkin's lymphoma, and 84.8% in Hodgkin's disease. CONCLUSION: The annual incidence of malignant lymphoma in Korea is 4.7 per million. In cases of chemotherapy-sensitive, refractory or relapsed malinant lymphoma, high dose chemotherapy followed by hematopoietic stem cell transplantation is vital for improved survival. For more systematic analysis of epidemiology on malignant lymphomas, better surveillance mechanisms on the occurrence of malignant lymphomas are crucial, and establishment of standardized treatment protocol for malignant lymphoma is required.

Pediatric Myelodysplastic Syndrome in Korea: Clinical Characteristics and Comparison of Prognostic Scoring Systems / 대한소아혈액종양학회지

PURPOSE: Myelodysplastic syndromes (MDS) are heterogeneous clonal stem cell disorders characterized by morphological and functional abnormal hematopoiesis, resulting in cytopenias in the peripheral blood. MDS in children are very rare and their clinical characteristics, natural history, the most effective treatment and prognostic factors need to be elucidated. In addition, consensus for the classification of pediatric MDS has not been reached yet. This multicenter, retrospective study aimed to describe the characteristics and the disease courses of 75 MDS patients from 11 University Hospitals in Korea, seen between 1991 and 2001. METHODS: Kaplan-Meier probability of leukemic transformation and overall survival were plotted. And the usefulness of prognostic scoring systems, including French-American-British (FAB) classification, Bournemouth scoring system (BSS), and International Prognostic Scoring System (IPSS) in the prediction of transformation to acute myelogenous leukemia (AML) and overall survival was evaluated. RESULTS: The median age was 65 months (2~175 months) and the sex ratio was 2.6: 1 (M: F). Fourteen patients (18.7%) were unable to be allocated into any subtype of FAB. The frequency of FAB subtypes in Korea was similar to that of Western countries except for higher proportion of refractory anemia (RA, 47.5%). Median survival was 54 months with Kaplan-Meier 5-yr survival probability of 31.9% and 2-yr probability of transformation to AML was 23.7%. None of the FAB, BSS, and IPSS was capable of discriminating subgroup of patients for the prediction of survival. However, all of the FAB (P=0.004), BSS (P=0.001), and IPSS (P=0.02) were able to subdivide subgroups for the prediction of transformation to AML. CONCLUSION: The characteristics of pediatric MDS in Korea were different from those of other countries, in light of the higher proportion of RA, the low percentage of inherited diseases, and the low percentage of cytogenetic abnormalities. However, the reasons of the differences were not clear. Moreover, none of the prognostic scoring systems, including IPSS, was reliably predictive of survival, reflecting differences from adult cases. With this multicenter study, we suggest the necessity of a prospective study for the classification and treatment. A newer, effective method should be developed for the prediction of disease progression and survival in pediatric MDS.

Clinical Characteristics of Biphenotypic Acute Leukemia in Childhood: A Single Institutional Experience / 대한소아혈액종양학회지

PURPOSE: The diagnostic criteria of the biphenotypic acute leukemia (BAL) are based on the number and degree of the specificity of the immunological markers expressed on the leukemic blasts. The newer diagnostic criteria proposed by The European Group for the Immunological Classification of Leukaemias (EGIL) is now well accepted. We have recently evaluated our BAL patients using the EGIL criteria and analyzed the clinical characteristics, treatment and clinical outcome. METHODS: Fourteen children diagnosed with BAL among 193 childhood acute leukemia patients in our hospital from January 1995 to December 2001 were retrospectively reviewed. RESULTS: The incidence of BAL was 7.3% (14 out of 193 cases). Of these 14 patients, 12 were de novo and 2 were secondary. In the de novo group, the immunological marker studies showed myeloid/B-lymphoid phenotype in 6 (50%), myeloid/T-lymphoid in 3 and B-lymphoid/T-lymphoid in 1. In addition, two patients showed trilineage differentiation. Cytogenetic analysis revealed various abnormal karyotypes in the majority of the cases, showing normal karyotype only in 3 cases. Among the karyotype abnormalities, two were t (9; 22) and one was t (4; 11). Chemotherapy was mostly based on the induction regimen of acute lymphoblastic leukemia therapy (12 of 14 cases). One patient was treated with acute myeloid leukemia regimen and one patient received combination of both acute lymphoid and myeloid regimen. Induction of complete remission was achieved in 100% of the patients and the median duration of induction therapy to complete remission was 33 days. Five of the 12 de novo patients died during the median follow-up of 16.5 months (4 months to 37.5 months) and the 2 year survival rate was only 52%. CONCLUSION: The incidence of BAL in children is relatively rare and the most common immunophenotypic expression consists of myeloid and B-lymphoid coexpression. Most of the cases showed chromosomal abnormalities. The outcome of BAL treated mostly with the traditional acute lymphoblastic leukemia induc without stem cell transplantation should be sought especially in those expressing poor prognostic cytogenetic abnormalities or strong myeloid marker expression.

The Frequency of HLA Alleles in Korean Children with Aplastic Anemia and the Correlation with the Response to Immunosuppressive Treatment / 대한소아혈액종양학회지

PURPOSE: Immune pathophysiology of aplastic anemia (AA) has been indirectly inferred from responses to immunosuppressive agents. An association between AA and HLA-A2, or HLA-DR2 (its serologic split, HLA-DR15; or its molecular correspondents, DRB1*1501) has been implicated. The presence of HLA-DR15 (including DR2 or DRB1*15) has been closely associated with a favorable response to immunosuppression in AA. This study was aimed to characterize Korean patients with AA by determining the association with certain HLA alleles, such as HLA-DR2 or HLA-A2, and their implications in terms of the response to immunosuppression. METHODS: One-hundred eighteen children with AA from 10 university hospitals between 1990 and 2001 were enrolled in this multicenter, retrospective study. Among them, HLA data were available from 80 patients. Tests of proportions were used to compare allelic frequencies. RESULTS: The frequency of HLA-A2 (58.8%) or HLA-DR2 (24.7%) in AA was not significantly different from those of the controls. Analysis of the patients treated with immunosuppression (N=86) showed that, 50.0% of patients showed a response, including 16.0% of complete response at 6 months. The presence of DR2 allele did not portend a favorable response to immunosuppressive therapy. CONCLUSION: Unlike Western countries, the association of AA with certain HLA alleles was not documented in the Korean population. Moreover, the presence of HLA-DR2 did not predict a favorable response to immunosuppression. This peculiar characteristics of Korean AA needs to be investigated whether these findings reflect ethnic differences, different contribution of immune-mediated AA, different immune mechanisms, or mere limitation by number of study patients.

Autologous Stem Cell Transplantation for the Treatment of Neuroblastoma in Korea

Autologous stem cell transplantation (ASCT) for the treatment of high-risk neuroblastoma (NBL) is an accepted method for restoring bone marrow depression after high dose chemotherapy. We retrospectively analyzed eighty eight cases of NBL that underwent ASCT following marrow ablative therapy at 12 transplant centers of the Korean Society of Pediatric Hematology-Oncology between January 1996 and September 2000. Seventy nine children were of stage IV NBL and 9 were of stage III with N-myc amplification. Various cytoreductive regimens were used. However, the main regimen was 'CEM' consisting of carboplatin, etoposide and melphalan, and this was used in 66 patients. Total body irradiation was also added in 36 patients for myeloablation. To reduce tumor cell contamination, stem cell infusions after CD34+ cell selection were performed in 16 patients. Post-transplantation therapies included the second transplantation in 18 patients, interleukin2 therapy in 45, 13-cis retinoic acid in 40, 131-meta-iodobenzylguanidine in 4, conventional chemotherapy in 11, and local radiotherapy in 8. Twenty two patients died, sixty six patients are surviving 1 to 46 months after ASCT (median followup duration, 14.5 months). Although the follow-up period was short and the number of patients small, we believe that ASCT might improve the survival rate in high-risk NBL.

TEL/AML1 Fusion Transcripts in Childhood B-Lineage Acute Lymphoblastic Leukemia / 대한혈액학회지

BACKGROUND: The t(12;21)(p13;q22), which fuses the TEL gene on chromosome 12p13 and the AML1 gene on chromosome 21q22, is observed in approximately 20~25% of childhood B-lineage acute lymphoblastic leukemia (ALL) cases and is associated with a favorable outcome. A retrospective study was conducted to investigate the frequency of TEL/AML1 fusion in the patients diagnosed as childhood B-precursor ALL. METHODS: Because of the low detection rate by routine karyotypic analysis, we studied 54 children with B-lineage ALL using the fluorescence in situ hybridization (FISH) analysis. RESULTS: Results of this analysis demonstrated a 9.3% frequency of TEL/AML1 fusion, relatively lower than Japanese, Taiwanese and Caucasian children. All five patients with TEL/AML1 fusion showed CD10 positivity and predominance of male patients (4:1). Two cases of TEL/AML1 positive groups expressed the myeloid antigens, but no significance was noted (P>0.05). In TEL/AML1 positive groups, the leukemia was developed between 4 and 5 years old age (favorable age) and showed low initial leukocyte counts (<50,000/micro L). CONCLUSION: Although these findings combined with earlier reports indicate that TEL/ AML1 fusion was frequent genetic abnormality in childhood ALL, relatively low frequency in Korean patients suggested the existence of geographic or racial variations in the genotype of ALL.