Epidemiology and Clinical Characteristics of Childhood Acute Lymphoblastic Leukemia in Korea / 대한소아혈액종양학회지

PURPOSE: Acute lymphoblastic leukemia (ALL) accounts for approximately 75% of all cases of childhood leukemia. We investigated epidemiology, clinical and laboratory features and treatment outcome of the children with ALL in Korea during recent 5 years. METHODS: One thousand forty nine patients were enrolled between January 1994 and December 1998 from 37 major hospitals in Korea. The data regarding the clinical and laboratory features including age, WBC counts at diagnosis, immunophenotype, morphology, cytogenetics and treatment outcome of patients were analyzed retrospectively by review of patient's medical records. Kaplan-Meier survival curves were constructed. The differences between groups analyzed by log-rank test. RESULTS: There were 597 males and 452 females. The distribution between the age 2 and 5 years is most common in 46.1%. The annual incidence rate per 100,000 population varied from 1.6 to 2.2. The 5 year event free survival (EFS) rates according to good prognostic factors were as follows: 67% bet ween 1-9 year of age at diagnosis, 69% in under 10,000/mm3of initial WBC count, 74% in early pre-B cell CALLA ( ) immunophenotype, 65% in L3 morphology, 68% in no CNS invasion. Most of patients were treated by CCG treatment protocol. The 5 year EFS was 63%. Main complications were sepsis (21.8%) and hemorrhage (12.5%). The relapse rate was 15.6%. The common causes of death were sepsis, DIC, pneumonia, relapse. CONCLUSION: Our results could provide the most recent and important information about acute lymphoblastic leukemia of children in Korea.

Response to Immunosuppressive Therapy and an HLA-DR Allele in Children with Aplastic Anemia / 대한혈액학회지

BACKGROUND: Genetic susceptibility to a variety of disease has been shown and it has recently been suggested that aplastic anemia is more common in adults who are HLA-DR2+ than in the general population. METHODS: To investigate whether certain HLA-DR gene is more common in children with aplastic anemia and HLA-DR2+ gene is associated with susceptibility to cyclosporine A (CyA), we analyzed the results of HLA-DR typing in 37 children with aplastic anemia with sequence specific oligonucleotide probe (SSOP) method. RESULTS: Eight patients were DR2+, and there was no more common than the normal population. All of the 8 patients with DR2+ were DRB1*1501+ with high resolution HLA typing. Of the 8 patients with DRB1*1501+, 3 patients were treated with CyA alone (2 patients) or CyA plus ATG (1 patient), 2 patients were treated with ATG (1 patient) or ALG alone (1 patient). Patients treated with CyA only or CyA plus ATG had either a complete (1 patient) or partial (2 patients) response and patients treated ATG or ALG alone had no response. CONCLUSION: Although incidence of HLA-DR2 was not significantly higher in children with aplastic anemia then normal population, response rate to CyA was significantly high in the DR2+ patients.

Evaluation of Clinical Characteristics and Prognostic Factors in the Epstein-Barr Virus-Associated Hemophagocytic Syndrome / 대한소아혈액종양학회지

BACKGROUND: A virus-associated hemophagocytic syndrome(VAHS) is a non-neoplastic, generalized histiocytic proliferation with prominent hemophagocytosis associated with a systemic viral infection. Although VAHS is generally a benign process, Epstein-Barr virus- associated hemophagocytic syndrome(EBV-AHS) is often fatal and has a high mortality rate. Therefore, clinical and laboratory findings, virology studies, treatment and prognosis in EBV- AHS are reviewed. METHODS: We retrospectively analyzed various clinical datas of 7 patients who were diagnosed as EBV-AHS by EBV panel test, mRNA in situ hybridization(1 case) and diagnostic guidelines of Histiocyte Society and followed up to the Department of Pediatrics, Severance Hospital, Yonsei University Medical College from January 1990 to December 1997. RESULTS: The mean age at diagnosis was 2.8 years(range; 0.8~5.4). EBV-AHS was caused by reactivation of EBV in 6 cases and primary infection in 1 case. Persistent fever and hepatosplenomegaly were observed in all cases. Hyperferritinemia was detected in 5 cases. Hypertriglyceridemia was noted in 4 cases among 5 cases tested and hypofibrinogenemia was detected in 5 cases among 5 cases tested. Benign histiocytic infiltration(at least above 5% of all nucleated marrow cells), hemophagocytosis and normocellularity in bone marrow were observed in all cases. The mortality rate was 57%, the main causes of death were bleeding and sepsis. In analysis of prognostic factors associated with death, there was a correlation between hypofibrinogenemia, hepatomegaly, hypoalbuminemia and death, although insignificant statistically. CONCLUSION: In our study, EBV-AHS was caused by reactivation of EBV in most cases. The mortality rate was 57% and the main causes of death were bleeding and sepsis. In analysis of prognostic factors associated with death, there was a correlation between hypofibrinogenemia, hepatomegaly and hypoalbuminemia to a certain degree. But, further study of larger numbers of patients and longer follow-up is needed to clarify the prognostic factors.

Method of RBC Depletion from Human Umbilical Cord Blood / 대한소아혈액종양학회지

BACKGROUND: Cord blood(CB) has been suggested as an alternate source of stem cells in transplantation because of lower incidence of graft versus host disease and ease of collection. To optimize storage space cord blood needs to be stored as separated product. Additionally, for cord blood bank to be economical and efficient, volumes smaller than that of whole packs needs to be stored. However, CB processing procedures described so far involve open systems and/or reagents which are not licensed for use in humans. Consequently, these procedures poorly match the needs for closed-system, large-scale CB banking. In our study, we use the triple bag system in which the CB is separated by centrifugation to maintain of sterility and volume reduction. And simple and effective RBC depletion method was evaluated with 10% pentastarch and 4% modified gelatin. METHODS: The collection of CB was performed from 45 full term newborns. The collection was made by gravity and uterine contraction before placental expulsion with triple transfusion bag containing CPD-A1. 10% Pentastarch(Group A) or 4% modified gelatin(Group B) is added directly to the CB containing bag. After RBC sedimentation, the WBC-rich supernatant is collected in a satellite bag. After RBC depletion, recovery of mononuclear cells(MNC), CD34+ cells were compared between two groups. RESULTS: Mean volume of collected CB and final RBC-depleted products were 68.1+/-17.0 mL and 18.1+/-4.1 mL in Group A and 68.0+/-15.8 mL, 23.1+/-6.3 mL in Group B, respectively. After RBC depletion, the number of MNC and CD 34+ cells were 2.61+/-1.51x108, 1.19+/-0.96x106 in Group A and 4.03+/-3.16x108, 1.43+/-0.86x106 in Group B. Mean recovery of MNC, CD34+ cells were 70.2+/-43.7%, 60.2+/-31.5% in Group A, and 84.7+/-39.9% and 87.7+/-7.5% in Group B, respectively. CONCLUSION: CB processing in closed-system using triple bag with 4% modified gelatin appears to be safe, easy, effective and particularly suitable for large-scale CB banking.

A Case of Paroxysmal Cold Hemoglobinuria Following Epstein-Barr Virus Infection / 대한소아혈액종양학회지

Paroxysmal cold hemoglobinuria(PCH), a rare type of autoimmune hemolytic process caused by a complement-binding IgG anti-P biphasic hemolysin, is associated with a positive Donath-Landsteiner(D-L) test. Historically, PCH has been associated with syphilis, but is now most often seen following viral infections especially in children. Epstein-Barr virus(EBV), a member of Herpesviridae, can cause various hematologic complications such as neutropenia, thrombocytopenia, aplastic anemia, virus associated hemophagocytic syndrome and hemolytic anemia. We report a case of PCH following EBV infection confirmed by EBV panel test and D-L test. The patient, a 4-year-old male was seen at Yonsei Medical Center in April, 1997, complained high fever, jaundice and hematuria for 2 days. Direct antiglobulin test using anti-C3d monovalent antisera was strong positive, but was negative against anti-IgG monovalent antisera. D-L test showed a characteristic biphasic hemolysin pattern. EBV panel test showed primary infection with a result of EBV EA(early antigen) IgM(+), EBV EA IgG(-), EBV NA(nuclear antigen) IgG(-). He was improved with transfusion of packed red cells and discharged on 13 th hospital day. He was completely recovered and then no relapse occurred during follow up. PCH is thought to be a rare form of autoimmune hemolytic anemia, but recent studies suggest that PCH may account for a large percentage of cases of autoimmune hemolytic anemia as acute transient form, especially in children. Therefore, in unexplained hemolytic anemia, more careful serological examination and attention will result in high detection rate of PCH and cause of PCH.

A Case of Kasabach-Merritt Syndrome with Involvement of Airway Obstruction Treated with Interferon Alfa-2a / 대한소아혈액종양학회지

We have recently encounted a case of Kasabach-Merritt syndrome which were characterized by hemangioma, thrombocytopenia, and disseminated intravascular coagulation. The skin of anterior neck and tongue was involved by large mass of hemangioma. Patient was taken ventilator care from upper airway obstruction of hemangioma. He was placed on combined therapy with steroid and interferon alfa-2a for 13weeks. Blood platelet count increased to acceptable range(>20000/mm3) after 10weeks of interferon alfa-2a treatment and the hemangioma decreased in size. But, he expired from failure of airway maintenance, uncontrollable bleeding and septic shock on hospital day 93. A brief review of the literature ensues with the case report.

Clinical Significance and Detection of Antibodies Against Platelet GP Ib/I X and Gp II b/IIIa in Childhood Chronic Idiopathic Thrombocytopenic Purpura / 대한소아혈액종양학회지

BACKGROUND: Chronic idiopathic thrombocytopenic purpura is an autoimmune disorder caused by sequestration of antibody-sensitized platelets in the reticuloendothelial system. However, uncertainty as to the specificity, frequency and clinical significance of such antibodies still remains. So, we tried to further clarify the above uncertainty in childhood chronic idiopathic thrombocytopenic purpura. METHODS: We analyzed sera from 29 patients. Twenty six patients were chronic ITP who were admitted or followed up to the Department of Pediatrics, Severance Hospital, Yonsei University Medical College from August 1996 to March 1997 by employing a modified antigen-capture ELISA(MACE), flow cytometry and electrophoresis(SDS-PAGE) and immuno-blotting(IB) assays. Three patients with ITP less than 6 months after onset of ITP were included to know the possibility to differrentiate between acute ITP and chronic ITP in this study. RESULTS: 1) Glycoprotein(GP)-specific antibodies were found in 28% (8/29) of patients, with 2 patients having antibodies directed solely to Gp II b/III a, no patients holding antibodies specific only for GPI b/I X and 6 possessing antibodies against both anti-GP I b/I X and Gp II b/III a antigen. 2) The detection rate of GP-specific antibodies of flow cytometry was about 10%. The positivity of anti-GPI b/I X antibodies by MACE and immunoblotting was 14% (4/29), respectively, the positivity of anti-Gp II b/III a antibodies by MACE and immunoblotting was, 21 % (6/29) respectively. The concordance rate between two assays(MACE and IB) was 79% (23/29). None of the three methods was good enough to stand alone. 3) Serum antibodies were not more frequently detected in active(p=1.0) or non-splenectomized(p=.54) chronic ITP patients. 4) No association was found between antibody specificity(anti-GPI b/I X, anti-Gp II b/ III a) and platelet counts(p : .87). CONCLUSION: We conclude that in korean childhood chronic ITP, antibodies against both anti-GPI b/I X and Gp II b/III a antigen were predominant antibody. But, the longterm follow-up in more cases is needed to further clarify the clinical significance of antral-platelet antibody in chronic ITP should be assessed.

The Prognostic Significance of Immunophenotype in Children with Acute Lymphoblastic Leukemia / 대한소아혈액종양학회지

PURPOSE: The prognostic factors in acute lymphoblastic leukemia was patient's age at diagnosis, sex, hepatosplenomegaly, initial WBC & platelet count. Recently immunophenotype has being studied as guidance for several treatment protocol. We performed a retrospective study to evaluate the significance of immunophenotype on clinical course & long-term survival in children with acute lymphoblastic leukemia. METHODS: One hundred two children with acute lymphoblastic leukemia were admitted to the Department of Pediatrics, Yonsei University College of Medicine from Jan.1991 to Dec. 1995, and bone marrow aspiration biopsies and immunophenotyping were performed. The prognostic significance of immunophenotype was evaluated base on the median event free survival and probability of survival at the end of follow-up. RESULTS: 1) In 102 children comprised 14 cases under 2 years old, 71 cases from 2 to 10 years of age and 17 cases above 10 year old. The ratio of male to female was 6 : 4. 2) By CCG risk grouping, standard risk in 21 cases, intermediate risk in 35 cases, high risk in 46 cases. 3) By cytologic classification of FAB, Ll in 65 cases, L2 in 31 cases, L3 in 2 cases 4) Remission induction rate in early pre-B ALL was 100% (39/39), among those recurrence rate 20% (8/39). 5) Remission induction rate in pre-B ALL was 90% (26/29), among those recurrence rate 54% (14/26). 6) Remission induction rate in B-cell ALL was 33%(113), and all cases was expired during follow-up. 7) Remission induction rate in T-cell ALL was 100% (12/12)), among those recurrence rate 41% (5/12). 8) Remission induction rate in T-B mixed ALL was 71%(517), among those recurrence rate 0% (0/5), but non-remission cases was expired during follow-up. 9) Remission induction rate in Myeloid Ag(+) ALL was 83%(516), among those recurrence rate 80% (415). CONCLUSIONS: These results suggest that better result on long-term survival was observed in early pre-B ALL than in T-cell, 7-B mixed, or Myeloid antigen positive ALL and immunophenotype have prognostic impact in acute Iymphoblastic leukemia.

T Cell Function before, during and after Chemotherapy in Children with Acute Lymphoblastic Leukemia / 대한소아혈액종양학회지

BACKGROUND: Modern intensive chemotherapy has dramatically improved the prognosis of acute lymphoblastic leukemia in children. However, quality of life and even survival may be threatened by infection. Immunosuppression is experted due to disease itself or therapy, and sometimes, immunosuppression itself may lead to reactivation of latent viral infections in these patients. Often the viruses involved in the most severe infections suggest that patients suffer from defect in the cellular immunity. The principal defects that predispose leukemia patients to infection are defects of T cell, B cell, stem cell, complement, and macrophage. These contributing factors interact in a complex manner resulting in spectrum of problems. But these may result from a T cell defect and, in this study, 7 cell responsiveness of patients at diagnosis, remission induction, maintenance chemotherapy and after chemotherapy for leukemia has been investigated. Studies of the immune competence of patients undergoing chemotherapy for leukemia is in progress, but results are different from each other. METHOD: Between July 1994 and May 1996, seventy patients with childhood ALL were enrolled in this study. In order to expect frequency and depth of infection and prognosis, we investigated concentrations of immunoglobulins G, A, M, peripheral total lymphocyte count, 7 cell subsets, phytohemmaglutinin responsiveness, interleukln-2(IL-2), gamma-interferon(gamma-INF), and natural killer cell activity. RESULTS: 1) IgA concentrations were often markedly raised at diagnosis, and IgG, IgM concentrations both were within normal limits. During and after chemotherapy, IgA had fallen significantly but IgG, IgM are within normal limits. 2) Total lymphocyte count had fallen during chemotherapy, and returned to normal levels after chemotherapy. CD4+ T cell were markedly decresed at diagnosis, during chemotherapy and returned to normal levels after chemotherapy. 3) In vitro proliferative response of peripheral blood lymphocytes to the T cell mitogen phytohenagglutinin were impaired at diagnosis, during chemotherapy but did not returned to normal levels. 4) Interlekin-2, gamma interferon were normal levels at diagnosis, and had fallen in the induction of remission and quickly returned to normal levels with the swish to maintenance chemotherapy. But Interleukin-2 had fallen during and after chemotherapy. Natural killer cell activity had fallen at diagnosis, during chemotherapy and returned to normal levels after chemotherapy. CONCLUSION: It is assumed that evidence of impaired T cell responses is somewhat definite. These observations suggest that proliferative responses to phytohemagglutinin, CD4+ T cell, natural killer cell activity defects are due to leukemia itself but others more likely are generalizable defects caused by chemotherapy. Further investigations, however, have suggested a persisting defect in IgA, proliferative reponses to phytohemagglutinin, and interleukln-2. Our observations also show that despite normal immunoglobulin levels, most of these children have nonprotective levels for common childhood bacterial or viral disease. These results support to the praxis to withdraw prophylactic antibiotics after discontinuation of intensive chemotherapy and to start the immunization. It is expect to try to use cytokine on treatment and to improve mortality and morbidity for children of acute leukemia also.

EBV-elicited familial hemophagocytic lymphohistiocytosis

Familial hemophagocytic lymphohistiocytosis (FHL) is a rapidly fatal illness, usually encountered in infancy, characterized by fever, hepatosplenomegaly, pancytopenia, and central nervous system involvement. Microscopic examination of tissue shows a non-malignant lymphohistiocytic infiltrate, with prominent erythrophagocytosis. FHL is an autosomal recessive hereditary disorder but may develop secondarily to other conditions such as immunosuppression, malignancies, fat overload and certain infections. We recently experienced a case of siblings developing FHL, which may be associated with EBV infection.