Most pediatric hematologists are indifferent to hemolytic anemias. In this article, several interesting researches mainly by Idiopathic Disorders of Hematopoietic Organs Research Committee, the Ministry of Health and Welfare of Japan are presented. Hereditary spherocytosis and elliptocytosis are consequences of a deficiency or a mutation of membrane skeletal proteins such as spectrin and ankyrin. Congenital dyserythropoietic anemia (CDA) type II (HEMPAS) is the most common CDA. Band 3 glycoproteins from HEMPAS red cells revealed truncated hybrid type structures. This suggests that the primary enzyme deficiency of HEMPAS is in N-acetylglucosaminyltransferase II (GnTII) or α-mannosidase II (α-MII). The incidence of hemolytic uremic syndrome (HUS) has an increasing tendency. Verotoxin-producing Escherichia coli has been recognized as the gastrointestinal pathogen most frequently associated with HUS. Affected erythrocytes of patients with paroxysmal nocturnal hemoglobinuria (PNH) are deficient in the complement regulatory proteins : GPI anchored proteins. cDNA cloning of deficient enzyme is in progress. High-dose intravenous gammaglobulin therapy for neonatal immune hemolytic anemia caused by blood group incompatibility seems to be useful.

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We studied the clinical and cytogenic characteristics in 11 cases of childhood leukemias with 11q23 chromosome abnormalities treated between 1984 and 1991 (2 ALL cases, 8 ANLL cases, one JCML at acute phase). Two infantile ALL cases had marked hepatosplenomegaly and hyperleukocytosis with CD 10-negative early B precursor phenotype. Both patients died within 1 year from the diagnosis. Seven ANLL cases with 11q23 abnormalities were at median 4-year-old (range, 1.2-12.5), consisted of 3 FAB-M4, 4 M5 and one M7 case. Hyperleukocytosis (> 100 × 10⁹/, u1) was present in 4 of the 8 cases. These ANLL patients had a poorer prognosis than those with other chromosome abnormalities or normal karyotype (p <0.05 and p <0.01, respectively), probably due to a high incidence of induction failure and relapse. More intensive chemotherapy including bone marrow transplantation and supportive therapy will be needed for such ANLL cases with 11q23 abnormalities. Acute leukemia with 11q23 abnormality was developed in a patient with JCML, following about two years of maintenance chemotherapy by etoposide (cumulative dose ; 8, 850 mg/m²), suggesting this could be secondary leukemia.

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Anemia is often complicated with severe physically and mentally handicapped patients (handicapped patients). For high quality of their life, we discussed the characteristics of their anemia compared with iron deficiency anemia (IDA) in children. One hundred twenty handicapped patients were evaluated and 52 patients (43.3%) had anemia. The normocytic, normochromic anemia was seen in 36.5% of the anemia patients and the IDA was seen in 38.5%. In handicapped patients, there were no significant differences in serum folic acid, vitamin B₁₂ and copper between the anemia group and the non-anemia group. The levels of Hb, serum iron and copper were significantly lower in the tube-feeding group than the non-tube-feeding group. In the group with IDA among handicapped patients, the average value of TIBC was 340 ± 46.4, μ g/dl and most of their TIBC levels were within normal range. The response to iron therapy was little effective, especially in the low-TIBC group (less than 350, μ g/dl). These findings indicate how we should give the balanced nutrition to the handicapped patients.

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Microcytic anemias are commonly encountered in clinical medicine and are frequently caused by disorders of heme synthesis [usually iron deficiency anemia (IDA) or anemia of chronic disease (ACD)]. Using the clinical history, standard laboratory tests and in some cases stainable bone marrow iron, we divided 56 children with microcytic anemia (Hb ≤ 11.0 g/dl and MCV ≤ 81 fl) as follows : 20 ACD, 11 ACD with iron deficiency and 25 IDA. The efficacy of iron parameters [MCV, MCH, MCHC, serum iron, unsaturated iron binding capacity, transferrin saturation, serum ferritin (Fr) and erythrocyte zinc protoporphyrin/heme ratio (ZPP)] was evaluated by how properly they classified microcytic anemias into iron deficient (IDA and ACD with iron deficiency) vs. non-iron deficient one (ACD). 89.3% of iron deficiency can be detected by Fr, 92.9% by ZPP and 94.4% by the combination of Fr and ZPP. Because of reliability and ease of measurement, we recommend the hematofluorometer ZPP as one of the best parameters to discriminate microcytic anemias.

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This study consists of 19 neuroblastoma cases that were treated with autologous bone marrow transplantation (A-BMT) involving marrow purged by magnetic immunobeads. To decide the timing of marrow harvesting, which appeared to increase the rate of hematological recovery, these cases were retrospectively studied regarding the relationship between the process of hematological recovery and the data of the peripheral blood at marrow harvesting and the number of infused stem cells. At the time of marrow harvesting, the white blood cell (WBC) and the neutrophil, the platelet were 4, 452 ±1, 963/, μl, 2, 154 ± 1, 460/μl, 24.5±7.4 × 10⁴/μl respectively. The number of CFU-GM colonies per mononucleated cells tended to decrease among cases that received chemotherapy in excess of 6 months compared with cases that received less than 6 months of chemotherapy. There was strong correlation between the number of infused mononucleated cells and the number of infused CFU-GM colonies in the group that received less than 6 months chemotherapy. This correlation was not found to exist in the group that received more than 6 months of chemotherapy. In the group receiving more than 5.0 × 10⁴/kg of CFU-GM, the recovery rate of the WBC counts and the neutrophil counts occurred sooner than in the group that received less than 5.0 × 10⁴/kg of CFU-GM. However, the platelet's recovery rate was not influenced by the number of infused CFU-GM colonies. In addition, receiving more than 5.0 × 10⁴/kg of infused CFU-GM appeared to shorten the duration of the fever experienced in each of these cases. In the use of A-BMT for neuroblastoma, our findings suggest that the harvesting of bone marrow be done as early as possible after obtaining complete remission and it appears to increase the rate of hematological recovery.

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Nineteen patients who have survived for more than 1 year after bone marrow transplantation (BMT) without diseases were examined for height and for endocrinological, cardiac and pulmonary functions in correlation with total dose of total body irradiation (TBI). The results show that thyroid and gonadal functions decreased after TBI dose dependently. Gonadal functions and height were more affected in girls than in boys. Abnormal findings of prolactin (PRL) secretion were obtained regardless of the dose of TBI. Subsequently, height in conjunction with endocrinological and cardiac functions has been compared between this BMT group and the chemotherapy group consisting of eleven patients with hematologic malignancies who have survived after completion of intensive chemotherapy, without any kind of irradiation. As a result, height and gonadal functions were more affected in the BMT group than in the chemotherapy group. Cardiomyopathy developed in only one case in chemotherapy group. We conclude that it is necessary to design conditioning regimens which reduce adverse effects on growth and developement in order to improve quality of life (QOL). We must also reevaluate the indication of BMT in comparison with the results of chemothrapy.

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Ten children with chronic idiopathic thrombocytopenic purpura were treated with high-dose vitamin C (800-3, 000 mg/day). Three cases achieved an increment of platelet of more than 50, 000/μl while seven out of ten failed to demonstrate any increment. And all the patients treated with high-dose vitamin C showed an improvement of clinical hemorrhagic symptoms and signs. Five cases who showed no clinical improvement with high-dose vitamin C were treated with cepharanthin (30 to 50 mg/day), a derivative of plant alkaloid, in addition to vitamin C. Three cases out of five showed an increment of platelet of more than 30, 000/μl within one to three months since the administration of cepharanthin had started. No adverse reaction was observed in the patients treated with cepharanthin while only limited gastrointestinal symptoms were noted in several patients treated with vitamin C. We consider both vitamin C and cepharanthin are useful in the treatment of children with chronic idiopathic thrombocytopenic purpura.

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Eight children undergoing allogeneic BMT for acute leukemia (one with AMoL, seven with ALL) were conditioned with a combination of CY-TBI or BuCy2 plus high-dose Ara-C and high-dose VP-16. Status at transplantation was as follows : three in first CR, two in second CR, one in third CR, two in relapse. One patient transplanted in early relapse received second BMT from same donor. Major regimen-related toxicities were oral mucositis and gastrointestinal tract symptoms such as nausea, vomiting and diarrhea.Acute GVHD greater than grade II was seen in two patients and one died with grade IV GVHD and cytomegalovirus pneumonitis. The incidence of chronic GVHD in seven patients who survived more than 100 days after BMT was 0%. Two children, one transplanted in 3rd CR and another in relapse, experienced relapse of leukemia and both died 48 and 57 weeks after BMT. Now five patients survive without disease 83+ -110+ weeks after BMT. Conditioning regimen which includes high-dose Ara-C and high-dose VP-16 for allogeneic bone marrow transplantation is well tolerated and effective for acute leukemia of children.

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Serum cytomegalovirus (CMV) titers (CF, EIA-IgG, -IgM) were analyzed in 122 pediatric leukemia and lymphoma patients (92 ALL, 12 AML, 16 NHL/HD, and 2 CML/JCML). At the study, 46 cases (38%) were seronegative (CF <4), 59 cases (48%) were seropositive with low titer (4-5. CF <64), and 17 cases (14%) with a high titer (CF ≥ 64). There was no correlation between CMV titers and the types of underlying disease or of chemotherapy, though the number of patients with a CMV high titer seemed to be increased between 15 to 60 months after the initiation of chemotherapy. In 52 of the 122 cases, CMV titers were compared before treatment and at the study. Of the 28 cases who were seronegative before treatment, 12 (43%) were seroconverted and of the 24 seropositive cases, 13 cases acquired more than 4-fold increase in CMV CF titer during the period. In analysis of the 17 patients with a high CMV titer, CMV-IgM was found to be positive in 4 (24%) (it was 0/59 in the low CMV titer group, p<0.01) and seven episodes of overt CMV disease were recorded in six cases. CMV genome was also positive in peripheral blood by PCR in 4 of these high CMV titer cases. These results show that pediatric leukemia/lymphoma patients with a high CMV titer are at high risk of CMV activation. Caution must be exercised that these patients are required to be checked routinely for immune function test and ophthalmological examinations. In addition, seronegative blood products should be supplied to seronegative patients to prevent CMV infection.

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We examined the combined effects of granulocyte colony-stimulating factor (G-CSF) and macrophage colony-stimulating factor (M-CSF) on CFU-GM colony and recovery of granulocyte count after chemotherapy of leukemia. Admixture of G-CSF and M-CSF increased more CFU-GM colonies than admixture of G-CSF or M-CSF, and the numbers of CFU-GM stimulated by G-CSF and M-CSF were more than the sum of CFU-GM stimulated by G-CSF or M-CSF alone. In administration of G-CSF and M-CSF after chemotherapy of leukemia, there were earlier recoveries of granulocyte count than in administration of G-CSF or M-CSF. These data suggested that G-CSF and M-CSF may be administered simultaneously when prompt recovery of granulocyte count is required.

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Toxicity assessment was made in 39 children with acute leukemia or malignant lymphoma who received the MCVAC high-dose combination chemotherapy without total body irradiation (TBI) and peripheral blood stem cell autograft (PBSCT). The regimen-related toxicity (RRT) observed within 28 days of autografts and pulmonary toxicity occurring within 100 days were analyzed for this purpose. Transient and mild RRT involving the mouth and gastrointestinal tract was the primary toxicity observed in almost all patients, but there was no case of hepatic veno-occlusive disease. No mortality or occurrence of severe RRT necessitating intense therapy was documented in this series of patients. The data suggest that the MCVAC regimen can be administered safely in children undergoing PBSCT. Evaluation of long-term toxicities and its effectiveness in the treatment of refractory childhood leukemia or lymphoma needs further clinical trial.

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Seven children (3-17 y; median, 10 y), who had acute lymphoblastic leukemia (ALL) or non-Hodgkin's lymphoma (NHL) associated with mediastinal mass, underwent high-dose chemotherapy (MCVAC therapy) and peripheral blood stem cell autografts (PBSCT). None received total body irradiation. Four patients had ALL and three had NHL. In all patients, cancer cells had T cell surface makers. Five patients, including one with initial induction failure ALL, underwent PBSCT in the first complete remission (CR) and two patients did in the second CR. One patient received mediastinal irradiation before PBSCT. After PBSCT, hematopoietic recovery speed was fast and five of the seven patients have survived without relapse for 11-58 months. One patient, who had underwent initial PBSCT in the 1st CR and developed relapse, underwent the second PBSCT and still has remained in unmaintained CR for 18 months post-PBSCT. The data suggest that high-dose chemotherapy and PBSCT will become an effective therapeutic option for this particular group of patients.

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Twenty-one of the 26 patients (80.8%) achieved a complete remission. This remission rate is consistent with the best results previously reported. In order to improve disease-free survival (DFS), we designed two consolidation protocols during two different time periods. The results of protocol 78 consisting of cytosine arabinoside, adriamycin and neocarzinostatin were discouraging because of a high relapse rate of 71.4% and the actuarial DFS at 10 years is 28.6%±33.5%. On the other hand, the results of protocol 80 were promising with a 30.8% relapse rate and DFS of 50.8%±28.3% at 6 years. Cardiotoxicity due to anthracyclines developed in 3 cases including 2 patients with Down's syndrome. One patient with Down's syndrome died of congestive heart failure during complete remission, while cardiac functions of the other two patients have improved gradually within almost normal limits. Therefore, we must devise more effective and less toxic regimen.

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Twenty one children with acute nonlymphoblastic leukemia (ANLL) have been treated with BHAC-AMP regimen and intermediate to high-dose cytarabine, since 1986. Six-year event-free survival (EFS) rates were estimated to be 54%. In 14 children with de novo ANLL, 6-year EFS rates were 71%, whereas the prognosis for secondary ANLL (prior history of myelodysplastic syndrome [MDS], post-treatment with acute lymphoblastic leukemia, and Down syndrome) was poor (3-year EFS rates : 21%). In addition, the prognosis of prior history of MDS was remarkably poor, and therefore, allogeneic bone marrow transplantation should be done for this syndrome.

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An 8-year-old patient was diagnosed as abetalipoproteinemia by confirming the Apo-B deficiency in the patient's serum, in which both apoprotein B-100 and B-48 were totally lacking. Marked decrement of plasma lipids and acanthocytosis (50%) were also observed. In red cell membrane lipids, phosphatidylcholine was decreased. Surprisingly, however, the total amounts of free cholesterol and total phospholipids in red cells were maintained almost normally, in spite of a marked depletion of plasma lipids. The calcium influx was markedly elevated with normal transport of sodium. Supplementary vitamin A, E, and K have been given for 8 years with minimal improvement.

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A 4-year-old male infant was admitted to our hospital with the complaint of the thrombocytopenia and the difficulty to judge his ABO blood type in January 1989. He has frequently suffered from bloody diarrhea since infancy. He was diagnosed to be RAEB by the data of peripheral blood and bone marrow in his clinical course. The morphologic data of RBC showed microcytic and hypochromic. Fetal hemoglobin was contained 39.4%. His blood type was certified as a subtype of A blood group (A3) due to the decrease of A antigen on RBC. He also suffered from remarkable lymphfollicular-hyperplasia all over large intestine. Our case is the first case in Japan that showed decreased A antigen on RBC with MDS in childhood.

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A 2-year-old girl with ANLL (M5a) showed acute neurological symptoms including gait disturbance, after receiving high-dose cytosine arabinoside (Ara-C). The onset was a month after the last chemotherapy, and she recovered almost completely two months later. CT and MRI of the brain revealed normal, while SPECT of the brain showed low perfusion. It was suggested that this transient neurological episode was due to neurotoxicity of high-dose Ara-C treatment rather than CNS involvement or acute leukoencephalopathy, according to her clinical evidence and course.

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An 8-year-old girl with acute lymphoblastic leukemia (high risk) was complicated with Candidia liver abscess during consolidation therapy. Amphotericin B (AMPH) was administrated intravenously (with a dose up to 0.8 mg/kg/day) in combination with intravenous fluconazole, but it was ineffective. Oral administration of high-dose AMPH (12, 000 mg/day) also failed to normalize C-reactive protein (CRP) although her fever resolved to normal. And then AMPH was administrated through a catheter inserted into the portal vein after laparotomy. In about 2 weeks after institution of this therapy, CRP became negative, and the multiple hepatic mass lesions on CT scans disappeared within 2 months. The patient received bone marrow transplantation (BMT) at the age of 9 years 9 months old. She remains disease free 15 months after BMT.

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A 13-year-old boy was admitted for the investigation of pale face and ecchymosis. According to remarkable pancytopenia in peripheral blood and hypoplastic bone marrow, the patient was diagnosed as severe aplastic anemia (SAA). Since methylprednisolone-pulse therapy was not effective and he hadno HLA-matched sibling, he was treated with recombinant granulocyte-colony stimulating factor (G-CSF), recombinant erythropoietin (Epo) and oxymetholone. Immediately, absolute neutrophil count increased to 3, 000/μ1. Three months later, also reticulocyte counts increased to 150, 000/, μ1 and he requiredno further red cell transfusion. Moreover, platelet counts reached 50, 000/μ1 five months after the start of treatment. At present, only G-CSF and Epo are administered once a week, and his peripheral blood and bone marrow findings are retaining within almost normal values. Even though it cannot be determined which drug was the most effective, we believe that this combination therapy is valuable to try for patients with SAA who have no bone marrow transplantation donors.

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This short communication deals with an 8-year-old boy with acute lymphocytic leukemia in third remission. He was initially planned to perform allogeneic bone marrow transplantation (BMT) from his HLA-identical and MLC-negative sibling in his CR3. However, he could not tolerate the conditioning regimen of high dose AraC because of increasing liver dysfunction and jaundice. Subsequently, he was diagnosed as having chronic active type C viral hepatitis by his liver biopsy and HCV-RNA positive result by the polymerase chain reaction (PCR) method. He was treated with interferon-α, to which he tolerated well and showed rapid clinical and laboratory improvement in terms of liver dysfunction. BMT was finally carried out using cyclophosphamide (CY) + total body irradiation (TBI) as conditioning regimen, when his liver function was almost normal and HCV-RNA became negative. During and after the preconditioning period, his liver function was stable and veno-occlusive disease (VOD) did not happen. We conclude that interferons therapy would be a choice of treatment for BMT recipient who was complicated with active type C viral hepatitis.

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We report an acute lymphoblastic leukemia (ALL) boy with hypothalamic syndrome and the breakdown of blood-brain barrier during the couse of recurrent central nerve system (CNS) leukemia. He was diagnosed as ALL at the age of three, and received the treatment with systemic chemotherapy and the prophylaxis for CNS leukemia. At the age of five, the first CNS leukemia was involved. Afterward, CNS leukemia occurred recurrently. Hypothalamic syndrome was noted eight years after the onset of ALL, and the analysis of the cerebrospinal fluid proteins indicated the breakdown of blood-brain barrier.

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We report a case of a one-year-old girl with Philadelphia chromosome (Ph¹) -positive acute lymphoblastic leukemia (ALL), who received allogeneic bone marrow transplantation during a second remission. The leucocyte count of peripheral blood was 8, 200/μl, 21% of which were blast cells. Bone marrow was occupied with 95.6% of blast cells, diagnosed as FAB L₁ on the basis of negative myeloperoxidase and negative periodic acid Schiff staining. Surface marker analysis showed CD19 and HLA-DR positive, and cytogenetic analysis showed t (12 ; 22) (p13 ; q 11), were not typical Philadelphia chromosome. She was treated with prednisolone, vincristine, THP-adriamycin, L-asparaginase and after 56 days of remission her bone marrow relapsed. Reinduction chemotherapy was started with prednisolone, vincristine, methotrexate, L-asparaginase. After she attained remission, she received the bone marrow transplantation from her HLA-identical sister. She has been in complete remission for 20 months after the transplantation. Ph¹-positive ALL has a poor prognosis in children. Although, it has been reported that variant translocation cases have a better prognosis than the typical, relapse cases, like our case should require more aggressive therapeutic approach such as marrow transplantation during a remission.

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