Hemophagocytic lymphohistiocytosis (HLH) is an immunohematologic emergency of infancy, which is characterized by high fever, hepatosplenomegaly, disseminated intravascular coagulopathy and bone marrow hemophagocytosis. This condition accounts for hypercytokinemia originating from the uncontrollable activation of lymphocytes and histiocytes associated with precipitating factors such as viral infection. The discovery of a perforin defect in familial HLH (FHL) patients led to the identification of responsible genes for inherited/primary HLH. Based on clinical data and experimental models, the molecular pathogenesis of primary HLH has been revealed to result from the defective metabolism of cytotoxic granules, by which cytotoxic T-cell processes govern the immune homeostasis. Primary immunodeficiency diseases and other genetic diseases are also associated with HLH, although the pathogenesis remains elusive. On the other hand, the genetic backgrounds of acquired/secondary HLH, including virus-or autoimmunity-associated HLH, have not been specified. The heterogeneity of underlying conditions and the diversity of treatment choices of HLH make it difficult for pediatricians to manage patients. Since the Epstein-Barr virus-HLH is occasionally encountered in Japan, foreign-made diagnostic guidelines and treatment protocols of FHL should be carefully applied to Japanese patients. We review recent advances in the diagnosis and management of HLH, and discuss the clinical approach to cases in Japan.

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Neutrophil alkaline phosphatase (NAP) activity was assessed cytochemically in 59 pediatric patients with various types of blood diseases. The mean±standard deviation of the NAP scores was 228±144 for the control group, and the 95% confidence limit was 147-302. In diseases of which more than 10 patients were enrolled, the NAP activity in chronic idiopathic thrombocytopenic purpura (ITP) and iron deficiency anemia were significantly lower than in the control group, but were significantly higher in acute ITP. On an individual basis, decreased scores were found in three patients (100%) with chronic myeloid leukemia, three (100%) with acute myeloid leukemia with t (8;21), one (6.3%) with acute ITP, six (54.5%) with chronic ITP, six (60%) with iron deficiency anemia, and two (100%) with paroxysmal nocturnal hemoglobinuria. In contrast, increased scores were found in two patients (50%) with acute lymphoid leukemia, six (37.5%) with acute ITP, four (80%) with aplastic anemia, and two (40%) with hemolytic anemia. In this paper, we describe the change of NAP activity in a variety of hematologic diseases in children. Further accumulation of NAP data is necessary to elucidate the diagnostic role of NAP in hematologic diseases

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We report a 5-year-old boy with acute myeloid leukemia (AML) who developed endophthalmitis under chemotherapy. His primary disease was FAB classification M2 with t (8;21) and AML1-MTG8 fusion transcript. He achieved remission with AML-99 protocol. The risk classification was “Low”. He experienced febrile neutropenia after consolidation therapy 1. His blood culture was negative, and β-D glucan was normal. His fever subsided after neutrophilia, but we diagnosed him with endophthalmitis because of the decreased visual acuity of his right eye and floating cells in the anterior chamber of his right eye. We collected aqueous fluid and observed many neutrophil cells upon microscopic examination, but the culture was negative. Since there are many reports of fungal endophthalmitis during chemotherapy, we administered fluconazole (FLCZ) and itraconazole (ITCZ), and ocular penetration was good. After treatment, the manifestation improved immediately, and eyesight was gradually restored. During consolidation therapy after that, there was no recurrence. His primary disease remained in complete remission 3 mo following chemotherapy, and the eyesight of naked right eye is 1.2.

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We report a relatively rare case of childhood thrombocytopenic purpura associated with Mycoplasma pneumoniae infection. Six-year-old girl was admitted to Hirosaki City Hospital because of pneumonia, petechiae and thrombocytopenia. A blood examination performed at the time of admission showed elevated Mycoplasma pneumoniae antibodies, and a bone marrow aspiration biopsy revealed an increase in non-platelet-producing megakaryocytes. Consequently, the patient was diagnosed as having immune-mediated thrombocytopenic purpura (ITP) associated with Mycoplasma pneumoniae infection. Steroid therapy was transiently effective for the treatment of thrombocytopenia. But the thrombocytopenia did not improve for more than one year. Six additional cases of ITP associated with Mycoplasma pneumoniae infection have been previously reported. The clinical features of these seven patients, including our case, were as follows : three patients showed severe hemorrhagic symptoms, four patients had abnormal immunologic examinations (low complement values, positive anti-globulin tests, or high IgM values), steroid administration or intravenous immunoglobulin therapy was effective in all patients, and the clinical course of six out of the seven patients was an acute episode. Careful follow-up is needed for patients with Mycoplasma pneumoniae infection whether or not thrombocytopenia is present.

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We examined the efficacy and safety of teicoplanin for the second-line therapy of malignant febrile neutropenia in pediatric patients. Ten patients, in which carbapenem-based empirical therapy was ineffective, were treated with teicoplanin-based second-line therapy. The teicoplanin dosage regimen was 10 mg/kg every 12 hr for three or seven doses, then every 24 hr. Concomitant antibiotics were fourth-generation cephalosporin or carbapenem. Treatments were effective in five patients and an improvement of symptoms was seen in three patients. There was no severe adverse event, and nine patients achieved efficacy and safety concentrations. Therefore, the monitoring of concentrations did not seem to be necessary. However, in order to ascertain that appropriate concentrations are been achieved, trough concentrations should be measured when teicoplanin is ineffective. We conclude that teicoplanin isuseful for second-line therapy of febrile neutropenia in pediatric patients.

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A 12-year-old boy developed a brief psychotic disorder during consolidation chemotherapy at 4 mo after the initiation of therapy for acute lymphoblastic leukemia (ALL), with symptoms such as confusion, illusion, delusion and disassociated conversation. Till then, his clinical course was uneventful with little side effect of chemotherapy. He had been informed of his laboratory data, and thus suspected the disease, but the ALL diagnosis was not openly notified to the patient. He could not confide anyone regarding the anxiety of his suspected illness although he had concerns he might not be getting well. With the assistance of counseling therapy and an antipsychotic drug (haloperidol), he managed to quickly recover from the psychotic disorder, at which time we found brain SPECT studies were useful. To avoid such psychotic episodes in ALL patients, providing sufficient information at the time of diagnosis announcement the disease and information on management to the patients seems necessary not only at the onset or discharge of the disease, but also at any time during treatment, whenever necessary. Needless to say, it is more important for pediatric hemato-oncologists to confirm how much patients understand about their disease status and release them from their anxieties.

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Autoimmune hemolytic anemia in an infant is often refractory to conventional treatment, requiring the prolonged administration of immunosuppressive therapy. However, high-dose corticosteroids can cause severe adverseevents, especially for infants. Therefore, an alternative therapy for refractory autoimmune hemolytic anemia is needed. Rituximab, a monoclonal antibody for CD20, has recently been used for the treatment of autoimmune disorders, but there have not been any reports of an infant treated with rituximab in Japan. We encountered a 3-month-old boy with autoimmune hemolytic anemia requiring high-dose steroid administration. To avoid complication from prolonged administration of high-dose steroids, we initiated rituximab treatment when the patient was 6 mo old. Hemolytic anemia improved dramatically, and there were no severe adverse effects. There are no laboratory data indicating hemolysis 1 yr after rituximab treatment was initiated.

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We report two cases of NK cell leukemia. Both cases did not express CD3, 19, 20, 13 or 33, but expressed CD56. We therefore diagnosed the cases as NK cell leukemia; NK cell leukemia is a very rare disease and there is no established treatment. We treated the two patients with a therapeutic regimen for mature B cell lymphoma, as we thought that, in leukemia of NK cell origin, cell turnover is rapid and short-term intensive therapy would be effective. The response to the initial treatment was good in both cases, but Case 1 had bone marrow relapse 8 mo after therapy termination. The patient underwent bone marrow transplantation from an unrelated donor, but died of a complication 4 mo later. Case 2 maintains complete remission 14 mo after therapy termination. We present here two cases of NK cell leukemia. NK cell leukemia is a rare disease, and it is important to accumulate therapeutic experience with more patients.

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This report summarizes data for 172 cases of chronic neutropenia in children in Japan. There are 29 cases of severe congenital neutropenia (Kostmann syndrome), five cases of cyclic neutropenia, 69 cases of auto-immune neutropenia, 39 cases of idiopathic neutropenia, 25 cases of chronic neutropenia that were not diagnosed as above 3 categories of chronic neutropenia and five cases of undiagnosed patients. For 26 cases of severe congenital neutropenia, stem cell transplantation was performed on 12 patients, and 12 of 12 cases are currently alive. Results from these patients suggest that stem cell transplantation is a beneficial treatment for severe congenital neutropenia patients.

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PURPOSE : The current study aims to compare tacrolimus/MTX with CSA/MTX for GVHD prophylaxis and to evaluate the effects of HLA-C and DQB1 mismatching on the outcome of 215 pediatric patients with SAA who received UBMT. METHOD : 1) A tacrolimus group (n=47) and CSA group (n=47) for GVHD prophylaxis were matched exactly for recipient age and conditioning regimens. 2) Seventy-nine recipient-donor pairs were selected, in which molecular typing of HLA-A, -B, -C, -DRB1, and DQB1 were performed. The incidence of graft failure, acute/chronic GVHD and survival were analyzed, respectively. RESULT : 1) There was no difference in the incidence of graft failure, or acute and chronic GVHD between the tacrolimus and CSA groups. Eight patients of the tacrolimus group died and 22 patients of CSA group died. There was a higher frequency of deaths from thrombomicroangiopathy in the CSA group than in the tacrolimus group. The 5 yr survival rate was 83% for the patients of the tacrolimus group and 53% for those of the CSA group (p=0.01). 2) The 5 yr survival rate did not differ between recipients receiving transplants from a full-matched donor and those from any single HLA-mismatched donor. However, the 5 yr survival rate was significantly worse (39%) for recipients who received transplants from HLA-A or -B mismatched and -C or -DRB 1 or -DQB 1 mismatched donors, and the rate was 0% for patients who were mismatched for three antigens (p<0.01). CONCLUSION : For pediatric patients with SAA who received UBMT, the superiority of tacrolimus/MTX over CSA/MTX was demonstrated, and the matching of HLA-C and -DQBI should be incorporated into algorithms for unrelated donor selection.

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The results of a prospective multi-center trial applying combined immunosuppressive therapy (IST), childhood AA97 consisting of antithymocyte globulin (ATG) and cyclosporine (CyA), for children with acquired aplastic anemia (AA) are reported. Among 262 patients with data available, patients were subclassified into the following groups : 61, moderate AA; 84, severe AA; and 117, very severe AA. The hematopoietic response rate was 53%, 66% and 72%, respectively, 6 mo after treatment. A randomized trial of ATG, with or without CyA, was conducted for the moderate AA group, showing that the failure-free survival (FFS) rate is significantly higher for the CyA+ATG regimen than ATG alone (54.8% vs. 26.7%, p=0.0002). Second-line therapy was attempted for 60 patients of the severe and very severe AA groups, for which initial IST failed. Consequently, 31 patients received hematopoietic stem cell transplantation (SCT) from alternative donors and 21 patients without suitable SCT donors underwent a second IST. The FFS rate was significantly higher for the SCT from alternative donors than in repeated IST (83.9% vs. 9.5%, p=0.0001).

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A retrospective comparative study under The Japanese Society of Pediatric Hematology Aplastic Anemia Committee was designed to assess the quality of life (QOL) in a group of children with acquired aplastic anemia (AA) treated with allogenic bone marrow transplantation (BMT) or immunosuppressive therapy (1ST). Children with AA that underwent an 1ST or an allogenic BMT from 1992 to 1997 were eligible for this study. The 1ST group was treated by the protocol of the Japan Childhood Aplastic Anemia Study Group. Questionnaires for QOL assessment were completed by patient's parents, from July 2004 to October 2005. QOL was assessed by evaluating the 30-item questionnaire numerically (QOL score). We evaluated a total of 48 children with AA who were treated. Twenty-four patients received 1ST and 22 patients received BMT. There was no difference statistically between the two groups regarding the QOL score. The comparative study of QOL indicated that both of the groups equally showed an excellent level of daily activities and social activity. Although the parents' anxieties for the patient's future improved over time, anxiety about infertility and second malignancy still remained strong. Particularly, the BMT group had a significantly lower QOL score as compared to the IST group regarding the infertility questionnaires (p=0.03). Continuous study is needed to prove the effect of time on treatment and QOL in the future.

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