A new era of cancer immunotherapy has arrived and is based on the molecular identification of human cancer antigen. Several antigen peptide epitopes recognized by human CD8⁺ cytotoxic T-lymphocyte (CTL) clones reactive with human cancer target cells have been reported. An analysis of CTLs reactive with melanoma cells has identified several different categories of antigen peptides. A wild-type proto-oncogene HER2 is expressed at high levels in a variety of human cancers, such as ovarian, breast, and nonsmall cell lung cancer. We established a CTL clone directed against a HER2-derived peptide from a HLA-A2402-positive healthy individual and a CTL clone lysed HER2-expressing cancer cell line with HLA-A2402 restriction. Vaccination with these peptides is now in an early phase of clinical trial. Antileukemia immunotherapy has been extensively investigated and clinically practiced. However, few tumor antigens that could be specifically recognized by CTL have been identified in leukemia. Some candidates such as PRAME, proteinase 3, WT1, and hTERT might be useful and applicable for the treatment of hematological malignancy. On the basis of reliable preclinical data, new immunotherapy protocols will need to be evaluated clinically. Careful monitoring of immune responses and side effects will soon ensure the identification of effective immunotherapy protocols for human malignancies.

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Clinical characteristics and treatment strategy of Japanese adolescent leukemia were analyzed and compared with those of the United States and Europe. The ratio of acute lymphoblastic leukemia (ALL) /acute myelogenous leukemia was decreased to 1 : 1 in the late adolescent period. Chronic myelogenous leukemia and myelodysplastic syndrome was increased in adolescents. The characteristics of adolescent ALL were found in the frequency of biological features, namely, a decrease of hyperdiploidy (>50 chromosomes) and TEL-AML1 translocation, which were favorable prognostic factors, an increase of Philadelphia chromosomes and hypodiploidy, which were unfavorable factors, an increase of FAB-L2 morphology and T cell phenotypes. In the U.S. and Europe, T cell ALL, formerly an unfavorable prognostic factor, has turned out to be a favorable prognostic factor by the intensive chemotherapy, indicating that treatment is the most important prognostic factor. Age remains an important prognostic factor. A collaborative study by pediatricians and internists should be undertaken to investigate the pathological features and to improve the treatment outcome of Japanese adolescent leukemia.

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Tandem duplication (TD) of the FLT3 gene has recently been reported in pediatric acute myeloid leukemia (AML) and in adult AML and myelodysplastic syndrome (MDS). The TD of the MLL gene was also reported in adult AML. The TD of these 2 genes was found to be associated with a poor prognosis. To clarify the role of TD of these genes, we examined whether TD of the FLT3 and MLL genes developed simultaneously. We analyzed TD of the MLL gene in 7 pediatric patients who had TD of the FLT3 gene by reverse transcriptase-polymerase chain reaction (RT-PCR). Our study revealed that one of 7 patients had TD of both the FLT3 and the MLL genes. The patient with the TD of both genes died earlier than the other 6. This is our first pediatric patient with TD of the MLL gene. The mechanisms of TD of both genes are different because TD of the FLT3 gene was considered to be caused by nonhomologous recombination, and TD of the MLL gene by homologous recombination. However, because very rare TD of the MLL and FLT3 genes developed in a single patient suggests that the development of the FLT3 gene and the MLL gene may be related to an unknown similar etiology, for example, genomic instability, in leukemia.

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The remission failure cases in childhood acute myeloid leukemia (AML) treated in our institute were retrospectively analyzed. From 1991 to 1999, twenty-three AML patients (10 boys and 13 girls), aged 2 months to 19 years, were admitted to our hospital. Six of 23 patients (26%) failed to achieve complete remission : 2 cases of FAB-M0, 1 case of M1, 1 case of M5, and 2 cases of M6. Among them, 2 cases manifesting hyperleukocytosis died before induction therapy and 4 could not achieve complete remission in spite of multimodal induction chemotherapy. Four refractory cases showed FAB-MO or M6 morphology previously reported as poor prognosis subtypes. No complication death during induction therapy was observed. The treatment strategy for these cases is discussed. Cases with hyperleukocytosis should receive immediate and sufficient preinduction leukapheresis and intensive supportive care. For the cases refractory to conventional chemotherapy, myeloablative therapy with stem cell transplantation (SCT) for remission induction is indicated. Double SCT may be taken into consideration for extreme refractory cases.

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We report our experiences using the ALL-REZ BFM87 for the relapsed childhood lymphocytic malignancy from 1994 to 1998 at Hirosaki University Hospital and affiliated hospitals. Among 19 patients, 12 were induced to their second complete remission (63.2% of remission induction rate), and they were then treated by the consolidation therapy of ALL-REZ BFM87. Two patients relapsed 6 and 10 months after starting chemotherapy. The other 10 received hematopoietic stem cell transplantation (HSCT), and 6 patients relapsed after HSCT. Only 4 patients are still alive in remission. One- and three-year overall survival rates were 63.2% and 31.6%, and one- and three-year disease-free survival rates were 52.6% and 19.7%, respectively. The remission induction rate was relatively good, so ALL-REZ BFM87 would be a useful protocol for the treatment of relapsed childhood lymphocytic malignancy. However, patients with isolated early and very early bone marrow relapse had the least possibility of inducing to the second complete remission. Consequently, more intensive remission induction chemotherapy would be required for these patients with poor prognosis. Furthermore, no patients were cured by the chemotherapy alone, and the three-year-survival rate was disappointing ; thus immediate HSCT could lead to a better outcome for patients with relapse.

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A 15-year-old girl who exhibited the clinical picture of pre-ALL at the onset of disease was reported. She had persistent low-grade fever and mild liver dysfunction on admission. A laboratory examination revealed leukopenia and thrombocytopenia, except for the appearance of blasts in a smear of peripheral blood. But the percentage of blasts in the marrow gradually increased following repeated examinations for 3 weeks, resulting in a diagnosis of ALL. This clinical picture is compatible with pre-ALL, which is manifested as leukopenia with scanty blasts in the marrow. However, two points are different from reported cases. One was older at the time of presentation, and the other was shorter in duration between the onset of disease and the overt leukemia than those of reported cases. G-CSF, which was used for the leukopenia at the initial presentation, seemed to have some role in the development of overt leukemia, considering that ALL was apparent shortly after its use. But blasts were not increased during remission induction and maintenance chemotherapy thereafter, in spite of routine G-CSF administration.

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Three patients, aged 1, 10, and 12 years old, with acute promyelocytic leukemia (APL) received induction, consolidation, and maintenance chemotherapy combined with all-trans retinoic acid (ATRA). They all achieved complete remission on days 27, 34, and 40, respectively, from induction therapy. PML-RARα fusion mRNA in bone marrow cells turned to an undetectable level by the third consolidation. One patient underwent autologous peripheral blood stem cell transplantation (auto-PBSCT) after two courses of consolidation with ATRA, and the remaining two received intermittent maintenance therapy containing ATRA for a year after six courses of consolidation with ATRA. All patients maintained complete remission for 27, 31, and 53 months, respectively. During the induction therapy with ATRA, retinoic acid (RA) syndrome occurred in one case. This case also developed interstitial pneumonia after auto-PBSCT. A cough and an interstitial shadow in the chest roentgenogram remained for several years. These pulmonary diseases might be caused not only by irreversible histological change in the respiratory tract as a sequel of RA syndrome, but also by busulfan used for the preconditioning of PBSCT. Although ATRA is an effective antileukemic agent for APL, there are few reports of childhood cases treated with ATRA for both consolidation and maintenance therapy. Furthermore, randomized studies are needed to assess its usefulness in the treatment of APL in childhood.

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We report a one-year-old boy with Down's syndrome and AML-M7, which was primarily refractory to chemotherapy. He was successfully induced into remission with a cord blood transplantation from an HLA A-locus mismatched unrelated donor following a conditioning regimen that consisted of cyclophosphamide, busulfan, and L-PAM. A grade III acute GVHD developed on day 7 and was well controlled with bolus methyl-prednisolone (mPSL). Severe bronchiolitis obliterance (BO) developed on day 91 and was treated with a megadose mPSL therapy (100 mg/kg/day × 7 days). The patient has been on a respirator because of extreme hypercapnia, but the BO has stopped progressing and is now stable. He is in hematological remission at 10 months posttransplant.

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We report here a case of intracranial bleeding in a 54-day-old breast-fed baby with vitamin K deficiency, in spite of the prophylactic administration of three oral doses of vitamin K2. He was anemic and exhibited hyperbilirubinemia and an elevation of serum transaminases and total bile acid. Levels of IgM antibody to cytomegalovirus (CMV) were increased. CMV C7-HRP was detected in his peripheral leukocytes, and CMV-DNA was isolated from his urine and the breast milk of his mother. The results suggested that his cholestatic liver disease resulted from CMV infection, and interfered with the gastrointestinal absorption of the fat-soluble vitamin K. The breast milk of his mother also contained lower levels of vitamin K. The prophylactic administration of oral vitamin K as recommended in Japan did not prevent hemorrhagic complications in this case. The findings demonstrated that it may be important to use alternative protocol to alleviate vitamin K deficiency in neonates with cholestatic liver disease.

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