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We investigated supportive therapy against coagulopathy associated with L-asparaginase treatment in patients with acute lymphoblastic leukemia who were enrolled in the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG), Japan Adult Leukemia Study Group (JALSG), and foreign institutes. Fresh frozen plasma (FFP) was administered as a supplement in 46% patients in the JPLSG and 86% in the JALSG. The threshold level of FFP infusion was less than 100 mg/dl plasma fibrinogen in 70% of the JALSG and 20% of the JPLSG, while in another 20% of the JPLSG, FFP was administered when the fibrinogen level was less than 50 mg/dl. The preventive use of antithrombin products (AT) was prescribed in 93% of the JPLSG and 63% of the JALSG: The threshold level of AT supplementation was less than 70% of plasma antithrombin activity, which was similar in both groups. Most foreign institutes do not routinely use FFP or AT.

Efficacy, safety and pharmacokinetics of meropenem (MEPM) were assessed when 1 g (40 mg/kg for some of the pediatric patients) t.i.d. was administered every 8hours to 101 adult and 6 pediatric patients with febrile neutropenia (FN) as diagnosed based on the Japanese guideline for FN treatment. The efficacy rate evaluated as antifebrile effect up to Day 4 of treatment was 40.0% (40/100) in adult and 66.7% (4/6) in pediatric patients. The antifebrile effect in adult patients was analyzed after stratifying them according to their neutrophil counts up to Day 4. Treatment with MEPM produced an antifebrile effect not only in patients with higher neutrophil counts (> or = 500/mm3) but also in those with lower counts (< 100/mm3), and the efficacy rate was comparable between the two groups: 38.2% in the < 100/mm3 group and 29.4 to 55.6% in the > or = 500/mm3 group. The bacteriological efficacy of MEPM evaluated as disappearance rate on Days 3 to 5 and Day 7 was both 100% (8/8 and 4/4, respectively). The time above minimal inhibitory concentration (% T > MIC) in the treatment interval was greater than 90% in 9 out of 10 patients for whom likely causative organism was isolated and identified after MEPM treatment or for whom causative organism emerging after treatment was isolated and identified. The incidence of adverse events was 93.1% in adult and 83.3% in pediatric patients. There were three deaths and one serious adverse event reported among the adult patients; however, all these cases were assessed as not related to the study medication. The incidence of adverse drug reactions was 45.5% and 66.7%, respectively. All the observed adverse drug reactions were mild or moderate in severity and none of them was severe. Adverse drug reactions which were unknown from the previous MEPM clinical studies and investigation of the results of clinical experience include 'chest discomfort', 'blood uric acid decreased', 'lymphocyte deformation', 'blood uric acid increased', 'abnormal funduscopy', 'hypesthesia' and 'hemorrhagic cystitis'. All these events were mild or moderate in severity and resolved without requiring any action or after providing symptomatic treatment. There was no unknown adverse drug reaction that resulted in treatment discontinuation. No nervous system disorders such as convulsion and impaired consciousness were reported. The results show that monotherapy of MEPM 1 g (or 40 mg/kg for some of the pediatric patients) t.i.d. every 8 hours was effective, and was also safe and well tolerated in adult and pediatric patients with FN. Therefore, MEPM monotherapy is expected to be useful as the initial treatment for Japanese patients with FN.

The revised WHO classification proposed the term "refractory cytopenia of childhood (RCC)" for children with myelodysplastic syndrome (MDS) with a low blast count. The differential diagnosis between RCC and aplastic anemia (AA) is challenging, especially when bone marrow is hypoplastic and there is no detectable chromosomal abnormality. To reveal the difference between AA and RCC with respect to the clinical and biological features, we retrospectively reviewed the bone marrow smears of 140 patients registered for childhood AA-97 study, which were classified into three groups as follows; the AA group was defined as having no morphologically dysplastic changes; the AA-RCC borderline group was defined as having <10% dysplastic changes in the erythroid lineage only; and the RCC group was defined as having dysplastic changes in more than two cell lineages or >10% in a single cell lineage. The patients were classified into the AA group (n=96, 69%), AA-RCC borderline group (n=20, 14%) and RCC group (n=24, 17%). Most of the patients in the AA group were classified as having very severe disease, whereas most of the patients in the RCC group were classified as non-severe disease. Only 2 patients in the AA group developed acute myeloid leukemia. The response rate to immunosuppressive therapy did not differ among the 3 groups. To demonstrate whether the two diseases are truly different entities, it is necessary to compare molecular backgrounds between the AA and RCC groups.

We conducted a multicenter postmarketing study to investigate the efficacy and safety of reinduction therapy with a high-dose cytarabine-containing regimen for pediatric patients with relapsed or refractory acute leukemia. Seven of 13 patients (53.8%) with ALL achieved complete or partial remission, and only 1 of 6 patients (16.7%) with AML achieved partial remission. The frequent non-hematologic adverse events were gastrointestinal toxicities, such as vomiting, diarrhea and abdominal pain, as well as pyrexia and headache. Infection appeared in 9 of 20 (45%) patients. There were two death during reinduction therapy. One died of invasive bronchopulmonary aspergillosis, and the other died of intracranial hemorrhage and renal failure. These results indicated that a high-dose cytarabine regimen is effective as reinduction therapy in pediatric patients with relapsed ALL, and supportive care is essential to prevent or control treatment-related adverse events, such as infection.