Takeo Fujimoto

Effectiveness of high-dose MCNU therapy and hematopoietic stem cell autografts treatment of childhood acute leukemia/lymphoma with high-risk features.

Clinical and pharmacokinetic studies were performed regarding the toxicity of methyl 6‐[3‐(2‐chloroethyl)‐3‐nitrosoureido]‐6‐deoxy‐α‐D‐glucopyranoside (MCNU) with other drugs, in conjunction with a peripheral blood stem cell autograft (PBSCT), for treating 26 children with acute leukemia or lymphoma associated with high‐risk features. In the early phase of the study, MCNU (300 to 500 mg/m2) was administered with cytosine arabinoside (Ara‐C) (1.6 to 16 g/m2),etoposide (VP‐16) (0.8 to 1.6 g/m2), cyclophosphamide (CY) (100 to 200 mg/kg), or busulfan (16 mg/kg). No acute toxicity was noticed after this high‐dose therapy. The dose‐limiting factor of the regimens was significant but reversible interstitial pneumonitis (IP). In a subsequent trial with an MCNU/VP‐16/Ara‐C/CY (MCVAC) regimen in which the dose of MCNU was reduced, the risk of IP diminished. This study is still in progress, but the clinical response has so far been encouraging. Fifteen of 26 children are alive and well in unmaintained complete remission (CR) with a median follow‐up period of 11 months (range, 3 to 34 months) after transplantation.

Comparison of intermittent or continuous methotrexate plus 6-mercaptopurine in regimens for standard-risk acute lymphoblastic leukemia in childhood (JCCLSG-S811)

From 1981 to 1983, 131 previously untreated patients with acute lymphoblastic leukemia (ALL) standard‐risk group were entered to the protocol JCCLSG‐S811. Of 119 eligible patients, 115 (96.6%) attained complete remission by treatment with prednisone (PRD) plus vincristine (VCR) or vindesine (VDS). After preventive central nervous system (CNS) therapy including 18 Gy cranial irradiation and three doses of intrathecal methotrexate (MTX), the patients were assigned randomly to the two maintenance chemotherapies, Regimen A and Regimen B. Regimen A (intermittent regimen) consisted of PRD (120 mg/m2/day by mouth for 5 days) plus 6‐mercaptopurine (6MP) (175 mg/m2/day by mouth for 5 days) plus VCR (2.0 mg/m2 intravenously) alternating biweekly with MTX (225 mg/m2 intravenously). Regimen B (continuous regimen) consisted of 6MP (50 mg/m2/day by mouth) plus MTX (20 mg/m2/ week by mouth) combined with pulses of PRD and VCR (the same dosages as Regimen A) every 4 weeks. As the late intensification therapy (LIT), five courses of high‐dose MTX (2000 mg/m2 per dose per week intravenously for three doses every 12 weeks) with leucovorin rescue were administered to all patients who were in continuous complete remission (CCR) for more than 2 years. Sixty and 55 patients, respectively, were registered in Regimen A and B. The CCR rates in Regimen A and B were 75.1% ± 5.8% (mean ± 1 SE) and 49.7% ± 7.3% (P < 0.01) at 4 years, and 72.1% ± 6.3% and 49.7% ± 7.3% (P < 0.05) at 5 years, respectively. In Regimen B, CNS and testicular relapses increased after 3 years of CCR. In addition, the patients in Regimen B had a much higher incidence of infections than Regimen A. The LIT did not seem to have important effects on the duration of CCR. From these data we conclude that the intermittent cyclic regimen of 6MP and MTX may be more effective as compared to the continuous administration of these drugs in the maintenance chemotherapy.

Prognostic Impact of CD45 Antigen Expression in High-Risk, Childhood B-Cell Precursor Acute Lymphoblastic Leukemia: Children's Cancer and Leukemia Study Group (CCLSG)

To evaluate the clinical implications of CD45 expression in acute childhood lymphoblastic leukemia (ALL), we measured the CD45 expression of blast cells from 133 untreated patients with childhood B-precursor ALL (n=118) or T-ALL (n=15). CD45 expression (≥20%) was detected in all 15 cases (100%) of T-ALL, and 101 cases (86%) of B-precursor ALL. In 122 cases, the fluorescence intensity of the CD45 expression was measured as a relative value; the ratio of average linear values (RALV) of CD45 on the blasts to that on CD3-positive T-lymphocytes from the same specimen. The expression was more intense in the T-ALL cases than in the B-precursor ALL cases (RALV, mean ± SE: T-ALL 0.230 ± 0.04 vs. pro-B ALL 0.150 ± 0.012/pre-B ALL 0.153 ± 0.019, p < 0.05). However, the intensity of the CD10, CD19, CD20 and CD34 antigen immunoreactivity did not correlate with the CD45 expression. Patients with hyperdiploidy (chromosome number >50) showed significantly lower levels of CD45 expression than patients with t(1;19) or normal karyotypes (RALV, mean ± SE: 0.081 ± 0.022 vs. 0.133 ± 0.03/0.143 ± 0.019, p < 0.05). Other clinical features such as age, gender and WBC count did not correlate with CD45 expression. The prognostic implications of CD45 expression were studied in non-high-risk (low-risk + intermediate-risk) (n=60) and high-risk patients (n=52) with B-precursor ALL who had been treated with the risk-directed protocol of ALL-941 trial. Although CD45 expression did not correlate with the event-free survival (EFS) of the non-high-risk patients, there was a significant correlation between the expression levels and the EFS of the high-risk patients: the 3-year EFS rate of the CD45lowgroup (n=26, RALV=0.017 - 0.132) was 88 ± 7% versus the CD45highgroup (n=26, RALV=0.133 - 0.450) at 34 ± 24% (p < 0.05). These results show that the levels of expression of the CD45 antigen on leukemic lymphoblasts are significantly correlated with the clinical features and prognosis of childhood ALL.

Prognostic implication of cellular DNA content in acute lymphoblastic leukemia

To assess the prognostic value of the cellular DNA content measured by flow cytometry in acute lymphoblastic leukemia (ALL), we studied the pretreatment distribution of the DNA content in marrow blasts from 74 children with this disease. They were divided into standard- and high-risk groups according to their white blood cell counts and age at the time of diagnosis and were followed for up to 44 months. Abnormal DNA stemlines were detected in 26 children, and all of them had a hyperdiploid DNA content (DNA index of greater than 1.0). The duration of remission was significantly longer in those with hyperdiploid DNA stemlines than in those with diploid DNA stemlines in both risk groups. In the standard-risk group, the DNA content and common ALL antigen were significant prognostic factors, especially the former. In the high-risk group, the DNA content also showed an independent significant correlation with the clinical outcome.

Osteosarcoma as a second malignancy after treatment for neuroblastoma.

A 4-month old girl was diagnosed as having stage IV neuroblastoma of the right adrenal gland. Preoperative chemotherapy was given, followed by local surgical excision. Postoperatively, irradiation of the tumor bed and adjuvant chemotherapy was given for 11 months. Nine years after cessation of chemotherapy, the patient developed left hip-joint pain. Biopsy of the ischium showed chondroblastic osteosarcoma. Limb salvage surgery was performed after preoperative chemotherapy. Postoperatively, adjuvant chemotherapy was given for 14 months. Twenty-two months after treatment for the secondary osteosarcoma, the patient has been remained in disease-free condition without any evidence of relapse. A second osteosarcoma occurring outside the radiation field after treatment for neuroblastoma is quite rare. This unusual case emphasized the need for close monitoring for development of second malignant neoplasms in survivors of neuroblastoma even in the absence of a known predisposing factor, such as radiation therapy.

Squamous cell carcinoma of the tongue as a second malignancy in a patient previously treated for osteosarcoma.

A 15-year-old girl was diagnosed with osteosarcoma; limb salvage surgery was performed after preoperative chemotherapy. Postoperatively, adjuvant chemotherapy was given for 2 years. One year after completion of chemotherapy, the patient was readmitted for systemic recurrence. Amputation of the lower extremity and wedge resection of lung metastasis were performed followed by combination chemotherapy. Two years after cessation of chemotherapy, ulcer of the tongue was noted and cervical lymph nodes were detected by palpation. Biopsy of the lesion showed squamous cell carcinoma. The patient underwent a radical partial tongue resection and postoperative irradiation, followed by chemotherapy. Six years after treatment for the second malignancy, the patient remains well without evidence of disease. Squamous cell carcinoma of the tongue as a second malignancy after treatment of osteosarcoma is quite rare. Long-term follow-up, with particular attention to the head and neck, may be warranted in children treated for osteosarcoma.

A Controlled, Dose-Comparison Study of Granisetron for Nausea and Vomiting Induced by Cancer Chemotherapy in Children

BackgroundWe investigated the efficacy and safety of granisetron in 40 pediatric oncology patients who received identical chemotherapy regimens for three courses.MethodsDuring the first course, the emetogenicity of each chemotherapy regimen was evaluated without granisetron. Next patients received one of two doses of intravenous granisetron, i.e. 20 or 40 mcg/kg during the second and third course of chemotherapy in a cross-over fashion.ResultsOut of the 40 patients, two children had no emetic episode during the 24 hour period following commencement of the first course of chemotherapy. Whereas, 23 patients receiving 20 μ/kg granisetron, and 22 patients receiving 40 μ/kg, obtained complete response (no emetic episode during the 24 hour period following commencement of chemotherapy) in the second or third course. When patients received 20 or 40 μ/kg of granisetron, all measured efficacy parameters were superior in comparison to the period when they were receiving no granisetron. There was no significant difference in the antiemetic effect between the two doses of granisetron. However, a dose-related improvement in efficacy was observed with granisetron in a certain subset of patients; that is, 4 of the 10 patients receiving 20 μ/kg, who had responded poorly with respect to nausea and vomiting, showed a complete or major response when the dose was increased to 40 μ/kg. One child developed somnolence. No other adverse events were observed.ConclusionGranisetron is an effective and safe antiemetic for children receiving intensive chemotherapy regimens containing cisplatin, cyclophosphamide or methotrexate. When comparing the two doses of 20 and 40 μ/kg, 40 μ/kg appeared more effective; although the difference was not statistically significant.

Hepatitis C virus infection and chronic liver diseases after treatment of malignant disease in children: A multicenter study from the Children's Cancer and Leukemia Study Group of Japan

BackgroundWe studied the prevalence of chronic liver diseases, including hepatitis C virus (HCV) and hepatitis B virus (HBV) infection, as late effects of therapeutic regimens against childhood malignancies in Japan.MethodsPatients were long-time survivors of acute lymphoblastic leukemia (ALL), acute non-lymphoblastic leukemia (ANLL), non-Hodgkins lymphoma (NHL), neuroblastoma, and osteosarcoma, who had been treated and completed the Childrens Cancer and Leukemia Study Group (CCLSG) protocols for more than 6 months at CCLSG participating institutions. The study was initially done in 1993, and as a follow-up study using a retrospective questionnaire in 1997.ResultsThe overall prevalence of HCV infection in the 1993 study was 8.1% of 443 children. Among those long-term survivors in the 1993 study, 36 (8.1%) children (24 with ALL, 6 with ANLL, 2 with NHL, and 4 others) showed liver dysfunction. The details of the HCV-positive long-term survivors were 26 (13.3%) with ALL, 4 (12.9%) with ANLL, 1 (2%) with NHL, and 5 (3%) with others. The overall prevalence of HCV infection in the 1997 study at the same institutions was 0.6%. Only a slight reduction (5.6%) of HCV antibody positivity was noted in the 1997 follow-up study, while marked reduction (77.2%) of chronic liver disorders was noted during the same follow-up period in 623 children.ConclusionsThe high frequency of HCV hepatitis among ALL children is thought to be related to frequent blood transfusions. The 1997 study is the lowest reported prevalence of HCV hepatitis among children with leukemia and malignant diseases.

Childhood acute megakaryoblastic leukemia with internalization of hemic cells

Two atypical cases of acute megakaryoblastic leukemia (AMKL) in infants diagnosed by immunophenotying are described. In both cases, the leukemic cells at diagnosis resembled monoblasts with reniform nuclei, fine reticular chromatin, and abundant grey-blue cytoplasm with pseudopods. In addition, these blasts frequently showed internalization of hemic cells. Therefore, the diagnosis of acute monocytic leukemia (AMOL) or malignant histiocytosis (MH) was initially suggested. However, alpha-naphthyl butyrate esterase stain was negative and immunologic studies determined megakaryocytic lineage of the blasts. Our observation in two consecutive cases of AMKL implies that there is a potential risk of misdiagnosing AMKL as AMOL or MH in infants. The incidence and significance of internalization of hemic cells by blast cells of AMKL in infancy are unknown and we cannot be certain whether these cases constitute a subgroup of AMKL in infancy.