Introduction Hemophilia is a genetic disorder that results in either an inactive or inadequate supply of a plasma protein needed for normal blood clotting. The two most common forms are hemophilia A and B, caused by a defect or deficiency in clotting factors VIII and IX, respectively. Both types are X-linked recessive disorders characterized by prolonged bleeding and hemorrhages, typically into joints and soft tissues. Hemophilia C is an autosomal recessive defect that results in a deficiency of factor XI. Marked by bleeding in mucous membranes, hemophilia C exhibits a somewhat different clinical pattern of hemorrhaging than hemophilia A or B but similar to that in von Willebrand disease. This review will focus on hemophilia A and B. Hemophilia has served as a model for the treatment of chronic illness through the comprehensive approach to care. If a child who has hemophilia is managed appropriately with early factor replacement therapy and attempts to avoid the long-term consequences of bleeding, the prospects for a long, full, and healthy life are very good. Epidemiology/Genetic Transmission The incidence of hemophilia A and B is about 15 to 20 per 100 000 males born worldwide and occurs in all races and socioeconomic groups. Hemophilia A, also known as "classical hemophilia," accounts for about 80% of cases of hemophilia, occurs in one of 10 000 male births, and affects about 17 500 individuals in North America.
Purpose A phase I trial was conducted in children with refractory solid tumors to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics, and pharmacodynamics for topotecan administered by a 30-min infusion for 5 consecutive days. Patients and Methods Forty children with a variety of recurrent solid tumors, including nine patients with neuroblastoma and 10 with brain tumors, were given topotecan as a 30-min infusion for 5 consecutive days, beginning with a dose of 1.4 mg/m2/day. The dose was escalated in 20% increments after establishing that DLT was not present at the prior dose. Drug toxicity was graded using standard criteria. Dose-limiting toxicity was defined as grade 3 or 4 nonhematopoietic toxicity or grade 4 hematopoietic toxicity lasting >7 days. Pharmacokinetic studies were performed during the first infusion course. Results The DLT was hematopoietic and involved both platelets and neutrophils. Grade 4 hematopoietic toxicity of brief duration was seen at all dose levels. Over half of the patients received red blood cell transfusion support, and 19/40 received platelet transfusions. Hospital admissions for fever and neutropenia or for documented infections occurred in 32 of 169 courses of therapy. Gastrointestinal symptoms with nausea and vomiting or diarrhea were mild to moderate in 12 of the 40 patients. Antitumor responses were seen in three patients with neuroblastoma. An additional four patients (one with neuroblastoma. two with anaplastic astrocytomas, one with Ewing) had stable disease with continued therapy for >6 months. Using a limited sampling model, pharmacokinetic studies were performed in 36 of the 40 patients. Topotecan lactone and total clearance were similar to those reported in other pediatric populations receiving topotecan by continuous infusion. A pharmacodynamic relation between systemic exposure to topotecan lactone and myelosuppression was observed. Conclusions In heavily pretreated children, the MTD for topotecan given by intermittent 30-min infusion for 5 days is 1.4 mg/m2 without GCSF and 2.0 mg/m2/day with GCSK. The dose-limiting toxicity is hematopoietic. Data from this study provide the basis for further studies of topotecan in children with cancer.
Introduction Hemophilia is a genetic disorder that results in either an inactive or inadequate supply of a plasma protein needed for normal blood clotting. The two most common forms are hemophilia A and B, caused by a defect or deficiency in clotting factors VIII and IX, respectively. Both types are X-linked recessive disorders characterized by prolonged bleeding and hemorrhages, typically into joints and soft tissues. Hemophilia C is an autosomal recessive defect that results in a deficiency of factor XI. Marked by bleeding in mucous membranes, hemophilia C exhibits a somewhat different clinical pattern of hemorrhaging than hemophilia A or B but similar to that in von Willebrand disease. This review will focus on hemophilia A and B. Hemophilia has served as a model for the treatment of chronic illness through the comprehensive approach to care. If a child who has hemophilia is managed appropriately with early factor replacement therapy and attempts to avoid the long-term consequences of bleeding, the prospects for a long, full, and healthy life are very good. Epidemiology/Genetic Transmission The incidence of hemophilia A and B is about 15 to 20 per 100 000 males born worldwide and occurs in all races and socioeconomic groups. Hemophilia A, also known as classical accounts for about 80% of cases of hemophilia, occurs in one of 10 000 male births, and affects about 17 500 individuals in North America.
Duffner, Patricia K. MD; Armstrong, Floyd Daniel PhD; Helton, Kathleen MD; Brecher, Martin L. MD; Bell, Beverly MD; Chauvenet, Allen R. MD, PhD Author Information
Abstract To determine the maximum tolerated dose of 5‐fluorouracil administered as a 120‐hour continuous intravenous infusion to pediatric patients, we performed a phase I study using a starting dosage of 900 mg/m 2 /day. The maximum tolerated dosage (MTD) was 1,100 mg/m 2 /day. At this dosage level 40% of courses were complicated by grade 3 mucositis. Three additional patients were treated at the dosage level of 1,000 mg/m 2 /day after the MTD was determined. We recommend the dosage level of 1,000 mg/m 2 /day for phase II studies of 5‐fluorouracil administered as a 120‐hour continuous intravenous infusion to pediatric patients.
To determine the maximum-tolerated dose (MTD) and dose-limiting toxicity of topotecan when combined with cyclophosphamide in pediatric patients with recurrent or refractory malignant solid tumors.A total of 33 patients received cyclophosphamide (250 mg/m2/dose) followed by topotecan in escalating doses (0.6 to 0.75 mg/m2/dose), each given as a 30-minute infusion daily for 5 days. A total of 154 fully assessable treatment courses were given to these patients.Neutropenia was the dose-limiting toxicity of the therapy at both topotecan dose levels. The addition of filgrastim allowed escalation of the topotecan dose to the 0.75-mg/m2 level with acceptable neutropenia. Other significant toxicities were anemia and thrombocytopenia. Nonhematopoietic toxicity of grades > or = 3 was not observed. Responses were reported in patients with Wilms' tumor (one complete response [CR], one partial response [PR]), neuroblastoma (one CR, one PR), rhabdomyosarcoma (one PR), and osteosarcoma (one PR). Pharmacokinetic studies indicate that cyclophosphamide administered on the schedule used in this study did not alter topotecan disposition on day 5. As with previous studies, a pharmacodynamic relation between systemic exposure and myelosuppression was noted.The combination of topotecan and cyclophosphamide shows activity in a wide variety of pediatric solid tumors and can be given with acceptable hematopoietic toxicity with the use of filgrastim support. We recommend that pediatric phase II trials use cyclophosphamide 250 mg/m2 followed by topotecan 0.75 mg/m2 daily for 5 days with filgrastim for amelioration of neutropenia.
Purpose After profound peripheral neurotoxicity during induction chemotherapy for acute lymphoblastic leukemia (ALL) in the index patient with Charcot-Marie-Tooth hereditary neuropathy (CMT), study coordinators of the Pediatric Oncology Group (POG) front-line ALL protocols reviewed patient registrations to identify any other patients with possible CMT. The goal was to provide preliminary information about patients with undiagnosed CMT who develop ALL. Patients and Methods Five children with ALL who were enrolled in POG B-precursor or T-cell ALL protocols from 1994 to 1999 subsequently were determined to have CMT hereditary neuropathy. Their clinical presentations and treatment records were reviewed in detail. Records of all patients entered on POG 9201 (lesser-risk ALL) were reviewed to identify all cases of significant vincristine toxicity noted in the first 6 months of treatment. Results The five identified patients all had substantial peripheral neurotoxicity that required alteration in treatment and/or orthopedic/physical therapy evaluation and follow-up. The POG 9201 review identified 25 of 686 patients (3.6%) with significant peripheral neuropathy. Three of 25 were diagnosed with CMT; the others have had no testing reported. Conclusions A family history of CMT or other peripheral neuropathy should be sought at the time of diagnosis of ALL. Testing for CMT should be considered in any child with substantial vincristine-induced peripheral neurotoxicity. Treatment of such patients must be individualized. Testing of all patients with significant peripheral neuropathy would be necessary to determine the percentage of such neuropathy explained by underlying CMT.
Concerns about long-term methotrexate (MTX) neurotoxicity in the 1990s led to modifications in intrathecal (IT) therapy, leucovorin rescue, and frequency of systemic MTX administration in children with acute lymphoblastic leukemia. In this study, neurocognitive outcomes and neuroradiologic evidence of leukoencephalopathy were compared in children treated with intense central nervous system (CNS)-directed therapy (P9605) versus those receiving fewer CNS-directed treatment days during intensive consolidation (P9201). A total of 66 children from 16 Pediatric Oncology Group institutions with "standard-risk" acute lymphoblastic leukemia, 1.00 to 9.99 years at diagnosis, without evidence of CNS leukemia at diagnosis were enrolled on ACCL0131: 28 from P9201 and 38 from P9605. Magnetic resonance imaging scans and standard neuropsychological tests were performed ≥2.6 years after the end of treatment. Significantly more P9605 patients developed leukoencephalopathy compared with P9201 patients (68%, 95% confidence interval 49%-83% vs. 22%, 95% confidence interval 5%-44%; P=0.001) identified as late as 7.7 years after the end of treatment. Overall, 40% of patients scored <85 on either Verbal or Performance IQ. Children on both studies had significant attention problems, but P9605 children scored below average on more neurocognitive measures than those treated on P9201 (82%, 14/17 measures vs. 24%, 4/17 measures). This supports ongoing concerns about intensive MTX exposure as a major contributor to CNS late effects.
