Alice G. Ettinger

Phase I study of temozolomide in children and adolescents with recurrent solid tumors: a report from the Children's Cancer Group.

PURPOSE The Childrens Cancer Group conducted a phase I trial of temozolomide stratified by prior craniospinal irradiation (CSI). PATIENTS AND METHODS Children and adolescents with recurrent or progressive cancer were enrolled. Temozolomide was administered orally daily for 5 days, with subsequent courses administered every 21 to 28 days after full hematologic recovery. Dose levels tested included 100, 150, 180, 215, 245, and 260 mg/m2 daily. RESULTS Twenty-seven patients on the non-CSI stratum were assessable for hematologic toxicity. During the first three dose levels (100, 150, and 180 mg/m2 daily), only grades 1 and 2 hematologic toxicity occurred. One patient at 215 mg/m2 daily had grade 3 hematologic toxicity. Three of eight patients (38%) treated at 245 to 260 mg/m2 daily had dose-limiting toxicity (DLT), which included both neutropenia and thrombocytopenia. Twenty-two patients on the CSI stratum were assessable for hematologic toxicity. Hematologic DLT occurred in one of six patients (17%) at 100 mg/m2 daily and in two of four patients (50%) at 215 mg/m2 daily. No nonhematologic DLT occurred; nausea and vomiting occurred in more than half of the patients. After two courses of temozolomide, 10 patients had stable disease (SD), and three patients had a partial response (PR), one of whom subsequently had a complete response (CR) that persists through 24 months of follow-up. CONCLUSION The maximum-tolerated dose (MTD) of temozolomide for children and adolescents without prior CSI is 215 mg/m2 daily and for those with prior CSI is 180 mg/m2 daily for 5 days, with subsequent courses that begin on day 28. Temozolomide is well tolerated and should undergo phase II testing in children and adolescents.

A pharmacoeconomic analysis of pegaspargase versus native Escherichia coli L-asparaginase for the treatment of children with standard-risk, acute lymphoblastic leukemia: the Children's Cancer Group study (CCG-1962).

Purpose The purpose of this pharmacoeconomic analysis was to compare pegaspargase, a newer chemotherapeutic agent used for treating acute lymphoblastic leukemia, with native Escherichia coli l-asparaginase in induction, delayed intensification 1 and delayed intensification 2. Materials and Methods A subset of patients with newly diagnosed, standard-risk, acute lymphoblastic leukemia enrolled in the Childrens Cancer Group (CCG) study CCG-1962 at seven participating institutions gave consent and was enrolled in our pharmacoeconomic analysis study. Societal (transportation, lodging, missed workdays, food, babysitter) and payer (frequency of encounters) cost data were collected from diaries (n = 27). Additional payer costs, such as drug costs, cost per clinic visit, and cost per inpatient day stay were collected from patients in CCG-1962 and participating institutions. We considered costs of therapy, including higher pegaspargase costs when comparing regimens of pegaspargase versus native E. coli l-asparaginase in induction, delayed intensification 1, and delayed intensification 2. Results Our results showed that the costs of the two therapies were similar from the payer perspective, with pegaspargase costing 1.8% more than E. coli l-asparaginase. The difference between groups also was small (<1%) from the societal perspective. Inpatient stay accounted for 88% of pegaspargase payer costs and 91% of the native E. coli l-asparaginase costs. Conclusion We recommend that pegaspargase not be withheld from treatment protocols solely because of its higher pharmacy costs.

Acute Lymphoblastic Leukaemia

SummaryThe cure rate for children with acute lymphoblastic leukaemia (ALL) has increased to approximately 70%, in part related to the use of the protein synthesis inhibitor drug asparaginase in multiagent chemotherapy regimens. Its lack of haematological toxicity allows its incorporation into phases of therapy in which myelosuppression would be expected either from the disease itself (induction therapy) or secondary to other chemotherapeutic agents (consolidation, intensification or reinduction phases of therapy). Its antileukaemic effect is related to the degree and duration of asparagine depletion.The 2 native forms of L-asparaginase are derived from Escherichia coli and Ewinia chrysantherni. The half-lives (t½) of these forms are approximately 1.2 and 0.6 days, respectively. In order to increase the biological t½, pegaspargase was synthesised by the covalent attachment of monomethoxypolyethylene glycol (PEG) to native E. coli L-asparaginase: it has a t½, of approximately 5.7 days. The duration of asparagine depletion, the substrate amino acid of the drug, is directly related to asparaginase t½.Asparaginase is associated with several unique toxicities, including hyperglycaemia, hypolipoproteinaemia, hypoalbuminaemia, coagulation factor deficiencies, hepatotoxicity and pancreatitis. Since asparaginase is a protein, it may induce hypersensitivity reactions. The incidence of these reactions increases with use. In addition, silent hypersensitivity, i.e. the development of IgG antibodies without clinical reactions, results in a decreased t½ of asparaginase, shortened duration of asparagine depletion, and probably decreased efficacy. The use of pegaspargase allows continued treatment with asparaginase in patients with clinical hypersensitivity reactions. In addition, its use in patients with silent hypersensitivity may maintain the efficacy of asparaginase.So far, the optimal use of the 3 forms of asparaginase has not been determined in children with ALL, partly due to the lack of appropriate pharmacokinetic monitoring methods. As the technology has become available, it has been demonstrated that there is little rationale for the dosage and administration schedules presently in use. Studies are required to determine appropriate dosages and administration methods (intravenous or intramuscular) and schedules for each form of asparaginase, based upon pharmacokinetic parameters. The incidence and time to onset of hypersensitivity (clinical or silent) reactions and the appropriate means of continuing asparaginase therapy with therapeutic effect needs to be evaluated. Pharmacokinetic studies are now available as a research tool. These will allow further investigation to determine if failure to maintain asparagine depletion is a remediable cause of treatment failure.

Pharmacokinetics of intravenous recombinant human granulocyte colony-stimulating factor (rhG-CSF) in children receiving myelosuppressive cancer chemotherapy: Clearance increases in relation to absolute neutrophil count with repeated dosing

Limited evidence suggests increased efficacy of rhG‐CSF by subcutaneous (SQ) compared with intravenous (IV) administration. To examine the possibility that rapid elimination of IV rhG‐CSF could substantially shorten the duration of systemic exposure and could explain a difference in pharmacodynamics, we characterized the pharmacokinetic profile of IV rhG‐CSF for comparison to that previously reported for SQ administration. Twelve children were randomly assigned to receive 10 or more days of IV rhG‐CSF at dosages of 5 or 10 μg/kg a day beginning 24 hr after chemotherapy. Enzyme‐linked immunosorbent assay (ELISA) was used to measure rhG‐CSF concentrations in timed serum samples on days 1 and 10. Pharmacokinetic parameters were estimated by nonlinear, least squares regression. All serum concentration‐time profiles were best described by a two‐compartment model of elimination. Mean t1/2β values ranged from 3.68 ± 0.86 to 22.4 ± 12.0 hr. ANC was correlated with log CLT (r = 0.72, P < 0.05), and inversely with log dose‐adjusted AUC (r = −0.75, P < 0.05) and log dose‐adjusted Cmax (r = −0.65, P < 0.05). Estimated duration of serum rhG‐CSF concentrations above 1 ng/ml exceeded 24 hr for all but the 5 μg/kg cohort on day 1. Pharmacokinetic parameters of IV rhG‐CSF are similar to those previously reported for SQ administration in children treated with myelosuppressive cancer chemotherapy. Daily IV administration should be suitable alternative route of administration in this patient population. Am. J. Hematol. 54:124–130, 1997

The effect of ABO and Rh blood type on the response to intravenous immune globulin (IVIG) in children with immune thrombocytopenic purpura (ITP).

Purpose Immune thrombocytopenic purpura (ITP) is a common childhood illness characterized by thrombocytopenia secondary to shortened platelet survival. Medical therapy includes corticosteroids, intravenous immune globulin (IVIG), and IV Rho (D) immunoglobulin (anti-D). Individuals with Rh-negative blood generally do not respond to treatment with anti-D, but little information is currently available regarding the potential relationship between blood type and response to IVIG. This study was designed to characterize the relationship between ABO and Rh blood type and the response to IVIG in children and adolescents with newly diagnosed ITP. Patients and Methods A retrospective chart review was performed for 52 children and adolescents with newly diagnosed ITP initially treated with IVIG by the Division of Pediatric Hematology-Oncology at Robert Wood Johnson University Hospital in New Brunswick, New Jersey. Results There were no significant differences in response rate or clinical outcome by ABO blood group or Rh type in children with ITP who received IVIG monotherapy as their initial treatment. Conclusions ABO blood group and Rh type do not appear to be prognostic factors when IVIG monotherapy is the initial treatment for childhood ITP.

A Phase II study of carboplatin as a treatment for children with acute leukemia recurring in bone marrow

Carboplatin is an analogue of cisplatin with less nonhematologic toxicity and a similar spectrum of antineoplastic activity. Although cisplatin has not been found to be an active agent against leukemia, carboplatin‐induced complete remissions have been observed in adults with acute myelogenous leukemia (AML), and antileukemic activity has been observed in a Phase I trial involving children with acute lymphoblastic leukemia (ALL) and AML. Therefore, a pediatric Phase II study was undertaken to determine the degree of activity of carboplatin in childhood ALL and AML.

The Influence of Epstein-Barr Virus Seropositivity on the Efficacy of Intravenous Immune Globulin in Children with Immune Thrombocytopenic Purpura

C hildhood immune thrombocytopenic purpura (ITP) most often presents following an acute viral infection and is characterized by immunemediated destruction ofantibodycoated platelets by the reticuloendothelial system.1,2Approximately 80%of children with acute or chronic ITP respond favorably to intravenous immune globulin (IVIG) within 1 week of beginning treatment.34 IVIG acts primarily by saturating Fc receptors on splenic and hepatic macrophages.5 Acute Epstein-Barr virus (EBV) infections may be associated with several immune-mediated hematologic abnormalities, including thrombocytopenia.6 A