Molecular alterations of the IDH1 gene in AML: a Children's Oncology Group and Southwest Oncology Group study.

Recent whole-genome sequencing efforts led to the identification of IDH1(R132) mutations in acute myeloid leukemia (AML) patients. We studied the prevalence and clinical implications of IDH1 genomic alterations in pediatric and adult AML. Diagnostic DNA from 531 AML patients treated on Children's Oncology Group trial COG-AAML03P1 (N=257), and Southwest Oncology Group trials SWOG-9031, SWOG-9333 and SWOG-9500 (N=274), were tested for IDH1 mutations. Codon R132 mutations were absent in the pediatric cohort, but were found in 12 of 274 adult patients (4.4%, 95% CI 2.3-7.5). IDH1(R132) mutations occurred most commonly in patients with normal karyotype, and those with FLT3/ITD and NPMc mutations. Patients with IDH1(R132) mutations trended toward higher median diagnostic white blood cell counts (59.2 x 10(9) vs 29.1 x 10(9) per liter, P=0.19) than those without mutations, but the two groups did not differ significantly in age, bone marrow blast percentage, overall survival or relapse-free survival. Eleven patients (2.1%) harbored a novel V71I sequence alteration, which was found to be a germ-line polymorphism. IDH1 mutations were not detected in pediatric AML, and are uncommon in adult AML.

Maternal hemoglobin concentration during pregnancy and risk of infant leukaemia: a children's oncology group study.

In contrast to the positive association found in three studies between maternal anaemia during pregnancy and childhood leukaemia, no such association was found in infant leukaemia (odds ratio 0.85, 95% confidence interval 0.53-1.37).

Phase II trial of intravenous lobradimil and carboplatin in childhood brain tumors: a report from the Children's Oncology Group.

BACKGROUND: [corrected] Lobradimil is a synthetic bradykinin analog that rapidly and transiently increases the permeability of the blood-brain barrier (BBB). The combination of lobradimil and carboplatin was studied in pediatric patients with primary brain tumors in a phase II trial, the primary endpoints of which were to estimate the response rate and time to disease progression. PATIENTS AND METHODS: Patients were stratified by histology into five cohorts: brainstem glioma, high-grade glioma, low-grade glioma, medullobastoma/primitive neuroectodermal tumor (PNET), and ependymoma. Patients received carboplatin adaptively dosed to achieve a target AUC of 3.5 mg min/ml per day (7 mg.min/ml/cycle) intravenously over 15 min on 2 consecutive days and lobradimil 600 ng/kg ideal body weight/day on 2 consecutive days each 28 day cycle. RESULTS: Forty-one patients, age 2-19 years, were enrolled; 38 patients, including 1 patient ultimately determined to have atypical neurocytoma, were evaluable for response. No objective responses were observed in the brainstem glioma (n=12) and high-grade glioma (n = 9) cohorts, although two patients with high-grade glioma had prolonged disease stabilization (>6 months). The study was closed for commercial reasons prior to achieving the accrual goals for the ependymoma (n = 8), medulloblastoma/PNET (n = 6) and low-grade glioma (n = 2) cohorts, although responses were observed in 1 patient with PNET and 2 patients with ependymoma. CONCLUSION: The combination of lobradimil and carboplatin was inactive in childhood high-grade gliomas and brainstem gliomas.

Phase II study of gemcitabine in children with relapsed acute lymphoblastic leukemia or acute myelogenous leukemia (ADVL0022): a Children's Oncology Group Report.

BACKGROUND: To determine the response rate and toxicity to gemcitabine administered as 10 mg/m2/min x 360 min weekly for 3 weeks in children with relapsed acute lymphoblastic leukemia (ALL) or acute myelogenous leukemia (AML). Gemcitabine is a deoxycytidine analog that inhibits DNA synthesis and repair and has a broad spectrum of antitumor activity. PROCEDURE: From April 2001 to April 2003, 23 male and 9 female eligible patients were recruited for the Children's Oncology Group (COG) phase II study of Gemcitabine (ADVL0022). RESULTS: One of 20 evaluable patients with ALL and none of 10 evaluable patients with AML had complete responses to gemcitabine; there were no partial responses. Grade 3 or 4 hematologic toxicity and liver toxicity were common during therapy. Only one patient was alive 1 year after entry. The estimated 1-year overall survival probability for the 32 patients was 4% (SE = 3%). CONCLUSIONS: Gemcitabine at the dose and schedule in this trial was not effective for children with relapsed AML or ALL.

Function and quality-of-life of survivors of pelvic and lower extremity osteosarcoma and Ewing's sarcoma: the Childhood Cancer Survivor Study.

Limb-sparing surgeries have been performed more frequently than amputation based on the belief that limb-sparing surgeries provide improved function and quality-of-life (QOL). However, this has not been extensively studied in the paediatric population, which has unique characteristics that have implications for function and QOL. Using the Childhood Cancer Survivor Study, 528 adult long-term survivors of pediatric lower extremity bone tumours, diagnosed between 1970 and 1986, were contacted and completed questionnaries assessing function and QOL. Survivors were an average of 21 years from diagnosis with an average age of 35 years. Overall they reported excellent function and QOL. Compared to those who had a limb-sparing procedure, amputees were not more likely to have lower function and QOL scores and self-perception of disability included general health status, lower educational attainment, older age and female gender. Findings from this study suggest that, over time, amputees do as well as those who underwent limb-sparing surgeries between 1970 and 1986. However, female gender, lower educational attainment and older current age appear to influence function, QOL and disability.

Chromosomal transformation in donor cells following allogeneic bone marrow transplantation.

We report here a monosomy 7 transformation of donor cells following matched-unrelated, same sex, allogeneic bone marrow transplantation in a patient with severe congenital aplastic anemia. A PCR technique was employed to amplify microsatellite markers on chromosome 7 to confirm donor/recipient identity. We found that the transformation of monosomy 7 occurred in previously genetically normal donor cells. This study suggests that the microenvironment of the bone marrow of our patient with severe congenital aplastic anemia may have played a critical role in the development of monosomy 7 of normal donor cells and we conclude that chromosomal microsatellite marker analysis can be a valuable tool for precise donor/recipient differentiation in engraftment monitoring.

Phase I study of gemcitabine (difluorodeoxycytidine) in children with relapsed or refractory leukemia (CCG-0955): a report from the Children's Cancer Group.

To determine the maximum tolerated dose (MTD) and assess the toxicity profile and pharmacokinetics of weekly gemcitabine infusions in pediatric patients with refractory hematologic malignancies. Fourteen patients under 21 years old were given infusions of gemcitabine for escalating durations at 10 mg/m2/min weekly for three consecutive weeks. Two males and two females were studied at each dose level. Pharmacokinetics of the drug's metabolism were measured by high pressure-liquid chromatography (HPLC) for 24 h after the first dose. Intracellular difluorodeoxycytidine triphosphate formation in leukemic blasts was measured in selected patients. The MTD of gemcitabine in these patients was 3600 mg/m2/week for three consecutive weeks (10 mg/m2/min for 360 min). Hepatotoxicity was the dose limiting toxicity. Thirty to fifty percent of patients exhibited fever, rash, or myalgia. Rare instances of hypotension and pulmonary toxicity were observed. Two of six patients [one acute lymphoblastic leukemia (ALL) and one acute myelogenous leukemia (AML)] treated at the MTD had at least M2 marrows, although peripheral blood counts did not recover sufficiently for the patients to be considered in complete response. Pharmacokinetics of gemcitabine fit a two-compartment open model with terminal half-life and plasma clearance value of 62 min and 2.2 l/min/m2, respectively. No gender differences were observed. In conclusion, the MTD of gemcitabine was 10 mg/m2/min for 360 min every week for 3 weeks. This is the recommended phase II dose schedule for children with leukemia. The activity of the drug at this schedule in heavily pretreated, refractory patients warrants a phase II trial in hematologic malignancies.

Ifosfamide, carboplatin and etoposide in children with poor-risk relapsed Wilms' tumor: a Children's Cancer Group report.

BACKGROUND: The outcome of children with relapsed Wilms' tumor is poor, especially with poor-risk factors such as unfavorable histology, early recurrence, previous three-drug therapy, relapse not confined to lungs and abdominal relapse following abdominal radiotherapy. We report the overall response rate, progression-free survival and overall survival of 11 children with relapsed and poor-risk Wilms' tumor following ifosfamide/carboplatin/etoposide (ICE) chemotherapy. PATIENTS AND METHODS: ICE therapy consisted of ifosfamide 1800 mg/m2/day (on day 0-4), carboplatin 400 mg/m2/day (on day 0-1) and etoposide 100 mg/m2/day (on day 0-4). The median age at diagnosis was 39 months (range from 13 months to 16 years) and the median time to relapse after initial diagnosis was 9 months (range 4-72 months). All but one patient had at least one poor prognostic feature, with eight patients showing three or four. RESULTS: After ICE chemotherapy the number of patients showing a complete response (CR) was three (27%) and a partial response (PR) was six (55%). The overall response rate (CR+PR) was 82%. Five of the six patients with a PR subsequently achieved a CR with further therapy. The 3-year event-free survival and overall survival were 63.6 +/- 14.5%. CONCLUSIONS: The response rate in children with relapsed and poor-risk Wilms' tumor is >80% with ICE re-induction chemotherapy followed by post-ICE therapy. The optimal approach for post-ICE consolidation therapy has yet to be determined.

A phase I trial and pharmacokinetic study of 9-cis-retinoic acid (ALRT1057) in pediatric patients with refractory cancer: a joint Pediatric Oncology Branch, National Cancer Institute, and Children's Cancer Group study.

PURPOSE: To determine the maximum tolerated dose and describe the toxicities of 9-cis-retinoic acid (9cRA, ALRT1057) administered p.o. tid in pediatric patients with refractory cancer and to study the pharmacokinetics of 9cRA and determine whether systemic drug exposure changes with chronic dosing. PATIENTS AND METHODS: Children with refractory cancer (stratified by age, < or =12 and >12 years) were treated with p.o. 9cRA for 28 consecutive days. The starting dose was 50 mg/m(2)/day divided into 3 doses with planned escalations to 65, 85, and 110 mg/m(2)/day. Pharmacokinetic sampling was performed on days 1 and 29 of the first cycle. RESULTS: Of the 37 patients entered, 18 patients < or =12 years of age and 11 patients >12 years of age were evaluable for toxicity. In patients >12 years of age, dose-limiting headache occurred in 2/2 patients at the 110 mg/m(2)/day dose level; 1/8 patients at 85 mg/m(2)/day developed dose-limiting pseudotumor cerebri. In patients < or =12 years of age, 3/5 patients at the starting dose level of 50 mg/m(2)/day developed dose-limiting pseudotumor cerebri; and 0/6 patients experienced dose-limiting toxicity at 35 mg/m(2)/day. Reversible non-dose-limiting hepatotoxicity was observed in 15 patients across all of the dose levels. There was considerable interpatient variability in 9cRA plasma concentrations. Peak plasma concentrations of 9cRA occurred at a median of 1.5 h after a p.o. dose, and the harmonic-mean terminal half-life was 43 min. By day 29 of 9cRA administration, the plasma 9cRA area under the curve declined by an average of 65% from day 1 values. CONCLUSIONS: The dose-limiting toxicity of 9cRA in pediatric patients was neurotoxicity, primarily pseudotumor cerebri. Younger children tolerate significantly lower doses of 9cRA than older children. Similar to all-trans-retinoic acid, the pharmacokinetics of 9cRA demonstrated a wide degree of interpatient variability and decreased over time when administered on a daily basis. The recommended Phase II dose of 9cRA in patients < or =12 and >12 years of age is 35 and 85 mg/m(2)/day, respectively.

Developmental therapeutics in childhood cancer. A perspective from the Children's Oncology Group and the US Food and Drug Administration.

Drug development in pediatric oncology has been reviewed, concentrating on overall development issues and COG studies of cytotoxic compounds. A variety of interesting molecules with more specific targeting are becoming available. The challenges that remain include the availability of such compounds for pediatric trial and their study in a timely fashion, and the subsequent incorporation of the new agents into more up-front regimens, with the ultimate shared goal of curing more children with less toxicity.

A phase I/II dose escalation and activity study of intravenous injections of OCaP1 for subjects with refractory osteosarcoma metastatic to lung.

Osteosarcomas are malignant tumors arising from skeletal tissue and occur most frequently during childhood and adolescence. Osteosarcoma was once fatal in more than 80% of patients who presented with apparently localized disease. Chemotherapy, better surgical techniques, and improved staging methods now allow most patients to be treated with limb-sparing surgery and to be cured of their disease. However, many patients still die of metastatic disease and new approaches are still needed. The lung is the most frequent metastatic site and is treated with chemotherapy and surgical resections. Multiple resections for repeated recurrences that are limited to the lung are not uncommon but are limited by the amount of lung tissue that can be removed and become futile as recurrences become more frequent. Although a main component of initial therapy, chemotherapy has not been shown to be of benefit for recurrent disease. Direct introduction of therapeutic genes into malignant cells in vivo may provide effective treatment of solid tumors. The proposed study will use the adenoviral vector Ad-OC-E1a (OCaP1), which contains a murine osteocalcin (OC) promoter to regulate the production of the adenoviral E1a protein to allow for restricted viral replication and subsequent lysis of tumor cells. The OC promoter is developmentally regulated, with peak expression in the neonate. It functions primarily in osteoblasts found in growing bone and is highly expressed in osteogenic sarcomas. Because adenovirus is quickly cleared by normal tissues, especially the liver, systemic administration has been problematic. Although bioavailability would be decreased following exposure to the liver, the OcaP1 construct should not be hepatotoxic due to OC-restricted tissue expression of the Ela protein. Metastatic disease to the lung is a major problem and often is the cause of death for patients with osteogenic sarcoma. Treatment of pulmonary metastases could potentially be accomplished using intravenously administered OcaP1 since the material would pass through the lung prior to reaching the systemic circulation. In animal models using OC expressing tumors, OCaP1 has been effective at reducing lung metastases following intravenous injection. This protocol is a phase I/II investigational study of bolus intravenous injections of Ad-OC-E1a for the treatment of chemotherapy-refractory osteogenic sarcoma that has metastasized to the lungs. Initially patients will receive one injection of 1 x 10(10), 1 X 10(11), 1 X 10(12), or 5 x 10(12) viral particles of Ad-OC-E1a using a standard Phase I dose escalation design that studies 3 to 6 patients per dose group. After safety has been established in the first part of the trial, we will evaluate the anti-tumor activity of OCaP1. Because the matrix associated with osteogenic sarcoma may not change despite tumor necrosis, radiographic evaluation alone has not been considered sufficient to evaluate response in this disease. Histologic criteria that assess the amount of necrosis have been shown to have prognostic significance and are a key component of the anti-tumor response assessment. Therefore, the anti-tumor assessments will be carried out in patients for whom resection of their pulmonary metastases is clinically indicated. These patients will receive one injection of OCaP1 and 28 to 42 days later undergo their planned pulmonary resection. Responses will be graded using radiographic and histologic objective response criteria that are considered standard for osteogenic sarcoma. A total of 14 to 25 patients, depending upon whether objective anti-tumor responses occur, will be studied in this part of the protocol.

Pet ownership and childhood acute leukemia (USA and Canada).

OBJECTIVES: For more than three decades there has been speculation regarding a possible role of zoonotic diseases in the development of human leukemia. This study investigated the potential relationship between exposure to pets and the development of childhood leukemia. METHODS: Data from 2359 cases of acute leukemia from two large case-control studies were analyzed. Cases were individually matched to population controls on telephone exchange, age, and race. Conditional logistic regression was used to estimate odds ratios (OR) associated with pet ownership. RESULTS: Overall, there was no association between pet ownership (either "any pet", dog, or cat) and childhood acute leukemia (OR(any pet:) = 1.01, 95% CI 0.89-1.2). Additionally, no relationship was found between exposure to an ill pet and childhood leukemia. CONCLUSION: The results of this analysis suggest that pet ownership (healthy or sick) is unrelated to an increased risk of childhood leukemia.

Osteoporosis in survivors of acute lymphoblastic leukemia.

Osteoporosis is currently receiving increasing attention as an important late effect in survivors of childhood cancer and its treatment because of their quality of life and its negative effect on the survivors' ability to perform developmentally appropriate activities. Survivors of childhood cancer are especially vulnerable because they are affected during childhood and adolescence, a time when peak bone mass should be achieved. This paper reviews decreased bone density in acute lymphoblastic leukemia (ALL), which is the most common childhood cancer and has a cure rate approaching 80%. Osteopenia/osteoporosis has been observed in all phases of the disease: at diagnosis, during treatment, and throughout the post-treatment period for as long as 20 years. Among the findings that have been described are musculoskeletal pain, disturbed gait, fractures, kyphosis, lordosis, and growth failure. Risk factors not specifically related to ALL include smoking, ingestion of carbonated beverages, and family history of "brittle bone" or fractures. Patients should be counseled in regard to diet, exercise, smoking cessation, and avoidance of carbonated beverages. There are a number of options for specific drug therapy; however, the administration of bisphosponates to children and adolescents must be approached with caution. Research is needed to determine how extensive the problem is and how to best prevent and treat the osteopenia/osteoporosis associated with ALL.

INK4A/ARF deletions are acquired at relapse in childhood acute lymphoblastic leukaemia: a paired study on 25 patients using real-time polymerase chain reaction.

Current risk-adjusted intensive therapies for childhood acute lymphoblastic leukaemia (ALL) are expected to result in an event-free survival of greater than 75%. In sharp contrast, relapsed paediatric ALL is a difficult disease to treat. In this study, 25 paediatric patients with ALL were analysed at diagnosis and relapse for their p16 (exon 2) status using the most accurate method of detection, real-time polymerase chain reaction (PCR). The median time to relapse for the group was 27 months. At diagnosis, the incidence of p16 homozygous and hemizygous deletion in this group was 32% and 20% respectively. The incidence of homozygous p16 deletion at relapse was 64%. A large number of patients, eight of 16 (50%), developed p16 homozygous deletion at relapse. Of those eight patients, four were hemizygous and four were germline at diagnosis. At diagnosis, those patients with a homozygous or hemizygous p16 deletion relapsed sooner than those germline for p16. We have shown that p16 alterations are frequently present in relapsed lymphoblastic leukaemia in children.

Plasma pharmacokinetics and cerebrospinal fluid penetration of thioguanine in children with acute lymphoblastic leukemia: a collaborative Pediatric Oncology Branch, NCI, and Children's Cancer Group study.

PURPOSE: In preclinical studies, thioguanine (TG) has been shown to be more potent than the standard acute lymphoblastic leukemia (ALL) maintenance agent, mercaptopurine (MP), suggesting that TG may be more efficacious than MP in the treatment of childhood ALL. As part of a pilot trial in which TG was used in place of MP, we studied the plasma pharmacokinetics of oral TG and measured steady-state plasma and CSF TG concentrations during a continuous intravenous infusion (CIVI) in children with newly diagnosed standard-risk ALL. METHODS: Nine plasma samples were collected after each patient's first 60 mg/m2 oral TG dose during maintenance. CIVI TG (20 mg/m2/h over 24 h) was administered during the consolidation phase of therapy, and simultaneous plasma and CSF samples were collected near the end of the infusion. TG was measured by reverse-phase HPLC with ultraviolet detection. Erythrocyte TG nucleotide (TGN) concentrations were measured 7 days after a course of CIVI TG and prior to the start of each maintenance cycle. RESULTS: After oral TG (n = 35), the mean (+/- SD) peak plasma concentration was 0.46 +/- 0.68 microM and the AUC ranged from 0.18 to 9.5 microM.h (mean 1.5 microM.h). Mean steady-state plasma and CSF TG concentrations during CIVI (n = 33) were 2.7 and 0.5 microM, respectively. The mean (+/- SD) TG clearance was 935 +/- 463 ml/min per m2. Plasma TG concentrations did not correlate with erythrocyte TGN concentrations after oral or CIVI TG. The 8-OH-TG metabolite was detected in plasma and CSF. CONCLUSIONS: TG concentrations that are cytotoxic to human leukemia cell lines can be achieved in plasma after a 60 mg/m2 oral dose of TG and in plasma and CSF during CIVI of TG.

Phase I study of CI-958 in children and adolescents with recurrent solid tumors.

BACKGROUND: CI-958 is a synthetic intercalating agent of a new chemical class, the benzopyranoindazoles, with promising preclinical activity. Its mechanism of action is thought to be stabilization of the cleavable complex of DNA with topoisomerase II, as well as DNA helicase blockade. It is thought to have less cardiotoxicity than the anthracyclines. Early Phase I studies in adults showed the drug to be well tolerated, making it an attractive agent to pursue in Phase I clinical trials in children. METHODS: Children and adolescents with recurrent solid tumors received CI-958 at an initial dose of 450 mg/m(2) over 2 hours. Dose escalation was performed in a standard fashion in cohorts of three patients until dose limiting toxicity and the maximum tolerated dose were determined. RESULTS: Twenty-one patients were entered on the study. The maximum tolerated dose was found to be 650 mg/m(2). Dose limiting toxicities were Grade 4 neutropenia and Grade 4 hypotension at the dose level of 700 mg/m(2). CONCLUSIONS: The maximum tolerated dose of CI-958 in children and adolescents is 650 mg/m(2). No antitumor activity has been observed.

A phase I clinical, pharmacological, and biological trial of interleukin 6 plus granulocyte-colony stimulating factor after ifosfamide, carboplatin, and etoposide in children with recurrent/refractory solid tumors: enhanced hematological responses but a high incidence of grade III/IV constitutional toxicities.

A Phase I trial was conducted to determine the safety, biological activity, and hematopoietic recovery by the combination of interleukin 6 (IL-6) and granulocyte-colony stimulating factor (G-CSF) after myelosuppressive chemotherapy in children. Patients <22 years of age at diagnosis with either recurrent or refractory solid tumors received ifosfamide 1,800 mg/m2/day x 5 days, carboplatin 400 mg/m2/ day x 2 days, and etoposide 100 mg/m2/day x 5 days, followed by daily s.c. G-CSF (5 microg/kg/day) and IL-6 (2.5, 3.75, or 5.0 microg/kg/day). Pharmacokinetic, proinflammatory mediator levels, hematopoietic colony assays, and cytokine receptor expression studies were performed during course one. Nineteen patients were evaluable for toxicity and received IL-6 at doses of 2.5 (n = 8), 3.75 (n = 5), or 5.0 (n = 6) microg/kg/day. Dose-limiting constitutional toxicity occurred in two of six patients at 5.0 microg/kg/day, two of five patients at 3.75 microg/kg/day, and two of eight patients at 2.5 microg/kg/day. The maximum tolerated dose (MTD) exceeded the lowest dose tested. Because of lack of drug availability, an MTD was not established. The maximum concentration of IL-6 (2.5 microg/kg/day) was 0.799 +/- 1.055 ng/ml (mean +/- SD). During the first course, the median time to absolute neutrophil count > or = 1,000/mm3 and platelets > or = 100,000 mm3 was estimated at 19 and 23 days, respectively. Peripheral blood progenitor cells expressing receptors to IL-3, IL-6, and G-CSF increased significantly over baseline (P < 0.05). After the first dose of IL-6, IFN-gamma levels were abnormal in 13 patients, and IL-1beta levels were abnormal in 10 patients. IL-6 has a high incidence of constitutional toxicity and a lower MTD in children compared with adults. In vivo use of IL-6 in children after chemotherapy remains limited. However, IL-6 may be more optimally investigated in children under ex vivo conditions.

Prospective randomized trial between two doses of granulocyte colony-stimulating factor after ifosfamide, carboplatin, and etoposide in children with recurrent or refractory solid tumors: a children's cancer group report.

PURPOSE: The objectives of this study were: 1) to compare the time to hematologic recovery (absolute neutrophil count [ANC] > or = 1,000/mm3 and platelet count > or = 100,000/mm3) in a randomized prospective study of two doses of granulocyte colony-stimulating factor (G-CSF) (5.0 vs. 10.0 microg/kg per day) after ifosfamide, carboplatin, and etoposide (ICE) chemotherapy; and 2) to determine the response rate (complete response [CR] + partial response [PR]) of ICE in children with refractory or recurrent solid tumors. PATIENTS AND METHODS: From June 1992 until November 1994, 123 patients with recurrent or refractory pediatric solid tumors were treated with ifosfamide (1,800 mg/m2 per day x 5), carboplatin (400 mg/m2 per day x 2), and etoposide (100 mg/m2 per day x 5) and randomized to receive either 5.0 microg/kg per day or 10.0 microg/kg per day of G-CSF subcutaneously until recovery of ANC to > or = 1,000/mm3. RESULTS: The incidence of grade 4 neutropenia during the first course was 88%. Median time from the start of chemotherapy to ANC > or = 1,000/mm(-3) for all patients during courses 1 and 2 was 21 and 19 days, respectively. The incidence of developing platelet count < or = 20,000/mm3 during course 1 was 82%. The median time from the start of the course of chemotherapy to platelet recovery > or =100,000/mm3 for all patients during courses 1 and 2 was 27 days. There was no significant difference in the median time of ANC recovery, platelet recovery, or incidence of grade 4 neutropenia; and in the median days of fever and the incidence of infections requiring hospitalization and intravenous antibiotics during courses 1 and 2, there was no significant difference between the two doses of G-CSF. One hundred eighteen patients were evaluated for response to ICE. The overall response rate (CR + PR) in this study was 51% (90% confidence interval, 43%-59%). The CR rate for all diagnostic categories was 27%. The Kaplan-Meier estimates of 1-year and 2-year survival probabilities for all patients were 52% and 30%, respectively. CONCLUSION: In summary, this combination of chemotherapy (ICE) was associated with a high CR rate (27%) in children with recurrent or refractory solid tumors, but also with a high incidence of grade 4 neutropenia and thrombocytopenia. Doubling the dose of G-CSF from 5.0 to 10.0 microg/kg per day after ICE chemotherapy did not result in an enhancement of neutrophil or platelet recovery or the incidence of grade 4 neutropenia developing.

Recombinant urate oxidase for the prophylaxis or treatment of hyperuricemia in patients With leukemia or lymphoma.

PURPOSE: To improve the control of hyperuricemia in patients with leukemia or lymphoma, we tested a newly developed uricolytic agent, recombinant urate oxidase (SR29142; Rasburicase; Sanofi-Synthelabo, Inc, Paris, France), which catalyzes the oxidation of uric acid to allantoin, a highly water-soluble metabolite readily excreted by the kidneys. PATIENTS AND METHODS: We administered Rasburicase intravenously, at 0.15 or 0.20 mg/kg, for 5 to 7 consecutive days to 131 children, adolescents, and young adults with newly diagnosed leukemia or lymphoma, who either presented with abnormally high plasma uric acid concentrations or had large tumor cell burdens. Blood levels of uric acid, creatinine, phosphorus, and potassium were measured daily. The pharmacokinetics of Rasburicase, the urinary excretion rate of allantoin, and antibodies to Rasburicase were also studied. RESULTS: At either dosage, the recombinant enzyme produced a rapid and sharp decrease in plasma uric acid concentrations in all patients. The median level decreased by 4 hours after treatment, from 9.7 to 1 mg/dL (P =.0001), in the 65 patients who presented with hyperuricemia, and from 4.3 to 0.5 mg/dL (P =.0001) in the remaining 66 patients. Despite cytoreductive chemotherapy, plasma uric acid concentrations remained low throughout the treatment (daily median level, 0.5 mg/dL). The urinary excretion rate of allantoin increased during Rasburicase treatment, peaking on day 3. Serum phosphorus concentrations did not change significantly during the first 3 days of treatment, decreased significantly by day 4 in patients presenting with hyperuricemia (P =.0003), and fell within the normal range in all patients by 48 hours after treatment. Serum creatinine levels decreased significantly after 1 day of treatment in patients with or without hyperuricemia at diagnosis (P =.0003 and P =.02, respectively) and returned to normal range in all patients by day 6 of treatment. Toxicity was negligible, and none of the patients required dialysis. The mean plasma half-lives of the agent were 16.0 +/- 6.3 (SD) hours and 21.1 +/- 12.0 hours, respectively, in patients treated at dosages of 0.15 or 0.20 mg/kg. Seventeen of the 121 assessable patients developed antibodies to the enzyme. CONCLUSION: Rasburicase is safe and highly effective for the prophylaxis or treatment of hyperuricemia in patients with leukemia or lymphoma.