Anne-Marie R Langevin

Systemic Exposure to Mercaptopurine as a Prognostic Factor in Acute Lymphocytic Leukemia in Children

BACKGROUND Despite a success rate of more than 90 percent in inducing remission in children with acute lymphocytic leukemia, 30 to 40 percent of such children relapse. Maintenance therapy during remission usually includes oral mercaptopurine and methotrexate. Recently, wide variability in the bioavailability of oral mercaptopurine has been demonstrated, and there is concern that this may affect the risk of relapse. METHODS To investigate whether lower systemic exposure to mercaptopurine may increase the risk of relapse in acute lymphocytic leukemia, we prospectively studied 23 children receiving maintenance therapy. On the basis of disease features, 11 were classified as being at low risk of relapse, and 12 at standard risk. Those who relapsed (n = 10) did not differ from those who did not in their mean age, hemoglobin level, mean daily dose of mercaptopurine and weekly dose of methotrexate, or the total number of days during which mercaptopurine and methotrexate therapy was interrupted. RESULTS There was a significant difference in the mean (+/- SEM) area under the mercaptopurine concentration-time curve achieved by a dose of 1 mg of mercaptopurine per square meter of body-surface area: 1636 +/- 197 nmol per liter x minutes in those who relapsed, as compared with 2424 +/- 177 nmol per liter x minutes in those who did not (P less than 0.005). This caused a significantly lower total daily systemic exposure to mercaptopurine in those who relapsed (104,043 +/- 12,812 nmol per liter x minutes) than in those who did not (168,862 +/- 18,830 nmol per liter x minutes) (P less than 0.005). An identical tendency prevailed when patients at low risk and patients at standard risk were analyzed separately. Kaplan-Meier analysis revealed that children in whom an area under the curve of less than 1971 nmol per liter x minutes was achieved by a dose of 1 mg of mercaptopurine per square meter had a significantly poorer prognosis than those with larger areas under the curve (P less than 0.01). Similarly, those with a total daily systemic exposure of more than 137,970 nmol per liter x minutes had a significantly better prognosis than those with a lower exposure (P less than 0.005). CONCLUSIONS Low systemic exposure to oral mercaptopurine during maintenance therapy for acute lymphocytic leukemia in childhood adversely affects prognosis. Children should be studied at the beginning of maintenance therapy to establish the pharmacokinetics of mercaptopurine, and the dose should be tailored to achieve an appropriate systemic exposure.

Phase I Therapy Trials in Children With Cancer

Purpose: This study examined the response and toxicity rates of antineoplastic drugs evaluated in phase I clinical trials in children to identify trends in response and toxicity over time. Patients and Methods: Full length, peer-reviewed articles describing the results of single agent phase I therapy trials in children younger than 21 years with cancer were reviewed. Tumor-specific response data and doses of drugs that resulted in objective responses were noted. Deaths that occurred on study caused by drug toxicity. progressive disease (PD). or complications of marrow aplasia were identified, along with drug doses that resulted in toxic death. Temporal trends in response rates, toxicity. and number of patients entered in trials were examined. Results: A total of 1.606 patients with cancer were enrolled in 56 single-agent pediatric phase I therapy trials published between 1978 and 1996. Of these. 1,257 were evaluated for response by tumor type. The overall objective response rate was 7.9%. Response rates were highest for patients with neuroblastoma (17.7%) and acute myelogenous leukemia (11.6%). Patients with osteosarcoma and rhabdomyosarcoma had response rates of <3%. Sixty percent of responses in patients with solid tumors occurred at 81 to 100% of the maximum tolerated dose (MTD). although 42% of responses in patients with leukemia occurred at >100% of the MTD. Death on study was noted in 7.0% of all patients entered in trials. Only 0.7% of patients experienced a death related to drug toxicity. PD accounted for the death of 5.6% of study participants. A trend of increasing response rate despite smaller trial size was noted over the last 7 years of this period. Conclusion: Phase I trials in children with cancer represent a safe mechanism to determine the MTD. toxicity profile, and pharmacokinetics of new agents for use in children with cancer.

Hemophagocytic lymphohistiocytosis in Texas: Observations on ethnicity and race

Early recognition and aggressive treatment of hemophagocytic lymphohistiocytosis (HLH) has changed a uniformly fatal disease to one 55% survive. We examined the diagnosis and treatment of pediatric patients with HLH from the three largest academic medical centers in Texas for information on modern non‐study treatment and survival. In contrast with previously reported series, the racial and ethnic composition of Texas provided a unique opportunity to evaluate the impact of race and ethnicity on survival with HLH.

Transient hyperglycemia in hispanic children with acute lymphoblastic leukemia

Transient hyperglycemia occurs commonly during the treatment for childhood acute lymphoblastic leukemia (ALL). The purpose of this study was to examine the incidence of and risk factors for transient hyperglycemia during induction chemotherapy in Hispanic pediatric patients diagnosed with B‐Precursor ALL.

Therapy-related changes in body size in Hispanic children with acute lymphoblastic leukemia†

The objective of this study was to examine changes over time in body mass index (BMI) from diagnosis through chemotherapy for pediatric patients with B‐precursor acute lymphoblastic leukemia (ALL).

Obesity and survival in a cohort of predominantly hispanic children with acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL), the most common malignancy in children, constitutes 25% of all pediatric cancer. Childhood cancer patients who are obese at diagnosis represent a particular challenge for the oncologist. Obesity may complicate chemotherapy dose determination, and has been associated with decreased overall and event-free survival in a number of adult cancer patients, and more recently in pediatric patients. The purpose of the present study was to examine whether obesity at diagnosis was associated with decreased overall and event-free survival in a cohort of 322 predominantly Hispanic pediatric patients with B-precursor ALL. Obesity was classified as an age-standardized and sex-standardized body mass index z-score at or above the 95th percentile. Hazard ratios (HRs) for overall and event-free survival were assessed using Cox proportional hazards regression modeling. Obesity at diagnosis was not associated with decreased overall survival (HR=1.40, 95% confidence interval=0.69-2.87) or event-free survival (HR=1.08, 95% confidence interval=0.65-1.82) in the overall cohort or in either of the 2 age-at-diagnosis (2 to 9 y; 10 to 18 y) subgroups. Our finding of no obesity-related prognostic effect in the overall cohort and in the under 2 to 9-year age-at-diagnosis cohort was consistent with the previous large-scale study of ALL patients; the absence of a prognostic effect in the 10 to 18-year age-at-diagnosis cohort, however, conflicted with previous findings.

Outcome of Patients With Recurrent Osteosarcoma Enrolled in Seven Phase II Trials Through Children's Cancer Group, Pediatric Oncology Group, and Children's Oncology Group: Learning From the Past to Move Forward

PURPOSE The use of radiographic response as the primary end point in phase II osteosarcoma trials may limit optimal detection of treatment response because of the calcified tumor matrix. We performed this study to determine if time to progression could be used as an end point for subsequent studies. PATIENTS AND METHODS We performed a retrospective analysis of outcome for patients with recurrent/refractory osteosarcoma enrolled in one of seven phase II trials conducted by the Childrens Oncology Group and predecessor groups from 1997 to 2007. All trials used RECIST or WHO radiographic response criteria and the primary end point of response rate. The following potential prognostic factors-age, trial, number of prior chemotherapy regimens, sex, and race/ethnicity-were evaluated for their impact on event-free survival (EFS). We used data from a phase II study (AOST0221) of patients with osteosarcoma who were given inhaled granulocyte-macrophage colony-stimulating factor with first pulmonary recurrence who had an EFS as well as biologic end point to determine the historical disease control rate for patients with fully resected disease. RESULTS In each included trial, the drugs tested were determined to be inactive on the basis of radiographic response rates. The EFS for 96 patients with osteosarcoma and measurable disease was 12% at 4 months (95% CI, 6% to 19%). There was no significant difference in EFS across trials according to number of prior treatment regimens or patient age, sex, and ethnicity. The 12-month EFS for the 42 evaluable patients enrolled in AOST0221 was 20% (95% CI, 10% to 34%). CONCLUSION The EFS was uniformly poor for children with recurrent/refractory osteosarcoma in these single-arm phase II trials. We have now constructed baseline EFS outcomes that can be used as a comparison for future phase II trials for recurrent osteosarcoma.

A phase II trial of rebeccamycin analogue (NSC #655649) in children with solid tumors: a Children's Oncology Group study.

Rebeccamycin Analogue (NSC #655649), a chemically synthesized glycosyl‐dichloro‐indolocarbazole derivative of rebeccamycin with topoisomerase inhibiting activity, has in vitro activity against pediatric tumor cell lines and tumor specimens including rhabdomyosarcoma, neuroblastoma, Ewings sarcoma and medulloblastoma.

Demographic correlates of body size changes in children undergoing treatment for acute lymphoblastic leukemia

While it is known that leukemia therapy is associated with obesity in survivorship, limited information is available on its time‐related pattern of development and its variation across patient subgroups. The goal of the present study was to examine demographic correlates of body mass index (BMI) changes over time from diagnosis through chemotherapy for children with B‐precursor acute lymphoblastic leukemia (ALL).

Phase I trial of 9-aminocamptothecin in children with refractory solid tumors: a Pediatric Oncology Group study.

PURPOSE A phase I trial of 9-aminocamptothecin (9-AC) was performed in children with solid tumors to establish the dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), and the pharmacokinetic profile in children and to document any evidence of activity. PATIENTS AND METHODS A 72-hour infusion of 9-AC dimethylacetamide formulation was administered every 21 days to 23 patients younger than 21 years of age with malignant tumors refractory to conventional therapy. Doses ranged from 36 to 62 microg/m2 per hour. Pharmacokinetics were to be performed in at least three patients per dose level. The first course was used to determine the DLT and MTD. RESULTS Nineteen patients on four dose levels were assessable for toxicities. At 62 microg/m2 per hour, three patients experienced dose-limiting neutropenia and one patient experienced dose-limiting thrombocytopenia. Pharmacokinetics were performed on 15 patients (nine patients had complete sets of plasma sampling performed). The pharmacokinetics of both lactone and total 9-AC were highly variable. The percentage of 9-AC lactone at steady-state was 10.8% +/- 3.6%. Total 9-AC and its lactone form had a terminal half-life of 8.1 +/- 3.8 and 7.1 +/- 3.9 hours, respectively, and a volume of distribution at steady-state (Vdss) of 21.2 +/- 13.3 L/m2 and 135.3 +/- 52.5 L/m2, respectively. Hepatic metabolism and biliary transport had an important role in 9-AC disposition. CONCLUSION The recommended phase II dose of 9-AC administered as a 72-hour infusion every 21 days to children with solid tumors is 52 microg/m2 per hour. Neutropenia and thrombocytopenia were dose limiting.