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

INTRODUCTION: 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). METHODS: The study cohort consisted of 307 pediatric patients diagnosed with ALL who were treated at four South Texas pediatric oncology centers between 1990 and 2002. To minimize treatment-related variability, we excluded patients who received cranial irradiation as part of their treatment. Variation in age- and gender-standardized BMI z-scores according to age at diagnosis, gender, and ethnicity were assessed. RESULTS: The overall study cohort exhibited an increase in age- and gender-adjusted BMI z-scores for the first 24 months of chemotherapy followed by a slight decrease in BMI at 30 months (end of therapy). A repeated measures analysis indicated a statistically significant difference in the time-related pattern of BMI changes for age at diagnosis (P = 0.001) but no significant effect for gender (P = 0.32) or Hispanic versus non-Hispanic ethnicity (P = 0.89). DISCUSSION: In our cohort of ALL patients, BMI was elevated at diagnosis (mean standardized BMI z-score = 0.22, standard deviation = 1.4) then increased and remained elevated for the entire duration of chemotherapy. Children who were 2-9 years of age at diagnosis began therapy with a substantially lower BMI and remained lower over the course of chemotherapy than patients aged 10-18 years at diagnosis. It will be important for future investigations to explore the biological and behavioral factors that may underlie such differential patterns of BMI change over time.

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.

Phase I trial and pharmacokinetic study of the farnesyltransferase inhibitor tipifarnib in children with refractory solid tumors or neurofibromatosis type I and plexiform neurofibromas.

PURPOSE: This pediatric phase I trial of tipifarnib determined the maximum-tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of tipifarnib in children with refractory solid tumors and neurofibromatosis type 1 (NF1) -related plexiform neurofibromas. PATIENTS AND METHODS: Tipifarnib was administered twice daily for 21 days, repeated every 28 days starting at 150 mg/m2/dose (n = 4), with escalations to 200 (n = 12), 275 (n = 12), and 375 (n = 6) mg/m2/dose. The MTD was also evaluated on a chronic continuous dosing schedule (n = 6). Pharmacokinetic sampling was performed for 36 hours after the first dose and peripheral-blood mononuclear cells (PBMCs) were collected at baseline and steady state for determination of farnesyl protein transferase (FTase) activity and HDJ-2 farnesylation. RESULTS: Twenty-three solid tumor and 17 NF1 patients were assessable for toxicity. The MTD was 200 mg/m2/dose, and dose-limiting toxicities on cycle 1 were myelosuppression, rash, nausea, vomiting, and diarrhea. The 200 mg/m2/dose was also tolerable on the continuous dosing schedule. Cumulative toxicity was not observed in the 17 NF1 patients who received a median of 10 cycles (range, 1 to 32 cycles). The plasma pharmacokinetics of tipifarnib were highly variable but not age dependent. At steady state on 200 mg/m2/dose, FTase activity was 30% compared with baseline, and farnesylation of HDJ-2 was inhibited in PBMCs. CONCLUSION: Oral tipifarnib is well tolerated in children receiving the drug twice daily for 21 days and a continuous dosing schedule at 200 mg/m2/dose, which is equivalent to the MTD in adults. The pharmacokinetic profile of tipifarnib in children is similar to that in adults, and at the MTD, FTase is inhibited in PBMC in vivo.

The bioavailability of oral methotrexate in children with inflammatory bowel disease.

OBJECTIVES: Methotrexate is used to treat patients with inflammatory bowel disease. Although no available pharmacologic data support the assumption that the bioavailability of methotrexate is diminished in patients with inflammatory bowel disease, most such patients receive methotrexate parenterally. METHODS: The oral bioavailability of methotrexate was determined in 11 pediatric patients being treated with methotrexate for inflammatory bowel disease. Serial plasma methotrexate concentrations were determined after equal subcutaneous and oral doses of methotrexate. RESULTS: The mean bioavailability of methotrexate in patients with inflammatory bowel disease was 84% +/- 38%. Interpatient variability in drug exposure was similar after oral and subcutaneous administration. CONCLUSIONS: The bioavailability of methotrexate in patients with inflammatory bowel disease is no different from that observed in other disease states. Subcutaneous administration of methotrexate does not appear to decrease the interpatient variability in drug exposure. There is no sound pharmacologic basis for favoring administration of methotrexate via the subcutaneous route for patients with inflammatory bowel disease.

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

BACKGROUND: 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). METHODS: The study cohort consisted of 141 white Hispanic pediatric patients who were diagnosed with ALL and were treated at 2 South Texas pediatric oncology centers between 1993 and 2002. Changes in age-standardized and gender-standardized BMI scores were assessed. RESULTS: The study cohort exhibited a steady increase in age-adjusted and gender-adjusted BMI scores for the first 12 months of therapy, a modest increase in BMI scores during the 18-23 month and 24-29 month periods, followed by a slight decrease in BMI scores at 30 months (end of therapy). A repeated-measures analysis indicated significant effects for time (P = 0.019) and time by baseline BMI category interaction (P = 0.0001) but no significant interaction effect between time and gender (P = 0.65). CONCLUSIONS: Although it is known that leukemia therapy is associated with prevalent obesity in survivorship, its pattern of development during therapy has not been elucidated. In the current cohort of Hispanic children with ALL, BMI scores were elevated at diagnosis (mean +/- standard deviation standardized BMI Z score, 0.33 +/- 1.4), then increased, and remained elevated for the entire duration of chemotherapy. Patients who were classified as normal weight exhibited an increase in BMI over time; patients who were classified as overweight at diagnosis exhibited BMI patterns that were relatively stable; and patients who were classified as obese exhibited a very slight decline over time. These findings suggest that the risk for chemotherapy-related weight gain applies predominantly to children who begin ALL therapy within a normal weight range.

Transient hyperglycemia in Hispanic children with acute lymphoblastic leukemia.

BACKGROUND: 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. PROCEDURE: The study cohort consisted of 155 Hispanic pediatric patients diagnosed with ALL and treated at one of two South Texas pediatric oncology centers between 1993 and 2002. Hyperglycemia was defined as > or = 2 glucose determinations of > or = 200 mg/dl during the first 28 days of induction chemotherapy. RESULTS: Overall, 11.0% of the study cohort developed transient hyperglycemia during induction chemotherapy. Age and body mass index (BMI) were both positively associated with the risk of hyperglycemia. Females exhibited a substantially higher risk of hyperglycemia than males, but this association did not reach statistical significance after adjusting for other covariates. Among patients who developed hyperglycemia, 100% of those who required insulin were in the 13-18-year age group and reported a family history of diabetes. Hyperglycemic patients classified as obese (BMI > or = 95 centile) were more than twice as likely to have required insulin therapy compared to overweight patients (BMI 85-<95 centile) and three times as likely to have required insulin compared to normal weight (BMI < 85 centile) patients. CONCLUSIONS: The incidence of chemotherapy-induced transient hyperglycemia in the present study cohort is comparable to that reported in previous pediatric ALL patients. This finding is interesting in view of the elevated prevalence of obesity and the underlying dietary behaviors in this Hispanic study cohort.

Acute splenic rupture in an adult with homozygous sickle cell anemia treated with chronic transfusions.

Splenic rupture is a very rare event in adult homozygous sickle cell patients. The authors describe a 19-year-old patient with homozygous sickle cell disease who experienced an acute splenic rupture crisis requiring emergent splenectomy. He had been receiving chronic blood transfusions regularly for 7 years secondary to a previous stroke. It is possible that these transfusions contributed to regeneration of splenic red pulp, which allowed a crisis to occur at an advanced age.