Phase IIa study of dabigatran etexilate in children with venous thrombosis: pharmacokinetics, safety, and tolerability.

Essentials Dabigatran etexilate may provide a new treatment option for pediatric venous thromboembolism. Children aged 1 to < 12 years were given dabigatran etexilate in an open-label, single-arm study. The pharmacokinetic-pharmacodynamic relationship was similar to that seen in adult patients. There were no serious adverse events, bleeding events or recurrent venous thromboembolism. SUMMARY: Background The current standard-of-care treatments for pediatric venous thromboembolism (VTE) have limitations. Dabigatran etexilate (DE), a direct thrombin inhibitor, may offer an alternative therapeutic option. Objectives To assess the pharmacokinetics, pharmacodynamics, safety, and tolerability of a DE oral liquid formulation (OLF) in pediatric patients with VTE. Patients/Methods Patients who had completed planned treatment with low molecular weight heparin or oral anticoagulants for VTE were enrolled in two age groups (2 to < 12 years and 1 to < 2 years), and received a DE OLF based on an age-adjusted and weight-adjusted nomogram. Originally, patients were to receive a DE OLF twice daily for 3 days, but the protocol was amended to a single dose on day 1. The primary endpoints were pharmacokinetics/pharmacodynamics-related: plasma concentrations of DE and its metabolites; activated partial thromboplastin time (APTT), ecarin clotting time (ECT), and dilute thrombin time (dTT); and pharmacokinetic (PK)-pharmacodynamic (PD) correlation. Safety endpoints included incidence rates of bleeding events and all other adverse events (AEs). Results Eighteen patients entered the study and received the DE OLF (an exposure equivalent to a dose of 150 mg twice daily in adults). The projected steady-state dabigatran trough concentrations were largely comparable between pediatric patients and adults. The PK/PD relationship was linear for ECT and dTT, and non-linear for APTT. No serious or severe AEs, bleeding events, or recurrent VTEs were reported. Mild AEs were reported in three patients in the single-dose group (screening period) and in one patient in the multiple-dose group (on-treatment period). Conclusion The current study supports the further evaluation of DE OLFs in pediatric patients with VTE.

Magnesium absorption using stable isotope tracers in healthy children and children treated for leukemia.

Intestinal magnesium (Mg) absorption was measured in six healthy children (control) and in four children treated for acute lymphoblastic leukemia with the single-isotope fecal recovery technique (SIFRT). The objective of this study was to determine Mg absorption in young children with acute lymphoblastic leukemia using stable isotope tracers. Fractional and absolute absorption levels determined by SIFRT were not significantly different between children with acute lymphoblastic leukemia (fractional absorption: 58.3 +/- 10.6% [mean +/- SEM], absolute absorption: 3.66 +/- 0.71 mg x kg(-1) x d(-1), [0.15 +/- 0.03 mmol x kg(-1) x d(-1)]) and control children (fractional absorption: 61.4 +/- 7.5%, absolute absorption: 5.69 +/- 0.85 mg x kg(-1) x d(-1), [0.23 +/- 0.03 mmol x kg(-1) x d(-1)]). Average Mg absorption in young children (aged 3--8 y) was 60.2 +/- 5.8%. This study describes the first application of the SIFRT to assess Mg absorption in young children and illustrates the feasibility of the SIFRT in this age group to obtain more accurate information on Mg absorption.

Limitation of ankle range of motion in survivors of acute lymphoblastic leukemia: a cross-sectional study.

BACKGROUND: The purpose of this study was to evaluate and determine the factors related to active and passive dorsiflexion range of motion (DF-ROM) in survivors of acute lymphoblastic leukemia (ALL), which is the most obvious impairment of musculoskeletal function in such children. PROCEDURE: The subjects included 54 survivors of ALL treated on Dana-Farber Cancer Institute protocols and 54 comparable healthy children. Bilateral active and passive DF-ROM were measured with the knee extended. RESULTS: The survivors of ALL had significantly less active and passive DF-ROM (6.4 vs. 16.8, 10.5 vs. 18.8 degrees, respectively, P < 0.001) than the comparison children. Weight for age at the time of assessment and change in height during treatment showed significant negative correlations with DF-ROM. Length of time-off treatment was not associated with DF-ROM. CONCLUSIONS: Multiple regression analyses identified the variables of age at diagnosis and gender as significant predictors of both DF-ROM measures following treatment. Children diagnosed at a younger age and females were at greater risk for restricted DF-ROM. Close monitoring and preventative therapy programs for this complication are warranted for children, especially young girls receiving treatment for ALL.

Long-term gross motor performance following treatment for acute lymphoblastic leukemia.

BACKGROUND: The primary purpose of this descriptive study was to determine the long-term effects of cancer treatment in childhood on musculoskeletal function and gross motor skills. PROCEDURE: Musculoskeletal and gross motor function were assessed in a cohort of 36 survivors of acute lymphoblastic leukemia (ALL) seen in a pediatric tertiary care referral centre, compared to 36 age and gender matched comparison subjects. Basic gross motor skills were assessed using dimensions D: standing, and E: walking, running, and jumping of the Gross Motor Function Measure (GMFM). Strength, balance, and running speed and agility were assessed using the Bruininks-Oseretsky Test of Motor Proficiency (BOTMP). Hand grip strength and ankle dorsiflexion range of motion were also measured. Findings in the children with ALL were compared by dependent (paired) t-tests to those in age and gender matched children. RESULTS: The GMFM scores for standing were 98.7% and for walking, running, and jumping were 99% of normal. The mean standard scores for the BOTMP were significantly lower than those of the comparison group: strength 11.5 vs. 19.4, balance 9.4 vs. 15.5, and running speed and agility 9.9 vs. 16.6. The ALL subjects had less hand grip strength 156.3 vs. 190.2, and less ankle dorsiflexion 7.5 vs. 16.1 degrees than the comparison group. The survivors of childhood leukemia were able to perform most basic gross motor functions. However, musculoskeletal impairment was evident and levels of motor proficiency were significantly poorer than those of age and gender matched children. CONCLUSIONS: Programs to promote physical activity and limit disability may improve gross motor function and increase overall quality-of-life in survivors of leukemia in childhood.

Blood lipid profiles in children with acute lymphoblastic leukemia.

BACKGROUND: Abnormal blood lipid profiles have been associated with cancer. The objective of this study was to investigate the frequency and clinical significance of altered lipid profiles in children with acute lymphoblastic leukemia (ALL), the most common form of malignant disease in this age group. METHODS: Fasting blood lipid profiles (cholesterol [C], triglycerides [TG], high density lipoprotein [HDL], low density lipoprotein, very low density lipoprotein, apolipoproteins A1 [apo A1] and B, and lipoprotein a [Lp(a)]) were obtained in 24 children with ALL at diagnosis, 16 children during consolidation therapy with L-asparaginase, and 18 children during maintenance therapy without L-asparaginase. For comparison the authors studied lipid profiles in 15 children previously treated for leukemia, 15 healthy control children, and 17 children with other forms of cancer, both localized and widespread. RESULTS: An altered blood lipid profile was observed at the time of diagnosis of ALL. Statistically significant values included elevated TG (1.82+/-1.23 mmol/L), reduced HDL-C (0.54+/-0.24 mmol/L), and reduced ApoA1 (0.77+/-0.18 g/L) levels. A wide range of Lp(a) levels (0-1990 mg/L) were observed. Significantly reduced HDL-C (0.55+/-0.20 mmol/L) and ApoA1 (0.69+/-0.22 g/L) were observed in children with widespread but not localized solid tumors at diagnosis. C and TG correlated with serum albumin levels. Significant therapy-related changes in lipid profiles were observed in children with ALL during combination therapy with L-asparaginase (extremely elevated TG levels [3.34+/-2.82 mmol/L] and a striking reduction in Lp(a) levels) that were not observed during combination therapy without L-asparaginase or in children during treatment for solid tumors. In this small study there was no relation between these abnormalities and either thromboembolic events or pancreatitis. Blood lipid profiles in children with ALL returned to normal on completion of therapy. CONCLUSIONS: The lipid abnormalities observed at diagnosis in children with widespread cancer (ALL or solid tumors) may reflect altered nutritional states or altered lipid metabolism. Reduced concentrations of Lp(a) and elevated TG levels suggest L-asparaginase specific alterations and may provide insight into the toxicity associated with this drug.

Bone and mineral abnormalities in childhood acute lymphoblastic leukemia: influence of disease, drugs and nutrition.

In children with acute lymphoblastic leukemia (ALL), abnormalities in mineral homeostasis and bone mass were first reported by our group in the late 1980s. Prospective longitudinal cohort studies in 40 consecutive patients receiving treatment according to the Dana-Farber Cancer Institute (DFCI) protocol 87-001 and 16 children receiving DFCI protocol 91-001 afforded us the opportunity to explore various etiologies of the observed abnormalities in mineral and bone metabolism, specifically the leukemic disease process and chemotherapeutic drugs such as steroids and aminoglycoside antibiotics. At diagnosis of ALL, > 70% of children had abnormally low plasma 1,25-dihydroxyvitamin D, 73% had low osteocalcin and 64% had hypercalciuria, indicating an effect of the leukemic process on vitamin D metabolism and bone turnover. During remission induction, treatment with high-dose steroid (prednisone or dexamethasone) resulted in further reduction in plasma osteocalcin and elevated parathyroid hormone levels. During 24 months of chemotherapy-maintained remission, reduction in bone mineral content (BMC), as measured by Z-scores, occurred in 64% of children, most severely affecting those > 11 years of age. A reduction in BMC during the first 6 months had a positive predictive value of 64% for subsequent fracture. By the end of 2 years of therapy, fractures occurred in 39% of children and radiographic evidence of osteopenia was found in 83% of the entire study group. Investigations of the biochemical basis of the bone abnormalities revealed that by 6 months hypomagnesemia developed in 84% of children (of whom 52% were hypermagnesuric) and plasma 1,25-dihydroxyvitamin D remained abnormally low in 70%. Altered magnesium status was attributed to renal wastage of magnesium following cyclical prednisone therapy and treatment with aminoglycoside antibiotics such as amikacin for fever accompanying neutropenia. Dietary intake and absorption of magnesium were normal. In 10 children treated for hypomagnesemia with supplemental magnesium for up to 16-20 weeks, plasma magnesium normalized in only 50% of subjects.

Growth and body composition in response to chemotherapy in children with acute lymphoblastic leukemia.

Severely malnourished children afflicted by acute lymphoblastic leukemia (ALL), particularly in developing countries, have reduced tolerance to chemotherapy and a compromised prospect for survival. We investigated the prevalence and severity of alterations in growth and nutritional status in children with ALL from population-based referral areas in Canada. All children were treated with Dana-Farber Cancer Institute ALL Consortium protocols. First, the relative impact of cranial irradiation (CI) and chemotherapy on growth was studied in 116 children at diagnosis and at 6-month intervals during treatment. We observed a decline in height standard deviation (SD) score in the first year in all children, and a further decline in height SD score during the second year only in the children who received CI. Weight reduction occurred in the first year, but during the second year there was a disproportionate increase in weight compared with height, suggesting that children treated with ALL have a tendency toward obesity. Both chemotherapy and CI contribute to the altered growth observed in children treated for ALL. Second, intestinal functional integrity was assessed in 16 children during post-induction chemotherapy. Nutrient intake was adequate and there was minimal evidence of malabsorption: fat malabsorption occurred in only 1 child (after treatment-related pancreatitis), abnormal D-xylose absorption occurred in 2 children at 6 months of therapy (returning to normal 6 months later) and abnormal lactose absorption occurred in 4 children. Third, weight, height, whole body lean and fat mass measured by dual-energy X-ray absorptiometry and serum albumin were determined at diagnosis and at 6-month intervals throughout therapy in 19 children with ALL. Height SD scores decreased significantly during treatment. Serum albumin was abnormally low in 6/19 at diagnosis and 14/18 during intensive consolidation therapy. The mean change in the ratio of lean mass to total body weight showed a 5% reduction by 6 months of therapy. Body fat increased from a mean of 22% at diagnosis to 28% at completion of therapy. The majority of children treated for ALL thus have significant changes in nutritional status manifested by reductions in growth, alterations in lean and fat body mass and abnormally low serum proteins during intensive therapy.

Altered mineral metabolism and bone mass in children during treatment for acute lymphoblastic leukemia.

Children with acute lymphoblastic leukemia (ALL) often develop bone pain, abnormal gait, and unusual fractures while in remission and receiving continuing chemotherapy. A prospective longitudinal cohort study was undertaken of bone mass and biochemical mineral status in 40 consecutive children (27 male, 13 female, aged 0.3-17.0 years) receiving therapy on the Dana-Farber Cancer Institute protocol 87-01. Radiography, lumbar spine dual-photon absorptiometry, and biochemical measurements of mineral status were performed at diagnosis and at 6-month intervals throughout 24 months of chemotherapy. Eleven patients were not completely evaluated (4 deaths and 7 off study). Radiographic evidence of osteopenia was observed in 10, 64, and 76% at diagnosis, 12 and 24 months, respectively. Fractures occurred in 39% of children during treatment. Reduction in bone mineral content (BMC), as measured by Z scores, occurred in 64% of patients and was most severe in those greater than 11 years of age at diagnosis. Reduction in BMC during the first 6 months of therapy had a positive predictive value of 64%, while an increase in BMC had a negative predictive value of 82% for subsequent fracture. By 6 months of therapy, 31/37 (84%) children were hypomagnesemic, of whom 16 (52%) were hypermagnesuric. Plasma osteocalcin was subnormal at diagnosis in 29/40 (73%) but increased to normal by 6 months of treatment. Vitamin D status was normal throughout, but plasma 1,25-dihydroxyvitamin D remained subnormal in greater than 70% of children. Urinary cross-link N-telopeptide was normal at diagnosis and became elevated in 58% of children by the end of therapy. Suppressed bone mineralization is evident at diagnosis in a minority of children with ALL. Skeletal morbidity and a reduction in bone mineral mass become more prevalent during treatment, with increased bone resorption, perhaps mainly as a consequence of corticosteroid administration.

Hypermagnesiuria and hypercalciuria in childhood leukemia: an effect of amikacin therapy.

PURPOSE: The purpose of this study is to assess the effects of amikacin on renal proximal tubular function, and on magnesium (Mg) and calcium (Ca) status in children treated for acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Eighteen children (11 male/7 female, ages 2-18 years) receiving antileukemic therapy (Dana Farber Cancer Institute protocols 87-001 or 91-001) and admitted for febrile neutropenia to The Children's Hospital at Chedoke-McMaster, Hamilton, Ontario were recruited into this descriptive prospective study. Each child was treated with amikacin (7.5 mg/kg/12 h x 10-14 days) for one or more courses. RESULTS: No patient demonstrated elevations in amikacin trough levels. beta 2-Microglobulinuria, glucosuria, proteinuria, and hyperphosphaturia were absent. Children (50% presenting with hypomagnesemia (< 0.77 mmol/L) had a significant rise in mean urinary Mg:creatinine (0.46 +/- 0.27 versus 0.82 +/- 0.38 mmol, mean +/- SD, p < 0.05) in response to amikacin therapy and the mean Ca:creatinine ratio increased by 95% after 10-14 days of amikacin treatment. Serum Mg and Ca did not change notably after treatment, irrespective of initial Mg status. CONCLUSIONS: Aminoglycoside therapy in children with ALL is not associated with overt nephrotoxicity. A transient renal leak of Mg and Ca does occur. Screening of ALL children for mild hypomagnesemia may help to identify those most at risk of disruption of renal conservation of Mg and possibly Ca.

Mineral homeostasis and bone mass at diagnosis in children with acute lymphoblastic leukemia.

OBJECTIVE: To determine whether the osteopenia and unusual fractures observed in children with acute lymphoblastic leukemia (ALL) were related to the disease rather than to its treatment. DESIGN: Prospective analysis of the bone and mineral status in 40 consecutive children with ALL seen in a pediatric tertiary-care referral center. METHODS: Biochemical indicators of mineral, endocrine, and vitamin D status were measured before initiation of therapy. Bone mass was determined radiographically and by dual-photon absorptiometry of the lumbar region of the spine (L2-L4). Correlations between clinical observations, leukemia variables, bone mass, and biochemical assessment were determined. RESULTS: At the time of diagnosis musculoskeletal pain was present in 36% of patients and was more common in children with CD10-positive leukemia and leukocyte counts less than 20 x 10(9) cells/L. Radiographic evidence of osteopenia and fractures was observed in 13% and 10% of children, respectively. The mean bone mineral content was normal. Bone mass measurement z scores correlated with plasma 1,25-dihydroxyvitamin D3 concentrations (r = 0.43, p < 0.05). Plasma calcium, magnesium, phosphorus, and 25-hydroxyvitamin D3 levels were normal. Low plasma osteocalcin (mean +/- SD, 1.6 +/- 1.6 nmol/L) and 1,25-dihydroxyvitamin D3 (33.4 +/- 26.4 pmol/L) values were observed. Parathyroid hormone levels were low in 14% of children. Hypercalciuria was detected in 64% of children. Urinary deoxypyridinoline was lower (p < 0.01) than in age-matched control subjects. Histomorphometric measurements of iliac bone showed abnormalities in mineralization in the biopsy specimens from three of nine children. CONCLUSION: Most children with ALL have alterations in bone metabolism and bone mass when first examined. These data suggest defective mineralization as the mechanism for decreased bone mass and implicate the leukemic process as causative.

Fresh frozen plasma has no beneficial effect on the hemostatic system in children receiving L-asparaginase.

L-Asparaginase (ASP), a chemotherapeutic agent used in the treatment of children with acute lymphoblastic leukaemia (ALL), is linked to thromboembolic complications secondary to an acquired deficiency of antithrombin III (ATIII). Fresh frozen plasma (FFP) is used to prevent and/or treat thrombotic complications in these children. However, the effect of FFP on plasma concentrations of ATIII and biochemical markers of activation of coagulation has never been tested. In this study, FFP (20 ml/kg) was administered to eight children with ALL receiving ASP in the consolidation phase of their treatment. Plasma samples were drawn pre-infusion, and following infusion at 1, 24, and 48 hr. Prior to the FFP infusions, plasma concentrations of prothrombin, fibrinogen, alpha 2-macroglobulin, heparin cofactor II, protein C, and protein S were similar to levels in healthy children. Only plasma concentrations of ATIII were significantly decreased (0.55 U/ml). Following FFP infusions, there was no statistical or clinically important increase in plasma concentrations of any coagulation protein at any time point. Pre-infusion plasma concentrations of markers of endogenous thrombin generation (thrombin-antithrombin III complexes (TAT)) and activation of the fibrinolytic system in response to activation of the coagulation system (D-dimer levels) were significantly increased. However, FFP had no statistical or clinically important effect on concentrations of these markers. We conclude that FFP administration for the prevention and treatment of acquired ATIII deficiency secondary to ASP has no demonstrable benefit on plasma levels of coagulation proteins and is unlikely to be of clinical benefit.

Effect of disease and chemotherapy on hemostasis in children with acute lymphoid leukemia.

PURPOSE: We sought to determine the effect of disease and combination chemotherapy on the hemostatic system in children with acute lymphoid leukemia (ALL). PATIENTS AND METHODS: We conducted a prospective study of children newly diagnosed with ALL. Plasma samples were obtained at four time points: at diagnosis before therapy, 5 days after administration of L-asparaginase alone, after the remission induction program, and at completion of the consolidation phase. Plasma levels of 21 hemostatic proteins were measured. The amount of thrombin generated following activation with an APTT reagent was quantitated. RESULTS: At diagnosis there were significant elevations in factors VIII, IX, von Willebrand, alpha 2-macroglobulin and protein S. In contrast, there were significant reductions in protein C, prekallikrein, and factors XIIIA and XIIIS. L-asparaginase treatment alone decreased concentrations of 11 proteins, with antithrombin III being affected to the greatest extent. After multiagent chemotherapy, not including L-asparaginase, concentrations of most proteins increased to or above baseline. At completion of consolidation therapy, which included weekly L-asparaginase administration, concentrations of most proteins were decreased compared with baseline values. The amount of thrombin generated following activation with an APTT reagent was similar to adults. CONCLUSION: Plasma concentrations of coagulation proteins are affected by disease (ALL) alone and by combination chemotherapy with or without L-asparaginase. There is no impairment of in vitro capacity to generate thrombin. L-asparaginase alone caused a decrease in almost all proteins; however, ATIII was affected to the greatest extent.

The contributions of growth and puberty to peak bone mass.

Lumbar spine bone mass was measured by dual photon absorptiometry (DPA) in 236 subjects aged between 3 and 30 years. Expected values of bone mineral density (BMD) and bone mass (BMC) for the lumbar vertebrae L2 to L4 were derived as a function of age, by non-linear regression analysis. The selected regression equation was the sum of two logistic expressions, one of which was assigned to growth at the time of puberty and the other to the slower long term component of growth. Growth during puberty contributed about 50% of peak bone mass in females, while in males this contribution was closer to 15%. No increase was found in lumbar spine bone mass in females after puberty.