Dosing and monitoring of enoxaparin therapy in children: experience in a tertiary care hospital.

Pediatric deep vein thrombosis (DVT) is an emerging problem in tertiary care hospitals, recent reviews shows a rate of 40.2/10,000 admissions. Experts affirm that enoxaparin has become in the drug of choice for DVT therapy. Despite this, there is a little information regarding the optimal dose schedule for enoxaparin therapy in children and the therapeutic guidelines for enoxaparin use in children are extrapolated from adult guidelines. Monitoring by antifactor Xa (anti-Xa) measurement and target concentrations between 0.5-1 U/ml at 4-6 h postdose are recommended. This study was designed to analyse our experience in paediatric-specific dosage requirements for enoxaparin therapy. A retrospective study was performed with patients less than 16 years old, who were treated with enoxaparin for DVT and monitored by anti-Xa concentration, between January 2005 and March 2012. Demographic and clinical characteristics and outcomes were obtained. Fourteen patients were analyzed: boy/girl ratio, 8/4; median age, 3.5 months. Cerebral venous sinus thrombosis was the most common indication for therapy. All patients presented thrombosis risks factors. Dose increases were necessary only in patients less than 6 years old. Target anti-Xa concentrations were achieved in 12 (85%) patients. Children younger than 1 year required a higher dose of enoxaparin/kg (1.5-2.7 mg/kg per 12 h). Complete resolutions of DVT were registered in all cases. The mean number of dose increases was three and a median of 11 days to achieve target anti-Xa concentration. This study indicates that an initial higher enoxaparin dose may be necessary in neonates and infants, but other factors must be considered to improve management.

Nonmyeloablative stem cell transplantation is an effective therapy for refractory or relapsed hodgkin lymphoma: results of a spanish prospective cooperative protocol.

We report the results of reduced-intensity conditioning allogeneic stem cell transplantation (allo-RIC) in patients with advanced Hodgkin lymphoma (HL). Forty patients with relapsed or refractory HL were homogeneously treated with an RIC protocol (fludarabine 150 mg/m(2) intravenously plus melphalan 140 mg/m(2) intravenously) and cyclosporin A and methotrexate as graft-versus-host disease (GVHD) prophylaxis. Twenty-one patients (53%) had received >2 lines of chemotherapy, 23 patients (58%) had received radiotherapy, and 29 patients (73%) had experienced treatment failure with a previous autologous stem cell transplantation. Twenty patients (50%) were allografted in resistant relapse, and 38 patients received hematopoietic cells from an HLA-identical sibling. Five patients (12%) died from early transplant-related mortality (before day +100 after allo-RIC). One-year transplant-related mortality was 25%. Acute GVHD developed in 18 patients (45%). Chronic GVHD developed in 17 (45%) of the 31 evaluable patients. The response rate 3 months after the allo-RIC was 67% (21 [52%] complete remissions and 6 [15%] partial remissions). Eleven patients received donor lymphocyte infusions (DLIs) for disease relapse. The response rate after DLI was 54% (3 complete remissions and 3 partial remissions). Overall survival (OS) and progression-free survival (PFS) were 48% +/- 10% and 32% +/- 10% at 2 years, respectively. Refractoriness to chemotherapy was the only adverse prognostic factor for both OS (63% +/- 12% versus 35% +/- 13%; P = .05) and PFS (55% +/- 16% versus 10% +/- 9%; P = .006). For patients with failure of a prior autologous hematopoietic stem cell transplantation, results were especially good for those who experienced late relapses (>/=12 months: 2-year OS and PFS were 75% +/- 16% and 70% +/- 18%, respectively). These data suggest that allo-RIC is feasible in heavily pretreated HL patients and has an acceptable early transplant-related mortality. Results are better in patients allografted in sensitive disease. Both responses observed after the development of GVHD and DLI may suggest a graft-versus-HL effect. Allo-RIC has to be considered an effective therapeutic approach for patients who have had treatment failure with a previous autologous hematopoietic stem cell transplantation.

Quality of life related to type 1 Gaucher disease: Spanish experience.

UNLABELLED: The impact of type 1 Gaucher disease and its therapy on health-related quality of life (QOL) was investigated and the results were compared with a Spanish adult normative group. PATIENTS AND METHODS: Between January 1998 and December 2002, a prospective clinical QOL trial was conducted by application of a Spanish version of the Health Survey SF-36 questionnaire. Patients receiving ERT (69 cases) filled in the questionnaire two times, prior to starting ERT and after two years under ERT. The patients were stratified by gender and age group. Clinical and X-ray data to assess bone disease were obtained from the Spanish Gaucher Register. Demographic, clinical, genotype and analytical data and the response to therapy were evaluated. Four grades of severity were established according to bone disease (no symptoms = 0, moderate bone pain = 1, severe bone crisis = 2, fracture/necrosis = 3). Correlation analysis was made between QOL score and grade of bone disease. RESULTS: Mean age+/-SD 33.6+/-11.7 (range 18-66), M/F,ratio 33/36; bone disease: 0 in 27 patients (47.3%), 1 in 11 (19.3%), 2 in 5 (8.8%) and 3 in 14 (24.5%). Physical activity: 11 patients (19.3%) showed severe restriction and 41 patients (71.9%) were only limited for strenuous activities. The mean score for QOL questionnaire was 11.9+/-10.4 (range 2-46). Correlation between score and bone disease was significant only for 1 and 3 grades (p = 0.02). Improvement in self perception of global health was observed ranging from 34.3% before ERT to 91.4% after ERT (p = 0.001). Nevertheless physical activity remained unsatisfactory in 24.5% of patients due mainly to bone sequelae. COMMENTS: Physical activities and bone disease grade 1 and 3 are negatively related to QOL. Nevertheless no correlation was found with bone pain crisis, possibly due to the transitory character of this event. In spite of the improvement induced by ERT, a quarter of patients remained with physical limitations related to bone disease as well as in need of orthopaedic correction of bone sequelae. In order to improve the QOL an accurate evaluation of bone disease to define therapeutic approaches must be considered.

p53 Aberrations do not predict individual response to fludarabine in patients with B-cell chronic lymphocytic leukaemia in advanced stages Rai III/IV.

Abnormalities of p53 have been associated with short survival and non-response to therapy in chronic lymphocytic leukaemia (CLL). We have evaluated the rate of response to fludarabine as first-line therapy in 54 patients with advanced stage CLL, analysing the cytogenetic profile, aberrations in p53, including the methylation status of its promoter, and the immunoglobulin heavy-chain variable-region (IGVH) mutation status. According to the advanced stage of the disease in this series, 75% of patients presented genetic aberrations associated with poor prognosis: del(17p) and/or del(11q), and no-mutated IGVH genes. Ten patients (18.5%) had methylation in the promoter region of p53. Eighty-three per cent of patients treated achieved a response, with a high rate of complete remission (47.6%). Although we found a significant correlation between failures and the presence of p53 aberrations (P = 0.0065), either with methylation (P = 0.018) or deletion (P = 0.015), 64% of the patients with aberrations in this gene responded to treatment (11/17), suggesting that fludarabine induces high remission rates, even in these patients. This is the first time that the significance of p53 promoter methylation status is described in this pathology, and our data support that this epigenetic phenomenon could be involved in the pathogenesis and clinical evolution of CLL.

Insulin-like growth factors in childhood-onset Gaucher disease.

There is a high prevalence of growth retardation in children with type 1 Gaucher disease. The cause of this poor growth is not yet known; however, studies have shown acceleration of growth with enzyme replacement therapy (ERT). IGF are recognized as important determinants of somatic growth. It has been proven that chronic diseases with liver involvement might cause IGF deficiency. The aim of this study was to assess the IGF system in patients with childhood-onset Gaucher disease, before and after ERT, and its association with other clinical and analytical parameters. Twenty-two patients with type I Gaucher disease were included. The diagnosis was established before 14 y of age in all patients. Baseline determinations of total IGF-I, free IGF-I, and IGF binding protein 3 (IGFBP-3) were obtained in 19 patients before starting ERT at a mean age of 13.8 +/- 11.2 y. A Spearman test was performed to establish the association with other clinical and analytical parameters. In a group of 13 patients receiving IGF, changes were evaluated during the initial 2 y of treatment. A Wilcoxon test was performed for the statistical analysis. Total IGF-I, free IGF-I, and IGFBP-3 were expressed as SD scores (SDS). We found low levels of IGF and its binding proteins before ERT. A significant association was found between the total IGF-I SDS before treatment and the age-adjusted severity score index: r = -0.62, p < 0.05. Total IGF-I and IGFBP-3 SDS correlated negatively with the presence of the L444P mutation (r = -0.53 and -0.5, respectively, p < 0.05). Height SDS correlated with total IGF-I and IGFBP-3 SDS in eight children (r = 0.84 and 0.78, respectively, p < 0.05). Total IGF-I SDS increased from -1.8 +/- 0.8 to -0.8 +/- 1.4 (p = 0.005) and free IGF-I increased from -1.2 +/- 1 to 1.1 +/- 2.1 after 12 +/- 6.8 mo (p = 0.011) of ERT. IGFBP-3 SDS increased from -1.3 +/- 0.6 to -0.2 +/- 1.2 (p = 0.012) after 12 +/- 4.5 mo of ERT. Type 1 Gaucher disease is associated with low levels of IGF and its binding proteins, which could be a consequence of liver involvement. Total IGF-I deficiency is associated with the severity of the illness. Growth retardation in pediatric patients with Gaucher disease is related to the alterations in IGF axis. Total IGF-I and IGFBP-3 are the two parameters that better correlate with height before treatment. ERT results in significant increase of total IGF-I, free IGF-I, and IGFBP-3 during the first year of treatment.