Sluis, I.M. van der

Cost-analysis of treatment of childhood acute lymphoblastic leukemia with asparaginase preparations: The impact of expensive chemotherapy (Article)

2013-05-01T00:00:00Z

Asparaginase is an expensive drug, but important in childhood acute lymphoblastic leukemia. In order to compare costs of PEGasparaginase, Erwinia asparaginase and native E. coli asparaginase, we performed a cost-analysis in the Dutch Childhood Oncology Group ALL-10 medium-risk group intensification protocol. Treatment costs were calculated based on patient level data of 84 subjects, and were related to the occurrence of allergy to PEGasparaginase. Simultaneously, decision tree and sensitivity analyses were conducted. The total costs of the intensification course of 30 weeks were $57,893 in patients without PEGasparaginase allergy (n=64). The costs were significantly higher ($113,558) in case of allergy (n=20) necessitating a switch to Erwinia asparaginase. Simulated scenarios (decision tree analysis) using native E. coli asparaginase in intensification showed that the costs of PEGasparaginase were equal to those of native E. coli asparaginase. Also after sensitivity analyses, the costs for PEGasparaginase were equal to those of native E. coli asparaginase. Intensification treatment with native E. coli asparaginase, followed by a switch to PEGasparaginase, and subsequently to Erwinia asparaginase in case of allergy had similar overall costs compared to the treatment with PEGasparaginase as the first-line drug (followed by Erwinia asparaginase in the case of allergy). PEGasparaginase is preferred over native E. coli asparaginase, because it is administered less frequently, with less day care visits. PEGasparaginase is less immunogenic than native E. coli asparaginase and is not more expensive. Asparaginase costs are mainly determined by the percentage of patients who are allergic and require a switch to Erwinia asparaginase.

Prospective study on incidence, risk factors, and long-term outcome of osteonecrosis in pediatric acute lymphoblastic leukemia (Article)

2011-11-01T00:00:00Z

Purpose: We studied cumulative incidence, risk factors, therapeutic strategies, and outcome of symptomatic osteonecrosis in pediatric patients with acute lymphoblastic leukemia (ALL). Patients and Methods: Cumulative incidence of osteonecrosis was assessed prospectively in 694 patients treated with the dexamethasone-based Dutch Child Oncology Group-ALL9 protocol. Osteonecrosis was defined by development of symptoms (National Cancer Institute grade 2 to 4) during treatment or within 1 year after treatment discontinuation, confirmed by magnetic resonance imaging. We evaluated risk factors for osteonecrosis using logistic multivariate regression. To describe outcome, we reviewed clinical and radiologic information after antileukemic treatment 1 year or more after osteonecrosis diagnosis. Results: Cumulative incidence of osteonecrosis at 3 years was 6.1%. After adjustment for treatment center, logistic multivariate regression identified age (odds ratio [OR], 1.47; P < .01) and female sex (OR, 2.23; P = .04) as independent risk factors. Median age at diagnosis of ALL in patients with osteonecrosis was 13.5 years, compared with 4.7 years in those without. In 21 (55%) of 38 patients with osteonecrosis, chemotherapy was adjusted. Seven patients (18%) underwent surgery: five joint-preserving procedures and two total-hip arthroplasties. Clinical follow-up of 35 patients was evaluated; median follow-up was 4.9 years. In 14 patients (40%), symptoms completely resolved; 14 (40%) had symptoms interfering with function but not with activities of daily living (ADLs; grade 2); seven (20%) had symptoms interfering with ADLs (grade 3). In 24 patients, radiologic follow-up was available; in six (25%), lesions improved/disappeared; in 13 (54%), lesions remained stable; five (21%) had progressive lesions. Conclusion: Six percent of pediatric patients with ALL developed symptomatic osteonecrosis during or shortly after treatment. Older age and female sex were risk factors. After a median follow-up of 5 years, 60% of patients had persistent symptoms.

Germline variation in the MTHFR and MTRR genes determines the nadir of bone density in pediatric acute lymphoblastic leukemia: A prospective study (Article)

2011-03-01T00:00:00Z

Background: This study aims to identify folate-metabolism-related genetic risk factors for low bone mineral density (BMD) during/after pediatric acute lymphoblastic leukemia (ALL) treatment. Patients and methods: We investigated the influence of methylenetetrahydrofolate reductase (MTHFR 677C>T and 1298A>C) and methionine synthase reductase (MTRR 66A>G) single nucleotide polymorphisms (SNPs) on total body BMD (BMDTB) and lumbar spine BMD (BMDLS) in 83 patients. Homocysteine, folate and vitamin B12 were determined. BMD was measured repeatedly using dual-energy X-ray absorptiometry in patients ≥4years (n=68). Results: Carriers of the MTHFR 677 T-allele showed a lower baseline BMDTBthan non-carriers (-0.38 SDS vs. +0.55 SDS, p=0.01) and BMDTBremained lower during/after treatment. MTHFR 677C>T did not influence treatment-related loss of BMDTB(p=0.39). The MTRR 66 G-allele carriers showed a trend towards a lower BMDTBcompared with non-carriers. Combining these two SNPs, patients carrying ≥2 risk alleles had a significantly lower BMDTB(-1.40 SDS) than patients with one (-0.80 SDS) or no risk alleles (-0.31 SDS). Although carriers of the MTHFR 1298A>C had higher homocysteine levels, this SNP was not related to BMDTB. BMDLSof carriers was similar to non-carriers of the investigated SNPs. Conclusions: The MTHFR 677C>T SNP and the MTRR 66A>G SNP were identified as determinants of impaired BMDTBin childhood ALL patients.

Bone mineral density and body composition in adolescents with childhood-onset growth hormone deficiency (Article)

2009-06-01T00:00:00Z

Background/Aims: The aim of the present study was to evaluate bone mineral density (BMD) and body composition of patients with childhood-onset growth hormone (GH) deficiency (GHD) treated with GH during the transition period. Methods: BMD and body composition, measured by dual-energy X-ray absorptiometry, were evaluated at final height and yearly thereafter during 2 years. Twenty-nine of the 40 patients had also been measured before start and during GH therapy. Results: Mean lumbar spine BMD and bone mineral apparent density (BMAD) as well as total body BMD and lean body mass (LBM) SD score (SDS) were significantly lower than normal at final height and during the 2 years thereafter for all patients. Final-height SDS was related to the change in height SDS as well as in LBM SDS during the first year of GH treatment. LBM SDS decreased significantly in the group of patients with GHD without GH treatment (p < 0.01, n = 19). Fat mass SDS increased in all patients. Conclusion: Mean BMD, BMAD and LBM SDS were significantly lower than normal in adolescents with childhood-onset GHD at and 2 years after the attainment of final height.

Fatal aspergillus rhinosinusitis during induction chemotherapy in a child with acute lymphoblastic leukemia (Article)

2009-05-01T00:00:00Z

Invasive fungal infections are a major problem in patients treated for hematologic malignancies. We report a 3-year-old girl who suffered from febrile neutropenia during induction therapy for acute lymphoblastic leukemia. Initial chest computed tomography revealed no evidence of intrapulmonary fungal lesions, however, plasma galactomannan ratio was positive. Aspergillus flavus was cultured from nasal swab and endoscopic biopsy confirmed Aspergillus rhinosinusitis. After an initially good response to voriconazole and extensive debridement, she developed late intracranial hemorrhage and infarction with fatal outcome. This case stresses the importance of early suspicion and aggressive treatment of Aspergillus rhinosinusitis in patients with febrile neutropenia.

Osteoporosis in children with cancer (Article)

2008-02-01T00:00:00Z

As increasing numbers of childhood cancer patients are surviving, the long-term complications of the disease and its treatment have become ever more increasingly important. Reduced bone mineral density and increased fracture risk have been reported during and after treatment of children with cancer. The causes of osteoporosis are multifactorial. Among others, the disease itself, chemotherapy, irradiation and genetic susceptibility play a role. Bone mineral density in later life depends largely on the peak bone mass achieved in adolescence or young adulthood. Therefore, optimizing peak bone mass is of clinical importance. Preventive and therapeutic strategies, such as calcium and vitamin D supplementation, physical activity and bisphosphonates, are considered.

Children's bone health (Doctoral Thesis)

2002-01-23T00:00:00Z

The thesis can be divided in two main parts. In the first part (Chapter 2 to 5) bone mineral density, bone metabolism and body composition in healthy children and young adults have been evaluated, while in the second part (Chapter 6 to 10) these issues were studied in children with various diseases. Healthy children were studied to gain references for parameters of bone turnover, and to extend our reference data for bone density and body composition. Furthermore, the effect of polymorphisms in two candidate genes, e.g. polymorphisms in the vitamin D receptor gene and the collagen la1 gene, were studied. For a proper interpretation of our findings in diseased children, it is essential to have, preferably own reference data for serum markers of bone turnover, bone density, and body composition. Results of our studies in healthy children are presented in Part I (Chapter 2 to 5). The long-term survival of acute lymphoblastic leukemia (ALL) has improved dramatically during the last decades, consequently more emphasis is being placed on the long- and shortterm side effects of ALL and its treatment. Some of these side-effects, such as osteoporosis, growth retardation and adiposity, have been investigated cross-sectionally in children ten years after diagnosis (Chapter 6). Furthermore, we longitudinally studied children who were newly diagnosed and followed during and after cessation of chemotherapy (Chapter 7). In Chapter 8 and 9 treatment with growth hormone will be discussed. Growth-retarded children with chronic renal failure were treated with growth hormone. The effects of GH treatment on bone density and body composition were compared to children with chronic renal failure but without growth hormone treatment (Chapter 8). Bone density, body composition and serum lipid levels in growth hormone deficient children, and the longitudinal effects of growth hormone treatment on these parameters will be described in Chapter 9. Puberty is considered to be a crucial period for bone mass acquisition. It is therefore important to know whether children with a disorder in pubertal development will achieve an adequate peak bone mass. The effects of gonadotrophin-releasing hormone-agonist (GnRH-a) on bone density and body composition were evaluated in children with precocious or early puberty (Chapter 10). Patients were studied before, during and after cessation of GnRH-a. In Chapter 11 & 12 results will be summarised and discussed, and recommendations for future research are made.