Children's bone health

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 coll

Asparaginase-Associated toxicity in children with acute lymphoblastic leukemia

Asparaginase is an integral component of multiagent chemotherapy regimens for the treatment of children with acute lymphoblastic leukemia. Positive outcomes are seen in patients who are able to complete their entire prescribed course of asparaginase therapy. Toxicities associated with asparaginase use include hypersensitivity (clinical and subclinical), pancreatitis, thrombosis, encephalopathy, and liver dysfunction. Depending on the nature and severity of the toxicity, aspara

Allergic-like reactions to asparaginase: Atypical allergies without asparaginase inactivation

Background: Asparaginase is an important component of pediatric acute lymphoblastic leukemia (ALL) therapy. Unfortunately, this treatment is hampered by hypersensitivity reactions. In general, allergies – regardless of severity – cause complete inactivation of the drug. However, we report atypical allergic reactions without inactivation of asparaginase, here called allergic-like reactions. Procedure: Patients with an allergic-like reaction, who were treated according to the Dutch Childhood Oncology Group ALL-11 or the CoALL 08–09 protocol, were described. The reactions were identified by continual measurement of asparaginase activity levels. Characteristics, including timing of occurrence, symptoms, grade, and the presence of antiasparaginase antibodies, were compared to those of real allergies. Results: Fourteen allergic-like reactions occurred in nine patients. Five reactions were to PEGasparaginase and nine to Erwinia asparaginase. Allergic-like reactions occurred relatively late after the start of infusion compared to real allergies. Antibodies were absent in all but one patient with an allergic-like reaction, while they were detected in all patients with a real allergy. Symptoms and grade did not differ between the groups. Asparaginase was continued with the same formulation in six patients of whom four finished treatment with adequate activity levels. Conclusions: In conclusion, allergic-like reactions occur relatively late after the start of infusion and without antibodies. Despite these clinical differences, allergic-like reactions can only be distinguished from real allergies by continually measuring asparaginase activity levels. If clinically tolerated, formulations should not be switched in case of allergic-like reactions. Moreover, failure to recognize these reactions may lead to a less favorable prognosis if asparaginase therapy is terminated unnecessarily

Longitudinal follow-up of bone density and body composition in children with precocious or early puberty before, during and after cessation of GnRH agonist therapy

We studied bone mineral density (BMD), bone metabolism, and body composition in 47 children with central precocious puberty (n = 36) or early puberty (n = 11) before, during, and after cessation of GnRH agonist. Bone density and body composition were measured with dual energy x-ray absorptiometry and expressed as SD scores. Bone age and biochemical parameters of bone turnover were assessed. Measurements were performed at baseline, after 6 months, and on a year

Acute lymphoblastic leukaemia patients treated with PEGasparaginase develop antibodies to PEG and the succinate linker

Polyethylene glycol (PEG) conjugated asparaginase (PEGasparaginase) is essential for treatment of paediatric acute lymphoblastic leukaemia. We developed an assay identifying antibodies against the PEG-moiety, the linker and the drug itself in patients experiencing hypersensitivity reactions to PEGasparaginase. Eighteen patients treated according to the DCOG ALL-11 protocol, with a neutralizing hypersensitivity reaction to PEGasparaginase to the first PEGasparaginase doses in induction (12 patients) or during intensification after interruption of several months (6 patients) were included. ELISA was used to measure antibodies, coating with the succinimidyl succinate linker conjugated to BSA, PEGfilgrastim and Escherichia coli asparaginase, and using hydrolysed PEGasparaginase and mPEG5,000 for competition. Anti-PEG antibodies were detected in all patients (IgG 100%; IgM 67%) of whom 39% had anti-PEG antibodies exclusively. Pre-existing anti-PEG antibodies were also detected in patients who not previously received a PEGylated therapeutic (58% IgG; 21% IgM). Antibodies against the SS-linker were predominantly detected during induction (50% IgG; 42% IgM). Anti-asparaginase antibodies were detected in only 11% during induction but 94% during intensification. In conclusion, anti-PEG and anti-SS-linker antibodies predominantly play a role in the immunogenic response to PEGasparaginase during induction. Thus, switching to native E. coli asparaginase would be an option for adequate asparaginase treatment

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

__Abstract__ 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 na

The effect of asparaginase therapy on methotrexate toxicity and efficacy in children with acute lymphoblastic leukemia

ABSTRACT Asparaginase and methotrexate (MTX), both essential for pediatric acute lymphoblastic leukemia therapy, are often used concomitantly. Depending on the sequence, in vitro, asparaginase inhibits MTX-polyglutamate (MTXPG) formation, and side effects overlap. MTX toxicity and efficacy, reflected by intracellular erythrocyte MTXPG’s, were compared between children treated with and without asparaginase during high dose MTX (HD-MTX) courses of the DCOG ALL-11 protocol (NL50250.078.14). Seventy-three patients, of whom 23 received asparaginase during the HDMTX courses, were included. Grade 3–4 leukopenia and neutropenia occurred more often (59% and 86% vs. 30% and 62%). The number of infections, grade 3–4 hepatotoxicity, nephrotoxicity, and neurotoxicity did not differ. Patients with asparaginase had lower MTXPG levels, although to a lesser extent than in vitro studies. Although patients with asparaginase during HD-MTX courses showed more myelosuppression, this had no (serious) clinical consequences. Regarding the MTX efficacy, the schedule-related antagonism seen in in vitro seems less important in vivo

Parental functioning during maintenance treatment for childhood acute lymphoblastic leukemia: Effects of treatment intensity and dexamethasone pulses

Background: During maintenance treatment, Dutch pediatric patients with medium-risk (MR) acute lymphoblastic leukemia (ALL) receive intravenous chemotherapy and cyclic dexamethasone. Dexamethasone affects child's sleep and behavior. Standard-risk (SR) patients only receive oral chemotherapy, without dexamethasone. Effects of stratified therapy on parents are not well known. This study compares parental sleep, distress and quality of life (QoL) with the general population, between MR and SR groups, and on- and off-dexamethasone (MR group). Procedure: One year after diagnosis, parents of MR patients completed the Medical Outcomes Study (MOS) sleep, distress thermometer for parents and Short Form-12 (SF-12) twice; once on-dexamethasone and once off-dexamethasone. SR parents completed one measurement. Sleep problems, distress and QoL scores (off-dexamethasone) were compared to reference values and between MR and SR. Score differences on- and off-dexamethasone were assessed by multilevel regression analysis. Results: Parents (80% mothers) of 121 patients (57% males; 75% MR, 25% SR) completed 191 measurements. Compared to reference values, parents reported more sleep disturbances, higher distress, and lower mental QoL. Additionally, MR parents reported clinical distress (score ≥ 4), whereas SR parents (on average) did not (mean 4.8 ± 2.4 vs 3.5 ± 2.4, P =.02). Within the MR group, outcomes did not significantly differ on- and off-dexamethasone. Conclusions: Parents of ALL patients report sleep problems, high distress, and QoL impairment. Within the MR group, parental functioning did not differ on- and off-dexamethasone. However, MR parents reported clinical distress more often than SR parents, possibly reflecting differences in prognostic estimates and treatment burden. This perhaps includes the overall strain of cyclic dexamethasone. This study highlights the need for psychosocial support throughout treatment, regardless of risk stratification

A cost-effectiveness analysis of Erwinia asparaginase therapy in children with acute lymphoblastic leukemia

Objectives: Erwinia asparaginase is used as a second-line formulation after a neutralizing hypersensitivity reaction to the first-line formulation of asparaginase. Here, we have performed a costeffectiveness analysis of Erwinia asparaginase treatment. Methods: Children with acute lymphoblastic leukemia treated according to the Dutch Childhood Oncology ALL-10 or ALL-11 protocol were included and initially treated with PEGasparaginase in the intensification phase. The total treatment costs of this treatment phase, quality of life (QoL), and life years saved (LYS) were studied for two scenarios: (a) patients were switched to Erwinia asparaginase treatment after a hypersensitivity reaction, or (b) asparaginase would have been permanently stopped. Results: Sixty-eight patients were included. There was no difference in QoL between patients with and without a hypersensitivity reaction. The mean costs of the intensification phase per patient were $40,925 if PEGasparaginase could be continued,$175,632 if patients had to switch to Erwinia asparaginase, and $21,190 if asparaginase would have been permanently stopped. An extrapolation of the literature suggests that the 5-year event-free survival would be 10.3 without intensive asparaginase treatment if asparaginase is stopped after a reaction. Thus, the costs per LYS were$1892 for scenario 1 and $872 for scenario 2. Conclusions: Switching to Erwinia asparaginase increases the costs per LYS by$1020, which is modest in view of the total costs. Moreover, when asparaginase treatment can be completed by switching to Erwinia asparaginase, relapses—and consequential costs—will be avoided. Therefore, from a cost perspective, we recommend a switch to Erwinia asparaginase to complete asparaginase treatment

The evaluation of red blood cell folate and methotrexate levels during protocol M in childhood acute lymphoblastic leukemia

Background: After High-Dose Methotrexate (HD-MTX), folinic acid rescue therapy (Leucovorin) is administered to reduce side effects in pediatric acute lymphoblastic leukemia (ALL) patients. Leucovorin and MTX are structural analogues, possibly competing for cellular transport and intracellular metabolism. We hypothesize that Leucovorin accumulates during consecutive courses, which might result in a lower MTX uptake. Methods: We prospectively measured red blood cell (RBC) folate and MTX levels during four HD-MTX and Leucovorin courses in 43 patients treated according the DCOG ALL-11 protocol with 2-weekly HD-MTX (5 g/m2 /dose) and Leucovorin (15 mg/m2 /dose) using LC-MS/MS. We estimated a linear mixed model to assess the relationship between these variables over time. Results: Both RBC MTX-PG and folate levels increased significantly during protocol M. MTX-PG2–5 levels increased most substantially after the first two HD-MTX courses (until median 113.0 nmol/L, IQR 76.8–165.2) after which levels plateaued during the 3d and 4th course (until median 141.3 nmol/L, IQR 100.2–190.2). In parallel, folate levels increased most substantially after the first two HD-MTX courses (until median 401.6 nmol/L, IQR 163.3–594.2) after which levels plateaued during the 3d and 4th course (until median 411.5 nmol/L, IQR 240.3–665.6). The ratio folate/MTX-PG decreased significantly over time, which was mostly due to the relatively higher increase (delta) of MTX-PG. Conclusion: These results suggest that the increase in RBC folate levels does not seem to have a large effect on RBC MTX levels. Future studies, assessing competition of Leucovorin and MTX on other cellular mechanisms which might negatively affect treatment efficacy, are necessary